Johnson Matthey Technology Review...Contents SPECIAL ISSUE 12 ‘PALLADIUM CATALYSED CROSS-COUPLING...

JOHNSON MATTHEY TECHNOLOGY REVIEW

Johnson Matthey’s international journal of research exploring science and technology in industrial applications

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SPECIAL ISSUE 12 ‘PALLADIUM CATALYSED CROSS-COUPLING – PRACTICAL ASPECTS’ APRIL 2017Published by Johnson Matthey

ISSN 2056-5135


© Copyright 2017 Johnson Matthey

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Contents SPECIAL ISSUE 12 ‘PALLADIUM CATALYSED CROSS-COUPLING – PRACTICAL ASPECTS’ APRIL 2017




Cleaning Up Catalysis Palladium Impurity Removal from Active Pharmaceutical Ingredient Process

StreamsBy Stephanie Phillips, Duncan Holdsworth, Pasi Kauppinen and Carl Mac NamaraOriginal publication: Johnson Matthey Technol. Rev., 2016, 60, (4), 277

Final Analysis: The Use of Metal Scavengers for Recovery of Palladium Catalyst from Solution By Stephanie Phillips and Pasi KauppinenOriginal publication: Platinum Metals Rev., 2010, 54, (1), 69

Safer, Faster and Cleaner Reactions Using Encapsulated Metal Catalysts and Microwave HeatingBy Mike R. PittsOriginal publication: Platinum Metals Rev., 2008, 52, (2), 64

Catalysis in the Service of Green Chemistry: Nobel Prize-Winning Palladium-Catalysed Cross-Couplings, Run in Water at Room TemperatureBy Bruce H. Lipshutz, Benjamin R. Taft, Alexander R. Abela, Subir Ghorai, Arkady Krasovskiy and Christophe Duplais

Original publication: Platinum Metals Rev., 2012, 56, (2), 62

The Nobel Prize The 2010 Nobel Prize in Chemistry: Palladium-Catalysed Cross-Coupling

By Thomas J. ColacotOriginal publication: Platinum Metals Rev., 2014, 58, (3), 12

Note: all page numbers are as originally published

Contents (continued)




‘From the Bench’ Tips “Palladium-Catalyzed Coupling Reactions: Practical Aspects and Future Developments” A book review by Robert Hanley Original publication: Platinum Metals Rev., 2014, 58, (2), 93

The Directed ortho Metallation–Cross-Coupling Fusion: Development and Application in SynthesisBy Johnathan Board, Jennifer L. Cosman, Toni Rantanen, Suneel P. Singh and Victor SnieckusOriginal publication: Platinum Metals Rev., 2013, 57, (4), 234

Palladium/Nucleophlic Carbene Catalysts for Cross-Coupling ReactionsBy Anna C. Hillier and Steven P. Nolan


A Highly Active Palladium(I) Dimer for Pharmaceutical ApplicationsBy Thomas J. Colacot


And Finally...

Final Analysis: Is Gold a Catalyst in Cross-Coupling Reactions in the Absence of Palladium?By Madeleine Livendahl, Pablo Espinet and Antonio M. EchavarrenOriginal publication: Platinum Metals Rev., 2011, 55, (3), 212

Note: all page numbers are as originally published

www.technology.matthey.com JOHNSON MATTHEY TECHNOLOGY REVIEW

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Palladium Impurity Removal from Active Pharmaceutical Ingredient Process Streams A method for scale-up

By Stephanie Phillips* and Duncan Holdsworth Johnson Matthey Plc, Orchard Road, Royston, Hertfordshire, SG8 5HE, UK

Pasi Kauppinen** Johnson Matthey Finland Oy, Autokatu 6, FI-20380 Turku, Finland

and Carl Mac Namara Johnson Matthey Plc, PO Box 1, Billingham, Cleveland, TS23 1LB, UK

Email: *[email protected], **[email protected]

In this article, we will look at palladium impurity removal from active pharmaceutical ingredient (API) process streams using metal scavengers and the drivers for the implementation of such processes. The article will review some of the available scavengers and detail how Johnson Matthey approaches the trial work and the methods used for screening, optimisation and scale-up of the scavenger process. It will outline the steps taken to ensure smooth transfer of the metal impurity removal process from lab to plant. This will include Johnson Matthey data from batch isotherm, kinetic and fixed bed trials and the application of mathematical models for performance characterisation and scale-up, which all feed into the final system design. Performance data for

a number of the Johnson Matthey range of scavengers will be referenced both in batch and cartridge systems and the benefits of using the scavengers in a cartridge system will be presented.

Introduction

The need to remove palladium (Pd) from API process streams is driven by International Conference on Harmonisation (ICH) Q3D guidelines which dictate the permissible levels of Pd allowed in the final drug product. The platinum group metals (pgms), including Pd as well as platinum, rhodium and ruthenium are generally considered as route-dependent human toxicants (ICH Classification 2b), (1), therefore the limits for these metals are low – 10 µg g–1 as an oral concentration in the drug product, drug substance or excipient. This oral concentration is conver ted into a permitted daily exposure limit for each platinum group metal of 100 µg d–1, which is based on an assumed worst-case dosage level of 10 g d–1. If the dosage rate is known to be lower, the permitted oral concentration may be increased. For the pgms, it may also be an option to use a component approach, whereby the overall level of the element in the excipient would be considered. As the pgms would only come from a catalyst source, the overall level of the element in the excipient could then be determined. For a chemist developing or manufacturing the API, a target of 10 µg g–1 or even lower may still be put in place to avoid process re-works (1).

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Despite the challenges of removal, the use of homogeneous Pd catalysts offers many benefits over classical, often stoichiometric reaction protocols (2–4). It is often possible to achieve a reduction of the number of steps in a multi-step synthesis of a target compound, as well as increasing overall yields, by employing Pd catalysis. In order to achieve the benefits offered by the catalysts, there will be a subsequent need for Pd removal (4–10).

Numerous Pd removal methods are available to the chemist and the optimal method is typically selected based on cost, time, quality and ease of implementation. When considering which Pd removal method to use, the default is often to use standard methods such as distillation, crystallisation or carbon adsorption to remove the Pd (10, 11). All are efficient methods of separation; however, the process costs, and their robustness, may be challenged during scale-up. Equally, consideration needs to be given to the time taken to run the process and any impacts that the removal method may have on product yield.

Scavengers provide an excellent solution for Pd removal issues, particularly at low metal levels (6, 8). Johnson Matthey’s screening programme ensures that the best scavenger is selected based on the reaction conditions, but also that the process is robust and that consistent removal of Pd is achieved, irrespective of process scale.

Scavenger Products

There are a range of different scavengers available on the market for product purification (5–8). A significant portion of these are based on a silica support, however others, such as those based on polymer resins and polymer fibres (5, 7) are also available. The Johnson Matthey range includes all three classes of support materials and details of the core product types are listed in Table I, with specific product details provided in Table II.

Screening Method

Below is an outline of the steps involved in achieving a robust, long-term metal removal solution. This full screening package can be completed by Johnson Matthey or at the customer site with technical support provided.

The extent to which a scavenger can remove Pd to the required levels is critical. The initial trials within the screening programme look at a number of scavengers for Pd removal efficiency. Conditions can then be optimised with respect to the amount of scavenger, the temperature and whether a mix of scavengers with different functionalities should be used together. Time taken for Pd removal is considered within the batch isotherm, and kinetic and fixed bed studies are

Table I Overview of Johnson Matthey Scavenging Product Types

Product type Support material Key benefits Processing options

QuadraSil® Silica üZero swell üBatch (low shear stirring)

üImproved sorption kinetics based on the external

üCartridge preferred

functionality

üExcellent recoveries at room temperature

QuadraPure® Polymer resin üSpecific particle size distribution üBatch (low shear stirring) (PSD) for optimised flow

üCartridge preferredcharacteristics

Smopex® Fibre üFastest kinetics due to small particle size and external functionality

üVery stable in batch due to flexibility of fibres (no fines under high shear stirring)

üSuitable across the pH range üSuitable for use in column when feed flow rate is low

© 2016 Johnson Matthey

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Table II Chemical Functionalisation of the Core Scavenger Range

Scavenger Abbreviation Functionality

MercaptoQuadraSil® MP QS-MP SH

Primary amineQuadraSil® AP QS-AP NH2

QuadraSil® TA QS-TA H Triamine

NH2N H

N

QuadraPure® TU QP-TU S Thiourea

NH2N H

NH2 BenzylamineQuadraPure® BZA QP-BZA

Tertiary amine QuadraPure® DMA QP-DMA N

MercaptoSmopex®-234 S-234 SH

MercaptoSmopex®-111 S-111

SH

O

O

N

PyridineSmopex®-105 S-105

carried out to generate the performance data required to model, scale-up and design an optimised process for full-scale application.

The Screening Programme: Initial Screening

The initial screen is used as a feasibility study to determine the most suitable scavenger for Pd impurity removal from a particular sample or application. All scavengers used in the screen are commercially

available and all screening is completed on representative process samples. Where solid samples are provided, these are dissolved in an appropriate solvent.

Prior to carrying out any screening, customer process data is required to ensure optimal results taking into account any constraints relating to operating conditions.

Initial screening can be carried out using a variety of equipment, with the two preferred options being: (a) roller mixer machine; or (b) flask with overhead


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stirrer to allow best mixing of and contact with the scavengers. A hot plate, with a magnetic stirrer or a Radleys CarouselTM , have also been used, with care being taken to ensure suitable contact with the scavenger material.

Initial Screening: Experimental

All solutions are filtered prior to screening to ensure homogeneous sampling. A sample of mother liquor is retained for analysis. Typically 1 w/v% scavenger is allowed for Pd concentrations up to 500 mg l–1 . However, if a single element (or the total pgm concentration) has a higher concentration than this, the amount of scavenger is increased. For solutions with a pgm concentration in the region of 500–1000 ppm, for example, 3 w/v% is recommended for initial screening. During optimised screening, the amount of scavenger will be adjusted based on knowledge of the API process and the type of Pd catalyst used during it. Consideration will also be given to the presence of other reagents and metals which may be present and could compete for sites on the scavenger.

Initial screening is completed at room temperature for 2 h. Approximately six to eight scavengers are included in the initial screening. All solution samples are analysed using inductively coupled plasma-optical emission spectroscopy (ICP-OES) or atomic absorption spectroscopy (AAS) to determine the Pd concentration pre- and post-screening (12).

In the examples shown below, an organic process solution used in an API manufacturing process with an oncology indication was the selected material for the screening programme. This was a more

challenging Pd removal project, both in terms of the ease with which the Pd was removed and the low initial concentrations of the Pd in solution. The final target level was 10 µg g –1 in the API, equating to >1 mg l–1 in the solution.

Initial Screening: Results

Results from this screening can be presented in a number of ways. In this case they are shown as: (a) Table III, where the initial raw data is given and the

difference in concentration between the original solution and the solution following scavenger treatment is shown. Conversion of this to the actual concentration in the API stream is given in the final column; and

(b) Figure 1, where the scavenger performance is shown from left to right in terms of optimal performance.

In this example the solid API, with 98 µg g–1 Pd present as an impurity, was diluted with 15 volumes of process solvent prior to analysis. The analytical results on the solution were therefore multiplied, based on this dilution factor, and taking into consideration the density of the solvent to give: (a) the initial Pd levels present in the API; and (b) the Pd levels present after scavenger treatment. At this stage of the screening, the final Pd levels

following scavenger treatment were all above the target required by the process, necessitating further optimisation. For most screening, the best three performing scavengers from the initial screening are taken through to the optimisation stage.

Table III Initial Screening Results with Respect to Palladium Concentrationa

Scavenger type Scavenger added, w/v% Pd in the process solvent,mg l–1 Pd in API, calculated, µg g–1

Initial sample 0 6.5 74

Smopex®-234 0.5 5.5 62

QuadraPure® DMA 0.5 5.0 57

Smopex®-105 0.5 4.8 54

QuadraPure® TU 0.5 3.8 43

QuadraSil® AP 0.5 3.5 40

QuadraSil® MP 0.5 2.5 28 aTrials were conducted at 10 ml scale


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4

0

QS-MP


7 7 6 6 5

5

1 w/v% loading 2 w/v% loading

Pd,

mg

l–1

3

2

1 Pd,

mg

l–1

4

3

Initial QP-TU QS-MP QS-AP sample

Initial S-234 QP-DMA S-105 QP-TU QS-AP QS-MP sample

Fig. 1. Pd concentration pre- and post-scavenger screening: initial screen

Screening Optimisation

Based on the results from the initial screening, three scavengers were taken through to the optimisation stage: QuadraPure® TU (thiourea functionalised polymer resin), QuadraSil® MP (mercapto propyl functionalised silica) and QuadraSil® AP (amino propyl functionalised silica). During this phase, testing focused on modifying the amount of scavenger used,

2

1

0

Fig. 2. Effect of amount of scavenger on Pd removal. Specification was met by QuadraSil® MP at 2 w/v% loading

7 Initial sample6

5

Pd,

mg

l–1

4

3

22ºC 40ºC

the effects of temperature increase on the scavenging performance and possible use of a multi-scavenger system. Time taken for recovery was determined during the later kinetic trials.

Optimisation: Experimental

Based on the Pd removal rates from the first screen, the amount of scavenger used was modified accordingly. As a 0.5 w/v% addition (with respect to volume of process solution) did not yield complete metal removal, the amount of scavenger added was increased to 1 w/v% and 2 w/v% (Figure 2).

Typically the higher temperature would be: (a) 60ºC

2

1

0

Fig. 3. Effect of temperature increase with 1 w/v% scavenger

7 Initial sample

6 QS-MP 5

Pd,

mg

l–1

4

3

22ºC 40ºC

(b) 10ºC below the boiling point of the solvent, or (c) dictated by the process conditions or API stability.

In this case, the agreed higher temperature was 40ºC and QuadraSil® MP was screened at 1 w/v% and 2 w/v% to determine the effect due to temperature (Figures 3 and 4).

From these results, the optimal conditions were found to be 2 w/v% of QuadraSil® MP for 2 h at room temperature to give 0.5 mg l–1 in the solution, which equated to 5.65 µg g–1 in the API. This was below the required upper limit of 10 µg g–1. No performance improvements were seen by increasing the temperature

2

1

0

Fig. 4. Effect of temperature increase with 2 w/v% scavenger

and, from a processing point of view, room temperature was preferable. It was also deemed unnecessary to test a mixture of scavengers as the targeted Pd removal was achieved with a single scavenger.


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6


At this stage in the screening programme, the scavenger and the conditions under which that scavenger will be best utilised have been determined using a fixed time under batch conditions. The decision for the process chemist now is whether the process will be transferred to the pilot plant in batch or in a cartridge system. To support this decision, a batch isotherm will be run followed by a kinetic trial for cartridge systems. This data is then utilised in a first principles modelling system and the actual and theoretical data compared before the system is defined.

Batch Isotherms and Kinetic Studies

During this phase of the screening, we are looking at: (a) the theoretical maximum metal loadings which can

be achieved for the target scavenging process. Data from this stage will help to determine the weight or volume of scavenger required in the larger scale process

(b) the breakthrough point (where the metal is no longer being removed by the scavenger) to determine at what point the chemist or engineer stops the process

(c) the kinetics of the adsorption process, considering the various mass transfer resistances which control the Pd from the liquid phase to the solid phase. This will indicate what contact time is required to ensure the metal content is reduced to the required levels.

For this project, a kinetic trial in batch was considered for the three best per forming scavengers, shown as raw data in Figure 5. Due to the more challenging nature of the solution, kinetics were slower than is often seen, with target recovery in 4 h. This was within process requirements. Note that kinetics for

Pd removal are typically fast with up to 99% recovery often being seen within 10 min. Factors that can affect the metal uptake are: (a) nature of the Pd catalyst (in terms of accessibility of

the Pd species) (b) presence of other reagents that can compete with

the metal uptake, and (c) reactions within the API itself.

A batch isotherm trial was carried out to determine the maximum loading capacity of the material as well as investigating how changing initial concentrations of the feed solution may affect this capacity (Figure 6).

Prior to designing a full-scale cartridge system, a column trial is carried out in which feed solution is flowed through a fixed bed of the ion exchange material and the outlet concentration from the column is measured over time. An outlet concentration of 0 mg l–1 indicates that all of the Pd has been recovered from the feed solution. An outlet concentration above 0 mg l–1 indicates that the material has almost reached its maximum loading capacity and that the feed flow should be stopped. The time before the outlet concentration rises above 0 mg l–1 can be increased by increasing the column size (Figure 7).

First Principles Modelling

The results obtained from laboratory isotherm and column trials are used to estimate several equilibrium and kinetic parameters which describe the adsorption

1.2

Equ

ilibr

ium

load

ing,

wt% 1.0

0.8

0.6

0.4

Experimental results

5 QS-MP QS-AP QP-TU

0.2

Pd,

mg

l–1 4 03

0 5 10 15 2 Equilibrium concentration, mg l–1

1 Fig. 6. Results of isotherm trial where varying masses of QuadraSil® MP material were added to 20 ml solutions of

Initial 30 120 240 30 120 240 30 120 240 customer solution with initial Pd concentration of 14 mg l–1

sample Sample intervals, min

0

and mixed until equilibrium was reached. Equilibrium concentration was measured by ICP-MS and the equilibrium

Fig. 5. Batch kinetic trial raw data: Pd removal profile with respect to time

loading estimated by calculation (10)


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6

5

1.2


Experimental results

∂C ∂C ∂2C rb ∂q = – uv + Dax – (ii)

2∂t ∂z ∂z e ∂t

Out

let c

once

ntra

tion,

mg

l–1

4

3

2

1

0 0 2 4 6 8 10 12

Time, h Fig. 7. Results of the column trial where a feed solution

Equation (ii) is fitted to the results shown in Figure 7 to determine the kinetics parameters of adsorption (contained within the ∂q/∂t parameter in the equation which represents the rate of adsorption). The results of this fitting are shown in Figure 9. Again a very high R2

value of 0.99 was obtained. Once these model parameters have been estimated,

Equations (i) and (ii) can be used to determine the performance of the QuadraSil® MP material as a function of time, feed flow rate, concentration and the size or scale of the column through which the feed is having an initial concentration of 5.5 mg l–1 Pd was flowed

through a column of QuadraSil® MP at a flow rate of flowed, effectively allowing scale-up and optimisation 17.0 ml h–1 equivalent to three bed volumes per hour, where one bed volume is equal to the volume occupied by the Quadrasil® MP in the column). The outlet Pd concentration of samples collected from the column outlet were analysed by ICP-MS (10)

of Pd from solution. The parameters are part of the models described in Equations (i) and (ii) (13, 14) and by fitting these models to the experimental data the values of these parameters are estimated.

qtKCe qe = (i)

1 + KCe

Equation (i) is fitted to the results shown in Figure 6 to determine K and qt, the material equilibrium constant and maximum capacity respectively. The results of this fitting are shown in Figure 8. An R2 value of 0.99 was obtained indicating the fitting is very good.

of the process design to ensure full Pd recovery, as further discussed in the next section.

Scale-Up

The ultimate aim of scale-up is to take the understanding obtained from the small-scale scavenger performance and propose a system that can achieve 100% scavenger utilisation at the end of the system life, i.e. the entire scavenger mass should be loaded to its maximum capacity at the point of scavenger change out. In reality this is an impossible task as, for example, in a column system axial diffusion, radial velocity gradients, near-wall effects and slow kinetics inevitably lead to broadening of the mass transfer zone and non-ideal behaviour (15, 16). However, a robust engineered solution should aim to get as close to full utilisation of the scavenger as is possible for a given set of conditions as this helps to minimise the installed

6

Equ

ilibr

ium

load

ing,

wt% 1.0

0.8

0.6

0.4

Experimental results Predicted results

R2 = 0.99

Out

let c

once

ntra

tion,

mg

l–1 Experimental results Predicted results

R2 = 0.99

0 2 6 104 8 Time, h

Fig. 9. The experimental results from Fig. 7 are shown again, as well as the predicted results from Equation (ii)

5

4

3

2

1

00 0 5 10 15

Equilibrium concentration, mg l–1

Fig. 8. The experimental results from Fig. 6 are shown, as well as the predicted results from Equation (i)


0.2

12

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284 © 2016 Johnson Matthey


scavenger volume and, ultimately, the process cost. For a batch system, the challenge is even greater, which drives Johnson Matthey to recommend a cartridge system wherever possible. Scavenger systems using cartridges also offer the added benefit of containment when a potent API is being manufactured.

Optimisation can be achieved by manipulating variables such as the liquid linear velocity, the column diameter and the aspect ratio of the scavenger bed (17), while being mindful of customer requirements that could place limits on the proposed design. Such requirements might include the need for the system to be either a once-through or a recycle system; the processing time requirements; the need for a reusable or disposable system depending on the potency of the API; and the operability of the system. At this point the scavenger system will be well-defined, leaving only the mechanical design and the selection of the final conditions and materials of construction to satisfy the needs of the process, the relevant regulations and ultimately the characterisation of a safe and robust system. At this final stage, all of the data from the screening

programme is collated and used in the design of the final system used during piloting. Examples of a scalable system, the sealed flow cartridge system, are shown in Figure 10.

Conclusion

The use of a screening programme has been demonstrated and the steps required outlined in this article along with the results obtained, in order to design a robust plant-scale recovery process. Whether the process will be run in batch or a cartridge system, the method is essential in ensuring that optimal use of the scavenger is achieved while attaining Pd removal targets. For challenging processes, such as the one highlighted here where the nature of the process solution is complex and the initial metal levels are low (in the diluted form), the screening process becomes even more valuable.

Johnson Matthey provides screening and scale-up services to the pharmaceutical industry and has become expert through its application of knowledge in this area. To date, numerous plant-scale scavenging projects are running globally.

Acknowledgements

The authors would like to thank Steve Colley, Les Hutton, Jade Osei-Tutu and Carin Seechurn (Johnson Matthey Plc, UK) and Andrew Teasdale, Principal Scientist at AstraZeneca, UK, also Chair of the AstraZeneca impurities advisory board.

References 1. “ICH Harmonised Guideline, Guideline for Elemental

Impurities, Q3D”, Current Step 4 Version, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 16th December, 2014: http://www. ich.org/fileadmin/Public_Web_Site/ICH_Products/ Guidelines/Quality/Q3D/Q3D_Step_4.pdf (Accessed on 26th August 2016)

2. C. C. C. Johansson Seechurn, M. O. Kitching, T. J. Colacot and V. Snieckus, Angew. Chem. Int. Ed., 2012, 51, (21), 5062

3. J. Magano, ‘Large-Scale Applications of Transition Metal Removal Techniques in the Manufacture of Pharmaceuticals’, in “Transition Metal-Catalyzed Couplings in Process Chemistry: Case Studies from the Pharmaceutical Industry”, eds. J. Magano, J. R. Dunetz, Wiley-VCH Verlag, Weinheim, Germany, 2013, p. 313

4. E. J. Flahive, B. L. Ewanicki, N. W. Sach, S. A. O’Neill-Slawecki, N. S. Stankovic, S. Yu, S. M. Guinness and J. Dunn, Org. Process Res. Dev., 2008, 12, (4), 637

Fig. 10. Sealed flow cartridge systems for use at different scales: (a) large-scale laboratory use; (b) plant-scale system

(a)

(b)



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8. C. J. Welch, J. Albaneze-Walker, W. R. Leonard, M. Biba, J. DaSilva, D. Henderson, B. Laing, D. J. Mathre, S. Spencer, X. Bu and T. Wang, Org. Process Res. Dev., 2005, 9, (2), 198

9. M. J. Girgis, L. E. Kuczynski, S. M. Berberena, C. A. Boyd, P. L. Kubinski, M. L. Scherholz, D. E. Drinkwater, X. Shen, S. Babiak and B. G. Lefebvre, Org. Process Res. Dev., 2008, 12, (6), 1209

10. C. E. Garrett and K. Prasad, Adv. Synth. Catal., 2004, 346, (8), 889

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12. G. Lecornet, ‘Analysis of Elemental Impurities in Drug Products using the Thermo Scientific iCAP 7600 ICP-OES Duo’, Application Note 43149, Thermo Fisher Scientific Inc, Massachusetts, USA, 2016

13. C. E. Borba, G. H. F. Santos and E. A. Silva, Chem. Eng. J., 2012, 189–190, 49

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The Authors

Stephanie Phillips is the Market Specialist for Johnson Matthey’s Advanced Ion Exchange (AIX) business at Royston, UK. Stephanie has worked in Sales and Marketing since 2001 and has been involved with the development and marketing of the Smopex® range of products since that time. Stephanie has a BSc in Chemistry and an MSc in Analytical Chemistry.

Duncan Holdsworth is a Senior Process Engineer in the Johnson Matthey AIX business and is based in Royston, UK. Duncan has worked as a Process Engineer within the various Johnson Matthey business divisions since 2010. He most recently joined AIX where he manages the scale up, design, fabrication and commissioning of the various process units operating in both the pharmaceutical and industrial chemicals markets. Duncan gained his MEng in Chemical Engineering from the University of Sheffield, UK.

Pasi Kauppinen gained his PhD in University of Oulu, Finland, and works currently as a Principal Scientist in AIX at the Johnson Matthey plant in Turku, Finland. In this role he is focused on developing AIX processes and products globally

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Carl Mac Namara is a Process Engineer within the Johnson Matthey Water Technologies group, Chilton, UK. He obtained his MEng in Chemical Engineering from Cork Institute of Technology, Ireland, and an Engineering Doctorate from the University of Birmingham, UK. His doctorate and post-doctoral projects were based in Procter & Gamble’s Newcastle Innovation Centre, UK, where he carried out fundamental research on textile cleaning processes. His current role is focused on modelling and developing new water treatment technologies all the way from R&D through to commercial stages.

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doi:10.1595/147106709X481093 •Platinum Metals Rev., 2010, 54, (1), 69–70•

The Use of Metal Scavengers for Recoveryof Palladium Catalyst from SolutionIntroduction Cross-coupling reactions are among the most impor-

tant chemical processes in the fine chemical and phar-

maceutical industries. Widely used procedures such

as the Heck, Suzuki and Sonogashira cross-coupling

reactions and Buckwald-Hartwig aminations most

commonly employ a palladium-based catalyst (1).

Initially these reactions used simple Pd catalysts such

as palladium chloride and palladium acetate,often in

conjunction with a ligand.However, the need to carry

out more challenging coupling reactions (for exam-

ple those using less reactive aryl halides or pseudo-

halides, including aryl chlorides) has resulted in the

development of more advanced Pd catalysts (1, 2).

Product Clean-UpOnce the reaction is complete, the catalyst must be

separated from the product to avoid contamination

by Pd as well as the loss of precious metal into the

product or waste stream. Heterogeneous catalysts

may be separated quite easily from the product solu-

tion and sent for refining to recover the metal, but

homogeneous catalysts are more problematic. One

way to achieve separation is by recrystallisation of the

product; however this can result in the loss of up to

1% of the product yield.

Therefore an alternative method for removing the

residual Pd is required. Scavengers such as Smopex®

can be used to recover platinum group metals

(pgms) including Pd down to parts per billion

(ppb) levels. Smopex® is a fibrous material with a

polypropylene or viscose backbone grafted with

functional groups that can selectively remove the

pgms from solution (Figure 1).The fibres can carry a

metal loading of up to 10 wt%, and the loaded fibres

can then be collected and sent for traditional refining

to recover the precious metal (3).

Smopex® Metal ScavengersThe choice of scavenger for a particular process

depends on several factors. These include the oxida-

tion state of the Pd catalyst, the nature of the solvent

system (aqueous or organic), the presence of byprod-

ucts or unreacted reagents in solution and whether

the scavenger will be applied in a batch process or

continuous flow system. Some examples of Smopex®

fibres that can be applied under different conditions

are shown in Figure 2.

Process ScreeningPrior to using a scavenger in a particular process, it is

common practice to screen a selection of scavengers

to determine the most selective individual or combi-

nation of scavengers. Properties including the type of

scavenger used (based on metal species), amount of

scavenger used (based on concentration),and effects

of solvent and permitted temperature will be investi-

gated and optimised, as well as the kinetics and flow

system requirements. Data is also available on the

scavengers which are known to perform best for spe-

cific reactions (4),and this can be used to make a rec-

ommendation on the scavenger that is likely to offer

the best recovery in each case.

Two examples to illustrate the screening process

follow.

FINAL ANALYSIS

Fig. 1. (a) Smopex®, a fibrous material with a polypropyleneor viscose backbone; (b) Schematic representation of thefunctional groups (red) located on the surface of theSmopex® fibres (3)

(a)

(b)

Case Study 1: Suzuki ReactionThe process stream from a Suzuki coupling reaction

using the catalyst trans-dichlorobis(triphenylphos-

phine)palladium(II) (PdCl2(PPh3)2) in toluene was

analysed and found to contain 100 parts per million

(ppm) of Pd as well as triphenylphosphine and inor-

ganic salts. For Pd present following a reaction using

PdCl2(PPh3)2, thiol-based scavengers are known to be

the most suitable as they are able to break down any

Pd complexes in the solution and bind strongly to the

metal.An excess of Smopex® was applied for the ini-

tial screening process at a rate of 1 wt% Smopex® for

100 ppm Pd.

In this case toluene was used as the process sol-

vent, therefore hydrophobic fibres were recommend-

ed. A process temperature of 80ºC was used in the

coupling step, but the preferred stage for Pd recovery

was after the washing step, at a slightly lower temper-

ature of 60ºC. Screening was carried out using

Smopex®-111 and Smopex®-234, both thiol-based

scavengers (see Figure 2). In both cases, 1 wt% of

Smopex® was stirred at 60ºC for 1 hour, the liquor was

then filtered off and the filtrate was found to contain

<2 ppm Pd when Smopex®-111 was used,and <5 ppm

with Smopex®-234. After further optimisation it was

determined that the amount of Smopex® could be

reduced by half if 3 hours’ contact time was applied.

Case Study 2: Multiple Palladium SpeciesA process stream from a tetrakis(triphenylphos-

phine)palladium(0) (Pd(PPh3)4)-catalysed coupling

reaction with tetrahydrofuran as the solvent was

analysed and found to contain 30 ppm of Pd. In this

case,the Pd was present as both Pd(II) and Pd(0) and

therefore two different scavengers were tested.

Scavenging conditions of 60ºC for 1 hour were again

applied, and a first pass with Smopex®-105 (an anion

exchanger) gave 85% Pd recovery. A further treatment

with Smopex®-101 (a cation exchanger) recovered

the additional 15%, giving an overall recovery of

100%. In some similar cases a thiol fibre such as

Smopex®-111 can give total recovery on its own, but

where this is not achievable, a mixture offers another

way to achieve full recovery of the Pd.

In ConclusionThe widespread use of Pd catalysts for coupling reac-

tions continues to precipitate a requirement for Pd

scavenging of the product solution. Metal scavengers

such as Smopex® fibres can be used with a wide vari-

ety of processes to recover Pd, other pgms or base

metals down to ppb levels, and offer a viable alterna-

tive to traditional procedures such as product recrys-

tallisation.

STEPHANIE PHILLIPS and PASI KAUPPINEN

References1 C. Barnard, Platinum Metals Rev., 2008, 52, (1), 38

2 T. J. Colacot, Platinum Metals Rev., 2009, 53, (4), 183

3 Smopex® Metal Scavengers, A powerful and effectiveway to recover metal from solution:http://www.smopex.com/ (Accessed on 30th October2009)

4 Smopex® Metal Scavengers, ‘Fibre Selection Guide’:http://www.smopex.com/userfiles/file/Smopex%20selection%20guide2.pdf (Accessed on 1st December 2009)

The Authors

Stephanie Phillips is the Product Specialist for Smopex® working forJohnson Matthey’s Chemical Products and Refining Technologies atRoyston, UK. Stephanie has worked in Sales and Marketing since2001 and has been involved with the development and marketingof the Smopex® range of products since that time. Stephanie has aBSc in Chemistry and an MSc in Analytical Chemistry.

Dr Pasi Kauppinen works as Smopex® Development Manager at theJohnson Matthey plant in Turku, Finland. He has expertise in therecovery of platinum group metals and catalysts from solution, polymer absorbents, catalysis and the Smopex® product range.


doi:10.1595/147106709X481093 •Platinum Metals Rev., 2010, 54, (1)•

SO3–H+

SH

SH

Smopex®-101Styryl sulfonic acidgrafted fibre

Smopex®-105Vinyl pyridine graftedfibre

NH+Cl–

Smopex®-111Styryl thiol graftedfibre

Smopex®-234Mercaptoethylacrylategrafted fibre

O

O

Fig. 2. Examples of Smopex® functional groups graftedonto polypropylene fibres (3)

Platinum Metals Rev., 2008, 52, (2), 64–70 64

Microwave heating has developed as an impor-tant tool for research chemists, enabling reactionsto be carried out and optimised more quickly thanusing traditional heating methods (1–3). Directirradiation of the reaction mixture produces amore uniform and homogeneous heating profilethan does, for example, an oil bath. In most casesthe observed increase in rate can be explained bythe extremely efficient energy transfer and homo-geneous heating effect. This can lead tosuperheating of the reaction mixture (4): indeed,even microwave heating of an open vessel canachieve temperatures several degrees higher thanthe boiling point of the solvent (5).

In certain cases the presence of elements thatstrongly absorb microwave energy and release itefficiently as heat can cause localised ‘hotspots’tens of degrees higher than the bulk temperature,generating significant rate enhancements (6–8).This effect can be exploited to heat materials oflow microwave absorbance by the use of ‘passiveheating elements’ (9). Non-polar and poorlyabsorbing solvents can also be superheated byadding small amounts of a strongly absorbingcosolvent such as an ionic liquid (10–13). Theapplication of this selective heating can be particu-larly striking when the element is a heterogeneous

catalyst (14–16). A localised increase in tempera-ture at a catalyst surface over the bulk temperature,or a selective absorption of microwave energy bycatalytic species or organometallic intermediateson a reaction pathway, can lead to increased selec-tivity for the catalytic process while unwanted(thermally driven) side reactions are minimised bya relatively low bulk temperature (17). A synergis-tic advantage between microwave heating andplatinum group metal catalysis can therefore bedemonstrated (18).

The use of commercially available focused(monomode) microwave units (19–21) enhancesthe safety and reproducibility of reactions. Thestandard integration of monomode units intomany laboratory environments has expanded thearmoury of techniques available to chemists, allow-ing ready access to previously difficult-to-achievechemistries. These include high-temperature reac-tions such as Ullmann couplings (22); someheterocycle preparations previously requiringmetal baths (23, 24); the use of near-critical wateras solvent (25–29); and shortening the reactiontime on slow processes such as cycloadditions (30)to practically useful timescales, including replacingthe need for autoclaves (31); and automated pep-tide synthesis (32, 33).

Safer, Faster and Cleaner Reactions UsingEncapsulated Metal Catalysts andMicrowave HeatingPERFORMANCE ENHANCEMENT OF PALLADIUM, PLATINUM AND OSMIUM CATALYSTS

By M. R. Pitts*Reaxa Ltd., Hexagon Tower, Blackley, Manchester M9 8ZS, U.K.; E-mail: [email protected]

The combination of focused microwave heating and encapsulated metal promoters (EnCatTM)offers a safer, cleaner and more cost-effective solution to a wide range of catalyst-mediatedreactions, some of which are not widely accessible to the bench chemist due to high hazardratings. These include the palladium-catalysed Sonogashira cross-coupling, palladium-catalysed transfer hydrogenation, platinum-mediated hydrogenation and osmium tetroxide-catalysed dihydroxylation.

*Present address: Chemistry Innovation KTN, The Heath, Runcorn WA7 4QZ, U.K.; E-mail: [email protected]

DOI: 10.1595/147106708X292526

For the reasons discussed, metal-catalysedreactions work particularly well under microwave irra-diation; however safety and isolation issues still arisefrom their use. Elemental metal can deposit fromreaction mixtures onto the side of the glass tube,causing localised superheating of the glass and explo-sive rupture of the vessel (34). This can occur withboth homogeneous and heterogeneous catalysts. Itcan also be difficult to remove metal species selective-ly from the product on completion of the reaction.

The EnCatTM range of encapsulated metal cata-lysts were designed to address these issues ofpurification and reuse. Unlike other immobilisedhomogeneous catalysts such as FibreCatTM, wherephosphine ligands are attached to polyethylene fibres(35), the homogenous catalyst in EnCat is containedwithin a resin microcapsule. The use of such support-ed or ‘heterogenised’ catalysts industrially is beingdriven by regulatory pressures towards lower residuallevels of metal catalysts within active pharmaceuticalintermediates (APIs) (36, 37).

EnCats are prepared by an interfacial micropoly-merisation of an organic solution containing thehomogeneous metal catalyst, monomers (function-alised isocyanates) and additives, dispersed as asuspension in an aqueous phase. Reactive groupsgenerated at the interface combine to form polymerwalls and, as the surrounding matrix forms, the cata-lyst is entrapped to give spherical microcapsules (38).The individual catalytic species gain additional stabil-isation through interaction with the amidefunctionality of the polyurea matrix, resulting in verylow levels of metal leaching. Consequently the cata-lyst can be recovered efficiently by simple filtrationand reused.

Examples of catalysts already encapsulated thisway include palladium(II) acetate (39, 40) with andwithout various phosphine ligands (41), palladium(0)nanoparticles (42), platinum(0) (43) and osmiumtetroxide (44). Here we describe how EnCats providea homogeneous catalyst in a more effective form foruse with microwave heating.

EnCats in Microwave HeatedReactions

EnCats have been shown to be highly compatiblewith microwave heating (45, 46). Following the excel-

lent work by Ley and coworkers in demonstratingmicrowave-enhanced palladium EnCat-catalysedSuzuki couplings in both batch and flow modes (47),we were keen to understand the role of EnCat inheating bulk solution. Ley found that cooling reac-tions while providing a fixed microwave powerequivalent to that required for good conversion in thenon-cooled method resulted in cleaner products atsimilar or better conversions. The lower bulk temper-ature in the case of cooling may explain the reductionin side reactions, with the temperature ‘inside’ theEnCat beads potentially much higher. It is knownthat Pd/C preferentially absorbs microwave energywhen suspended in a virtually microwave-transparentsolvent, and ‘passively’ heats the surroundings (48).To investigate whether EnCat acts in the same way, a5 cm3 sample of anhydrous toluene, with variousadditives, was irradiated at a constant power of 200W for 5 minutes and the temperature recorded(Figure 1). Adding 250 mg of Pd EnCat had a negli-gible effect on the heating profile, as did the additionof ‘blank’ EnCat beads containing no metal. Additionof an equivalent amount of homogeneous palladiumacetate (27 mg) also had no effect on the heatingbehaviour, whereas 50 mg of palladium (5%) on car-bon caused a significantly increased rate of heating.

These results suggest Pd EnCat does not causesuperheating of the bulk solution, and behaves morelike homogeneous palladium acetate than palladiumon carbon.

Palladium(II) for Cross-CouplingReactions

Considerable effort has been focused on the useof Pd EnCat to facilitate cross-coupling reactions(41). The extremely low leaching of metal species andease of handling of EnCat beads greatly simplifypurification of these reactions. Many examples havebeen published regarding the use of EnCats withmicrowave heating for the acceleration of specificreactions (49–52). An important advantage, often notconsidered, is improved safety when using EnCats ina microwave reactor. Deposition of a film of elemen-tal metal on the glass walls of microwave tubes byprecipitation from solution is a common problemwith conventional metal catalysts. This has beenshown not to occur with Pd EnCat (53). Where a

Platinum Metals Rev., 2008, 52, (2) 65

film is deposited, it absorbs microwave energystrongly, and hotspots can form, resulting in vesselfailure. With modern microwave reactor designssuch ruptures are well contained; however therelease of vapours and subsequent decontamina-tion pose serious issues. These can lead torestrictions on the use of particularly hazardousreagents.

By way of example, a useful palladium-mediatedmicrowave process is the carbonylation of arylhalides with solid sources of carbon monoxide(54). Molybdenum hexacarbonyl has been shownto be an effective carbon monoxide releasing agent(55, 56), however it is a very toxic substance withrelatively high volatility (57). The risk of vessel rup-ture in such procedures can be greatly reduced bysubstituting Pd EnCat for the traditional palladiumcatalyst. The reaction proceeds with quantitativeconversion as shown in Scheme I.

EnCats have been applied in flow chemistrywith the beads packed in simple columns and

reagents passed over them. The initial work inthis area is extremely promising for the process-intensification of homogeneous catalytic reactions(47, 58–60).

A low degree of leaching of the catalytic speciesis vital in a continuous process, in order to avoidrapid deactivation and resulting contamination ofthe product flow stream. Certain substrates areknown to induce leaching of palladium fromEnCat resins, with aryl iodides and alkynes show-ing a high propensity. Indeed, running themicrowave-assisted Sonogashira reaction inScheme II with Pd EnCat 30 resulted in productwith a palladium content of 83 ppm. The triph-enylphosphine-entrapped Pd EnCat (polyTPP30)resin demonstrates an extremely high retention ofboth the palladium and phosphorus ligand, and hasbeen used to great effect in the same reaction(Scheme II). Using Pd EnCat polyTPP30 as thecatalyst, the residual palladium concentration in theproduct was only 14 ppm.


0

20

40

60

80

100

120

140

160

180

0 62000 124000 186000 248000 310000 372000 434000

time (data points)

tem

pera

ture

(C)

tolueneblank beads0.48 mmol/g Pd EnCatpalladium acetate5% Pd/C

Time, 1000 data points

0 62 124 186 248 310 372 434

Tem

pera

ture

, ºC 5%Pd/C

PdEnCat(0.48mmol Pd g–1 )BlankbeadsToluenePalladiumacetate

Fig. 1 Rate of heating of toluene containing various dopants under microwave irradiation

Pd EnCat 30Mo(CO)6

DBU, THFMicrowave

120ºC30 min

Me

I

Ph+ H2N

Yield 98%

PhN

H

NH

Me

O

DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene

Scheme I


Palladium(0) for HydrogenationReactions

The nanoparticulate palladium(0) EnCatcatalyst has been demonstrated as a highlychemoselective hydrogenation and transferhydrogenation catalyst (61, 62). In additionto the improved selectivity shown by PdEnCat NP30, a superior safety profile andease of handling make it a powerful alterna-tive to palladium on charcoal.

Transfer hydrogenation with Pd EnCatNP30 is easily performed in the microwave,allowing reactions in minutes rather thanhours. A recent paper by Quai and coworkersdemonstrated the efficiency of microwave-assisted transfer hydrogenation for O-benzyldeprotection (Scheme III) (63). The use ofEnCat was recommended to improve thesafety of the process and reduce palladiumcontamination of the products.

Scheme IV shows a representative exam-ple of an aromatic nitro reduction. Thesereactions are conventionally carried out atambient temperature overnight (64). How-ever, the microwave transfer hydrogenationprocedure gave a quantitative conversion tothe final product in only 5 minutes.

Platinum(0) for Hydrogenation andReduction Reactions

To complement the palladium(0) EnCatrange, a platinum(0) EnCat has recently beendeveloped, offering the same benefits over itscarbon-supported equivalents as the palladiumversion: improved safety profile, ease of handlingand low metal leaching. Pt(0) EnCat 40 performssimilarly to Pt/C in hydrogenation reactions, andis particularly useful in selective reductions in thepresence of aryl chlorides. The reaction shown inScheme V gave 3-chloroaniline with > 98%selectivity at room temperature under an atmos-phere of hydrogen after one hour (65).Microwave-assisted hydrogenations have recent-ly been investigated (66), and equipment to runthem in the laboratory is becoming commerciallyavailable (67, 68). With microwave reactorsdesigned to meter pressures up to 15 bar and runat them, such technology offers the benchchemist simple, safe access to hydrogenation.

The microwave-assisted hydrogenation of 3-chloronitrobenzene shown in Scheme V was runusing a standard microwave vial. A hydrogenatmosphere (at slight positive pressure) wasintroduced via a needle and manifold cycledbetween vacuum and hydrogen from a lecture

Pd EnCat 30or polyTPP30

CuI, Et3N, THFMicrowave

140ºC20 min Yield 99%

Ph

Me

O

Ph

Me

O

I

+ Scheme II

Pd(0) EnCat NP30HCOONH4, DMF

Microwave (cooled)80ºC

10 minOPh

R

R = NH2, NHMe, COOH, CN, COR, heterocycle, etc.

HO

R

Scheme III

Yield > 99%

Pd(0) EnCat NP30HCOONH4, EtOH

Microwave80ºC5 min

HO HO

NH2NO2

Scheme IV


bottle. Following irradiation at a constant power(30 W) for 13 minutes all the starting materialwas consumed, giving 3-chloroaniline in 85%yield. With equipment designed to charge gas to agiven pressure and monitor the pressure drop, it isto be expected that this reaction could be opti-mised to higher selectivities.

Encapsulated Osmium Tetroxidefor Dihydroxylation Reactions

The osmium tetroxide-catalysed dihydroxyla-tion reaction is Nobel Prize-winning chemistry(69); however the routine use of osmium in thelaboratory is avoided where possible due to its tox-icity, the likelihood of contact due to its volatilityand its propensity to cause burns (70). Os EnCat40 is an encapsulated osmium tetroxide that issafer to handle because no osmium tetroxidevapour can escape the polymer matrix (44). TheEnCat acts as a reservoir of osmium tetroxide,releasing catalytic amounts under oxidation reac-tion conditions, but retaining sufficient activity forrecycling (71). Following the reaction only verylow levels of residual osmium are detectable in thereaction media. Os EnCat 40 has been successful-ly applied to asymmetric dihydroxylation reactions(72). To demonstrate the application of Os EnCat40 under microwave conditions, the simple dihy-droxylation in Scheme VI was carried out at 80ºCand was complete in 20 minutes. The correspond-ing reaction at ambient temperature, when allowedto proceed overnight, gave the product in 86%yield (73). With the reaction performed in a sealedmicrowave tube, the contents could be removed

via syringe with a fine filter fitting, minimising con-tact and potential hazards, and allowing routine,safe use of such chemistry.

ConclusionsMicrowave heating has expanded the arsenal of

synthetic methods available to the bench chemist.The use of encapsulated platinum group metal cat-alysts coupled with the inherently safe design ofmodern microwave apparatus enables safe accessto an even greater range of useful transformations.Such a synergistic combination of technologiesenables reactions to be performed that furnishclean products with very low levels of residualmetal, thus simplifying the preparation of complexmolecules.

Pt(0) EnCat 40H2, EtOH

Microwave 30 W13 min

Yield 85%

Cl NO2 Cl NH2

Scheme V

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Tierney and P. Lidström, Blackwell Publishing Ltd.,Oxford, U.K., 2005

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8 X. Zhang, D. O. Hayward and D. M. P. Mingos,Catal. Lett., 2003, 88, (1–2), 33

Ph

Os EnCatNMO

H2O/acetone

Microwave80ºC

20 min

Ph

OH

Ph

OH

PhScheme VI

Yield 91%NMO = N-methylmorpholine N-oxide


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The AuthorMike Pitts obtained his first degree at LoughboroughUniversity, U.K., in 1997. Zeneca sponsored a project ondioxirane chemistry in his final year, following a successfulindustrial placement year as part of the degree. He then movedto the University of Exeter, U.K., to obtain a Ph.D. withProfessor Chris Moody on ‘Selective Reductions with IndiumMetal’. A postdoctoral stay with Professor Johann Mulzer at theUniversity of Vienna, Austria, followed, where he completed aformal total synthesis of laulimalide as part of a European

Network focused on antitumour natural products. Mike returned to the U.K. in 2002to work for StylaCats Ltd., a start-up company from the University of Liverpool,where he initiated and developed a microwave research platform. In September 2005he moved to Reaxa Ltd. in Manchester, a technology spin-out from Avecia, to developmicrowave processes with their proprietary catalysts. In August 2007 he took up hiscurrent position managing Sustainable Technologies at the Chemistry InnovationKnowledge Transfer Network.

um, Alfa Aesar GmbH & Co. KG, 08.02.2008:http://www.avocadochem.com/daten_msds/GB/13057_-_GB.pdf

58 C. K. Y. Lee, A. B. Holmes, S. V. Ley, I. F.McConvey, B. Al-Duri, G. A. Leeke, R. C. D. Santosand J. P. K. Seville, Chem. Commun., 2005, 2175

59 G. A. Leeke, R. C. D. Santos, B. Al-Duri, J. P. K.Seville, C. J. Smith, C. K. Y. Lee, A. B. Holmes andI. F. McConvey, Org. Process Res. Dev., 2007, 11, (1),144

60 I. R. Baxendale and M. R. Pitts, Chem. Today, 2006,24, (3), 41

61 S. V. Ley, C. Mitchell, D. Pears, C. Ramarao, J.-Q.Yu and W. Zhou, Org. Lett., 2003, 5, (24), 4665

62 S. V. Ley, A. J. P. Stewart-Liddon, D. Pears, R. H.Perni and K. Treacher, Beilstein J. Org. Chem., 2006,2:15

63 M. Quai, C. Repetto, W. Barbaglia and E. Cereda,Tetrahedron Lett., 2007, 48, (7), 1241

64 Results from Reaxa laboratories are available in‘Pd(0) EnCatTM NP30 Hydrogenation & TransferHydrogenation User Guide’, Reaxa Ltd., April 2006:http://www.reaxa.com/images/stories/reaxa_pd0_encat_30np_user_guide_2006.pdf

65 Results from Reaxa laboratories are available in

‘Pt(0) EnCatTM 40 User Guide’, Reaxa Ltd., March2007:http://www.reaxa.com/images/stories/Reaxa%20Pt(0)%20EnCatT%20User%20Guide_mar_07.pdf

66 G. S. Vanier, Synlett, 2007, 13167 C. M. Kormos and N. E. Leadbeater, Synlett, 2006,

166368 E. Heller, W. Lautenschläger and U. Holzgrabe,

Tetrahedron Lett., 2005, 46, (8), 124769 K. B. Sharpless, Angew. Chem. Int. Ed., 2002, 41, (12),

202470 Material Safety Data Sheet, Osmium(VIII) Oxide,

Alfa Aesar GmbH & Co. KG, 08.02.2008:http://www.avocadochem.com/daten_msds/GB/12103_-_GB.pdf

71 D. C. Whitehead, B. R. Travis and B. Borhan,Tetrahedron Lett., 2006, 47, (22), 3797

72 A.-L. Lee and S. V. Ley, Org. Biomol. Chem., 2003, 1,3957

73 Results from Reaxa laboratories are available in‘User Guide – Catalytic Oxidations with OsEnCatTM Microencapsulated Osmium TetroxideCatalysts’, Reaxa Ltd.:http://www.reaxa.com/images/stories/reaxaosencatuserguide.pdf

•Platinum Metals Rev., 2012, 56, (2), 62–74•


http://dx.doi.org/10.1595/147106712X629761 http://www.platinummetalsreview.com/

By Bruce H. Lipshutz*, Benjamin R. Taft and Alexander R. Abela

Department of Chemistry, University of California, Santa Barbara, CA 93106, USA

*Email: [email protected]

Subir Ghorai

New Product Research & Development, Sigma-Aldrich Chemical Company, Sheboygan Falls, WI 53085, USA

Email: [email protected]

Arkady Krasovskiy

Dow Chemical Company, 1776 Building, E-10C, Midland, MI 48674, USA


Christophe Duplais

UMR-CNRS Ecofog, Institut Pasteur de la Guyane, 23 Avenue Pasteur, 97306 Cayenne, French Guyana


Palladium-catalysed cross-couplings, in particular Heck,

Suzuki-Miyaura and Negishi reactions developed over

three decades ago, are routinely carried out in organic

solvents. However, alternative media are currently of

considerable interest given an increasing emphasis

on making organic processes ‘greener’; for example,

by minimising organic waste in the form of organic

solvents. Water is the obvious leading candidate in this

regard. Hence, this review focuses on the application

of micellar catalysis, in which a ‘designer’ surfactant

enables these award-winning coupling reactions to be

run in water at room temperature.

1. IntroductionDecades ago, before palladium-catalysed cross-

couplings arrived, copper was the transition metal of

choice for mediating carbon–carbon bond formation,

regardless of which organometallic complex was used

as the precursor to arrive at various Cu(I) reagents.

However, palladium eventually gained in popularity,

and in 2010 with the recognition of Heck, Suzuki and

Negishi as Nobel Prize recipients (1), the importance of

Pd-catalysed carbon-carbon bond-forming reactions

in organic synthesis was confi rmed.

Each modern organic synthetic reaction was

developed along traditional lines; that is, the chemistry

was matched, not surprisingly, to an organic solvent in

which the coupling best took place (Scheme I). And

while the presence of varying percentages of water

is not an issue for Heck reactions that lead (2–4) to

products such as cinnamates, and Suzuki-Miyaura

reactions that afford (5–7), for example, arylated

aromatics, the far more basic nature of organozinc

halides (RZnX; R = alkyl) (8–11) in Negishi couplings

(12, 13) that give products such as alkylated aromatics

Heck, Suzuki-Miyaura and Negishi reactions carried out in the absence of organic solvents, enabled by micellar catalysis

Catalysis in the Service of Green Chemistry: Nobel Prize-Winning Palladium-Catalysed Cross-Couplings, Run in Water at Room Temperature

http://dx.doi.org/10.1595/147106712X629761 •Platinum Metals Rev., 2012, 56, (2)•


precludes their use under aqueous conditions. None

of these would typically be thought of as amenable to

use in pure water especially at ambient temperatures,

pKa issues aside, if for no other reason than that

organic substrates are not normally soluble in water.

The world is paying increased attention to organic

waste produced by the chemical enterprise, and

organic solvents play a considerable role in this regard

(14).‘Sustainability’ is becoming a guiding principle in

many areas of science and engineering (15), and the

concept of ‘green chemistry’ is gaining in importance

(16–21). Much emphasis, therefore, is being directed

towards ‘alternative media’ (22, 23) in which synthetic

chemistry can be conducted. In this way, our

dependence on organic solvents, whether derived

from petroleum reserves or otherwise, is minimised.

It should be appreciated that green chemistry is an

all-inclusive term, and an evaluation of the full cycle

(a full life cycle assessment (LCA)) of all components

associated with a given process should be considered

in order to fully evaluate the ‘greenness’ of that

process (24–26). Clearly, reductions in major factors

such as the number of steps, the number of changes

in solvent(s), and the number of product isolations

can play a huge role in controlling the generation of

organic waste. Notwithstanding the many virtues of

water as a medium, its use could be costly in terms

of its downstream handling and processing, and if

heating is required either during a reaction or for its

eventual evaporation. But it is also acknowledged that

total LCAs can be both challenging to produce, and

expensive, while on the other hand, solvents, whether

organic or otherwise, are well known entities that can

be readily assessed, quantifi ed, and analysed in terms

of their use in manufacturing and waste disposal.

Scheme I. Traditional cross-coupling reactions going ‘green’

Replace with

water

Product

Organic solvent

Heck Suzuki Negishi

CO2R R–B(OH)2 R–ZnX

Therefore this review considers solvents alone with

regard to ‘greener’ processes.

The most likely alternative among the various

choices available (for example, ionic liquids (27–30),

supercritical carbon dioxide (31–37) etc.), in terms

of potential generality, is water (38–41). To get around

the substrate solubility issue, the leading candidate

technology appears to be micellar catalysis, in which

reactants can be ‘solubilised’ within the surrounding

aqueous phase by the addition of surfactants (42,

43). Although this approach to mixing ‘oil and water’

is decades old, the nature of the surfactants available

to the organic chemist through normal commercial

channels is actually very modest; a handful of each

type (ionic, nonionic and zwitterionic) is all that is

normally seen in the literature. It seems odd, given the

importance of solvent effects in organic chemistry

(24–26), that the choice of amphiphile supplying the

organic medium in which the chemistry is to take

place would be so limited. Moreover, most common

surfactants were created for use in the manufacture of

paint, cosmetics, oil, cleaning fl uids, leather, etc. rather

than for their use in organic synthesis.

To be able to run Heck, Suzuki-Miyaura and Negishi

cross-couplings in water at room temperature, thereby

totally bypassing organic solvents as the reaction

medium, as well as to derive energy savings by

avoiding any need for either heating or cooling reaction

mixtures, the requirements are: (a) identifi cation of an

existing, or possibly newly designed and synthesised

surfactant that leads to results that are as good as or

better than those in organic media; and (b) assurance

that any amphiphile chosen is fully compliant with

‘The 12 Principles of Green Chemistry’ (44).

2. The Amphiphile TPGS-750-MUnlike many surfactants that contain lipophilic, usually

hydrocarbon fragments that have been ‘PEGylated’

(PEG = polyethylene glycol), the newly designed

amphiphile DL--tocopherol methoxypolyethylene

glycol succinate (TPGS-750-M) (1, Figure 1) has three

components (45): non-natural -tocopherol (vitamin

E), a succinic acid linker, and methoxy polyethylene

glycol (‘MPEG-750’). This latter, hydrophilic portion

is monomethylated at one terminus and contains

on average 17 oxyethanyl units (750 divided by 44).

The ‘TPGS’ nomenclature derives originally from

Kodak’s ‘TPGS’, which by analogy is TPGS-1000, and

contains the same -tocopherol (albeit in its natural,

nonracemic form) and succinic acid linker, while the

PEG is PEG-1000 (which has ca. 23 oxyethanyl units

Catalyst LnPdR’

X



and a free hydroxyl residue at its terminus) (46).

These look very similar on paper, but their chemistry

is very different, allowing opportunities to fi ne-tune

the nanoreactors formed during micellar catalysis

that serve as an organic solvent-like medium for

homogeneous cross-coupling reactions in water.

In designing TPGS-750-M (45), it was anticipated

that the economics of its synthesis would be quite

favourable, since it is based on racemic vitamin E,

succinic anhydride, and a commercially available

MPEG. It can be prepared in >90% overall yield using

a simple two-step procedure (45). Couplings within

its larger nanomicellar interior should be as fast or

faster than those in other surfactants that form smaller

particles in water, since both size and shape appear

to be signifi cant (for example, TPGS-1000 forms ca. 13

nm spherical micelles, while TPGS-750-M forms ca. 60

nm particles). An important implication was that a Pd

catalyst would be found for each reaction type that

would function well under the high concentrations

typically found in micelles. However, it was far from

obvious whether the ‘rules’ of modern homogeneous

catalysis, in which each process and catalyst is

precisely matched with a particular organic solvent,

would apply to homogeneous catalysis taking place

at much higher concentrations within nanomicelles.

Therefore, a wide range of Pd catalysts, obtained from

Johnson Matthey, were screened for applicability

to transition metal-catalysed couplings under the

infl uence of the hydrophobic effect.

3. Heck ReactionsCinnamate-forming reactions between aryl bromides

and acrylates take place very smoothly at room

temperature within the nanomicellar environment of

TPGS-750-M (5 wt%) (45, 47), akin to those seen earlier

in the fi rst generation surfactant polyoxyethanyl

-tocopheryl sebacate PTS (PTS-600; Figure 2)

(48, 49). The keys to success in this type of coupling

are the use of 3 M sodium chloride solutions in

Fig. 1. Comparison of structures between ‘TPGS’ (TPGS-1000) and newly engineered TPGS-750-M

TPGS-750-M1(ca. 60 nm micelles)

Racemic vitamin E

MPEG-750

Succinic acid

Succinic acid

Nonracemic vitamin E

PEG-1000

TPGS-1000‘TPGS’(ca. 13 nm micelles)

H3C

CH3 CH3 CH3

CH3 CH3

CH3

CH3

O

OO

OO

H23

O

H3C

CH3 CH3 CH3

CH3 CH3

CH3

CH3

O

OO

OO

Me17

O



place of water alone, and either of the electron-rich

Johnson Matthey catalysts bis(tri-tert-butylphosphine)-

palladium(0) (Pd(tBu3P)2) or dichloro[1,1’-bis(di-tert-

butylphosphino)]ferrocene palladium(II) (PdCl2(dtbpf))

(Figure 2). Other catalysts, such as those derived

from various Pd(II) salts (for example palladium(II)

acetate (Pd(OAc)2), palladium(II) chloride (PdCl2), or

tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3))

as Pd(0) precursors in the presence of various

bidentate phosphine ligands were all less effective.

The ‘salting out’ effect (50) of the NaCl leads to a

complete alteration from spherical to worm-like

micellar arrays (as seen by cryogenic transmission

electron microscopy (cryo-TEM) analysis) (49) with

presumably greater binding constants of substrates

within the particles and hence, faster rates of reactions.

Triethylamine appears to be the common base for

these Heck couplings. Representative examples, in

general, of (E)-favoured arylated products are shown

in Scheme II.Likewise, (E)-stilbenes constructed from aryl halides

and styrene derivatives can be readily fashioned under

similar micellar conditions (Scheme III) (45, 47).

Reactions with aryl iodides and styrene derivatives

can be performed at room temperature in aqueous

micellar solutions using either deionised water or 3

M NaCl and typically are complete in less than four

hours (global concentration = 0.50 M). The product

stilbenes are obtained in excellent yields with >8:1

E:Z selectivity, and often precipitate directly from

the reaction mixture. As with the case of acrylates

(Scheme II), 3 M NaCl can be used to enhance the

rates of otherwise sluggish reactions.

4. Suzuki-Miyaura Cross-CouplingsBiaryl-forming reactions of arylboronic acids and

aryl or heteroaryl bromides can be effi ciently

catalysed by PdCl2(dtbpf) at room temperature in

aqueous solutions of either PTS or TPGS-750-M. Three

representative cases are illustrated in Scheme IV,

including the cross-coupling of a relatively hindered

2,4,6-triisopropyl-substituted bromide.

The air stable complex, PdCl2(dtbpf), has seen less

extensive use in organic solvents for Suzuki-Miyaura

chemistry than its diphenyl analogue, dichloro-

[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)

(PdCl2(dppf)). Nonetheless, early reports from

Johnson Matthey suggested far greater activity

Fig. 2. Catalysts used in Heck reactions run in water at room temperature

Bis(tri-tert-butylphosphine)palladium(0)

Dichloro[1,1’-bis(di-tert-butylphosphino)]ferrocene palladium(II)

Pd(tBu3P)2

PdCl2(dtbpf)

PTS-600‘PTS’(ca. 25 nm micelles) Sebacic acid

Racemic vitamin E

PEG-600

H3C

CH3 CH3 CH3

CH3 CH3

CH3

CH3

O

OO

O

13O

H

O

P Pd PFe

P

P

PdCl2



of PdCl2(dtbpf) in promoting cross-couplings of

aryl chlorides over its more established relative

(51). However, under micellar conditions, with

challenging aryl chlorides, PdCl2(dtbpf) appears

not to be the catalyst of choice (Scheme V). The

Pd(0) catalyst Pd(tBu3P)2 showed little improvement,

despite the tBu3P ligand’s effectiveness at promoting

Suzuki-Miyaura couplings at room temperature in

tetrahydrofuran (THF) (52). And while dichlorobis(p-

methylaminophenyl-di-tert-butylphosphine)palladium(II)

(PdCl2(Amphos)2) showed a marked improvement,

the N-heterocyclic carbene (NHC) bound catalyst

phenylallylchloro[1,3-bis(diisopropylphenyl)imidazole-

2-ylidene]palladium(II) ([(IPr)Pd(cinnamyl)Cl] or

Neolyst CX31), which has been shown to be highly

effi cient in an organic solvent (53), was the most

effective for these reactions being carried out in

nanomicelles.

Interestingly, the scope of Suzuki-Miyaura couplings

in surfactant-water catalysed by this NHC-ligated

catalyst proved to be rather narrow, as PdCl2(Amphos)2

generally provided superior results with heteroaryl

chlorides (Scheme VI). More surprisingly, a large

number of aryl bromide combinations for which

PdCl2(dtbpf) had previously proven effective

(Scheme VII) failed to reach completion under

catalysis with the NHC complex, despite this catalyst’s

demonstrated competence with these substrate

types in organic solvents (53). The effectiveness of

PdCl2(Amphos)2 with heteroaryl coupling partners

was not unexpected given early reports by Amgen

researchers of its high effi ciency with educts of

this type in Suzuki-Miyaura reactions (54, 55).

trans-Dichlorobis(tricyclohexylphosphine)palladium(II)

(PdCl2(Cy3P)2) notably led to very low conversions with

heteroaromatic chlorides under PTS-water conditions,

in spite of previous reports of the Cy3P ligand’s

effectiveness in this role for reactions in dioxane/

water (albeit at elevated temperatures) (56). While an

extensive study comparing specifi c catalysts’ effi cacy

in water vs. organic solvent has not been undertaken,

and notwithstanding the corresponding change of

other parameters (most notably the choice of base),

catalysts PdCl2(dtbpf) and PdCl2(Amphos)2 clearly do

seem especially well-suited to use in water relative to

organic solvents.

5. Negishi-Like Couplings in WaterNegishi couplings today have come to imply a Group 10

metal-catalysed cross-coupling between an organozinc

reagent and an sp2-hybridised electrophilic partner

(12, 13). In fact, there were several other organometallics

Scheme II. Representative Heck couplings in water at room temperature using [Pd(tBu3P)]2

Pd(tBu3P)2 (2 mol%) Et3N (3 equiv.)

PTS or TPGS-750-M (5 wt%) 3 M NaCl, H2O, 4–14 h, RT

86%

90%

82%

84%

76%

O

O

O

OMeO

MeO

OMe

O O

OMe

O

O

O

O O

Cl

Cl

Cl NO2

CO2R’RR

Br+ CO2R’

NH



Scheme III. Representative Heck couplings to form stilbenes using PdCl2(dtbpf) in water at room temperature

PdCl2(dtbpf) (2 mol%) Et3N (3 equiv.)

PTS or TPGS-750-M (5 wt%) H2O or 3 M NaCl, 2–4 h, RT

95% 94% 94%

95% 96% 97%

(>8:1 E/Z)

Scheme IV. Representative Suzuki-Miyaura couplings in water at room temperature

PdCl2(dtbpf) (2 mol%) Surfactant-H2O (2 wt%)

Et3N (3.0 equiv.), RT

93% (2 h) (TPGS-750-M)

88% (24 h) (TPGS-750-M)

99% (6 h) (PTS)

that were utilised by the Negishi school before zinc

(for example, aluminium, zirconium and boron)

(57–61). The synthetic potential of zinc reagents, RZnX,

however, is undeniable, as they possess a suitable level

of nucleophilicity to participate in a transmetalation

step to a Pd(II) intermediate, while being especially

IR

BnOOH

OBn

NC

+ Ar RAr

NNN

octyl

NTs

Me

MeOMe

F

MeO

Cl

OMe OMe

EtO2C

ArBr + Ar’B(OH)2 Ar Ar’

OMeN

N

S

N



tolerant of most functionality (62). Unfortunately,

however, they are defi nitely not tolerant of water (12,

13). Nonetheless, Negishi couplings can be, and have

been, conducted in pure water (63–65). The secret

to success in this unlikely methodology is avoidance

of the traditional up-front use of stoichiometric Zn

reagents; this is achieved by generating a zinc reagent

over time on the surface of the metal, surrounded

by the hydrophobic pocket of a nanomicelle. The

catalyst must: (a) be readily available while tolerating

exposure to water; and (b) respond favourably to the

hydrophobic effect associated with micellar catalysis.

One species has been identifi ed to date that meets

these criteria: PdCl2(Amphos)2 (54, 55) (2, Figure 3). Other species, including the parent bis-desamino

system PdCl2(tBu2PhP)2 (Figure 3), were screened,

but the rates of conversion were too low to make the

reaction synthetically viable. Interestingly, among the

Scheme V. Comparison of catalysts for Suzuki-Miyaura couplings of aryl chlorides in water at room temperature

Scheme VI. Comparison of NHC-containing catalysts with phosphine-ligand containing catalysts

GC conversion, Catalyst %, 23 h, RT

CX31 68CX32 68PdCl2(Cy3P)2 10PdCl2(Amphos)2 100

Conditions: 2% catalyst, 1 wt% PTS in water, 3.0 equiv. Et3N [(SIPr)Pd(cinnamyl)Cl] (Umicore Neolyst CX32)

Catalyst (2 mol%) PTS-H2O (1 wt%)

Et3N (3.0 equiv.)ArCl + Ar’B(OH)2 Ar Ar’

NF3C

NN

PdCl

Catalyst Time, h Temp., ºC Yield, %

PdCl2(dtbpf) 24 50 28CX31 4 RT 98

GC conversion after 24 h at 50ºC: PdCl2(dtbpf) 38%PdCl2(Amphos)2 83%PdCl2(

tBu3P)2 47%CX31 100%

Catalyst Time, h Temp., ºC Yield, %

PdCl2(dtbpf) 24 50 82CX31 11 RT 99

[(IPr)Pd(cinnamyl)Cl] (Umicore Neolyst CX31)

OMe

NN

PdCl



catalysts shown in Figure 3 are selected cases that

are well known to mediate Negishi couplings in THF

(66, 67). Clearly, in a nanomicelle, they are not the

preferred species.

There is a third essential component: the ‘gatekeeper’,

without which there is no coupling whatsoever:

tetramethylethylenediamine (TMEDA). TMEDA likely

plays several important roles in these couplings: (i)

to clean the metal surface for subsequent electron

transfer; (ii) to chelate and thereby stabilise the newly

formed RZnX; and (iii) to enhance the transfer of

RZnX into the nanomicellar interior.

When an alkyl halide (iodide or bromide), an

aryl bromide, excess TMEDA, and PdCl2(Amphos)2

are mixed together in water containing 2 wt% TPGS-

750-M (or PTS), nanomicelles are formed containing

high concentrations of these species. Upon addition

of either Zn powder or dust, chemistry takes place in

water at room temperature. The selective insertion of

Zn into the sp3-carbon-halogen bond via successive

electron transfer steps is presumed to form RZnX

on the metal surface, protected momentarily by the

surrounding micelle. The newly formed organozinc

halide, thought to be chelated by TMEDA, then enters

the hydrophobic interior where a coupling partner

and associated reagents are located.

As illustrated in Scheme VIII, C–C bond formation

takes place smoothly with aryl bromides, including

coupling with a secondary alkylzinc reagent to give

product 3 in good yield (45, 63). It is especially

worthy of note that traditional Negishi couplings

with aryl bromides in THF do not typically occur

at room temperature (Scheme IX; C) (12, 13);

heating at reflux is common, especially for non-

activated substrates. A control experiment using

RZnX (prepared in THF) in an aqueous surfactant

environment gave the expected low level of

conversion due to quenching of the organozinc

halide (A in Scheme IX). Thus, the hydrophobic

effect adds yet another benefit to these reactions

(B in Scheme IX).

Several heteroaromatic halides have also

been studied under micellar catalysis conditions

(Scheme X) (64). Here again, PdCl2(Amphos)2, used

in catalytic amounts (2 mol%), is crucial for success.

Bromides located on each position on a substituted

pyridyl ring lead to good yields of alkylated products,

although the parent 2-, 3- or 4-bromopyridines gave

Scheme VII. Comparison of catalysts for Suzuki-Miyaura couplings of aryl bromidesArBr + Ar’B(OH)2 Ar Ar’

Catalyst (2 mol%) PTS-H2O (2 wt%)

Et3N (3.0 equiv.)

PdCl2(dtbpf): 78% yield CX31: 47% GC conversion


OMe

F OMe

MeO


F




Fig. 3. Ligands/catalysts screened for Zn-mediated, Pd-catalysed cross-couplings in water at room temperature

Pd PCy3Cy3PCl

Cl

only traces of substitution. Heteroaromatics including

thiophenes, benzothiophenes, indoles and quinolines

appear to be amenable. As expected for organozinc

reagents, excellent tolerance to functionality in either

partner is observed. Noteworthy is the case of indole

derivative 4, where a secondary centre can be directly

inserted onto the ring in high yield.

In addition to aryl bromides, cross-couplings

involving alkenyl halides are also amenable using

catalyst PdCl2(Amphos)2, although in these cases the

added feature of olefi n geometry is present (Scheme

XI) (65). As anticipated, (E)-alkenyl halides, whether

iodides or bromides, retain their original geometry in

the coupled products. Likewise, (Z)-alkenyl halides

maintain their stereochemical integrity (45) which

was unexpectedly found not to be the case for the

corresponding reactions under traditional Negishi

coupling conditions in THF (66, 67). The positive

stereochemical outcome for these reactions in water is

a fortunate occurrence, since the choice of ligands that

help mediate these couplings (as noted above), at least

to date, is not broad.

[Pd(OAc)2]3 +

PCy2iPr

iPr

iPr Pd(OAc)2 + P(tBu)2Me

PhPh

PPd(dba)2 +

Pd PP OHHOCl

Cl

N

NN

iPr iPr

iPriPrPd ClCl

Cl

FeP

PPd

tButBu

tButBu

ClCl

Pd P(tBu)3(tBu)3P

Br

BrPdPd P(tBu)3(tBu)3P

Pd PPh3Ph3PCl

Cl

Pd PPh3Ph3PPPh3

PPh3

Pd PPCl

Cl

Pd PPCl

ClMe2N NMe2

2, PdCl2(Amphos)2



Scheme VIII. Representative Negishi-like couplings between two halides, in water at room temperature

R–X +

(R = primary or secondary alkyl)

Br

R’

PdCl2(Amphos)2 (0.5 mol%) TMEDA (3–5 equiv.)

Zn dust (3 equiv.) Surfactant-H2O (2 wt%), RT

R

R’

EtO2C

C7H15-n

82% (with PTS; X = I) 93% (with PTS; X = I) 74% (with PTS; X = I)MOM = methoxymethyl

3, 75% (with TPGS-750-M; X = Br)

Coupling with a secondary alkyl halide

71% (with TPGS-750-M; X = Br)

EtO2C EtO2C

CO2Et

BocOMOM

C10H21-n

O

N

Scheme IX. Comparison reactions: traditional Negishi coupling conditions vs. micellar conditions

OMe

Br

OMe

C7H15–n

n-C7H15ZnI in THF 2 mol% catalyst 2

2% PTS-H2O, RT, 12 h

n-C7H15I, Zn, TMEDA 2 mol% catalyst 2

2% PTS-H2O, RT, 12 h

n-C7H15ZnI or n-C7H15I, Zn 2 mol% catalyst 2

THF, RT, 12 h

A

C

B

Conversion = 30%

Conversion < 20%

Isolated yield = 90%



Scheme X. Cross-couplings of heteroaromatic and alkyl halides using catalyst PdCl2(Amphos)2 in water at room temperature

+

Zn/TMEDAPdCl2(Amphos)2

PTS-H2O, RT

(FG)

X

(FG’)

X

Scheme XI. Representative cross-couplings of alkenyl and alkyl halides, in water at room temperature

6. ConclusionsThe Nobel Prize awarded for the Heck, Negishi and

Suzuki cross-coupling reactions is further recognition

of the importance of the role that catalysis, in

particular by Pd, plays in society. But catalysis is

also a key component of green chemistry, and this

requires ligands on the metal that adjust catalyst

reactivity and selectivity. Catalysts that work well in

traditional organic solvents at modest concentrations

(usually 0.1 to 1 M in substrate) may not be the

species of choice under far higher concentrations in

an alternative medium such as nanomicelles in water.

A completely new set of factors that control catalyst

motion in and out of micelles and result in greater time

spent within nanoreactors (greater binding constants)

may require alternative or even newly devised ligands

for Pd-catalysed cross-couplings. Thus, as an outgrowth

of the hydrophobic effect, some rules for catalysis

may change, giving rise to both new discoveries and

opportunities for new catalysts.

Heteroaromatic

(FG’)

Heteroaromatic-alkyl

(FG)

Alkyl+

FG = functional group

N

OTBS

TIPS86%

N

SOO

S O N

O

CO2EtPh

Cl

CO2Et

Boc

71% 74%

82% 89% 4, 97%

3

n-C7H15BnO

85% (from the iodide; PTS) 87% (from the bromide; TPGS-750-M)

CO2Et4

(Z)-Alkenyl halides give (Z)-alkenyl products

CO2Et

91% (from the bromide; PTS)



AcknowledgementsFinancial support provided by the National Institutes

of Health (GM 86485) is warmly acknowledged. We are

indebted to Johnson Matthey for generously providing

the catalysts and ligands that were successfully applied

to the cross-coupling chemistry discussed herein.

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The AuthorsBruce Lipshutz began his career at University of California (UC) Santa Barbara, USA, in 1979, where today he is Professor of Chemistry. His programme has recently shifted towards green chemistry, with the specifi c goal of getting organic solvents out of organic reactions. For this, ‘designer’ surfactants have been introduced that allow for transition metal-catalysed cross-couplings to be carried out in water at room temperature.

Ben Taft received his BS in Chemistry at California State University, Chico, in 2004. He took a PhD from UC Santa Barbara in 2008 with Bruce H. Lipshutz. He then moved to Stanford as an NIH postdoctoral fellow under Barry Trost. He began at Novartis, in Emeryville, in 2011, where he works in the oncology discovery group.

Alexander Abela carried out his graduate work in the Lipshutz group at UC Santa Barbara, focusing on transition metal-catalysed Suzuki-Miyaura cross-coupling reactions in water and C–H activation chemistry. Following completion of his PhD, he joined the Guerrero group at UC San Diego in 2012 to continue his studies as a postdoctoral scholar.

Subir Ghorai took his PhD in 2005 from the Indian Institute of Chemical Biology. After a year of research at UC Riverside, he joined the Lipshutz group at UC Santa Barbara. Currently, he is in the Catalysis and Organometallics group at Sigma-Aldrich in Wisconsin, USA. His research interests are focused on catalysis, organometallics, and green chemistry.

Arkady Krasovskiy holds a PhD in organic chemistry from M. V. Lomonosov Moscow State University, Russia. He has extensive training in synthetic/organometallic chemistry gained during his postdoctoral time in the Knochel (2003–2006), Nicolaou (2006–2008), and Lipshutz (2008–2011) laboratories. Currently he is working in Core Research & Development at the Dow Chemical Company in Midland, MI, USA.

Christophe Duplais took his PhD in 2008 from the University Cergy-Pontoise in France, under the guidance of Gerard Cahiez. He then did a postdoctoral stay in the labs of Bruce Lipshutz at UC Santa Barbara, before accepting a position in 2011 with the CNRS, located in French Guyana.

By Thomas J. Colacot

Johnson Matthey, Catalysis and Chiral Technologies,2001 Nolte Drive, West Deptford, New Jersey 08066,USA;

E-mmail: [email protected]

The 2010 Nobel Prize in Chemistry was awarded joint-

ly to Professor Richard F. Heck (University of Delaware,

USA), Professor Ei-ichi Negishi (Purdue University,

USA) and Professor Akira Suzuki (Hokkaido University,

Japan) for their work on palladium-catalysed cross-

coupling in organic synthesis. This article presents a

brief history of the development of the protocols for

palladium-catalysed coupling in the context of Heck,

Negishi and Suzuki coupling. Further developments in

the area of palladium-catalysed cross-coupling are also

briefly discussed, and the importance of these reac-

tions for real world applications is highlighted.

The 2010 Nobel Prize in chemistry was the third

awarded during the last ten years in the area of plat-

inum group metal (pgm)-based homogeneous cataly-

sis for organic synthesis. Previous prizes had been

awarded to Dr William S. Knowles (Monsanto, USA),

Professor Ryoji Noyori (Nagoya University, Japan) and

Professor K. Barry Sharpless (The Scripps Research

Institute, USA) in 2001, for their development of asym-

metric synthesis reactions catalysed by rhodium,

ruthenium and osmium complexes, and to Dr Yves

Chauvin (Institut Français du Pétrole, France),

Professor Robert H. Grubbs (California Institute of

Technology (Caltech), USA) and Professor Richard

R. Schrock (Massachusetts Institute of Technology

(MIT), USA) in 2005 for the development of the

ruthenium- and molybdenum-catalysed olefin

metathesis method in organic synthesis.

Figure 1 shows some of the researchers who have

made significant contributions in the area of palladi-

um-catalysed cross-coupling, including 2010 Nobel

laureate, Professor Akira Suzuki, during a cross-

coupling conference at the University of Lyon, France,

in 2007 (1).

Palladium-Catalysed ReactionsOrganometallic compounds of pgms are vitally

important as catalysts for real world applications in



The 2010 Nobel Prize in Chemistry:Palladium-Catalysed Cross-CouplingThe importance of carbon–carbon coupling for real world applications

doi:10.1595/147106711X558301 http://www.platinummetalsreview.com/

synthetic organic chemistry. Chemists are continually

striving to improve the efficiency of industrial

processes by maximising their yield, selectivity and

safety. Process economics are also important, and

chemists work to minimise the number of steps

required and thereby reduce the potential for waste

and improve the sustainability of the process.

Homogeneous catalysis is a powerful tool which can

help to achieve these goals. Of the three Nobel Prizes

in pgm-based homogeneous catalysis, perhaps the

most impact in practical terms has been made by

palladium-catalysed cross-coupling (2).

In order for an area to be recognised for the Nobel

Prize, its real world application has to be demon-

strated within 20 to 30 years of its discovery. Although

the area of metal-catalysed cross-coupling was initi-

ated in the early 1970s, there were a very limited num-

ber of publications and patents in this area before the

1990s (see Figure 2). However, the area has grown

rapidly from 1990 onwards, especially since 2000.

In terms of the number of scientific publications,

patents and industrial applications, Suzuki coupling

is by far the largest area, followed by Heck,

Sonogashira and Stille coupling (Figure 2). Negishi

coupling is smaller in terms of the number of pub-

lications, but its popularity is growing due to the

functional group tolerance of the zinc reagent in

comparison to magnesium, in addition to its signifi-

cant potential in sp3–sp2 coupling, natural product

synthesis and asymmetric carbon–carbon bond form-

ing reactions (1).

The history and development of the various types

of palladium-catalysed coupling reactions have been

covered in detail elsewhere (3, 4). This short article

will focus on the practical applications of palladium-

catalysed coupling reactions.

Heck CouplingBetween 1968 and

1972, Mizoroki and

coworkers (5, 6) and

Heck and coworkers

(7–9) independently

discovered the use of

Pd(0) catalysts for

coupling of aryl, ben-

zyl and styryl halides

with olefinic com-



Fig. 1. From left: Professor Kohei Tamao (a significant contributor in Kumada coupling),Professor Gregory C. Fu (a significant contributor in promoting the bulky electron-richtert-butyl phosphine for challenging cross-coupling), Professor Akira Suzuki (2010 NobelPrize in Chemistry Laureate), Dr Thomas J. Colacot (author of this article) and ProfessorTamejiro Hiyama (who first reported Hiyama coupling) in front of a photograph ofProfessor Victor Grignard (who initiated the new method of carbon–carbon coupling) inthe library of the University of Lyon, France

Cop

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The

Nob

el F

ound

atio

n.Ph

oto:

Ulla

Mon

tan

pounds, now known as the Heck coupling reaction

(Scheme I) as Heck was the first to uncover the mech-

anism of the reaction.

The applications of this chemistry include the syn-

thesis of hydrocarbons, conducting polymers, light-

emitting electrodes, active pharmaceutical ingredi-

ents and dyes. It can also be used for the enantio-

selective synthesis of natural products.

Heck coupling has a broader range of uses than the

other coupling reactions as it can produce products

of different regio (linear and branched) and stereo

(cis and trans) isomers. Typically, olefins possessing

electron-withdrawing groups favour linear products

while electron-rich groups give a mixture of branched

and linear products.The selectivity is also influenced

by the nature of ligands, halides, additives and sol-

vents, and by the nature of the palladium source. The

reaction has recently been extended to include direct

arylation and hydroarylation, which may have future

potential in terms of practical applications. Heck cou-

pling also has the unique advantage of making chiral

C–C bonds,with the exception of α-arylation reactions.

The Negishi ReactionDuring 1976–1977,

Negishi and co-

workers (10–12) and

Fauvarque and Jutand

(13) reported the use

of zinc reagents in

cross-coupling reac-

tions.During the same

period Kumada et al.

(14–17) and Corriu

et al. (18) independ-

ently reported that nickel–phosphine complexes

were able to catalyse the coupling of aryl and alkenyl

halides with Grignard reagents. Kumada and cowork-

ers later reported (in 1979) the use of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)

(PdCl2(dppf)) as an effective catalyst for the cross-

coupling of secondary alkyl Grignard reagents with

organic halides (19). One common limitation to both

Ni- and Pd-catalysed Kumada coupling is that cou-

pling partners bearing base sensitive functionalities



8000

7000

6000

5000

4000

3000

2000

1000

0

Tota

l num

ber

of p

ublic

atio

ns

and

pate

nts

DecadesPre-1990 1991–2000 2001–2010

SuzukiHeckSonogashiraStilleNegishiBuchwald-HartwigKumadaHiyamaAlpha ketone arylation

Fig. 2. Growth in the number of scientific publications and patents on platinumgroup metal-catalysed coupling reactions

RX +R’ H

H H

R’ H

H R

Pd catalyst

Base

R, R’ = aryl, vinyl, alkylX = halide, triflate, etc.

Scheme I. The Heck coupling reaction

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Mon

tan

are not tolerated due to the nature of the organomag-

nesium reagents.

In 1982 Negishi and coworkers therefore carried out

a metal screening in order to identify other possible

organometallic reagents as coupling partners (20).

Several metals were screened in the coupling of an

aryl iodide with an acetylene organometallic reagent,

catalysed by bis(triphenylphosphine)palladium(II)

dichloride (PdCl2(PPh3)2). In this study, the use of

zinc, boron and tin were identified as viable counter-

cations, and provided the desired alkyne product in

good yields. The use of organozinc reagents as cou-

pling partners for palladium-catalysed cross-coupling

to form a C–C single bond is now known as the

Negishi reaction (Scheme II).

The Negishi reaction has been used as an essential

step in the synthesis of natural products and fine

chemicals (21–23).

Suzuki CouplingDuring the same

period as the initial

reports of the use of

palladium–phosphine

complexes in Kumada

couplings, the palla-

dium-catalysed cou-

pling of acetylenes

with aryl or vinyl

halides was concur-

rently disclosed by

three independent research groups, led by

Sonogashira (24), Cassar (25) and Heck (26).

A year after the seminal report on the Stille cou-

pling (27, 28), Suzuki picked up on boron as the last

remaining element out of the three (Zn, Sn and B)

identified by Negishi as suitable countercations in

cross-coupling reactions, and reported the palladium-

catalysed coupling between 1-alkenylboranes and

aryl halides (29) that is now known as Suzuki cou-

pling (Scheme III).

It should be noted that Heck had already demon-

strated in 1975 the transmetallation of a vinyl boronic

acid reagent (30). Perhaps the greatest acomplish-

ment of Suzuki was that he identified PdCl2(PPh3)2 as

an efficient cross-coupling catalyst, thereby demon-

strating the relatively easy reduction of Pd(II) to

Pd(0) during catalysis.

The Suzuki coupling reaction is widely used in

the synthesis of pharmaceutical ingredients such

as losartan. Its use has been extended to include

coupling with alkyl groups and aryl chlorides

through the work of other groups including Fu and

coworkers (31). Subsequent work from Buchwald,

Hartwig, Nolan, Beller and others, including Johnson

Matthey, has expanded the scope of this reaction.

Other Name Reactions in Carbon–CarbonCoupling In 1976, Eaborn et al. published the first palladium-

catalysed reaction of organotin reagents (32), fol-

lowed by Kosugi et al. in 1977 on the use of organotin

reagents (33,34). Stille and Milstein disclosed in 1978

the synthesis of ketones (27) under significantly

milder reaction conditions than Kosugi. At the begin-

ning of the 1980s, Stille further explored and improved

this reaction protocol, to develop it into a highly ver-

satile methodology displaying very broad functional

group compatibility (28).

In 1988, Hiyama and Hatanaka published their work

on the Pd- or Ni-catalysed coupling of organosilanes

with aryl halides or trifluoromethanesulfonates (tri-

flates) (35). Although silicon is less toxic than tin,

a fluoride source, such as tris(dimethylamino)-

sulfonium difluorotrimethylsilicate (TASF) (35) or cae-

sium fluoride (CsF) (36), is required to activate the

organosilane towards transmetallation. Professor S. E.

Denmark has also contributed significantly to this area.

Industrial ApplicationsIn the early 1990s the Merck Corporation was able to

develop two significant drug molecules, losartan, 11,



RZnY + R’X R–R’Pd catalyst

R, R’ = aryl, vinyl, alkylX = halide, triflate, etc.Y = halide

Scheme II. The Negishi coupling reaction

RBZ2 + R’X R–R’Pd catalyst

Base

R, R’ = aryl, vinyl, alkylX = halide, triflate, etc.Z = OH, OR, etc.

Scheme III. The Suzuki coupling reaction

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(also known as CozaarTM, for the treatment of hyper-

tension) (37) and montelukast, 22, (also known as

SingulairTM, for the treatment of asthma) (38, 39),

(Figure 3) using Suzuki and Heck coupling processes

respectively. This also increased awareness among

related industries to look into similar processes.

Today, coupling reactions are essential steps in the

preparation of many drugs. Recent reviews by Beller

(40) and by Sigman (41) summarise the applications

of Pd-catalysed coupling in the pharmaceutical,agro-

chemical and fine chemicals industries. Apart from

the major applications in the pharmaceutical and

agrochemical industries (the boscalid process is the

world’s largest commercial Suzuki process), cross-

coupling is also being practiced in the electronics

industry for liquid crystal and organic light-emitting

diode (OLED) applications in display screens (42,

43).

The research and development group at Johnson

Matthey’s Catalysis and Chiral Technologies has devel-

oped commercial processes for preformed catalysts

such as PdCl2(dtbpf) (Pd-118), 33, (44–46), L2Pd(0)

complexes, 44, (47) and precursors to twelve-electron

species such as [Pd(µ-Br)tBu3P]2 (Pd-113), 55, (48)

and LPd(η3-allyl)Cl, 66, (49, 50) (Figure 4). These cata-

lysts are all highly active for various cross-coupling

reactions which are used for real world applications.

More details on the applications of these catalysts

are given elsewhere (48, 51, 52). A special issue of

Accounts of Chemical Research also covered recent

updates of these coupling reactions from academia

in detail (53).



PdBr

PtBu2

3

Fe

PtBu2

Pd

Cl

ClL L

4

tBu3P–Pd Pd–PtBu3

Br

5Pd

Cl

P

6

4a L = PtBu34b L = PtBu2Np4c L = PCy34d L = Q-Phos4e L = Ata-Phos4f L = P(o-tolyl)34g L = PPhtBu2

Fe

PtBu2

Ph

PhPh

Ph

Q-Phos ligand

Me2N

Ata-Phos ligand

PtBu2

Ph

2 Montelukast 1 Losartan

Fig. 4. Examples of highly active Pd cross-coupling catalysts developed and commercialised by Johnson Matthey

Fig. 3. Structures of losartan and montelukast

In order to address the issue of residual palladium

in the final product, several solid-supported

preformed palladium complexes have been devel-

oped and launched onto the catalyst market

(54–56).

ConclusionsPalladium-catalysed cross-coupling is of great impor-

tance to real world applications in the pharmaceu-

tical, agrochemicals, fine chemicals and electronics

industries. The area has developed quite rapidly

beyond the work of Heck, Negishi and Suzuki,

though all three reactions are widely used. Academic

groups such as those of Beller, Buchwald, Fu, Hartwig

and Nolan as well as industrial groups such as that

at Johnson Matthey, are now developing the field even

further. Buchwald-Hartwig coupling has become par-

ticularly important for developing compounds con-

taining carbon–nitrogen bonds for applications in

industry, as well as α-arylation of carbonyl com-

pounds such as ketones, esters, amides, aldehydes

etc., and nitriles (57). The significant growth of cross-

coupling reactions can be summarised in Professor

K. C. Nicolaou’s words:

“In the last quarter of the 20th century, a new

paradigm for carbon–carbon bond formation has

emerged that has enabled considerably the prowess

of synthetic organic chemists to assemble complex

molecular frameworks and has changed the way

we think about synthesis” (58).

More detailed articles summarising the history of

cross-coupling in the context of the 2010 Nobel Prize

in Chemistry with an outlook on the future of cross-

coupling will be published elsewhere (59, 60).



Glossary

Ligand Name

Ata-Phos p-dimethylaminophenyl(di-tert-butyl)phosphine

Cy cyclohexyl

dppf 1,1′-bis(diphenylphosphino)ferrocene

dtbpf 1,1′-bis(di-tert-butylphosphino)ferrocene

Np neopentyl

Ph phenyl

Q-Phos 1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocenetBu tert-butyl

References1 T. Colacot, Platinum Metals Rev., 2008, 52, (3), 172

2 “Metal-Catalyzed Cross-Coupling Reactions”, 2nd Edn.,eds. A. de Meijere and F. Diederich, Wiley-VCH,Weinheim, Germany, 2004

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37 R. D. Larsen, A. O. King, C. Y. Chen, E. G. Corley, B. S.Foster, F. E. Roberts, C. Yang, D. R. Lieberman and R. A.Reamer, J. Org. Chem., 1994, 59, (21), 6391

38 A. O. King, E. G. Corley, R. K. Anderson, R. D. Larsen,T. R. Verhoeven, P. J. Reider, Y. B. Xiang, M. Belley andY. Leblanc, J. Org. Chem., 1993, 58, (14), 3731

39 R. D. Larsen, E. G. Corley, A. O. King, J. D. Carroll, P. Davis,T. R. Verhoeven, P. J. Reider, M. Labelle, J. Y. Gauthier, Y. B.Xiang and R. J. Zamboni, J. Org. Chem., 1996, 61, (10),3398

40 C. Torborg and M. Beller, Adv. Synth. Catal., 2009, 351,(18), 3027

41 R. Jana, T. P. Pathak and M. S. Sigman, Chem. Rev.,2011, 111, (3), 1417

42 X. Zhan, S. Barlow and S. R. Marder, Chem. Commun.,2009, (15), 1948 and references therein

43 H. Jung, H. Hwang, K.-M. Park, J. Kim, D.-H. Kim and Y. Kang, Organometallics, 2010, 29, (12), 2715

44 G. A. Grasa and T. J. Colacot, Org. Process Res. Dev.,2008, 12, (3), 522

45 G. A. Grasa and T. J. Colacot, Org. Lett., 2007, 9, (26),5489

46 T. J. Colacot and H. A. Shea, Org Lett., 2004, 6, (21),3731

47 H. Li, G. A. Grasa and T. J. Colacot, Org. Lett., 2010, 12,(15), 3332

48 T. J. Colacot, Platinum Metals Rev., 2009, 53,(4), 183

49 L. L. Hill, J. L. Crowell, S. L. Tutwiler, N. L. Massie, C. C. Hines,S. T. Griffin, R. D. Rogers, K. H. Shaughnessy, G. A. Grasa,C. C. C. Johansson Seechurn, H. Li, T. J. Colacot, J. Chou andC. J. Woltermann, J. Org. Chem., 2010, 75, (19), 6477

50 L. L. Hill, L. R. Moore, R. Huang, R. Craciun, A. J. Vincent,D. A. Dixon, J. Chou, C. J. Woltermann and K. H.Shaughnessy, J. Org. Chem., 2006, 71, (14), 5117

51 T. J. Colacot and S. Parisel, ‘Synthesis, CoordinationChemistry and Catalytic Use of dppf Analogs’, in“Ferrocenes: Ligands, Materials and Biomolecules”, ed.P. Stepnicka, John Wiley & Sons, New York, USA, 2008

52 T. J. Colacot, ‘Dichloro[1,1’-bis(di-tert-butylphosphino)-ferrocene]palladium(II)’, in “e-EROS Encyclopedia ofReagents for Organic Synthesis”, eds. L. A. Paquette,D. Crich, P. L. Fuchs and G. Molander, John Wiley & Sons,published online 2009

53 Cross-Coupling Special Issue, Acc. Chem. Res., 2008, 41,(11), 1439–1564

54 T. J. Colacot, W. A. Carole, B. A. Neide and A. Harad,Organometallics, 2008, 27, (21), 5605

55 T. J. Colacot, ‘FibreCat’, in “e-EROS Encyclopedia ofReagents for Organic Synthesis”, eds. L. A. Paquette,D. Crich, P. L. Fuchs and G. Molander, John Wiley & Sons,published online 2009

56 W. Carole and T. J. Colacot, Chim. Oggi-Chem. Today,May/June 2010, 28, (3)

57 C. C. C. Johansson Seechurn and T. J. Colacot, Angew.Chem. Int. Ed., 2010, 49, (4), 676

58 K. C. Nicolaou, P. G. Bulger and D. Sarlah, Angew. Chem.Int. Ed., 2005, 44, (29), 4442

59 C. C. C. Johansson Seechurn, T. J. Colacot, M. Kitchingand V. Snieckus, Angew. Chem. Int. Ed., manuscript underpreparation

60 H. Li, T. J. Colacot and V. Snieckus, ACS Catal., manuscriptunder preparation

The AuthorDr Thomas J. Colacot, FRSC, is aResearch and Development Managerin Homogeneous Catalysis (Global) ofJohnson Matthey’s Catalysis andChiral Technologies business unit.Since 2003 his responsibilities includedeveloping and managing a new cat-alyst development programme, cat-alytic organic chemistry processes,scale up, customer presentations andtechnology transfers of processesglobally. He is a member of PlatinumMetals Review’s Editorial Board,among other responsibilities. He hasco-authored about 100 publicationsand holds several patents.





“Palladium-Catalyzed Coupling Reactions: Practical Aspects and Future Developments”Edited by Árpád Molnár (University of Szeged, Hungary), Wiley-VCH Verlag GmbH & Co KGaA, Weinheim, Germany, 2013, 692 pages, ISBN: 978-3-527-33254-0, £125.00, €150.00, US$190.00


Reviewed by Robert Hanley

Johnson Matthey Emission Control Technologies,

Orchard Road, Royston, Hertfordshire SG8 5HE, UK


“Palladium-Catalyzed Coupling Reactions”, published

by Wiley in 2013, is a comprehensive handbook and

guide to modern aspects of this reaction type. The

book focuses on state of the art techniques. The use of

different reaction media, catalyst recycling, supported

catalysts, microwave assisted synthesis and continuous

fl ow reaction systems are all examined, making this

book an excellent resource. The book avoids delving

into the specifi cs of each type of coupling reaction and

instead presents a variety of topics, discussing recent

progress and potential future work in each given area.

It was edited by Árpád Molnár, a Professor of Chemistry

in the University of Szeged, Hungary, who has no less

than 200 publications to his name. Numerous research

papers in the fi eld of catalyst development, coupled

with review papers on many of the subjects covered

in this book, qualify Professor Molnár for his position

of editor.

The content of this book covers fi ve general topics:

an introduction and background to Pd-catalysed

coupling reactions, Pd catalysts on various support

materials, coupling reactions in different reaction

media, reaction conditions for coupling reactions

and industrial applications of Pd catalysed coupling

reactions.

IntroductionThe area of Pd-catalysed coupling reactions has

experienced a huge growth in popularity and has

swiftly increased in maturity in its relatively short

lifetime, having moved from using stoichiometric

amounts of Pd-based reagents to achieving impressively

high turnover numbers (TONs) in just a few decades.

Since the initial Pd-catalysed coupling reactions

described by Heck (1), Negishi (2) and Suzuki (3)

during the 1970s a wide range of coupling reactions,

using different organic halides and organometallic

compounds have been discovered (Figure 1).



The fi rst chapter of this book gives a comprehensive

introduction to the area of Pd-catalysed coupling

reactions, covering the history and characteristics

of the reactions and classifi cation of the various

reaction types, which numbered 72 in a recent

review (4). A mechanistic overview is given along

with considerations to be taken with regards to the

effect of the halides and nucleophiles employed, the

nature of the Pd species, ligands employed and other

related topics. The introduction is concluded with a

section on future challenges for Pd-catalysed coupling

reactions. Here aspects relating to practical, real world

applications are discussed along with developments

that will enable these reactions to be brought into

common usage. Even though this introduction is

relatively brief it gives an excellent and comprehensive

overview of Pd-catalysed coupling reactions, explains

why Pd is the catalytic metal of choice and provides a

basis for the following chapters.

Support MaterialsThere are four chapters that discuss the effects of the

support material on the performance of Pd-catalysed

coupling reactions. These are dealuminated ultrastable

Y (USY) zeolites, magnetically separable nanocatalysts,

ordered porous solids and polymers. In the fi rst chapter,

written by Kazu Okumura (Tottori University, Japan)

the high TONs achievable by the use of USY zeolites

is discussed. These materials are widely available due

to their use in alkane cracking and make a suitable

support for Pd due to nanometre sized pores within

the zeolite structure. The preparation of USY zeolites,

the dealumination process of the zeolite framework

and the preparation of Pd/USY zeolite catalysts are

discussed briefl y followed by a number of examples of

coupling reactions performed using these catalysts. As

an introduction to this support type the author describes

a typical Suzuki-Miyaura coupling of bromobenzene

and phenylboronic acid in o-xylene with potassium

carbonate as a base, used by Durgun et al. (5) to

screen activity of Pd salts loaded on USY zeolites.

[Pd(NH3)4]Cl2/USY exhibited high activity and using

0.7 × 10–4 mol% of catalyst for the coupling reaction a

TON of 1.3 × 106 and a 99% yield were obtained. Work

by the same group proved this catalyst type suitable for

Suzuki-Miyaura coupling of heterocyclic compounds.

High TONs and good yields were achieved in the

coupling of 2-bromothiophene and thiophene-2-boronic

acid indicating the possible use of Pd/USY catalyst in

the synthesis of organic semiconductors.

The second chapter in this section, written by Kifah

S. M. Salih and Werner R. Thiel (TU Kaiserslautern,

Germany), concerned magnetically separable

nanocatalysts. Using magnetically separable

supports offers an easy solution to what can be a

diffi cult problem – removing the catalyst from the

reaction mixture. In the introduction the authors

describe the solid state properties required of the

paramagnetic particles, factors affecting the lifetime

of the supported catalyst, some of the characterisation

techniques employed and the types of catalyst

attached to the magnetic particles. For example,

Manorama et al. reported nickel ferrite particles with

a dopamine functionalised surface on which they

grafted Pd nanoparticles (6). This Pd catalyst was

employed in high yielding Suzuki coupling reactions

between aryl chlorides and phenylboronic acid and

also Heck reactions between aryl chlorides and

styrene. Once the reaction was complete the catalyst

was magnetically removed from the reaction mixture

and successive reactions were performed with similar

yields (Figure 2).

Ease of separation of this catalyst type is key to its

functionality. Pd leaching was looked at in several of

the examples described. There was low or negligible

leaching of metal from the nanoparticles after several

uses of the catalyst. In one case, leaching of Pd was

observed during the reaction with reabsorption of

the metal back onto the support occurring after the

reaction mixture had cooled to room temperature.

A number of other magnetically separable catalysts

are described, including catalysts based on Pd

nanoparticles and also Pd complexes supported on

magnetic particles.

The third chapter in this section discussed the

use of ordered porous solids as a support for Pd

Suzuki R X + R’ BY2 R R’

Heck R X + R’ R R’

Sonogashira R X + R’ R R’

Pd cat.Base

Fig. 1. Schematic of the Suzuki, Heck and Sonogashira coupling reactions



catalysts and was written by the editor of the book,

Árpád Molnár. The physical properties of ordered

porous solids make them ideal for use in catalysis:

high surface area, uniform pore size and a defi ned,

tunable structure. Materials that fall under the category

of ordered porous solids include zeolites, ordered

porous silica-based materials and metal organic

frameworks amongst others. The chapter opens with

an in-depth look at the synthesis and characterisation

of these materials, focusing on two examples: the

mesoporous silicas MCM and SBA. A background to

the materials, techniques employed to control pore

size and distribution, methods to tailor properties

and functionalisation are all covered extensively. An

Ullmann coupling of iodobenzene using a range of

mesoporous silica-based materials performed by Li et

al. highlighted the catalytic performance and ability

to tailor a catalyst to a reaction (7). Under the selected

reaction conditions a conversion of 27% and a yield of

just 7% were obtained using Pd supported on SiO2. By

altering the ordered porous silica materials to suit the

reaction, with large pores of SBA-15 to accommodate

the biaryl product and aluminium doped MCM-41 to

increase the Lewis acidity, promoting adsorption of

the iodobenzene, much improved conversion and

reaction yields were obtained. The chapter concludes

with a summary of the current state of these materials

together with a discussion of future prospects and

challenges.

Reaction MediaChapters six and seven discuss reaction media

employed for coupling reactions, namely ionic

liquids (ILs) and aqueous media. The solvent

employed as reaction medium has a considerable

effect on the performance, outcome, cost and

environmental impact of a chemical transformation,

so it is appropriate that some consideration is given

to the solvent selection. Traditional solvents used for

Pd-catalysed couplings include dimethylformamide,

N-methylpyrrolidinone and other polar solvents, many

of which have undesirable health implications, and as

with most volatile organic solvents, are fl ammable and

environmentally unfriendly.

Chapter six, written by Michael T. Keßler, Frank

Galbrecht and Martin H. G. Prechtl (Universität zu Köln,

Germany) and Jackson D. Scholten (Universidade

Federal do Rio Grande do Sul, Brazil), is dedicated to

the use of ILs as a reaction medium for Pd-catalysed

coupling reactions. ILs are organic salts with low

melting points, generally below 100ºC. The author cites

a number of reasons for their use: tunable combination

Na[PdCl4]

N2H4, H2ORT

NiFe2O4 NiFe2O4

Pd0HO

HO

NH2

=

Pd@DA/NiFe2O4

Pd@DA/NiFe2O4(50 mg)DMF, 24–36 h

R

R

RX = Cl, Br, IR = H, Me, Ac, OMe, NO2

(1.0 equiv.) (1.2 equiv.)

(1.2 equiv.)

X

K3PO4 (2.0 equiv.), TBAB45–110ºC

(HO)2B

K2CO3 (3.0 equiv.), B45–130ºC

76–98%

72–97%

Fig. 2. Magnetically separable palladium catalyst used for Suzuki and Heck reactions (6) (Image courtesy of Wiley and Sons, Copyright 2013)



of anions and cations to suit a particular reaction,

stabilising effect of ILs on ligands and Pd complexes,

solubility of organometallic compounds and ease of

separation of reaction products once the reaction is

complete. Again here, the authors detail a number of

coupling reactions performed in ILs, discussing the use

of both Pd complex-catalysed and Pd nanoparticle-

catalysed reactions. The emphasis is on the advantages

of ILs over more traditional solvents and the authors

use a number of examples to highlight this, often with

very high conversion rates, mild reaction conditions

and excellent catalyst reuse and recycling potential.

In chapter seven, written by Kevin H. Shaughnessy

(The University of Alabama, USA), cross-coupling

reactions in aqueous media is the topic. Water being

a cheap, non-toxic, non-fl ammable, renewable solvent

makes it a sensible solvent choice. However, with

organic compounds, problems of solubility along with

often water labile reaction systems mean that the use

of aqueous media is frequently avoided. The author

discusses the resurgence of aqueous based organic

chemistry, aspects of Pd that lend it to aqueous

reaction systems and developments in water soluble

ligands. The actual need for solubility is also discussed

with effi cient organic reactions being performed

‘on water’, that is, where solubility in the solvent is

not required to achieve chemical transformations. A

range of examples are given: fi rstly in aqueous media,

then in biphasic systems of water and organic solvent

mixtures. An example of a water-only mediated Suzuki

reaction was performed by Basu et al. (8). A ligand free

coupling of tropolone with an aryl trihydroxyborate

allowed Pd(OAc)2 and tetrabutylammonium bromide

to catalyse the reaction at low temperatures and short

reaction times in water (Figure 3).

Reaction Conditions The next section of the book, consisting of three

chapters, covers reaction conditions of coupling

reactions. The topics covered here are microwave

assisted synthesis, catalyst recycling and continuous

fl ow reactions. Despite microwave assisted reactions

and catalyst recycling appearing in numerous

described reactions in previous chapters the editor

considered the exceptional results possible when

employing these techniques worthy of separate

chapters. In the chapters on microwave synthesis and

catalyst recycling the ‘green’ aspects of the subject

are highlighted. In the case of microwave synthesis,

reduced reaction times, minimised side products

and improved yields are cited as reasons for its

consideration.

As in other chapters the authors, Ke-Hu Wang and

Jun-Xian Wang (Northwest Normal University, China),

discuss a range of microwave assisted coupling

reactions, most of which were reported within the

previous decade. In most cases the short reaction

times (with some reactions completing in a matter

of minutes) are emphasised as a unique feature of

microwave assisted synthesis, often coupled with

excellent yields.

In the chapter on catalyst recycling Árpád Molnár

places the focus on some of the shortcomings in

reported recyclable catalysts. In the lengthy introduction,

some common misconceptions with regards to what

is a stable, recyclable catalyst are addressed. Where at

times, effi cacy is maintained while catalytic metal is

being lost, the true recyclable nature of the catalyst is

brought into question. This topic is covered in detail

along with some techniques that can be utilised

to monitor low levels of Pd loss. Nanoparticle,

complex-based and polymer immobilised catalysts

are covered along with a number of other reusable

catalyst types. Here, numerous impressive examples of

robust catalysts are discussed, with some performing

twenty runs of a Heck coupling reaction without loss of

performance (9). The design of reactions is also brought

into question here. Low numbers of repeat runs using

O

O

OTBS

O

O

OTBS

(HO)2B+Br

MeO

O

MeO

O

95%

Pd(OAc)2 (20 mol%)

K2CO3, TBABH2O, 70ºC, 30 min

Fig. 3. A ligand free coupling of tropolone with an aryl trihydroxyborate catalysed by Pd(OAc)2 and tetrabutylammonium bromide using water as reaction solvent (8) (Image courtesy of Wiley and Sons, Copyright 2013)



the more reactive halides give impressive results,

whereas for transformations performed with less

reactive compounds, high numbers of test reactions

and adequate characterisation to ensure no loss of

catalyst are required to truly call a catalyst recyclable.

Chapter eleven written by William R. Reynolds and

Christopher G. Frost (University of Bath, UK) covers the

use of continuous fl ow reactors as a reaction system for

coupling reactions. In previous chapters reactions were

performed in batch style fl asks or vessels. Excellent

reaction effi ciencies, both in yield and cost reduction,

have been seen in bulk chemical processes for years. In

recent decades considerable time has been dedicated

to continuous fl ow reactors for organic synthesis and

good reaction effi ciencies have been achieved as a

result. Lower energy requirements, better temperature

control, improved mass transfer, lowered reaction

volume giving greater control over the chemical

reactions and ease of scaling from lab to industrial

scale are cited as some reasons for continuous fl ow

being an attractive alternative to batch type reactions.

An effective example of improved reaction effi ciency

was conducted by Li et al. (10). In this example

effi ciencies of fl ow reactors were compared to batch

reactors in the Suzuki coupling of aryl chlorides with

phenylboronic acids using Pd(OAc)2 as catalyst and

DABCO (1,4-diazabicyclo[2.2.2]octane) as a ligand.

After a 4 h residence time continuous fl ow reactions

of both electron-rich and electron-poor aryl chlorides

had completed with almost quantitative yields. The

batch reacted counterparts had considerably lower

conversions after 4 h and reaction times of 24 h

were required to bring the reactions to completion

(Figure 4). Reactor technology and design is

also discussed, along with catalyst immobilisation

techniques, continuous separation and the use of

microreactors.

All of the chapters so far have presented impressive

results but only in research scale coupling reactions.

The fi nal chapter in the book, by Andreas Dumrath,

Christa Lübbe, and Matthias Beller (Leibniz-Institut

für Katalyse e.V. an der Universität Rostock, Germany)

concerns industrial applications, mainly focusing

on examples from the recent past. The focus of the

introduction differs from the other chapters in that

it includes a discussion based on real life reaction

scale-up along with economic considerations, metal

prices, the cost of the base and reactants employed,

intellectual property implications and toxicity

of catalysts where pharmaceutical products are

concerned. A slightly different approach to examples

is taken in this chapter, often presenting a background

to the desired product, along with different reaction

options and routes taken to catalyst and reaction

selection. A Heck-Mizoroki coupling of benzyl acrylate

with a bromonaphthalene was used in the synthesis

of an oral pharmaceutical by GlaxoSmithKline (11).

By replacing a late stage reaction with this coupling,

the downstream chemistry was simplifi ed resulting

in better scalability along with a large reduction

R1

R1R2

R2Cl B(OH)2 Pd(OAc)2, DABCO+

Conversion, %

Entry Product Flow (4 h) Batch (4 h) Batch (24 h)

1 98 61 98

2 99 35 57OMe

Fig. 4. Comparison of a fl ow vs. batch process for a Suzuki reaction (Image courtesy of Wiley and Sons, Copyright 2013)



in raw material cost. Other techniques covered in

other chapters in this book are also used in industry

including microwave assisted synthesis, continuous

fl ow coupling reactions and reusable catalysts. This

chapter exhibits a number of excellent examples

of improvements to reaction rates and conditions

achieved by incorporating Pd catalysed coupling

reactions. Despite the complexity of a number of

these compounds, equivalent or improved yields and

stereocontrol was achieved by using these coupling

reactions, often with an economic benefi t due to fewer

side products, the use of lower quantities of reagents

and a reduced need for purifi cation steps.

SummaryThis book is an excellent, modern summary of the

state of Pd-catalysed coupling reactions. The focus

on highly effi cient reactions and recyclability of the

catalysts is in tune with the ethos being adopted by

many in the chemical industry. Atom effi ciency and

the application of cleaner, less wasteful chemistry is

now very achievable. This book would be an excellent

starting place for an organic chemist who is interested

in reducing costs and increasing effi ciencies of

existing reaction processes or one who is designing

new synthetic routes.

References 1 R. F. Heck and J. P. Nolley, J. Org. Chem., 1972, 37,

(14), 2320

2 A. O. King, N. Okukado and E.-i. Negishi, J. Chem. Soc., Chem. Commun., 1977, (19), 683

3 N. Miyaura, K. Yamada and A. Suzuki, Tetrahedron Lett., 1979, 20, (36), 3437

4 E.-i. Negishi, G. Wang, H. Rao and Z. Xu, J. Org. Chem., 2010, 75, (10), 3151

5 G. Durgun, Ö. Aksın and L. Artok, J. Mol. Catal. A: Chem., 2007, 278, (1–2), 189

6 B. Baruwati, D. Guin and S. V. Manorama, Org. Lett., 2007, 9, (26), 5377

7 H. Li, W. Chai, F. Zhang and J. Chen, Green Chem., 2007, 9, (11), 1223

8 B. Basu, K. Biswas, S. Kundu and S. Ghosh, Green Chem., 2010, 12, (10), 1734

9 Á. Mastalir, B. Rác, Z. Király and Á. Molnár, J. Mol. Catal. A: Chem., 2007, 264, (1–2), 170

10 J. Jin, M.-M. Cai and J.-X. Li, Synlett, 2009, (15), 2534

11 G. Bret, S. J. Harling, K. Herbal, N. Langlade, M. Loft, A. Negus, M. Saganee, S. Shanahan, J. B. Strachan, P. G. Turner and M. P. Whiting, Org. Process Res. Dev., 2011, 15, (1), 112

The ReviewerRobert Hanley obtained a BSc in pharmaceutical science from Cork Institute of Technology, Ireland, and a Master’s degree in green chemistry from Imperial College London, UK. He previously worked for Johnson Matthey Pharmaceutical Materials, Ireland, in the area of prostaglandin synthesis. Currently he is working as a development chemist for Johnson Matthey within the Emission Control Technologies division, his main area of research being diesel oxidation catalysts.

“Palladium-Catalyzed Coupling Reactions: Practical Aspects and Future Developments”



The Directed ortho Metallation–Cross-Coupling Fusion: Development and Application in SynthesisPlatinum group metals catalytic synthetic strategy for pharmaceutical, agrochemical and other industrial products


By Johnathan Board

Snieckus Innovations, Innovation Park, 945 Princess Street, Kingston, Ontario, K7L 3N6, Canada

Jennifer L. Cosman

Department of Chemistry, Queen’s University, 90 Bader Lane, Kingston, Ontario, K7L 3N6, Canada

Toni Rantanen, Suneel P. Singh and Victor Snieckus*

Snieckus Innovations, Innovation Park, 945 Princess Street, Kingston, Ontario, K7L 3N6, Canada


This review constitutes a detailed but non-exhaustive

examination of the directed ortho metallation (DoM)–

cross-coupling fusion in its many fl avours. Special

attention is paid to the application of the concept of the

linked reactions and the synthetic utility that it endows,

particularly in the case of one-pot reactions that can

greatly increase the ease and effi ciency of the process.

Personal experience of particular issues that can arise

from these reactions and examples of their solutions

are given, as well as illustrations of the rapid access to

complex molecules that the technique encourages.

IntroductionSince its disclosure, the combination of DoM and

transition metal-catalysed cross-coupling has evolved

into a common strategy in synthesis (1, 2) and,

in particular, has found widespread use in the

preparation of biologically interesting aromatic and

heteroaromatic compounds. A variety of functional

groups such as I, Br, Cl, SiR3, SnR3, B(OR)2 have been

introduced using DoM, followed by different cross-

coupling reactions to form carbon–carbon, carbon–

oxygen, carbon–nitrogen and carbon–sulfur bonds

in order to prepare synthetically and biologically

interesting molecules. Herein we present selected

examples of the use of the DoM–cross-coupling strategy

from the period of 2000 to 2012 in order to demonstrate

its advantages and outline the potential issues that

may be faced in its application. The main focus will

be on cross-couplings involving the platinum group

metals (pgms); however several examples using other

metals such as copper are included for comparison.

In order to make this review more accessible, it is

divided into sections according to the type of bond

being formed and the type of metallation reaction. For

further clarifi cation, a scheme describing the reaction

discussed appears at the beginning of each section.



1. DoM–C–C Cross-Coupling Reactions

1.1 Sequential (Multi-Pot) DoM–Cross-Coupling MethodsThe formation of C–C bonds through the sequence

of DoM–halogenation to insert an ortho halide

or pseudohalide, followed by cross-coupling has

been carried out using Ullmann, Heck, Sonogashira,

Negishi, Stille and Suzuki-Miyaura reactions,

among others. As an example, Sanz et al. (3) have

synthesised valuable 4-fl uoro-2-substituted-1H-

indoles 4 through a sequence involving DoM

mediated iodination of 3-fl uorotrifl uoroacetanilide

1, followed by reaction with terminal aromatic

or aliphatic alkynes by a Sonogashira coupling–

cyclisation process (Scheme I). When the DoM

reaction was carried out at temperatures higher

than –60ºC, competitive lithium fl uoride elimination

took place forming a benzyne intermediate 5 which

underwent subsequent intramolecular cyclisation to

provide iodinated benzoxazole 7. This phenomenon

occurring during the directed metallation of

3-fl uoroaniline bearing N-pivaloyl, N-Boc directing

metallation groups (DMGs) or an N-benzoyl group

had been previously observed (4).

The Suzuki-Miyaura cross-coupling is one of the

most popular and widely used reactions in the C–C

DoM–cross couple fusion strategy (for examples, see

(5, 6)). When partnered with DoM, the major advantage

of the Suzuki-Miyaura reaction is that boronation

reagents such as B(OR)3 are often compatible with

lithium bases (usually lithium dialkylamides, but

some boronates are even compatible with s-BuLi )

(7). This allows the boronating agent to be present

in the same reaction vessel as the base in order to

quench the metallated species as it is formed. These

conditions are known in our laboratories as either

Barbier or Martin (8, 9) type conditions according

to the order of addition. (Descriptions of these in

situ quench conditions are as follows: under Barbier

type conditions the base is added to a mixture of

substrate and electrophile; under inverse Barbier

conditions a solution of substrate and electrophile

are added to a solution of the base; under Martin

conditions the substrate is added to a solution of base

and electrophile; under inverse Martin conditions

a solution of base and electrophile are added to a

solution of the substrate. Compatible electrophiles

include, but are not limited to, trimethylsilyl

chloride (TMSCl), Me2SiCl2, B(OMe)3 and B(OiPr)3.)

Halide sources are not usually compatible with

strong bases; for instance, premixing I2 and lithium

DMG DMG

X

DMG

R

DoM Cross-coupling

X = Halide or pseudohalideR = Carbon-based substituent

F

OF3C

NH

1. tBuLi/TMEDA (2.3 equiv.)THF, –78ºC

2. I2 (1.4 equiv.)–78ºC to RT63% yield OLiF3C

N

LiF

OLiF3C

N

>–60ºC–LiF

21

5

3

6

4

7

R1 (1.5 equiv.)PdCl2(PPh3)2 (3 mol%)

CuI (5 mol%)

Et2NH (1.5 equiv.)DMA, 80ºC

R1 = Ph, 87% yieldR1 = nHex, 78% yield

OF3C

NH

IF F

Li IO

NCF3 33% yield

O

NCF3

NH

R1

Scheme I. Sequential DoM and Sonogashira cross-coupling for the synthesis of indoles



2,2,6,6-tetramethylpiperidide (LiTMP) before addition

of the metallation substrate has resulted in low yields

of iodinated material in our laboratories. Vedsø et al.

have shown that ester, cyano and halogen substituents

are tolerated when LiTMP/B(OiPr)3 is used for in situ

boronation of unstable ortho metallated species (10).

In our group we have found that the DoM–cross-

coupling strategy fi nds particular utility in the

functionalisation of indoles. Stimulated by work

performed by Iwao et al. (11), we have developed

routes to 3,4-substituted indoles by utilising DoM–

Negishi cross-coupling sequences to afford gramines

8 which undergo useful retro-Mannich fragmentation

to give indoles 9 (12). Similarly, C-7-substituted

indoles 12 have also been synthesised by either

sequential or one-pot C-2 metallation, C-2 silylation,

C-7 metallation and C-7 electrophile treatment of

indoles 10 to provide the boronates or halides 11,

followed by Suzuki-Miyaura cross-coupling to give

12 (13). In addition, 2-aryl/heteroarylindoles 15

have also been synthesised from N-carbamoyl-2-

bromoindoles using either Suzuki-Miyaura (13a) or

one-pot ipso borodesilylation–Suzuki-Miyaura (13b)

reactions to provide indoles 14, followed by a lithium

diisopropylamide (LDA)-induced anionic N–C

carbamoyl migration (Scheme II) (14).

Due to the higher C–H acidity of heteroaromatic

systems, the DoM component of the DoM–cross-

coupling fusion of these systems is dominated by the

use of bases other than butyllithium, such as the lower

N N

N N N

N

N

N

HN

C and Het

DME (refl ux) or DMF (100ºC)6–18 h, 85–92% yields

BCl3 (1.1 equiv.), CH2Cl2, –45ºC, 60 min, then pinacol (4 equiv.) and evaporate, then Ar3Br (0.8 equiv.),

Pd(PPh3)4 (5 mol%), K3PO4 (4 equiv.)

DMF, 100ºC, 12–20 h, 67–89% yields

Ar3B(OH)2 (1.2 equiv.), Pd(PPh3)4 (5 mol%)Na2CO3 (1.5 equiv.) or K3PO4 (3 equiv.)

LDA (4 equiv.), THF0ºC to RT, 1–12 h

R1 = Me, 50–92% yieldsR1 = H, 36%–quant.

yields17 examples

Ar2X (1.1–1.2 equiv.) Pd(PPh3)4

(2–10 mol%)K3PO4 (3 equiv.)

DMF, 80ºC15–20 h

83–99% yields

1. tBuLi (1.1 equiv.) TMSCl (1.05 equiv.)

2. sBuLi/TMEDA (1.5 equiv.)

3. I2, BrCH2CH2Br or B(OiPr)3 (1.5 equiv.), THF, –78ºC to RT, 5 h total

N-bromosuccinimide (1 equiv.)MeOH, RT, 2 min

or1. TBAF (1 equiv.), THF, RT, 10 min

2. N-iodosuccinimide (1 equiv.), MeOH, 0ºC, 5 min3. (Boc)2O (1.5 equiv.), Et3N (1.5 equiv.)

DMAP (cat.), CH2Cl2, RT, 15 min24–81% yields

TIPS

DoM/cross-coupling

NMe2Ar1 Ar1

Ar2

Ar3

PG

X

TMSTMS

TMS

CONEt2 CONEt2 CONEt2

CONEt2 CONEt2

CONEt2CONEt2

CONEt2CONEt2CONEt2

CONEt2

CONEt2

HN

HN

HN

HN

HN

E

Br

Me

Me Me OMe Me

R1 R1

N

SS

8 9

10 11 12

13a

14

13b

15

Select examples:

15a 92% yield from 13 15b 55% yield from 13 15c 56% yield from 13 15d 73% yield from 13 15e 75% yield from 13 using PhB(OH)2 using 2-MeOC6H4B(OH)2 using 3-thienylboronic acid using 3-bromothiophene using 3-bromopyridine

PG = TIPS or Boc; Ar1 = Ph, o-Tol, pyridin-3-yl; X = Br or IE = I, Br, BPin (after pinacolation); Ar2 = 8 examples including Ph, 2-MeOC6H4, pyridin-3-ylR1 = H, MeAr3 = CHCH(4-MeC6H4), Ph, 2-MeOC6H4, 3-MeOC6H4, 4-MeOC6H4, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, furan-3-yl, thiophen-3-yl, pyridin-3-yl, naphthalen-1-yl, isoquinolin-4-yl

Scheme II. Indole functionalisation utilising the DoM and cross-coupling protocol



pKa lithio dialkylamides or Grignard bases; the cross-

coupling component has been dominated by Suzuki-

Miyaura and Negishi reactions. The consideration

of which base to choose is heavily infl uenced by

the DMG and by the other functionalities within the

system. For instance, if the DMG is a halogen then

benzyne formation may need to be avoided through

the use of lower temperatures or milder bases

less prone to induce MX elimination. On the other

hand, if the DMG is weak and the system is electron

rich then stronger bases will be required which

may result in nucleophilic attack of the base upon

the heteroaromatic ring, especially in the case of

π-defi cient systems. Usually the accepted wisdom is to

use as mild a base as possible, at a temperature as close

to room temperature as is possible in order to achieve

the greatest degree of functional group compatibility

and experimental simplicity. Certain DMGs are less

tolerant of higher temperatures than others, such as

N,N-diethyl-O-carbamate which may undergo the

anionic ortho Fries rearrangement (1, 15, 16). We have

found also that the variation of solvents can have a

profound effect on the selectivity of the metallation; in

particular the switch between tetrahydrofuran (THF)

and diethyl ether can make the difference between

the success or failure of a reaction.

Although in many cases this type of DoM–cross-

coupling strategy can be performed with relative ease

simply by using conditions precedented for a similar

system, both the DoM and cross-coupling may have

non-trivial problems which should be solved through

methodical application of standard optimisation

techniques, such as variation of solvent, base and

catalyst system. An instructive example concerns work

which eventually led to the discovery of soraprazan

(16, Figure 1), a clinically studied H+/K+-ATPase

inhibitor (17).

Thus, as shown by deuterium quench experiments,

the ortho deprotonation of an N-pivaloyl

imidazo[1,2-a]pyridine 17 gave the highest ratio of

C-5:C-7 (18:19) deprotonation when t-butyllithium was

used in diethyl ether (Scheme III). When this reaction

was performed in THF, products 18 and 19 were

obtained in almost equal conversion. These results

were rationalised by the observed poor solubility of

the kinetically preferred C-7-anion in diethyl ether

which presumably prevented it from undergoing

equilibration with the more thermodynamically

preferred C-5-anion. On the other hand, in THF

the greater solubility of the C-7 anion allowed it to

equilibrate with the C-5 anion thereby eradicating

N

NH

OO

HOPh

Me

Me

MeN

16

Fig. 1. Soraprazan, a H+/K+-ATPase inhibitor (17)

tBuLi (2.8 equiv.)solvent, –78ºC, 15 min

then D2O quenchexamined using 1H NMR

Me

Me

tBu

O

HN

17tBuLi (3 equiv.), TMEDA (3 equiv.)

diethyl ether, –78ºCthen addn. of Bu3SnCl (3 equiv.)–78ºC, 1 h, then RT overnight1:9 ratio, 20:21 obtained in

41% yield

Me

Me

tBu

O

HN

18

Me

Me

tBu

O

HN

19

Me

Me

tBu

O

HN

20

Me

Me

tBu

O

HN

21

D

D

SnBu3

Bu3Sn

++

others, mainly bis-deuterated products

+

Solvent Conversion, %THF 23 25 53Ether 18 82 <3N

N

N

N

N

N

N

N

N

N

Scheme III. DoM studies of the N-pivaloyl-imidazo[1,2-a]pyridine 17 (17)



the selectivity. When the reaction was performed

using the weaker n-butyllithium, no selectivity

between C-5 and C-7 metallation was achieved, and

a large amount of starting material was recovered

even when the reaction was conducted over longer

periods of time or at higher temperatures. This is

presumably due to the moderate ortho-directing

ability of the N-pivaloyl group. Use of the optimised

deprotonation conditions followed by stannylation

afforded the desired C-7 product 21 in acceptable

yield in a 1:9 ratio together with the undesired C-5

regioisomer 20.

The derived compound 21 was used in acylative

Stille cross-couplings with cinnamoyl chlorides to

give compounds 23, which by straightforward acid-

mediated Michael cyclisation-depivaloylation afforded

compounds 24, which are intermediates for sorapazan

(16) and its analogues (Scheme IV). The execution

of the Stille cross-coupling was far from trivial and

therefore deserves comment. Experiments with a

variety of palladium sources were unsuccessful and

only the combination of PdCl2(MeCN)2 and a three-fold

excess of the cinnamoyl chloride led to cross-coupled

products 23, in poor yields, which precipitated from

the reaction mixture as the hydrochloride salts. The

known advantages of using halide salts in Stille cross-

couplings of aryl trifl ates (18–20) led to speculation

about the role of halide salts in the reaction. Thus,

on addition of one equivalent of lithium chloride to

the reaction mixture, conversion to products 23 was

achieved in moderate yield.

Despite the demonstration in our laboratories

of the advantages of performing a DoM–Suzuki

Miyaura cross-coupling in a one-pot fashion (such

as fewer chemicals used, eradication of at least one

workup step, higher effi ciency and convenience),

most reported reactions are performed with isolation

of the DoM products. Schemes V and VI (21, 22)

N

N

Me

Me Me

Me

Me

Me

tBu

O

HN tBu

O

HNBu3Sn

ArAr Ar

OO O

Cl

21 2223 24(1–1.28 equiv.)

Pd2(dba)3•CHCl3 (1 mol%)LiCl (1–1.28 equiv.)

THF, 60ºC, 2.5 hthen RT overnight

NH

N

NN

N

Conc. HClor 50% H2SO4

100ºC

3–4 h

Ar Yield, % Yield, %Ph 66 692-ClC6H4 4 732,6-Cl2C6H3 50 412-F3CC6H4 50 41

Scheme IV. Acylative Stille cross-coupling of 21 to provide products 23 and thence sorapazan precursors 24

N

25

NOMe

Ar1

NNOMe

Ar1

NNOMe

Ar1

1. nBuLi (2 equiv.)iPr2NH (2 equiv.)

Et2O, 30 min, 0ºC to –78ºC then 25 (1 equiv.)/Et2O, 1 h, then B(OiPr)3 (3 equiv.)

1.5 h, –78ºC to RT

2. Acidic workup 61–69% yields

B(OH)2

26

28

NNOMe

Ar1

27

BPinPinacol (1 equiv.)MgSO4, toluene

12–19 h, RT73–90% yields

Ar2

Ar2Br, Pd2(dba)3 (1 mol%)PCy3 (2.4 mol%)K3PO4 (aq. 1.3 M, 1.7 equiv.)1,4-dioxane, refl ux, 24 h18–76% yields

Ar1 = Ph, 4-MeOC6H4, 2-MeO-pyridin-5-yl, 2-F-pyridin-5-ylAr2 = pyridin-2-yl, 5-O2N-6-H2N-pyridin-2-yl, pyrimidin-5-yl

Scheme V. Sequential DoM–Suzuki Miyaura synthesis of arylpyridazines 28 (21)



depict cases in which the boronic acids 26 and 30, generated from DoM reactions, are isolated prior to

cross-coupling. Of particular note is the low yield of

boronic acid 30, which is likely attributable in part to

the instability of this heterocyclic boronic acid.

1.2 One-Pot DoM–Cross-Coupling MethodsA more effi cient process than shown so far is a DoM–

cross-coupling protocol carried out without isolation

of the intermediate species (boronic acid, zincate for

instance) which is most often accomplished using

Suzuki-Miyaura or Negishi cross-coupling reactions.

For instance, as part of a campaign towards the

synthesis of the antimicrobial agent GSK966587 (32,

Figure 2), a ‘one-pot’ DoM–cross-coupling method

was developed (23).

Thus, the DoM–iodination reaction of 33 was

investigated (Scheme VII) in preparation for Heck

coupling chemistry (Scheme VIII). The use of the

more traditional alkyllithium and lithium amide

bases was complicated by the formation of dianions

and by competitive fl uoride displacement. The use of

LDA at low temperatures under short reaction times

was promising but gave mixtures of both mono-

iodides 34 and 35 and bis-iodide 36. Although the

Uchiyama zincate mixed metal base TMPZn(tBu)2Li

gave predominantly the undesired mono-iodide 35,

the analogous (iPr)2NZn(tBu)2Li gave an encouraging

result. A further shift to (iPr)2NZnEt2Li (prepared by

mixing Et2Zn and LDA) gave excellent selectivity

for the desired iodide 34 which was eventually

isolated in 85% yield (74% from starting material 39, Scheme VIII).

After extensive screening, Heck coupling of iodide

34 with allyl alcohol was achieved to give the

-coupled product 37 in 77% yield (57% yield from

39, Scheme VIII). As a more effi cient alternative to this

sequential procedure, the Negishi cross-coupling of

the zincate intermediate 38 (the presumed metallated

species from the DoM reaction of 33) was realised and

gave a comparable yield of 37 (68% yield from 39)

but required no iodine and fewer purifi cation steps.

N29

ClR1O N30

ClR1O N31

ClR1O

(HO)2B Ar1. LDA (1.1 equiv.)2. B(OiPr)3 (1.2 equiv.)

THF, –78ºC to RTacidic workup, 13% yield

ArX (0.9 equiv.) Pd(PPh3)2Cl2 (5 mol%)

Na2CO3 (aq. 1 M)

1,4-dioxane, refl ux, 24 h, 29–98% yields

R1 = Me, EtAr2 = 2-MeO-pyridin-5-yl, 2-MeO-pyridin-6-yl, pyrimidin-5-yl, 2-MeO-pyrimidin-5-yl

Scheme VI. Sequential DoM–Suzuki Miyaura synthesis of aryl-2-chloropyridines 31 (22)

N

NHO

FO

NHO

ON

32

N

Fig. 2. Antimicrobial agent GSK966587

N

NMeO F

33N

NMeO F

34N

NMeO F

35N

NMeO F

36

++

I I

II

Base Equiv. Time, min Temp., ºC Area, %, by HPLC analysisLDA 1.5 15 –70 42 8 40LDA 1.1 5 –60 83 8 1.5TMPZn(tBu)2Li 1.1 30 23 26 34 23(iPr)2NZn(tBu)2Li 1.0 120 23 45 5 0(iPr)2NZnEt2Li 1.2 30 –10 96a 4 0a85% isolated yield

Scheme VII. DoM route to 7-fl uoro-8-iodo-2-methoxynaphthyridine 34 (23)



By its nature, the DoM–Negishi cross-coupling

protocol lends itself to a one-pot procedure whereby

the deprotonation, transmetallation (if necessary)

to a zincate and transition metal-catalysed cross-

coupling occur sequentially in the same reaction

vessel. Among the cases illustrated in Schemes IX–XI (24–26), of note is the use of the oxazole DMG which

by hydrolysis provides the desired carboxylic acid

in the target molecule 43 (Scheme IX). This is a

further demonstration of the use of tetrazole as a DMG

in the synthesis of the ‘sartan’ pharmaceutical 46

(Scheme X) and the use of catalytic zinc chloride and

of the pyridine N-oxide as a DMG in the preparation of

azabiaryl 49 (Scheme XI).

Recently, a one-pot DoM–Negishi cross-

coupling strategy that can utilise esters as DMGs

N

NMeO F

34

N

NMeO F

33N

HNO F

39N

NMeO F

N

NMeO F

37

I HO

Li+ –ZnEt2

38

1. SOCl2(nBu)2NCHO

toluene

2. MeOHno yield given

1. (iPr)2NZnEt2Li (1.1 equiv.)2. I2 (3.9 equiv.)

THF, –10ºC to RT, 85% yield74% yield from 39

HOBr (2.2 equiv.)

LDA (2.2 equiv., addn. at –30ºC)Tri(2-furyl)phosphine (8 mol%)Pd2(dba)3•CHCl3 (2 mol%)

THF, 45ºC, 60 min, 68% yield from 39

(iPr)2NZnEt2Li(1.1 equiv.)

THF, –10ºC to RT

Allyl alcohol (15 equiv.)Pd(OAc)2 (2.5 mol%)

dppf (5.5 mol%)NH4OAc (2 equiv.)

ethylene glycol130ºC, 7–8 h, 77% yield

57% yield from 39

Scheme VIII. Sequential and ‘one-pot’ DoM–Heck coupling synthesis of naphthyridine 37 (Note: The authors provide the yields for the optimisation, but also for a process whereby all of the batch is taken through the whole process with only minimal purifi cation. Hence overall yields comparing the two processes are given even though no yield is given for the conversion of 39 to 33)

N

O

Me

Me40

O

N

N

Me

Me

NnPr

N

OH

N

N

Me

Me

NnPr

N

Br

N

O

Me

Me

N

N

Me

Me

NnPr

N

42

41

43

nBuLi (1.2 equiv.)ZnCl2 (1.8 equiv.)0ºC, THF, 120 min

then Pd(PPh3)4 (1 mol%)41 (1 equiv.)

55ºC, 24 h, 55% yield

HCl, refl ux

30 min, 85% yield

Scheme IX. One-pot DoM–Negishi cross-coupling strategy for the synthesis of telmisartan 43 angiotensin II receptor antagonist (24)



has been developed by Knochel and coworkers

involving the amide bases tmpMgCl·LiCl (tmp =

2,2,6,6-tetramethylpiperidyl), tmp2Mg·2LiCl and

tmp2Zn·2MgCl2·2LiCl (27). These bases are used

in stoichiometric amounts (no extreme excess is

required), facilitated by LiCl which complexes and

solubilises the bases and leads to monomeric metallic

amides. Due to its stability (at least 6 months at 25ºC

under inert atmosphere) (28, 29) tmpMgCl·LiCl is

commercially available and is capable of metallating

moderately C–H acidic aromatic compounds. For

more demanding aromatic cases tmp2Mg·2LiCl (30)

may be used and for systems that contain sensitive

functional groups tmp2Zn·2MgCl2·2LiCl (31) has

proven to be effective. Unfortunately the latter two

bases are not as stable as tmpMgCl·LiCl; for instance

tmp2Mg·2LiCl is stable only for 24 h at 25ºC (27).

These reagents are usually prepared fresh for each

reaction, or set of reactions, from tmpMgCl·LiCl by

the addition of LiTMP or ZnCl2, respectively. The

use of these bases for combined metallation–cross-

coupling reactions greatly increases the potential

substrate scope of this strategy, as illustrated by

the synthesis of aromatic esters 51, 53 and 55

(Schemes XII–XIV). Noteworthy is the last case

since nitrile groups are not normally compatible

with the use of Grignard reagents. In addition, only

0.5 equivalents of tmp2Zn·2MgCl·2LiCl are required

(i.e. both potential TMP anions are available) and

transmetallation is unnecessary as this reagent

N NN NPh3C

44

N NN NPh3C

46

O

N

nBu

CO2Me

nBuLi (1.2 equiv.)ZnCl2 (1.8 equiv.)

–20ºC to RT, THF, 90 minthen

Pd(OAc)2 (5 mol%)QPhos (5 mol%)

45 (1 equiv.)75ºC, 2 h, 80% yield

O

N

nBu

CO2Me

45Br

Scheme X. One-pot DoM–Negishi cross-coupling strategy to synthesise valsartan 46 angiotensin II receptor agonist (25)

I+

–OTf

48

47 49

N+

O–

MeMe

N+

O–

MeMeiPrMgCl (1.2 equiv.)

–78ºC, 60 minthen

ZnCl2 (5 mol%)Pd(PPh3)4 (5 mol%)

48 (1.5 equiv.)70ºC, 10 min, 51% yield

Scheme XI. One-pot DoM–Negishi cross-coupling strategy using catalytic zinc chloride for the synthesis of azabiaryl N-oxide 49 (26)

1. TMPMgCl•LiCl (1.1 equiv.)0ºC, 6 h

2. Benzoyl chloride (1.0 equiv.)CuCN•2LiCl (10 mol%)

–40ºC to 25ºC, 3 h86% yield

50 51

Cl CO2Et Cl CO2Et

O PhScheme XII. One-pot DoM–Negishi cross-coupling protocol using commercially available tmpMgCl·LiCl



directly provides a zincate suitable for Negishi

cross-coupling under relatively standard conditions.

Although these reactions were developed and

optimised on 1–2 mmol scale, all of these examples

were performed on 80–100 mmol scale in order to

demonstrate good scale up potential.

The combined DoM–Suzuki-Miyaura cross-

coupling also lends itself to a one-pot procedure. An

illustration of this is our recent extension of previous

work on one-pot DoM–Suzuki-Miyaura reactions (32),

in which the synthesis of heterobiaryl sulfonamides

was developed with the aim of increasing the

available methodology for the construction of

bioactive molecules bearing the popular sulfonamide

pharmacophore (Scheme XV) (7).

This one-pot metallation-boronation–cross-coupling

procedure was generalised for tertiary and secondary

sulfonamides 56 in couplings with electron-rich and

-poor aryl and heteroaryl bromides and chlorides to

furnish biaryl sulfonamides 57. A change to a bulkier

catalyst was needed when meta or ortho substituted

sulfonamides were used as shown by example 57c.

1.3. Iridium-Catalysed Boronation–Suzuki-Miyaura Cross-Coupling: A Complementary MethodThe knowledge that iridium-catalysed boronation of

aromatics is qualitatively determined by steric effects

(33–37) led us to explore this reaction in DMG-bearing

substrates in order to establish complementarity with

52

CO2Et

53

CO2Et

Me

1. TMPMg•2LiCl (1.1 equiv.)25ºC, 45 h

2. ZnCl2 (1.1 equiv.)–40ºC, 15 min

3. 4-Bromotoluene (1.05 equiv.)Pd(OAc)2 (0.5 mol%)RuPHOS (1.0 mol%)–40ºC to 25ºC, 12 h

71% yield

Scheme XIII. One-pot DoM–Negishi cross-coupling protocol using tmp2Mg·2LiCl

54

CO2Et

55

CO2Et1. TMP2Zn•2MgCl•2LiCl (0.5 equiv.)25ºC, 48 h

2. Iodobenzene (1.0 equiv.)Pd(dba)2 (0.5 mol%)(o-Fur3)P (1.0 mol%)

25ºC, 6 h84% yield

PhNCNC

Scheme XIV. One-pot DoM–Negishi cross-coupling protocol using 0.5 equivalents tmp2Zn·2MgCl·2LiCl

1. nBuLi or LDA (1.3 equiv. or 2.3 equiv.)2. MeOBpin or iPrOBpin (3.5–4.0 equiv.)

THF, –78ºC to RT, 13 h

3. Pd(dppf)Cl2•CH2Cl2 (8 mol%)Na2CO3 (4 equiv.), DME:H2O (4:1), 80ºC, 12 h

15–74% yields

ArHetAr

H

SO2NRR1

56

ArHetAr

SO2NRR1

57

ArHetAr

57a (71%) 57b (65%) 57c (15%) [Pd(dppf)Cl2•CH2Cl2] (60%) [Pd(DtBPF)Cl2]

SO2NEt2

SO2PhN

SO2NEt2

SO2PhN

N

N

SO2NEt2

MOM

Scheme XV. One-pot DoM–Suzuki-Miyaura cross-coupling route to heterobiaryl sulfonamides 57 (7)



the DoM–Suzuki-Miyaura cross-coupling process

(Scheme XVI) (38). Thus, complementary methods

of considerable scope for the synthesis of biaryls and

heterobiaryls were demonstrated by C–H activation at C-2

(DoM) and at C-3 (Ir-catalysed boronation) of 58 which

offer new routes for the regioselective construction of

substituted biaryls 60 and 59 respectively.

1.4 The Use Of DoM–Cross-Coupling Strategies in Total SynthesisWe have also employed the DoM–cross-coupling

strategy as part of syntheses of targeted drugs and

natural product intermediates. In 2004, we reported

a synthesis of the tetracyclic A/B/C/D ring core 66 of

the antitumour agent camptothecin (Scheme XVII) (39).

This route is highlighted by an anionic ortho-Fries

rearrangement of O-carbamate 61 to give the

quinolone 62, a Negishi cross-coupling of trifl ate 63

to give biaryl 65, and a modifi ed Rosenmund–von

Braun reaction to provide the tetracyclic core 66 of

the antitumour alkaloid camptothecin in seven steps

with an overall 11% yield.

Most recently, we have completed a total synthesis

of schumanniophytine 72 (Scheme XVIII) (40), a

natural product which had been prepared only once

previously (41). Starting with DoM chemistry to obtain

the cross-coupling partners 68 from 67, our route

takes advantage of a combined DoM–cross-coupling

strategy using Stille or Suzuki-Miyaura reactions to

synthesise biaryl 69, and also incorporates a key ortho-

silicon-induced O-carbamate remote anionic Fries

rearrangement of carbamates 70 to provide amides 71.

ArHetAr

DMG

H

R

60

DMGR

DMGR

H HH

ArHetAr

5859

1. DoM

2. Suzuki-Miyaura

C2–H activation

1. Ir/B2Pin2

2. Suzuki-Miyaura

C3–H activation

DMG = CONEt2, OCONEt2, OMOM, SO2NEt2

Scheme XVI. Complementary ortho and meta boronation/Suzuki–Miyaura cross-coupling reactions of DMG bearing aromatics (38)

N OCONEt2

61 62 63

NH

CONEt2

O N

CONEt2

OTf

1. LDA (1.3 equiv.)THF, –78ºC, 1 h

2. MeOH61% yield

Tf2O (1 equiv.)NEt3 (1.8 equiv.)

CH2Cl2, 0ºC, 1 h70% yield

NBr OMe

N

CONEt2

N OMe

64 65

Steps

NN

O

66

1. tBuLi (2.0 equiv.)THF, –78ºC, 15 min

2. Anhyd. ZnBr2 (1.1 equiv.)–78ºC, 1 h

3. 63/Pd(PPh3)4 (3 mol%) THF/refl ux, 60 h

57% yield

Scheme XVII. Key reactions in the synthesis of the tetracyclic core 66 of camptothecin: anionic ortho-Fries rearrangement 61–62 and Negishi cross-coupling 64–65 (39)



2. DoM–C–Heteroatom (N, S, O) Cross-Coupling Reactions

With the advent of transition metal-catalysed C–N,

C–O and C–S cross-coupling technologies, these

reactions have also been fused with DoM and

the combined DoM–heteroatom cross-coupling

methodology has become viable for the construction

of biologically interesting molecules and natural

products. Thus the naphthyldihydroisoquinoline

alkaloid ancistrocladinium B 76 (Scheme XIX),

which shows high in vitro antileishmanial activities,

has been synthesised from 73 via methoxymethyl

(MOM) directed metallation-bromination to provide

bromide 74, followed by Buchwald-Hartwig amination

to furnish the key intermediate 75. The synthesis of

ancistrocladinium C (77) was also achieved using a

similar strategy (42).

Similarly, the construction of a C–O bond has been

accomplished using DoM–cross-coupling strategies.

Although copper catalysis is the preferred choice for

C–O bond formation (43–45), it is also possible to use

pgm catalysis as an alternative (46–48).

Among the DoM–C–heteroatom cross-coupling

strategies, the DoM–C–S regimen is far less evident in

the literature. In an instructive study which shows the

utility of inverting the coupling partners, substituted

2-iodo-anisoles 79 (Scheme XX) were synthesised

using DoM chemistry and subjected to Buchwald-

Hartwig coupling with 3-fl uorobenzenethiol 81,

to afford biaryl sulfi de derivatives 83 which were

further modifi ed to give the desired compounds 84.

Alternatively, 3-chloro-2-methoxyphenyl thiol 80

was coupled with 3-fl uoroiodobenzene 82 to furnish

similar analogues 83. These were demonstrated

to possess in vitro potency for blocking glycine

transporter-1 (GlyT-1), which has been recognised

as a potential strategy for the treatment of

schizophrenia (49).

OMeMeO

OCONEt2

OMeMeO

OCONEt2

OMeMeO

Et2NOCOR1

N

67 69

OMeMeO

Et2NOCO N

Yield, %R = Me 70a 94R = Et 70b 91

R3Si

OMeMeO

R2OR3Si

HO

72

N

OEt2N Me

O

OOSteps

TMEDA (1.3 equiv.)sBuLi (1.3 equiv.)

THF, <–72ºC, 10 min thenI2 (1.5 equiv.), <–72ºC to RT

or

1. B(OiPr)3 (2.6 equiv.), THFLDA (1.2 equiv.)

–78ºC, 1 h–78ºC to RT, 1 M HCl

2. Pinacol (1.05 equiv.), EtOAc

68a, PdCl2(PPh3)2 (10 mol%)4-tributylstannylpyridine (1.5 equiv.)

DMF, refl ux, 1 h, 73% yieldor

68b, Pd(PPh3)4 (4 mol%)4-bromopyridine hydrochloride (1.0 equiv.)/Na2CO3 (2 equiv.)

DME/Na2CO3 (2 M)90ºC, 20 h, 99% yield

LDA (3.5 equiv.), Me3SiCl(4.5 equiv.), THF

–78ºC to RT, 10 hor

nBuLi (1.2 equiv.), THF –100ºC, 5 min, then

Et3SiCl (2.5 equiv.)–100ºC, 1.5 h

LDA (4 equiv.)THF, 0ºC to RT, 1 h

then

Ac2O or BzCl (5 equiv.)0ºC to RT

Yield, %R2 = Ac 71a 75R2 = Bz 71b 65

Yield, %R1 = I 68a 86R1 = Bpin 68b 95

NO

Scheme XVIII. Key reactions in the total synthesis of schumanniophytine 72 (40)

DMG DMG

X

DMG

Y

DoM Cross-coupling

X = Halide or pseudohalideY = NR2, SR, OR



OMe

OMe

Me

O

73

OMe

OMe

Me

O

74

BrOMe

Me

OMe

O

MeO

OMe

NH2

Me

(1.2 equiv.)

1. nBuLi (1.9 equiv.)TMEDA (1.9 equiv.)

THF, –10ºC, 1 h

2. (CBrCl2)2 (1.5 equiv.)–10ºC to RT

74% yieldPd2(dba)3 (1 mol%)rac-BINAP (2 mol%)KOtBu (1.4 equiv.)toluene, refl ux, 2 d

49% yield

MeO

OMe

HN

Me

75

OMe

Me

OHN

Me

76

1. AcCl (3 equiv.)DMAP (3 equiv.)

toluene, refl ux, 1 h86% yield

2. POCl3 (5 equiv.) CH3CN, refl ux, 1 h

95% yield

+

MeOMe

MeOTFA–

OMeOHN

Me

77

+

MeOMe

MeOTFA–

Me

Scheme XIX. Synthesis of ancistrocladinium B 76 as atropo-diasteromers (P/M) 46/54 and ancistrocladinium C 77 as atropo-diasteromers (P/M) 3/2 using a DoM–C–N cross-coupling strategy (42)

OMe

R1

OMe

R1

OMe

R1O

R2

F

F

F

F

IHS

+

IOMeSHCl

+

S

S

N

O

HO

78 79 81

80 82

83

84

For R1 = 3-Cl:1. sBuLi, TMEDA THF, –95ºC, 1 h

2. I2, –95ºC to RT 16 h

Pd2(dba)3, KOtBu, toluene

Pd2(dba)3 DPEPhos, KOtBu

toluene, 100ºC, 90 min 55% yield

R1 = 3-Cl, 4-Cl, 5-Cl, 6-Cl, 4-Br, 5-BrR2 = 3-Cl, 4-Cl, 5-Cl, 6-Cl, 4-Ph, 4-thiophen-3-yl, 3-MeOC6H4-4-yl, 4-MeOC6H4-4-yl, 4-ClC6H4-4-yl, 5-Ph

Scheme XX. DoM–C–S cross-coupling route to diaryl sulfi des 84

3. DoM–Halogen Dance–Cross-Coupling Reactions

The DoM reaction on halogenated aromatic and

heteroaromatic compounds may be accompanied

by halogen dance reactions in which halogens, most

notably iodine, undergo migration to the incipient

DMG DMG

X

DMGDoMHalogen dance

X = Br, IR = Substituent inserted through cross-coupling

(Het) (Het) (Het)

R

X

R R

Cross-coupling DMG(Het)

R

R



anion and provide, generally but not invariably,

the most thermodynamically stable anion (50).

This not only provides an option to halogenate

positions which are otherwise diffi cult to access,

but also enables the introduction of an external

electrophile at the site bearing the newly formed

anion. In this context, we have developed routes

to polyfunctionalised pyridines (51) and others

have utilised halogen dance in the formation of

heterobiaryls (Scheme XXI) to provide substituted

2-arylquinolines as novel CRF1 receptor antagonists

(52). Thus, metallation-iodination of quinoline 85

afforded iodoquinoline 86 which, when subjected

to a second metallation-protonation, gave the

halogen dance product 87. Suzuki-Miyaura cross-

coupling and subsequent steps led to the substituted

arylquinolines 88. We have found that it is important

to be vigilant for potential undesired halogen dance

reactions which may arise in many metallation

reactions of halogenated heterocycles.

N

Cl

N

Cl

N

Cl

N

Cl

I

I

OMeMeO

OMe

Me

NEt2

LDA, THF, –78ºCI2

Metallation

LDA, THF, –78ºC

Halogen dance

85 86 (49% yield) 87 (56% yield)

88

Scheme XXI. Metallation–halogen dance–Suzuki-Miyaura route to 2-arylquinoline 88 CRF1 receptor antagonist

DMG DMG

X

DMGDoM Cross-coupling

R

O

( )nDreM

X = Halide or pseudohalideR = H, Men = 0, 1

4. DoM–Cross-Coupling–DreM Reactions

The synthesis of interesting polycyclic aromatic and

heteroaromatic molecules has a long history in the

Snieckus laboratories (a recent example uses the

Suzuki-Miyaura cross-coupling (53)). To construct

these systems, the directed remote metallation (DreM)

reaction (54, 55) on specifi cally designed 2-DMG

biaryls is the key reaction to forge the central aromatic

bridging ring. Generally this method complements

already established methods for their synthesis

and allows easy access to previously unreported

compounds. The standard conditions for a DreM

reaction are formation of the anion by treatment with

LDA at –20ºC or 0ºC, followed by warming to room

temperature to ensure completion of the anionic

cyclisation. Depending on the type of substituents

in the biaryl starting material, often a minimum of 2

equivalents of LDA is required, proposed to be due to

‘losing’ one or more equivalents to coordination with

these substituents.

4.1 Synthesis of Biaryls Using DoM–Cross-Coupling ReactionsFor the construction of requisite biaryls, the

DoM–Suzuki-Miyaura protocol is frequently

practiced, although other cross-coupling strategies

such as DoM–Negishi are also used. Thus, in

general (Scheme XXII), cross-coupling partners

2-halodiethylbenzamides 91 and boronic acids 92

are synthesised using standard DoM conditions

from diethylbenzamides 89 and by metal halogen

exchange on bromobenzenes 90 respectively,

although currently many of the boronic acids may be



purchased. Alternatively, the cross-coupling partners

may be inverted so that DoM derived boronic

acids 91 (X = B(OH)2) may be directly coupled with

aromatic trifl ates or with bromobenzenes 90 without

the need for metal halogen exchange. We have found

that the Suzuki-Miyaura reaction usually requires

only minimal development using standard palladium

sources and ligands, although the reactions are still

substrate dependent. On the other hand, certain

boronic acids, especially heteroaromatic cases,

can be diffi cult to handle and unstable due to their

propensity for protodeboronation. As a notable

example, we have learned from experience that

3-methoxy-N,N -diethylbenzamide-2-boronic acid

is diffi cult to isolate, and is reliably synthesised

only if the aqueous quench of the reaction mixture

is performed at –40ºC slowly by the addition of a

CH2Cl2/H2O mixture. Others have reported similar

problems regarding this boronic acid (56).

The absence of reports concerning aryl sulfonamide

ortho-boronic acids prompted a study in which the

problems associated with the synthesis of this class

of unstable boronic acids was solved, at least in this

particular case (7). Although it was determined

that metallation of aryl sulfonamides proceeds

uneventfully, as evidenced by deuterium quench

experiments, quenching the metallated species

with B(OR)3 reagents followed by aqueous workup

provided boronic acids in low yields, accompanied

by recovery of starting material, which suggested

instability of the ortho-boronic acids. This problem

was circumvented by utilising an in situ quench with

MeOBpin or iPrOBpin as electrophiles, leading directly

to the boropinacolate derivatives which are known to

be more stable than the corresponding boronic acids.

Similarly in the even more unstable pyridine boronic

acid series, in situ formation of boropinacolates was

advantageous in isolation of compounds useful for

Suzuki-Miyaura cross-coupling reactions (32).

Another solution for the synthesis of problematic

arylboronic acids stemming from our laboratories

is the ipso-borodesilylation reaction of trimethylsilyl

arenes (57). The silylated starting materials are

readily obtained in high yields using DoM chemistry,

and are quite stable with the exception of certain

heteroaromatic silanes. Treatment with BCl3 or BBr3

affords the Ar-BX2 species which, without isolation, may

be converted into the corresponding boropinacolates

by stirring with pinacol, or otherwise may be used

directly in a one-pot cross-coupling process.

4.2 Combined DoM–Suzuki-Miyaura–DreM Synthesis of FluorenonesTreatment of biaryl-2-amides 93a, derived from

DoM–cross-coupling reactions, under standard DreM

conditions results in alternate ring deprotonation

followed by cyclisation to provide fl uorenones 94

in good yields (Scheme XXIII). As ourselves and

others (58, 59) have demonstrated, various substituted

fl uorenones, azafl uorenones and two natural products

dengibsinin 95 and dengibsin 96 may be synthesised

using this strategy (60, 61).

Generally the highest yields are obtained for

biaryl cases bearing an additional 3-DMG which

promotes synergistic metallation, thereby leading

to regioselective cyclisation. In the synthesis of

azafl uorenones 99 using this strategy (Scheme XXIV),

the use of a one-pot DoM–Suzuki-Miyaura protocol was

CONEt2

R1DoM

Metal-halogen exchange

–

–R3

R2Br

CONEt2

R1

R2

R3

B(OH)2

X

Et2NOC

R1

R2

R3

Cross-coupling

1. sBuLi/TMEDA THF, –78ºC

2. Electrophile

1. nBuLi THF, –78ºC

2. Electrophile

X = halogen (or B(OH)2 when coupled with 90)R3 = H 93a Me 93b

89 91

90 92

93

Scheme XXII. DoM–Suzuki-Miyaura cross-coupling synthesis of biaryls 93



essential due to the instability of the pyridyl boronates

towards protodeboronation (32).

This method proved useful for the construction of

diverse azafl uorenones with electron-donating and

electron-withdrawing substituents. This sequential

DoM–cross-coupling–DreM strategy allows the

construction of azafl uorenones which are inaccessible

or afford isomeric mixtures by the traditional Friedel-

Crafts reactions.

4.3 Combined DoM–Suzuki-Miyaura–DreM Synthesis of Phenanthrols and PhenanthrenesTreatment of biaryls exhibiting 2-methyl substituents

93b under standard DreM conditions affords

9-phenanthrol derivatives 100 (Scheme XXV). The

deprotonation is often – but not always – indicated

by a deep red colour attributed to the generated tolyl

anion. Conversion of the resulting phenanthrols 100 to

phenanthrenes 101 is readily achieved using trifl ation

followed by palladium-catalysed hydrogenolysis. Often

no purifi cation is required for the intermediate steps,

and the fi nal phenanthrenes may be obtained in good

yield and high purity after a simple recrystallisation.

This route is scalable and reliably provides

substituted phenanthrenes in high purity which have

been used successfully in our collaborative projects

to conduct toxicity studies concerning the effects of

substituted polyaromatic hydrocarbons on fi sh (62).

R1

Et2NOCR2

R1 R2

OLDA (2.5 equiv.), THF –20ºC or 0ºC

93a 94O

OMeOH

OHO

OMeOH

OH

OMe

95 96

Scheme XXIII. Synthesis of fl uorenones using the combined DoM–cross-coupling–DreM strategy for dengibsinin 95 and dengibsin 96

DMGN DMG

N

RR

N

O

97 98 99

1. B(OiPr)3 (1.1 equiv.)THF, –78ºC to –10ºC

2. LDA (1.1 equiv.), 0ºC, 45 min3. Pinacol (1.2 equiv.), RT, 1 hor N-methyldiethanolamine

(1.1 equiv.), 0ºC, 2 h

3. ArBr (1.1 equiv.)Na2CO3 (aq., 2 M, 5 equiv.)

Pd(PPh3)4 (5 mol%)PhMe, refl ux, 12 h

30–76% yields

DMG = CONEt2

LDA (1.2–3.0 equiv.)THF, –78ºC to 10ºC

55–81% yields

DMG = 2-CONEt2, 3-CONEt2, 4-CONEt2, 4-Cl, 2-F, 3-OCONEt2ArBr = various, containing R = MeO, CN, NO2, CONEt2, Cl groups

Scheme XXIV. One-pot DoM–Suzuki-Miyaura–DreM synthesis of azafl uorenones 99 (32)

R1

Et2NOCR2

93bMe

R1

R2HO

100 101

R1

R2LDA, THF, –20ºC or 0ºC 1. Tf2O, pyridine, CH2Cl2 2. Pd(OAc)2, PPh3, Et3N

HCO2H, DMF

Scheme XXV. Synthesis of phenanthrenes 101 by the combined DoM–Suzuki-Miyaura–DreM strategy



4.4 Combined DoM–Suzuki-Miyaura–DreM Synthesis of Acridones and BenzazepinonesA DreM process analogous to that shown in

Scheme XXV may also be achieved on diarylamines

103, which are prepared using palladium-catalysed

Buchwald-Hartwig cross-coupling of anilines 102 with

DoM derived halo or pseudohalo diethylbenzamides

91, followed by N-alkylation. Thus treatment of

diarylamine 103a (R2 = H), under standard DreM

conditions provides acridones 104a (n = 0) in

good to excellent yields. In an analogous fashion to

the formation of phenanthrenes (Scheme XXV),

subjection of the diarylamine 103b (R2 = Me) to

standard DreM conditions affords dibenzazepinones

104b (n = 1), also in good to excellent yields

(Scheme XXVI) (63).

These protocols constitute anionic equivalents of

Friedel-Crafts type cyclisations affording acridones, and

complement existing syntheses of dibenzoazepinones,

compound classes which both exhibit signifi cant

bioactivities. For instance, acridone derivatives possess

antimalarial properties (64), and dibenzoazepinone

derivative trileptal is an antiepileptic drug (65).

In a collaborative study, we investigated the multi-

nitrogen-containing imidazo[1,5-a]pyrazine 105 for

use as a scaffold for the preparation of potentially

bioactive molecules. Without prediction based

on available precedent, the metallation of 105a and 105b followed by iodination afforded C-5

iodinated compounds 106a and 106b in high yields.

Subsequent Suzuki-Miyaura cross-coupling with

2-(diethylcarbamoyl)phenylboronic acid (synthesised

from N,N-diethylbenzamide using a DoM protocol)

provided biaryls 107a and 107b. Treatment of 107b

with LiTMP at cryogenic temperatures furnished

the previously unknown triazadibenzo[cd,f]azulen-

7(6H)-one 108b (Scheme XXVII) (66). To the

best of our knowledge, DreM processes of complex

heterocycles such as 107 had not been previously

reported.

91

R1

OEt2N

X

R3

R2

HN+

R2 = H 102a Me 102b

1. [Pd]

2. MeI

R2 = H 103a Me 103b

R1

OEt2N

R3

R2Me

NLDA (2–4 equiv.)

n = 0 104a 1 104b

R1 R3

( )n

O

NMe

Scheme XXVI. Synthesis of acridones and dibenzazepinones using DoM–C–N cross-coupling–DreM strategy

N

Me

X

X = Cl 105a OMe 105b

X = Cl (quant.) 106a OMe (79%) 106b

N

Me

X

I

B(OH)2CONEt2

(1.1–1.2 equiv.)Pd(PPh3)4 (5 mol%)

K2CO3 (3 equiv.)

DME:H2O (50:7) refl ux, 4 h

1. nBuLi (1.0–1.2 equiv.)15 min, THF, –78ºC

2. I2 (1.2–1.3 equiv.), 15 min THF, –78ºC

NN N

N

N

Me

X

NN

CONEt2

X = Cl (79%) 107a OMe (61%) 107b

N

OMe

NN

O

X = OMe (45%) 108

HTMP (3 equiv.), nBuLi (3 equiv.), THF, –78ºC, 90 min

107b

Scheme XXVII. DoM–Suzuki–DreM–cyclisation route to triazadibenzo[cd,f]azulen-7(6H)-one 108b (64)



5. Scale-Up and Industrial use of DoM–Cross-Coupling–DreM ReactionsIf proper safety protocols are followed and

temperature and stirring of the reaction mixture are

controlled and maintained, metallation chemistry

may be effectively used for large scale synthesis. In

fact, there is often no viable alternative to the use of

a DoM–cross-coupling sequence at multi-kilogram

scale in the pharmaceutical and fi ne chemical

industry (67–69). For instance, Merck has recently

demonstrated a practical, effi cient and multi-hundred

gram synthesis of 3-bromo-6-chloro-phenanthrene-

9,10-dione 113 using a DoM–cross-coupling–DreM

sequence (Scheme XXVIII) (70). Compound 113

is a useful building block for the preparation of

pharmaceutically important phenanthrenequinones

and phenanthreneimidazoles.

Similarly, as further evidence of utility, Merck

has achieved a kilogram-scale chromatography-

free synthesis of mPGE synthase I inhibitor

MK-7285 119 (Scheme XXIX) (71). Thus DoM–

boronation of 114 provided the lithioborate 115

Cl

CONEt2

Cl

CONEt2

Cl

Et2NOCB(OH)2

Me

HO

Cl Cl

O

O

Br

109 110 111(89% yield over 2 steps)

112 113

1. B(OiPr)3 (1.6 equiv.)DME

2. LDA (1.6 equiv.)–35ºC to 25ºC

3. H2O(regioselectivity 97>1)

2-Iodotoluene (0.93 equiv.) Pd(OAc)2 (0.5 mol%)

PPh3 (1 mol%)K2CO3 (2.5 equiv.)

DME/THF/H2O, 8 h, 70ºC

1. LiNEt2 (1.3 equiv.), DME, –45ºC, 2 h2. HCl (4 equiv.), 0ºC to 5ºC

85% yield

Scheme XXVIII. Large scale synthesis of phenanthrene-9,10-diones 113 using a combined DoM–cross-coupling–DreM strategy. 109 was used at a scale of 245.7 g, 111 was produced at a scale of 311.5 g and 112 at 200 g (68)

O O

CONEt2

MeBr

OH

MeMe

O

Li+ –B(OiPr)3CONEt2CONEt2

1. B(OiPr)3 (2 equiv.)THF, –25ºC

2. LDA (2 equiv.)<–20ºC, 2 h 3. H2O, 20ºC

quantitative conversion

(0.7 equiv.)

PdCl2•dppf (2.5 mol%)H2O, refl ux, 12 h

88–98% yield

114115

116

117

MeOH

MeMe

O

OH

OH

MeMe

118O

OH

MeMe

119

NC

NC

FN

NH

Et2NLi (3.5 equiv.)THF (<0.24 M)

0ºC to –5ºC, 14 h63% yield

Scheme XXIX. Large scale synthesis of mPGE synthase I inhibitor 119 using the combined DoM–cross-coupling–DreM strategy. 114 was used at a scale of 3.75 kg, 117 was produced at a scale of 7.69 kg (69)



which, without isolation, was subjected to Suzuki-

Miyaura cross-coupling with bromobenzene 116

to afford biaryl 117. In the key step, treatment of

biaryl 117 with lithium diethylamide resulted in

a DreM cyclisation to provide the phenanthrol

118 in acceptable yield. A significant observation

was that in the DreM reaction, at concentrations

greater than 0.24 M, competitive intermolecular

condensation provided 5–10% of an undesired

product.

6. Diversifi cation of the DoM–Cross-Coupling Strategy

The unique power and considerable synthetic

advantage of DoM chemistry is the regioselective ortho

introduction of only one functional group per DMG.

Furthermore, synthetic strategies may be devised

to use the same DMG to achieve 2,6-disubstitution

and thus to construct 1,2,3-trisubstituted aromatic

systems (72). Using the N-cumylsulfonamide DMG,

this strategy has been adapted for the synthesis of

7-substituted saccharins (Scheme XXX) (73). Thus,

as conceptually illustrated below, the straightforward

DMG DMG

R1

DMGFirst DoM

Cross-coupling R1

R1, R2 = Substituent introduced through cross-couplingR3 = Substituent introduced through DoM

Second DoM

Cross-coupling

Cross-coupling

DMG

R3

R2

DMG

R3

R1

First DoM

Second DoM

First DoM (E+ = halide source)

Second DoM (E+ = ClCONEt2)

SO2NHCumylFirst DoM

Cross-couplingSecond DoM

SO2NHCumyl

CONEt2

Ar

TFAAcOH

O

Ar

SO2

NH

SO2NHCumyl

120

SO2NHCumyl

SO2NHCumyl SO2NHCumyl

I

ArAr

CONEt2

121

122 123 124

O

Ar

S O2

NH

ArB(OH)2 (1.1–2.0 equiv.)Pd(PPh3)4 (5 mol%), A or B or C or D, 24 h

A. K3PO4 (3 equiv.), DMF, 100ºC B. Na2CO3 (8–10 equiv.), THF, 70ºCC. Cs2CO3 (2–8 equiv.), THF, 70ºCD. Na2CO3 (10 equiv.), DME, 90ºC

57–99% yields

1. sBuLi (2.2 equiv.)TMEDA (2.2 equiv.)

THF, –78ºC

2. I2 (1.2 equiv.)–78ºC to RT

3. NH4Cl (aq.)88% yield

1. nBuLi (2.2 equiv.)TMEDA (2.2 equiv.)

THF, 0ºC, 1 h

2. ClCONEt2 (1.2 equiv.)0ºC to RT

3. NH4Cl (aq.)78–99% yieldsa

1. TFA, RT, 10 min2. AcOH, refl ux, 12 h

3. HCl

42–89% yields (over two steps)

Ar = C6H5, 2,3-di-MeC6H3, 3,5-di-ClC6H3, 2-Et2NC(O)C6H4, naphthalen-2-yl, thiophen-3-yla Some of the products were taken to the next steps without purifi cation

–

–

Scheme XXX. Double use of the N-cumylsulfonamide DMG in the synthesis of substituted saccharins 124

122



DoM–halogenation–Suzuki-Miyaura coupling of

N-cumylbenzenesulfonamides 120 provided,

via iodide 121, the biaryls 122. Then the same

N-cumyl sulfonamide DMG served for a second

DoM–carbamoylation to furnish the biaryl amide

sulfonamide 123. Decumylation of 123 using TFA,

followed by acid-mediated cyclisation gave rapid

access to saccharins 124 in good overall yield.

Aside from interesting pharmaceutical properties

and use in the fi elds of fl avour, polymer and

coordination chemistry, the saccharin core has

played a role in the discovery of a human leukocyte

elastase inhibitor, KAN400473 (125, Figure 3), used

for the treatment of emphysema (74). It also features

in the Merck carbapenem antibacterial agents (126,

Figure 3) (75).

Double DoM–double cross-coupling reactions

involving multiple DMGs are also useful synthetic

tactics. Thus the fi rst total syntheses of natural,

unsymmetrical 2,3-diacyloxy-p-terphenyls, thelephantin

O 131a (Scheme XXXI) and terrestrins C and D

(131b and 131c, respectively), were achieved using

double DoM and bromination of 127 to give the

hexasubstituted benzene 128 which, after Suzuki-

Miyaura cross-coupling with 129, afforded the key

intermediate teraryl 130. Synthesis of the symmetrical

diesters vialinin A/terrestrin A 131d and terrestrin B

131e was also achieved using the same sequence (76).

O

O

O

NR3+

O

CO2–

HO Me

Me N

NSO2

126

NNN

N

NSS

O2

125

Fig. 3. Biologically active saccharins KAN400473 125 and Merck antibacterial agents 126

MeMe

OMOMMOMO

O O

MeMe

OMOMMOMO

O O

MeMe

OMOMMOMO

O O HO OH

O OO O

OHHO

R1 R2

Br Br

TBSO OTBS

127

130

128

131a–e

129

TBSOOB

(1.5 equiv.)3

1. nBuLi (3 equiv.)THF, 0ºC, 1 h

2. BrCF2CF2Br (3 equiv.)0ºC, 1 h3. H2O

94% yield

Pd(PPh3)4 (5 mol%)K2CO3 (6 equiv.)

1,4-dioxane:H2O (3:1) 2 h, refl ux78% yield

R1 R2

131a Ph CH2Ph131b Pr CH2Ph131c Me CH2Ph131d CH2Ph CH2Ph131e Pr Pr

Scheme XXXI. Synthesis of teraryl natural products using double DoM–Suzuki-Miyaura cross-coupling sequence



7. The DMG as a Pseudohalide in Cross-Coupling Reactions

As documented in this review, cross-coupling of DoM

derived species such as B, Zn, Sn and Mg has become

a highly useful synthetic strategy. The development of

DMGs that themselves act as cross-coupling partners

was fi rst achieved in our group with O -carbamates

(77) and subsequently with sulfonamides (78) under

Ni(acac)2 conditions. Furthermore, these DMGs may

be excised from the aromatic framework using the

-hydride donor properties of iPrMgCl and iPr2Mg

respectively, thus establishing the latency concept

of DMGs (77, 78). Recently additional DMGs such as

ethers, esters, O-carbamates under Suzuki-Miyaura

conditions (79, 80) and O -sulfamates (79) have

been established as cross-coupling partners (81).

The non-reactive nature of some of these groups in

palladium-catalysed coupling reactions allows the

establishment of orthogonal processes (82, 83). For

example, subsequent to work in our laboratories

(80), Garg et al. (84) recently explored regioselective

construction of biaryls based on differential reactivity

of bromide, O-carbamate and O-sulfamate groups

toward Pd and Ni catalysts (Scheme XXXII). Thus,

DoM–bromination of 132 furnishes aromatic bromide

133, which undergoes sequential and selective

palladium-catalysed Stille, nickel-catalysed Suzuki-

Miyaura and nickel-catalysed C–N cross-coupling

to rapidly provide biaryl 136 in good yield. Recent

efforts on transition metal-catalysed cross-coupling

reactions of new O-based electrophiles via C–O bond

activation have focused on nickel and iron based

catalysis (85–87).

Authors’ note added in proof: after the submission

of this review, Feringa and co-workers established the

palladium-catalysed cross-coupling of alkyl, alkenyl

and aromatic lithiates (some derived using DoM) with

aromatic bromides (88).

132

1. TMEDA (1.1 equiv.) sBuLi (1.1 equiv.)

THF, –93ºC, 45 min 2. BrCF2CF2Br (1.4 equiv.)

–93ºC to RT

3. NH4Cl (aq.)78% yield

LiCl (5 equiv.) PdCl2(PPh3)2Me4Sn, DMF100ºC, 16 h

74% yield

p-MeOArB(OH)2 (5 equiv.) NiCl2(PCy3)2 (20 mol%)

K3PO4 (7.2 equiv.)

toluene, 130ºC, 8 h52% yield

Morpholine (2.4 equiv.) Ni(cod)2 (10 mol%)SIPr4•HCl (20 mol%) NaOtBu (2.2 equiv.)

dioxane, 80ºC, 3 h64% yield

OCONEt2

OSO2NMe2

OCONEt2 OCONEt2

OCONEt2

133 134

135 136

Br Me

Me Me

OMeOMe

O

N

OSO2NMe2 OSO2NMe2

Scheme XXXII. Use of O-carbamate and O-sulfamate DMGs as cross-coupling partners

DMG DMG

R1

DoM

R1

Cross-coupling R2

R1 = Substituent introduced through DoMR2 = Substituent introduced through cross-coupling



Conclusions This brief review has demonstrated that the combined

DoM–cross-coupling strategy, fi rst developed in our

laboratories in the mid-1980s, has considerable value

in organic synthesis. In this aim, we have attempted

fi rstly to provide supportive evidence using selected

recent examples derived from industrial and

academic laboratories, including many from our own

work. Emphasis has been placed on heterocycles,

which constitute 80% of current marketed drugs,

with synthetic case studies on a variety of bioactive

molecules in early, clinical or process stages of

development, including soraprazan (Figure 1),

GSK966587 (Figure 2), ancistrocladinium B and

C (Scheme XIX) and CRF1 receptor antagonist

(Scheme XXI). As will be recognised, the

heterocycles range from recognisable to more

unusual and complex frameworks (for example

Scheme XXVII). The pgms, particularly palladium,

catalyse many of the processes, contributing to the

enormous versatility of this strategy.

The second aim of the review has been to offer,

in various described processes, practical from-the-

bench tips based on our experience, at least in

small-scale reactions. These include the advantage

of deuterium-quench experiments to establish the

extent of the DoM step before taking the road to

scale-up (for example Scheme III), and the caveat

regarding purity of starting materials and their

instability.

Prognosis for the DoM–Cross Coupling StrategyEmerging from the content of this review are the

following features:

1. DoM–C–C Cross-Coupling Reactions This section suggests that among the cross-

coupling reactions used in combination

with DoM: Ullmann, Heck, Sonogashira,

Negishi, Stille and Suzuki-Miyaura, the latter

dominates the synthetic landscape with

increasing presence of the Negishi protocol.

The advent of new nontraditional lithium

bases such as the commercial Knochel

type tmpMgCl·LiCl combined with zinc

transmetallation and Negishi coupling

(Scheme XII) are beginning to provide more

convenient conditions for the DoM–cross-

coupling strategy.

Iridium-catalysed boronation offers a

complementary method for meta boronation

compared to the DoM–Suzuki-Miyaura

coupling process (Scheme XVI).

Only an inkling has been given of the

potential for DoM–cross-coupling in natural

product synthesis (Schemes XVII and XVIII)

and this can only be expected to grow in

importance.

2. DoM–C–Heteroatom (N, S, O) Cross-Coupling Reactions Based on our literature review, this motif has

considerable use in combined DoM–Hartwig-

Buchwald C–N and C–O cross-coupling

processes and is as yet underdeveloped for

C–S fusion reactions.

3. DoM–Halogen Dance–Cross-Coupling Reactions Although the agreeably named halogen

dance is of some vintage, its application in

the construction of substituted aromatics

and heteroaromatics has considerable, as yet

unfulfi lled, promise.

Among the practical tips is the caveat that, to

eventual regret, it may be easy to overlook the

occurrence of the halogen dance in the dash

to publication.

4. DoM–Cross-Coupling–DreM Reactions The DoM–cross-coupling sequence fi nds

additional advantage in synthesis when

combined with the DreM process.

Thus, the regioselective synthesis of

substituted fl uorenones (Schemes XXIII and

XXIV), phenanthrenes (Scheme XXV) and

acridones and dibenzazepinones (Scheme XXVI) become feasible in practical, effi cient

and environmentally friendly ways compared

with, for example, traditional electrophilic

substitution methods. Specifi cally, the DreM

approach to fl uorenones and azafl uorenones

(Scheme XXIV) demonstrates the

complementarity between Friedel-Crafts and

DreM tactics.

5. Scale-Up and Industrial use of DoM–Cross-Coupling–DreM Reactions As in the case of DoM chemistry which

was dormant for about a decade after

developments in our laboratories in the late

1970s, the DreM concept has been nurtured

in industry and is now appearing in the

open literature. It is encouraging to see the

application of the combined DoM–cross-

coupling technology (Scheme XXVIII),



including DreM (Scheme XXIX) methods,

on a multi-kilogram scale.

6. Diversifi cation of the DoM–Cross-Coupling Strategy While DoM reactions constitute one

functional group per DMG for synthetic

considerations, signifi cant advantage is

gained in diversifi cation, with or without

protection requirements, to the creation of

2,6-disubstituted DMG-bearing aromatics.

Perhaps insuffi ciently appreciated and

adapted as yet, such a sequence is shown in

Scheme XXX.

Another conceptual element, a double DoM

process (Scheme XXXI), may also be the tip

of the iceberg in synthesis.

7. The DMG as a Pseudohalide in Cross-Coupling Reactions Adaption of methodology which uses the

DMG aromatic as a pseudohalide coupling

partner, already demonstrated in our Corriu-

Kumada reaction of aryl O-carbamates

in the early 1990s, has taken on new

possibilities in O-carbamate, O-sulfamate

and sulfonamide Corriu-Kumada and

Suzuki-Miyaura reactions (Scheme XXXII)

in our laboratories as well as others. The

potential of this chemistry, including the

excision of the DMG by transition metal-

catalysed -hydride elimination processes,

is only now surfacing in the literature.

We hope the aims of this review have been met and

will be valuable to synthetic chemists. The prognostic

views expressed throughout this fi nal section are, as

many times experienced by all, dangerous to place, as

we do, into the literature.

AcknowledgementsThis review is dedicated to Alfred Bader, benefactor

of Snieckus Innovations, for giving us the opportunity

to impel our basic knowledge of chemistry to reach

practical ends.

Victor Snieckus thanks the Natural Sciences and

Engineering Research Council of Canada (NSERC)

for support by the Discovery Grant program. Suneel

Singh is grateful to NSERC for an industrial post

doctoral fellowship award.

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DMG directed metallation group

Het heterocycle



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The Authors

Victor Snieckus was born in Kaunas, Lithuania and spent his childhood in Germany during World War II. His training was at the University of Alberta, Canada, (BSc Honors), strongly infl uenced by the iconoclastic teacher, Rube Sandin; the University of California, Berkeley, USA, (MSc), where he gained an appreciation of physical organic principles under D. S. Noyce; the University of Oregon, USA, (PhD), discovering his passion for organic synthesis under the excellent mentor, Virgil Boekelheide; and at the National Research Council, Ottawa, Canada, where he completed a postdoctoral tenure with the ardent Ted Edwards. His appointments have been at the University of Waterloo, USA, (Assistant Professor, 1966); Monsanto (NRC Industrial Research Chair, 1992–1998); and Queen’s University, Canada, (Inaugural Bader Chair in Organic Chemistry, 1998–2009). Some of his awards include A. C. Cope Scholar (2001, one of 4 Canadians); Order of the Grand Duke Gediminas (2002, from the President of Lithuania); Arfedson-Schlenk (2003, Geselschaft Deutscher Chemiker); Bernard Belleau (2005, Canadian Society for Chemistry); Givaudan-Karrer Medal (2008, University of Zurich, Switzerland); Honoris causa (2009, Technical University Tallinn, Estonia); and Global Lithuanian Leader in the Sciences (2012). In research, the Snieckus group has contributed to the development and application of the directed ortho metallation reaction

(DoM) and used it as a conceptual platform for the discovery of new effi cient methods for the regioselective synthesis of polysubstituted aromatics and heteroaromatics. The directed remote metallation (DreM) reaction and DoM–linked transition metal catalysed cross-coupling reactions (especially Suzuki-Miyaura) were fi rst uncovered in his laboratories. These have found broad application in the agrochemical and pharmaceutical industries, e.g. the fungicide silthiofam (Monsanto), the anti-AIDS medication efavirenz and the anti-infl ammatory losartan (Bristol-Myers Squibb). He continues fundamental research as Bader Chair Emeritus as well as Director of Snieckus Innovations, an academic unit that undertakes synthesis of small molecules for the pharmaceutical and agrochemical industries.

Johnathan Board received his MChem from the University of Sussex, UK, and subsequently undertook his PhD with Professor Philip J. Parsons, also at the University of Sussex, working towards the synthesis of the backbone of lactonamycin. He joined the Snieckus group at Queen’s University Kingston, Ontario, Canada in 2007 as a postdoctoral fellow and worked on projects with industrial partners. In 2010 he helped set up Snieckus Innovations in which organisation he is currently a laboratory and research manager.

Jennifer Cosman received her BScH in Chemistry at Queen’s University Kingston in 2010. She joined Snieckus Innovations in early 2011, working on the custom synthesis of small molecules. In 2013 she began her MSc degree under the co-supervision of Professors P. Andrew Evans and Victor Snieckus, and is currently at Queen’s University completing this programme.

Suneel Pratap Singh was born in India, where he obtained his PhD degree (Organic Chemistry) in 2008 from the Indian Institute of Technology, New Delhi, under the supervision of Professor H. M. Chawla. After postdoctoral training on synthetic aspects of organosulfur chemistry with Professor Adrian Schwan at University of Guelph, Guelph, Ontario, Canada, he joined Snieckus Innovations in 2011. His research interests include directed ortho metallation and development of new synthetic methodologies for heterocycles.

Toni Rantanen received his PhD from RWTH Aachen University, Germany, where he studied under the supervision of Professor Carsten Bolm on the topics of organocatalysis, microwave chemistry and ball milling. In 2007 he joined the Snieckus group fi rst as an industrial postdoctoral fellow followed by academic research on the synthesis and functionalisation of heterocycles. In 2010, he helped to inaugurate Snieckus Innovations at which he is currently utilising his formidable experience as a laboratory and research manager.

IntroductionThe palladium(I) dimer, di-μ-bromobis(tri-tert-

butylphosphine)dipalladium(I), [Pd(μ-Br)( tBu3P)]2,was synthesised and fully characterised by Mingos(1, 2). However, its potential as a unique C–C andC–N coupling catalyst (3) was first explored byHartwig (6). It has emerged as one of the bestthird-generation coupling catalysts for cross-cou-pling reactions, including C–heteroatom couplingand α-arylations. In this review, the physical andchemical characteristics of the Pd(I) dimer as a cat-alyst material are discussed from a practicalviewpoint, and up to date information on its appli-cations in coupling catalysis is provided.

Characteristics and HandlingThe Pd(I) dimer is a dark greenish-blue

crystalline material, which gives a single peak in the31P NMR spectrum at (δ) 87.0 ppm. The 1H NMRspectrum gives a peak at (δ) 1.33 ppm (singlet; onexpansion it appears as a distorted triplet) in deuter-ated benzene (1, 2). The compound decomposes in

chlorinated solvents, especially in deuterated chlo-roform. The X-ray crystal structure is reported inthe literature as a dimer with Pd–Pd bonding, stabilised by bromine atoms via bridge formation(1, 2). It can be handled in air as a solid for a shortperiod of time, allowing the user to place it into areactor in the absence of a solvent, degas and thencarry out catalysis under inert conditions. However,this compound is highly sensitive to air and mois-ture in the solution phase. It can also decompose inthe solid phase if not stored under strictly inert conditions. The solid state decomposition patternover time was monitored in our laboratory at 0, 48and 112 hours (Figure 1) (4). Its sensitivity towardsoxygen is well understood, and is based on the formation of an oxygen-inserted product with theelimination of hydrogen (Scheme I) (5). Figure 2shows the oxygen sensitivity of the Pd(I) dimer ona proton-decoupled 31P NMR spectrum recordedusing a solvent which was not degassed. The peakat 107 ppm indicates the presence of the oxygen-inserted decomposition product.

183Platinum Metals Rev., 2009, 53, (4), 183–188

A Highly Active Palladium(I) Dimer forPharmaceutical Applications[Pd(μ-Br)(tBu3P)]2 AS A PRACTICAL CROSS-COUPLING CATALYST

By Thomas J. ColacotJohnson Matthey, Catalysis and Chiral Technologies, West Deptford, New Jersey 08066, U.S.A.; E-mail: [email protected]

The Pd(I) dimer [Pd(μ-Br)( tBu3P)]2 is one of the best third-generation cross-coupling catalystsfor carbon–carbon and carbon–heteroatom coupling reactions. Information on itscharacterisation and handling are presented, including its decomposition mechanism in thepresence of oxygen. The catalytic activity of [Pd(μ-Br)( tBu3P)]2 is higher than either( tBu3P)Pd(0) or the in situ generated catalyst system based on Pd2(dba)3 with tBu3P. Examplesof suitable reactions for which the Pd(I) dimer offers superior performance are given.

DOI: 10.1595/147106709X472147

0 h 48 h 112 h

Fig. 1 The solid stateoxygen sensitivity of purePd(I) dimer, [Pd(μ-Br)( tBu3P)]2, withtime (4)

Applications in Coupling CatalysisThe high catalytic activity of the Pd(I) dimer

[Pd(μ-Br)(tBu3P)]2 is due to its ease of activation,presumably to a highly active, coordinatively unsat-urated and kinetically favoured ‘12-electron’catalyst species, (tBu3P)Pd(0) (Scheme II). Thisrenders the Pd(I) dimer more active than either theknown ‘14-electron Pd(0)’ catalyst, (tBu3P)2Pd(0),or the Pd(0) catalyst generated in situ by mixingPd2(dba)3 with two molar equivalents of tBu3P. Theapplications of the Pd(I) dimer in organic synthesisare described below.

Carbon–Heteroatom CouplingHartwig identified the potential of the Pd(I)

dimer as a highly active catalyst for C–N coupling

using aryl chlorides as substrates with variousamines at room temperature. A few examples areshown in Scheme III (6). Typically, aryl chloridecoupling requires higher temperatures and longerreaction times when using the in situ generatedPd(0) catalyst, or even the (tBu3P)2Pd(0) complex(7). Around the same time, Prashad and cowork-ers at Novartis reported an amination reactionusing [Pd(μ-Br)(tBu3P)]2 with challenging sub-strates such as hindered anilines (8). Scheme IVshows the coupling of N-cyclohexylaniline withbromobenzene, comparing the performance ofthe Pd(I) dimer with those of in situ generated cat-alysts derived from Pd(OAc)2 with tBu3P, BINAP,Xantphos or DPEphos. The performance of[Pd(μ-Br)(tBu3P)]2 is superior in each case.


180 140160 120 100 80 60 40 20 0 ppm

Fig. 2 The oxygensensitivity of Pd(I)dimer, [Pd(μ-Br)( tBu3P)]2, as observed in the 31P NMR (ppm)spectrum recordedusing non-degassedC6D6

P P B r

P d B r

P d O 2

-2 H

O P d

O P d

C H 2

C H 2

P

B r P

B r

3 1 P N M R : 8 7 P P M 3 1 P N M R : 1 0 7 P P M P d ( I ) d i m e r

31P NMR: 107 ppm

–2H

P P

Br

Pd

Br

Pd P Pd

Highly active 12-electron species

Scheme I Theoxygen sensitivityof Pd(I) dimer,[Pd(μ-Br)( tBu3P)]2,with the formationof an inactive Pd-Ospecies (5)

Scheme II The activationof Pd(I) dimer to a 12-electron catalystspecies during couplingcatalysis

Pd(I) dimer

31P NMR: 87 ppm

Hartwig’s group subsequently conducted adetailed study to understand the activity and scopeof [Pd(μ-Br)(tBu3P)]2 in the amination of five-membered heterocyclic halides. Variouscombinations of Pd precursors with tBu3P werestudied for a model system, the reaction of N-methylaniline with 3-bromothiophene. Thefastest reaction occurred with the Pd(I) dimer (9).

More recently, Eichman and Stambuli reporteda very interesting zinc-mediated Pd(I) dimer-catalysed C–S coupling, which should generatemuch interest in the area of C–S coupling(Scheme V) (10). For the reactions of alkyl thiolswith aryl bromides and iodides, potassium hydridewas the best base, as illustrated in Scheme V. Forthe Pd-catalysed cross-coupling reactions of aryl

bromides and benzenethiol using zinc chloride incatalytic amounts, with sodium tert-butoxide asthe base, most of the reactions were sluggish andgave low yields. However, the addition of stoi-chiometric amounts of lithium iodide increasedthe rate of the reaction significantly, which isspeculated to be due to the anionic effects pro-posed by Amatore and Jutand (11).

Carbon–Carbon Bond FormationHartwig’s group also studied the Suzuki cou-

pling of sterically hindered tri-substituted arylbromides. A Pd(I) dimer loading of 0.5 mol%, inthe presence of alkali metal hydroxide base, gavegood yields at room temperature within minutes(Scheme VI) (6).


0.5 mol% Pd(I) dimer

NaOtBu, RT

15 min–1 h

R = Bu, Ph

or R2NH = morpholine

R

Yield 88–99%

Cl R

R NH +

R

N

Scheme III Arylchloride coupling atroom temperature (6)

Pd catalysts

NaOtBu, Toluene, 110°C

Catalyst loading Yield

[Pd(μ-Br)(tBu3P)]2 0.25 mol% 93%

Pd(OAc)2 + tBu3P 0.5 mol% 86%

Pd(OAc)2 + BINAP 0.5 mol% 27%

Pd(OAc)2 + Xantphos 0.5 mol% 27%

Pd(OAc)2 + DPEphos 0.5 mol% none

Br

+

HN N

Scheme IV Pd(I) dimer-catalysed C–N coupling of N-cyclohexylaniline (8)

0.5–2.0 mol% Pd(I) dimer

THF

ZnCl2 (catalyst)

KH (1.1 equiv.)

X = Br, I

Ar-X + RSH Ar-S-R

Yield 46–99%

R = tBu,

nBu, PhCH2

Scheme V Zinc-mediatedPd(I) dimer-catalysed C–Scoupling (10)

Research work from Ryberg at Astra Zeneca(12) demonstrated a very practical, clean methodfor C–CN coupling using the Pd(I) dimer [Pd(μ-Br)(tBu3P)]2 to produce 3 kg to 7 kg ofproduct routinely (Scheme VII). During the initialin situ studies, Pd2(dba)3 in combination withcommercial ligands such as Q-Phos, tBu2P-biphenyl or Cy2P-biphenyl gave poor results,although with proper process tweaking improve-ments were made. The conventional ligands, suchas Ph3P and dppf, were not useful. However, theP(o-tol)3/Pd2(dba)3 system behaved somewhatwell with the formation of some byproducts. The

Pd loading was as high as 5 mol% (12).For the α-arylation (13) of fairly challenging

carbonyl compounds, Hartwig identified thePd(I) dimer [Pd(μ-Br)(tBu3P)]2 as one of the bestcatalysts, especially for amides and esters. Thework from Hartwig’s group provided generalconditions for α-arylations of esters and amides(14–16). The coupling reactions of aryl halideswith esters are summarised in Scheme VIII (17).For aryl bromides, lithium dicyclohexylamide(LiNCy2) was the best base, while sodium hexa-methyldisilazide (NaHMDS) was required for arylchloride substrates. Intermolecular α-arylation of


Yield 84–95%

0.5 mol% Pd(I) dimer

KOH, THF

15 min, RT

Ph

R1R2

R3

PhB(OH)2

X

R1R2

R3

+

Scheme VI Roomtemperature Suzukicoupling of stericallybulky aryl bromides (6)

Pd(I) dimer, Zn(CN)2

Zn, DMF

50ºC, 1–3 hN

HN

Br

OH

N

O

N

HN

NC

OH

N

O

Yield 71–88%R1, R2 = Me, H; R = Me,

tBu

X = Br, Cl; R3 = Me, MeO, F

(i) LiNCy2 (X = Br) or

NaHMDS (X = Cl)

Toluene, RT, 10 min

(ii) Pd(I) dimer

RT–100ºC, 4 hR2

R1

R3O

OR

+

X

R3

OR1

OR

R2

Scheme VIII α-Arylation of esters under milder conditions using the Pd(I) dimer catalyst (17)

Scheme VIIThe Pd(I)dimer-catalysedcyanationreaction, whichmay be carriedout on akilogram scale(12)

X = Br;

R1 = H, CN, CF3, OCH3 or CH3; R2, R3 = H or CH3

in situ generated zinc enolates of amides was alsoreported in excellent yield under Reformatskyconditions using the Pd(I) dimer, (Scheme IX)(18). The appropriate choice of base for the sub-strate is critical for this reaction.

The α-vinylation of carbonyl compounds hasbeen reported recently by Huang and coworkersat Amgen, catalysed by the Pd(I) dimer in con-junction with lithium hexamethyldisilazide(LiHMDS) base (Scheme X) (19). The same cat-alytic system can be extended to the α-vinylation

of ketones and esters. The combination ofPd2(dba)3 with Buchwald ligands such as X-Phosand S-Phos gave inferior results, as did in situcatalysis with ligands such as Xantphos, (S)-MOP,BINAP and IPr-HCl (carbene) in the presence ofPd2(dba)3. Amgen researchers also reported astereoselective α-arylation of 4-substituted cyclo-hexyl esters using the Pd(I) dimer at roomtemperature, with lithium diisopropylamide(LDA) as the base. Diastereomeric ratios, dr, ofup to 37:1 were achieved (Scheme XI) (20).


Glossary

Ligand Full name

BINAP 2,2' -bis(diphenylphosphino)-1,1' -binaphthyltBu2P-biphenyl 2-(di-tert-butylphosphino)biphenyltBu3 tri-tert-butylphosphine

Cy2P-biphenyl 2-(dicyclohexylphosphino)biphenyl

dba dibenzylideneacetone

DPEphos bis(2-diphenylphosphinophenyl)ether

dppf 1,1' -bis(diphenylphosphino)ferrocene

IPr-HCl (carbene) 1,3-bis-(2,6-diisopropylphenyl)imidazolium chloride

(S)-MOP 2-(diphenylphosphino)-2' -methoxy-1,1' -binaphthyl

OAc acetate

P(o-tol)3 tri(o-tolyl)phosphine

Ph3P triphenylphosphine

Q-Phos 1,2,3,4,5-pentaphenyl-1' -(di-tert-butylphosphino)ferrocene

S-Phos 2-dicyclohexylphosphanyl-2' ,6' -dimethoxybiphenyl

Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

X-Phos 2-dicyclohexylphosphino-2' ,4' ,6' -triisopropylbiphenyl

(i) 1.5 equiv. Zn*

THF, RT, 30 min

(ii) 2.5 mol% Pd(I) dimer

Yield

94%

O

X

NMe2

Br

N

O

NMe2

N

Yield 48–95%

Toluene, 80ºC, 24 h

Pd(I) dimer, LiHMDS

X = Br, OTf, OTs

R1

R3

X

R2

R'''R''R'

OR

1

R2

R3

R'''

R''R'

O

+

Scheme IX α-Arylation ofamides underReformatskyconditions (18);Zn* = activatedzinc species

Scheme X α-Vinylationreaction usingPd(I) dimercatalyst (19);OTf =trifluoromethanesulfonate; OTs = tosylate

ConclusionsThe Pd(I) dimer [Pd(μ-Br)(tBu3P)]2 stands out

as unique among the third generation catalysts forcross-coupling. It has a higher activity than othercatalysts, a fact which can be attributed to its abili-ty to form a 12-electron ‘ligand-Pd(0)’ speciesduring the activation step in the catalytic cycle. Itsapplication to a wide variety of C–C, C–N and C–S

cross-coupling reactions will enable higher yieldsand better product selectivities under relativelymild conditions.

AcknowledgementsFred Hancock and Gerard Compagnoni of

Johnson Matthey’s Catalysis and Chiral Technologiesare acknowledged for their support of this work.


The AuthorDr Thomas J. Colacot is a Research and DevelopmentManager in Homogeneous Catalysis (Global) ofJohnson Matthey’s Catalysis and Chiral Technologiesbusiness unit. Since 2003 his responsibilities includedeveloping and managing a new catalyst developmentprogramme, catalytic organic chemistry processes,scale up, customer presentations and technologytransfers of processes globally.

1 R. Vilar, D. M. P. Mingos and C. J. Cardin, J. Chem.Soc., Dalton Trans., 1996, (23), 4313

2 V. Durà-Vilà, D. M. P. Mingos, R. Vilar, A. J. P. Whiteand D. J. Williams, J. Organomet. Chem., 2000, 600, (1–2),198

3 T. J. Colacot, ‘Di-μ-bromobis(tri-tert-butylphos-phine)dipalladium(I)’, to be included in 2009 in“e-EROS Encyclopedia of Reagents for OrganicSynthesis” , eds. L. A. Paquette, D. Crich, P. L.Fuchs and G. Molander, John Wiley & Sons Ltd.,published online at: www.mrw.interscience.wiley.com/eros (Accessed on 30th July 2009)

4 Johnson Matthey Catalysts, ‘Coupling CatalysisApplication Table’, West Deptford, New Jersey, U.S.A.:http://www.jmcatalysts.com/pharma/pdfs-uploaded/Coupling%20%20Apps%20Table.pdf(Accessed on 30th July 2009)

5 V. Durà-Vilà, D. M. P. Mingos, R. Vilar, A. J. P. Whiteand D. J. Williams, Chem. Commun., 2000, (16), 1525

6 J. P. Stambuli, R. Kuwano and J. F. Hartwig, Angew.Chem. Int. Ed., 2002, 41, (24), 4746

7 R. Kuwano, M. Utsunomiya and J. F. Hartwig, J. Org.Chem., 2002, 67, (18), 6479

8 M. Prashad, X. Y. Mak, Y. Liu and O. Repic, J. Org.Chem., 2003, 68, (3), 1163

9 M. W. Hooper, M. Utsunomiya and J. F. Hartwig, J.Org. Chem., 2003, 68, (7), 2861

10 C. C. Eichman and J. P. Stambuli, J. Org. Chem., 2009,74, (10), 4005

11 C. Amatore and A. Jutand, Acc. Chem. Res., 2000, 33,(5), 314

12 P. Ryberg, Org. Process Res. Dev., 2008, 12, (3), 54013 C. C. C. Johansson and T. J. Colacot, Angew. Chem.,

2009, in press14 T. Hama and J. F. Hartwig, Org. Lett., 2008, 10, (8),

154915 T. Hama and J. F. Hartwig, Org. Lett., 2008, 10, (8),

154516 T. Hama, X. Liu, D. A. Culkin and J. F. Hartwig, J.

Am. Chem. Soc., 2003, 125, (37), 1117617 T. Hama and J. F. Hartwig, Synfacts, 2008, (7), 075018 T. Hama, D. A. Culkin and J. F. Hartwig, J. Am. Chem.

Soc., 2006, 128, (15), 497619 J. Huang, E. Bunel and M. M. Faul, Org. Lett., 2007,

9, (21), 434320 E. A. Bercot, S. Caille, T. M. Bostick, K. Ranganathan,

R. Jensen and M. F. Faul, Org. Lett., 2008, 10, (22),5251

Pd(I) dimer, LDA

Toluene, RT, 3–24 h

Yield 37–85%

Up to 37:1 dr

R1 R

1

CO2Et

R–X+

CO2Et

R

Scheme XI Roomtemperaturediasteroselectiveα-arylation of 4-substitutedcyclohexyl estersusing Pd(I) dimer(20)

References


doi:10.1595/147106711X579128 •Platinum Metals Rev., 2011, 55, (3) 212–214•

In the last decade gold has emerged as a kind of

“philosopher’s stone” in catalysis, being able to promote

a bewildering variety of transformations, including

cross-coupling reactions for the formation of carbon–

carbon bonds. These highly useful transformations

were developed in part by the 2010 Nobel Prize

awardees Richard Heck, Ei-ichi Negishi and Akira

Suzuki (1) and with contributions from many other

research groups. Recently, there has been some ques-

tion over whether gold can catalyse these reactions

which have been traditionally catalysed by palladium

complexes.

In 2007, Corma’s research group published a paper

with the suggestive title ‘Catalysis by Gold(I) and

Gold(III): A Parallelism between Homo- and Hetero-

geneous Catalysts for Copper-Free Sonogashira Cross-

Coupling Reactions’ (2). This work stressed the similar

behaviour of well-known homogeneous gold(I) com-

plexes such as AuCl(PPh3) with that of heterogeneous

gold on ceria (Au/CeO2) as catalysts for the Sonogashira

coupling reaction. In addition to AuCl(PPh3), a tri-

nuclear Au(I) complex was also claimed to be a cata-

lyst for this reaction (Scheme I) (2–6). These homo-

geneous gold(I) catalysts were also reported to

catalyse the Suzuki coupling of iodobenzenes with

arylboronic acids (5, 6).

Traces of PalladiumNevertheless, from a practical perspective, it is impor-

tant to note that all these reactions proceeded only

under much harsher conditions (130°C in o-xylene)

(2–6) than those required with palladium catalysts.

Moreover, only the most reactive iodobenzenes were

used as the coupling partners. Another group reported

that gold(I) iodide in the presence of mono- or diphos-

phines as ligands acted as a catalyst for the Sonoga-

shira coupling of iodo- and activated bromobenzenes

under similar conditions (130°C in toluene) (7).

A central argument behind the development of gold

catalysts for cross-coupling chemistry was that “Au(I),

having the same d10 confi guration as Pd(0) can cata-

lyse reactions typically catalysed by palladium” (2–6).

However, this is a rather simplistic argument, since

even elements within the same group often behave

very differently in catalysis.

The fi rst step in the catalytic cycle of haloarene cou-

pling reactions is the oxidative addition of aryl halides

(ArX) to the metal catalyst. Thus, for a gold-catalysed

reaction of ArX with a catalyst AuX(L) (L = ligand),

a square planar Au(III) complex AuArX2(L) would be

formed. There is no report for such oxidative addition.

In fact, our preliminary results are pointing towards

high activation barriers for these types of transforma-

tions and all our attempts to carry out the oxidative

addition of a variety of iodobenzenes to AuCl(PPh3)

and other Au(I) complexes in a variety of solvents

led to complete recovery of the staring materials (8).

This is in sharp contrast to the behaviour of PdL4 or

Pd2(dba)

3 L systems, which react readily with aryl

halides to give complexes PdArX(L)2. Furthermore,

we failed to observe any coupling reaction between

iodobenzene and phenylacetylene catalysed by gold

iodide and 1,2-(diphenylphosphino)ethane. Finally,

we examined a possible Sonogashira coupling

FINAL ANALYSIS

Is Gold a Catalyst in Cross-Coupling Reactions in the Absence of Palladium?

Homogeneous Au(I) catalyst

Scheme I. Can a homogeneous gold(I) complex catalyse the Sonogashira coupling reaction?



proceeding via a gold(I) acetylide (Scheme II), which

also met with failure.

It has been reported that as little as 50 ppb Pd

present in commercially available sodium carbonate

is able to catalyse the Suzuki coupling reaction (9).

Since high purity gold often contains traces of palla-

dium, we suspected that palladium was actually

responsible for the success of the Au(I)-catalysed

‘Pd-free Sonogashira reaction’. Indeed, low loadings

of palladium(0) were enough to carry out the couplings

in Schemes I and II (8). Therefore, we concluded that

it was very unlikely that gold(I) complexes alone

could act as homogeneous catalysts for cross-coupling

reactions of aryl halides and closely related organic

substrates (Csp2–X containing electrophiles) (8).

Gold NanoparticlesAll of the previous discussion here pertains to cou-

pling reactions catalysed under homogeneous condi-

tions. However, we should also consider the possibility

that the reaction proceeds via heterogeneous rather

than homogeneous catalysis. We have previously

shown that heterogeneous and homogeneous gold

catalysts activate small molecules such as alkynes

and alkenes by totally different mechanisms (10).

Accordingly, it is not entirely surprising to fi nd that

gold nanoparticles are effi cient catalysts for the Suzuki

coupling reaction (11). The reaction catalysed by

gold nanoparticles prepared from hydrogen tetra-

chloroaurate and 2-aminothiophenol proceeded sat-

isfactorily using chlorobenzenes as substrates, which

are less reactive than iodobenzene, under conditions

(80°C, 4 h) much milder that those required with Au/

CeO2 (150°C, 24 h) in o-xylene (2–6).

In addition to contamination by palladium, which

will depend on the particular source of gold used for

the preparation of the gold complexes, is there any

other way by which complexes like AuCl(PPh3) could

lead to species catalytically active in cross-coupling

reactions? This issue was addressed last year by

Lambert’s group, which demonstrated that gold

nanoparticles were formed as the active catalysts by

the slow decomposition of the AuCl(PPh3) complex

(12–14). Thus, in the reaction between iodobenzene

and phenylacetylene, long induction periods (145°C,

100 h) were required to detect the Sonogashira cou-

pling product in low yield.

Corma’s group has recently published results that

further confi rm the active role of gold nanoparticles

in cross-coupling reactions, along with theoretical

calculations that support the unlikeliness of a homo-

geneous Au(I)-catalysed Sonogashira coupling reac-

tion (15), in line with our own conclusions (8).

ConclusionsTaken together, all these results show that fundamen-

tal differences exist between heterogeneous and

homogeneous catalysts (10). In order to bridge the

gap between these two fi elds, a deeper understand-

ing of catalytic systems and their active species is

required.

Thus, while gold nanoparticles may play a role in

catalysing cross-coupling reactions, homogeneous

gold(I) complexes are unlikely to act as catalysts for

these reactions in the absence of palladium.

MADELEINE LIVENDAHL1, PABLO ESPINET2 ANDANTONIO M. ECHAVARREN1*

1Institute of Chemical Research of Catalonia (ICIQ),Av. Països Catalans 16, E-43007 Tarragona, Spain;

2IU CINQUIMA/Química Inorgánica, Facultad de Ciencias, Universidad de Valladolid, E-47071 Valladolid, Spain


References 1 ‘Scientifi c Background on the Nobel Prize in Chemistry

2010: Palladium-Catalyzed Cross Couplings in Organic Synthesis’, The Royal Swedish Academy of Sciences, Stockholm, Sweden, 6th October, 2010: http://nobelprize.org/nobel_prizes/chemistry/laureates/2010/sci. html (Accessed on 18th May 2011)

2 C. González-Arellano, A. Abad, A. Corma, H. García,M. Iglesias and F. Sánchez, Angew. Chem. Int. Ed., 2007, 46, (9), 1536

3 C. González-Arellano, A. Corma, M. Iglesias and F. Sánchez, Eur. J. Inorg. Chem., 2008, (7), 1107

4 A. Corma, C. González-Arellano, M. Iglesias, S. Pérez-Ferreras and F. Sánchez, Synlett, 2007, (11), 1771

Scheme II. A gold(I) acetylide complex does not catalyse Sonogashira coupling



5 C. González-Arellano, A. Corma, M. Iglesias and F. Sánchez, J. Catal., 2006, 238, (2), 497

6 A. Corma, E. Gutiérrez-Puebla, M. Iglesias, A. Monge,S. Pérez-Ferreras and F. Sánchez, Adv. Synth. Catal., 2006, 348, (14), 1899

7 P. Li, L. Wang, M. Wang and F. You, Eur. J. Org. Chem., 2008, (35), 5946

8 T. Lauterbach, M. Livendahl, A. Rosellón, P. Espinet and A. M. Echavarren, Org. Lett., 2010, 12, (13), 3006

9 R. K. Arvela, N. E. Leadbeater, M. S. Sangi, V. A. Williams, P. Granados and R. D. Singer, J. Org. Chem., 2005, 70, (1), 161

10 M. García-Mota, N. Cabello, F. Maseras, A. M. Echavarren, J. Pérez-Ramírez and N. López, ChemPhysChem, 2008,

9, (11), 1624

11 J. Han, Y. Liu and R. Guo, J. Am. Chem. Soc., 2009, 131, (6), 2060

12 G. Kyriakou, S. K. Beaumont, S. M. Humphrey,C. Antonetti and R. M. Lambert, ChemCatChem, 2010, 2, (11), 1444

13 V. K. Kanuru, G. Kyriakou, S. K. Beaumont, A. C. Papageorgiou, D. J. Watson and R. M. Lambert, J. Am. Chem. Soc., 2010, 132, (23), 8081

14 S. K. Beaumont, G. Kyriakou and R. M. Lambert, J. Am. Chem. Soc., 2010, 132, (35), 12246

15 A. Corma, R. Juárez, M. Boronat, F. Sánchez,M. Iglesias and H. García, Chem. Commun., 2010,47, (5), 1446

The Authors

Madeleine Livendahl was born in Stockholm, Sweden, in 1983. She obtained her Master of Science in Chemistry from Stockholm University. In 2009 she joined the research group of Professor Antonio M. Echavarren at the Institute of Chemical Research of Catalonia (ICIQ) in Tarragona, Spain, with a predoctoral ICIQ fellowship. Her research interests are the discovery of new transition metal-catalysed reactions.

Pablo Espinet, born in Borja (Zaragoza, Spain) is Professor of Inorganic Chemistry in the University of Valladolid, Spain. He is Director of the research institute CINQUIMA (Center for Innovation in Chemistry and Advanced Materials). His research covers the experimental study of reaction mechanisms of palladium-catalysed reactions and the synthesis of functional metal-containing molecules.

Antonio M. Echavarren, born in Bilbao (Basque Country, Spain) is Professor of Organic Chemistry and Group Leader in the Institute of Chemical Research of Catalonia (ICIQ) in Tarragona, Spain. His research interests centre on the development of new catalytic methods based on the organometallic chemistry of transition metals as well as the synthesis of natural products and polyarenes.

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Johnson Matthey Technology Review...Contents SPECIAL ISSUE 12 ‘PALLADIUM CATALYSED CROSS-COUPLING...

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