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Amine and us Named reactions Gabriel synthesis

Delepine synthesis

Ullmann-Goldberg reaction

Buchwald-Hartwig reaction

Leuckart-Wallach reaction

Eschweiler-Clarke reaction

Hofmann rearrangement

Curtius rearrangement

Lossen rearrangement

Schmidt rearrangement

Bamberger rearrangement

Overman rearrangement

Neber rearrangement

Mannich reaction

Strecker reaction

Chichibabin reaction

Bechamp reaction

Aza-Wittig reaction

Staudinger reaction

…..AND SO FORTH!!

ibotenic acid

nicotinic acid

cocaine

nicotine

quinine

nitrogen content

2.6wt% (1.8 kg/70 kg)

Annals of the ICRP Publication 1972, 23, 273 (Table 110).

“N” nucleophile + “C” electrophile – Traditional methodology

Direct C–H bond amination – An extremely attractive alternative

How does achieve this?

e.g. Gabriel amine synthesis

Pioneering work – Breslow (1983), cytochrome mimetic reaction of iminoiodinane

Breslow et al. JACS 1983, 105, 6728.

Mechanism of cytochrome P450 catalyzed oxidn: Chem. Rev. 2004, 104, 3947.

– Reaction requirement

» Hypervalent iodine(III) species (iodinane, TsN=IPh)

» Strong EWG on nitrogen

- Difficult to prepare

- Thermally unstable So what to do?

In situ preparation of iminoiodinane – Che (2000)

Che et al. OL 2000, 2, 2233.

Du Bois et al. ACIE 2001, 40, 598.

– Du Bois (2001)

stereospecific!» Substrate generality was

enlarged to many amide analogues.

Diastereoselective variant – Müller, Dodd, Dauban (2008)

Mueller, Dodd, Dauban et al. JACS 2008, 130, 343.

Davies et al. OL 2006, 8, 5013. Du Bois et al. JACS 2008, 130, 9220.

Enantioselective variant – Davies (2006), intramolecular

– Du Bois (2008), intermolecular

How to generates metal nitrenoid?

Catalytic cycle

» Concerted mechanism

» Similar to carbenoid

C–H insertion

Mechanistic insight: Du Bois et al. JACS 2007, 129, 562.

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The robust one – “No reaction was observed under a variety of reaction conditions;

azidoformate was remarkably stable in the presence of various

transition-metal complexes.” (Lebel, 2005)

– “The direct rhodium-catalyzed decomposition of azides is not an

effective method for generating rhodium nitrenes.” (Davies, 2006)

Lebel et al. JACS 2005, 127, 14198.

Davies et al. OL 2006, 8, 5013.

» EWG-bound azide does not have sufficient coordinating ability?

First successful example – Driver (2007), aryl sp2 C–H amination

Driver et al. JACS 2007, 129, 7500.

» Strong EWG ligand on Rh complex is the important feature.

» Deuterium-labeled

experiments suggest

stepwise mechanism.

Complementary solution – Driver (2008), vinyl sp2 C–H amination

Driver et al. ACIE 2008, 47, 5056.

» Both aryl and vinyl C–H amination was suggested to occur

through same stepwise pathway.

Actual mechanism?

Driver et al. JOC 2009, 74, 6442.

Key observation

» Rh catalyst is involved in the C–N bond-forming step.

» Differences between Rh arylnitrenoid and arylnitrene suggest that

arylnitrenes might not be the best models for Rh arylnitrenoids.

Driver et al. JOC 2009, 74, 6442.

Working hypothesis – Rh arylnitrenoid might be similar to an arylnitrenium ion.

Potential mechanisms

Adam et al. JACS 1994, 116, 3296.

Driver et al. JOC 2009, 74, 6442.

Kinetic isotope effect (KIE)

» C–H bond cleavage occurs after

product-determining step.

» Concerted insertion is not occurring.

Driver et al. JOC 2009, 74, 6442.

» Ar-fused product was favored when R = EDG,

but nonlinear correlation with σm value.

» C–N bond formation does not occur by SEAr.

Effect of electron density of aryl group - I. – on C–N bond formation: Hammett σm vs. product ratio

Driver et al. JOC 2009, 74, 6442.

» Hammett plot gave V-shaped correlation.

» R substituent assists in the extrusion of N2

from initial Rh-azide complex.

Effect of electron density of aryl group - II. – on Rh nitrenoid formation:

Hammett σ+ vs. product ratio

Driver et al. JOC 2009, 74, 6442.

Plausible mechanism – 4π-Electron-5-atom electrocyclization

1. Electronic donation by the biaryl

π-system to form the Rh nitrenoid.

2. The planar nature of quinoid 35

enables a 4π-electron-5-atom

electrocyclization to form C–N bond.

3. Upon formation of 8aH-carbazole 38,

1,5-H shift then provides carbazole.

Substrate dependent reactivity – EWG-nitrenoid likes carbenoid: concerted mechanism

– Arylnitrenoid likes arylnitrenium: stepwise mechanism

Driver et al. JOC 2009, 74, 6442.

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Can azide decomposes to form nitrene? – In current method, substrate should equip EWG on the azide.

– Decomposition catalyst is required redox activity (?)

Example of redox-driven azido decomposition, see: Zhang et al. Organometallics 2010, 29, 389.

Electron-neutral azide as N-atom source

» Current method

» This work

» Strong EWG or strong oxidant

is not requierd.

Screening of catalysts – Table 1.

» Only Rh2(II) complexes gave indoline.

Screening of additives – Table 1.

» Control experiment revealed

that oxidative decomposition

of the indoline occurred during

purification.

» In situ protection by Boc or Ac

improved yield.

» Aniline was formed when the

stronger acid byproducts were

produced.

para-Aryl and ortho-alkyl substituent – Table 2, 3.

» Both electron-rich or poor aryl azides

were suitable substrate.

» Most reactions proceeded in

a highly diastereoselective manner.

Reactivity trend

» Electron-rich aryl azides were more reactive..

» The increased reactivity could be due to either above reasons.

Again, isotope labeling study

– If concerted: insertion would produce only two products.

– If stepwise: β-stereocenter could scramble to racemize,

four product would be formed.

» In support of stepwise mechanism, two diastereomers and

two isotopomers were observed.

» H-abstraction: KIE = 12 to 14

» H-shift: KIE = approx. 2

Possible mechanism

1. Coordination of Rh to azide, then

extrusion of N2 form nitrenoid 8.

2. H-shift or H-abstraction to form

9 or 10 followed by reconbination

produces the C–N bond.

3. Finally, indoline is produced upon

dissociation of Rh complex.

– Efficient and diastereoselective aliphatic C–H amination

that uses an aryl azide as the N-atom source.

» Strong EWG on the N-atom is not required.

» Reaction occurred stepwise with the syn-C–H bond

investigated by using D-leveled azide.

» “Hydroxylation reactions catalyzed by P450s are NOT

always stereospecific.”

Chem. Rev. 2004, 104, 3947.

Driver et al. JOC 2009, 74, 6442.

Unusual reactivity of methoxy azidoacrylates

EAS = SEAr

Driver et al. JOC 2009, 74, 6442.

Requirement for a contiguous array of π-orbitals

>95% recovery

» “The lack of reactivity of 40 agrees with our proposed

electrocyclization mechanism and is inconsistent with an

electrophilic aromatic substitution mechanism, which would

not require a contiguous π-system.”

Temperature dependence of kH/kD

» Isokinetic temperature was

approx. 43 deg C.

Exceptional behavior of strained azide

» The spatial constraints of this reaction override these isotope effects.