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REVIEW 817
Recent Developments in Palladium-Catalyzed Formation of Five- and Six-Membered Fused HeterocyclesPalladium-Catalyzed Formation of Fused HeterocyclesK. C. Majumdar,*a,b Srikanta Samanta,a Biswajit Sinhaa
a Department of Chemistry, University of Kalyani, Kalyani 741235, IndiaFax +91(33)25828282; E-mail: [email protected]
b Department of Chemical Sciences, Tezpur University, Napaam, Tezpur 784 028, IndiaReceived 23 December 2011
SYNTHESIS 2012, 44, 817–847xx.xx.2012Advanced online publication: 01.03.2012DOI: 10.1055/s-0031-1289734; Art ID: E117911SS© Georg Thieme Verlag Stuttgart · New York
Abstract: Palladium-mediated cyclization reactions have been rec-ognized as some of the simplest and useful tools for regio- as wellas stereoselective syntheses of carbo- and heterocyclic compounds.In the multi-step syntheses of natural products it is frequently usedas one of the most important steps. In this review article, we havesummarized the various ways of constructing five- and six-mem-bered heterocyclic rings by palladium-catalyzed intramolecular cy-clizations published between 2008 and 2010.
1 Introduction2 Synthesis of Heterocycles via Alkene Cyclizations2.1 Intramolecular Heck Cyclizations of Vinylic Halides2.2 Intramolecular Heck Cyclizations of Aryl Halides2.3 Intramolecular Heck Reactions of Aryl Triflates2.4 Intramolecular Hydroxylations of Alkenes2.5 Intramolecular Aminations of Alkenes2.6 Intramolecular Annulations of Alkenes via Double C–H
Activations2.7 Intermolecular Annulations of Alkenes3 Synthesis of Heterocycles via Alkyne Cyclizations 3.1 Intramolecular Cyclizations of Internal Alkynes3.2 Intramolecular Cyclizations of Terminal Alkynes3.3 Intermolecular Annulations of Alkynes4 Synthesis of Heterocycles via Allene Cyclizations5 Intramolecular Biaryl-Coupling Reactions 6.1 Biaryl Couplings via C–X Functionalizations6.2 Biaryl Couplings via Double C–H Activations6 Heterocycles via Carbonylative Cyclizations7 Synthesis of Heterocycles from Alkane Substrates8 Miscellaneous 9 Conclusion
Key words: palladium catalysis, fused heterocycles, C–H activa-tion, C–C coupling, regioselectivity, stereoselectivity
1 Introduction
A wide diversity of natural products possess heterocyclicscaffolds in their molecular architecture.1 A number ofsynthetic approaches to the heterocyclic ring structure areavailable in the literature, and most of these have beencompiled in comprehensive reviews devoted to this field.2
Five- and six-membered nitrogen and oxygen heterocy-cles are probably among the most common structural mo-tifs spread across a broad array of biologically active andmedicinally significant molecules.3 The increasing world-
wide demand for heterocyclic compounds, owing to theirpharmacological and biological activities, has promptedsynthetic organic chemists to engage themselves in stud-ies directed towards the development of simple, novel andmore effective synthetic strategies. In this context, transi-tion-metal-catalyzed cyclization reactions of acyclic pre-cursors are among the most important ways to constructcomplex heterocycles under mild reaction conditions.4
Palladium is one of the most commonly used transitionmetals as it enables a number of very different reactions,including reactions that form carbon–carbon, carbon–oxygen, carbon–nitrogen and carbon–sulfur bonds. Somepalladium catalysts can usually be used in only catalyticamounts. Palladium tolerates a wide range of functionalgroups and thus avoids protecting group chemistry.5
Moreover, most palladium-based methodologies proceedstereo- and regioselectively in excellent yields. These ad-vantages have led to significant growth in organopalladi-um chemistry over the last two decades, thus palladiumcatalysts are now known to be extremely active and reli-able reagents for the syntheses of heterocyclic com-pounds. The palladium-based methodologies have beendemonstrated as an efficient tool in the synthesis of highlyfunctionalized indole, furan, thiophene, benzoxazole andthiazole derivatives6–10 commonly employing palladi-um(II) acetate, palladium(II) chloride, bis(triphenylphos-phine)palladium(II) dichloride and tetrakis(triphenyl-phosphine)palladium(0), among others, as the catalyst.
Though a wealth of books11 and reviews12,13 covering par-ticular and limited aspects of organopalladium chemistryare available, there are still many reports on this topic thathave not been reviewed. Moreover, during the last twoyears it has been used in many multi-step natural productsyntheses. A further improvement, also of economical in-terest, is the development and use of multiple palladium-catalyzed transformations that are performed in a dominofashion.14 The main purpose of this review is to presentthe ongoing importance of palladium-catalyzed cycliza-tion reactions in the field of five- and six-membered het-erocycle syntheses. Procedures in which palladiumcatalysts are not used in the construction of the heterocy-clic ring are not included in this review. Moreover, as N-arylation reactions in the context of the synthesis of five-and six-membered fused heterocyles is a very large area,these are not included in this review article.
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2 Syntheses of Heterocycles via Alkene Cyclizations
2.1 Intramolecular Heck Cyclizations of Vinylic Halides
The synthesis of fused tetrahydropyridine derivatives 2can be readily achieved by palladium-catalyzed intramo-lecular Heck reactions of substituted cyclic derivatives ofN-allyl-N-aryl amines 1. The synthesis of cyclopropane-fused isoquinoline derivatives 3 can also be achieved fromN-aryl-N-methallyl amines 1 by palladium-catalyzedHeck reaction involving sequential 6-exo-trig and 3-exo-trig cyclizations with subsequent b-hydride elimination.The reaction of 1 with palladium(II) acetate (10 mol%),triphenylphosphine (0.25 equiv) and cesium carbonate(1.2 equiv) in N,N-dimethylformamide (6 mL) at 90–100 °C afforded the fused tetrahydropyridine derivatives2 in excellent yields by 6-exo-trig cyclization(Scheme 1).15
Scheme 1
When N-methallyl derivatives 1 were subjected to theHeck reaction under the same reaction conditions, howev-er, the cyclopropane-fused isoquinoline derivatives (3)were obtained in good yields.
Ray and co-workers16 also reported the synthesis of vari-ous pyran-fused heterocycles by the implementation ofpalladium-catalyzed intramolecular Heck reactions. This
N
N
Br
N
Br
NR1
XX
X
R1
X
Pd(OAc)2, Ph3P
Cs2CO3, DMF90–100 °C80–90%
Cs2CO3, DMF90–100 °C70–80%
1 2
13
X = Cl, Me
R1 = H, MeX = F, Cl
Pd(OAc)2, Ph3P
Krishna C. Majumdar re-ceived his B.Sc. (1966) andM.Sc. (1968) degrees fromthe University of Calcuttaand Ph.D. from the Univer-sity of Idaho (USA), com-pleted his doctoral thesis in1972 under the direction ofProfessor B. S. Thyagarajanand continued in the sameuniversity as a research as-sociate until mid-1974. Healso carried out postdoctoralwork at the University of
Alberta with Professor J. W.Lown until mid-1977. Afterreturning to India, he heldappointments with the Uni-versity of Kalyani, as lectur-er (1977), reader (1984),and professor (1995). Healso served at North EasternHill University as a visitingprofessor (1996). His re-search interests centeredaround synthetic organicchemistry with over 370publications. He is presently
a professor of eminence atTezpur University. His re-cent research interests in-clude the design andsynthesis of liquid crystals.He is a fellow of the WestBengal Academy of Scienceand Technology, and recipi-ent of the Chemical Re-search Society of IndiaMedal (2004) and IndianChemical Society Award(2006).
Srikanta Samanta wasborn in Haldia (Purba Me-dinipore), West Bengal. Hereceived his B.Sc. (2003)and M.Sc. (2005) from Cal-cutta University. He joinedthe research group of Pro-
fessor K. C. Majumdar atthe University of Kalyaniwith a CSIR (NET) fellow-ship in 2006. He mainlyworked on aza-Claisen rear-rangement, different transi-tion-metal-catalyzed and
molecular iodine mediatedsyntheses of heterocycleswith biological relevance.He has completed his thesiswork and was awarded hisPh.D. in 2011.
Biswajit Sinha was born inKrishnagar (Nadia), WestBengal. He received hisB.Sc. in 2004 and M.Sc. in2006 from the University ofKalyani. He then joined the
research group of Prof. K.C. Majumdar at the Univer-sity of Kalyani with a CSIR(NET) fellowship. He ismainly working on metal-mediated synthesis of het-
erocycles and molecular io-dine mediated synthesis ofpotentially bioactive hetero-cycles.
Biographical Sketches
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REVIEW Palladium-Catalyzed Formation of Fused Heterocycles 819
© Thieme Stuttgart · New York Synthesis 2012, 44, 817–847
was performed with O-allyl substrate 4 in the presence ofpalladium(II) acetate, triphenylphosphine, cesium car-bonate and tetrabutylammonium chloride (TBAC) in N,N-dimethylformamide at 80–85 °C and afforded pyran de-rivatives 5 (Scheme 2). In contrast, the O-methallyl com-pounds 6a–c, under the same reaction conditions,afforded tetracyclic pyrans 7a–c in 55–65% yields.
Scheme 2
2.2 Intramolecular Heck Cyclizations of Aryl Halides
The palladium-catalyzed intramolecular C–H insertion re-action of 2-bromobenzyl imidazolinones was reported inthe synthesis of aryl imidazoisoindolones17 and proceededin moderate to high yields. The reaction tolerated a varietyof aryl substitutions (Scheme 3).18 The nature as well asthe position of the substituents on the aromatic ring affect-ed the yield of the reaction. Electron-donating substituentsresulted in lower yields, perhaps owing to decompositionof the cyclized products during the workup and/or purifi-cation.
Scheme 3
Nishida and co-workers19 developed a new type of palla-dium-catalyzed cyclization step that proceeds via the se-lective isomerization of a double bond in the enaminoester structure followed by a formal 5-endo-trig cycliza-tion. This reaction is useful for synthesizing 2,3-cyclo-
alkane-fused indoles from N-cycloalkenyl-o-iodoanilinesin up to 71% yield (Scheme 4).
A palladium-catalyzed Heck reaction and dealkylationdomino process was used in the synthesis of a large vari-ety of 2-substituted indole derivatives in 40–70% yields(Scheme 5).20 The reaction of 2-iodoaniline and readilyavailable chalcones smoothly gave the o-iodo-N-allyl-imine 12 that then underwent the novel transformation un-der palladium catalysis [Pd(OAc)2 (5 mol%), Ph3P (10mol%), KOt-Bu (2 equiv), DMSO]. The results of thisstudy demonstrated an unprecedented reaction patterncompared to classical Heck reaction. This study, there-fore, provides useful information for new reaction designusing palladium catalysis.
Scheme 5
A library of indole-type structures was prepared throughthe multi-component reaction of 2-iodophenols or pyrim-idinols 18, alkyl isocyanides 19, aldehydes 20 and ally-lamine (21) that led to highly functionalized derivatives23. This sequence included a one-pot Ugi–Smiles cou-pling reaction followed by an intramolecular tandemHeck cyclization and isomerization21 (Scheme 6).22
To carry out the reactions in one pot, a significant amount(0.6–0.8 equiv) of palladium(0) is required to carry the re-action to completion because of the interaction of the re-sidual isocyanide with palladium in the catalytic cycle.After completion of the Ugi–Smiles coupling, addition of0.2–0.3 equivalent of trifluoroacetic acid at room temper-ature allows for the hydrolysis of the remaining isocya-nide. The Heck coupling reaction was then carried out onthe crude mixture using the same amount of palladium asin the two-pot procedure. The desired indoles 23 were ob-tained in 51–75% yields using this new one-pot, three-step procedure.
The Heck reaction of 24 was sluggish under palladium(0)catalysis and a 91% yield of dehydroisoindolinobenzaze-pinone 25 was obtained in the presence of palladium(II)acetate in N,N-dimethylformamide containing potassiumcarbonate (2 equiv) and tetrabutylammonium bromide (1equiv) at 110 °C for seven hours (Scheme 7).23 The tetra-cyclic product 25, upon catalytic hydrogenation, fur-nished the corresponding isoindolino-benzazepinone. Thecyclization of 24 was also carried out under acid-mediated
Br
O O
Pd(OAc)2, Ph3PCs2CO3
TBAC, DMF80–85 °C65–75%
X
Br OPd(OAc)2, Ph3P
Cs2CO3
TBAC, DMF80–85 °C55–65%
X
O
R R
6a R = H, X = CH2
6b R = H, X = O6c R = OMe, X = CH2
4 5
7a–c
Br N
N
O
Boc
R
Cs2CO3 (1.5 equiv)DMF, 80 °C
28–90%
N
HN O
R
8 9
R = F, Cl, Br, Me, OMe, -OCH2O-, NO2
K3PO4⋅H2O (20 mol%)MeOH, reflux, 30 minPd(PPh3)4 (20 mol%)
Scheme 4
10a n = 110b n = 210c n = 3
I
NH
CO2Me
n
NH
CO2Me
nPd(PPh3)4(10 mol%)
Ag3PO4 (1 equiv)DMSO, 100 °C
43–71%11a–c
N
I
Ph
R
Pd(OAc)2 (5 mol%)
Ph3P (10 mol%)KOt-Bu (2 equiv)
DMSO, 12–16 h
NH
R
N
PdIPh
R
L
NR
PhPdI
H
L
unfavored
β-H elimination
N
Ph
R
PhIPd
L
12
13
HPd(L)I+
Pd-L
KOt-BuPd-L
1415 16
40–70%
R = Ph, 4-MeC6H4, 4-MeOC6H4, 4-FC6H4, 4-ClC6H4 4-BrC6H4, 4-F3CC6H4, 4-O2NC6H4
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conditions, but the Heck reaction protocol was found to besuperior.23
Palladium catalysis has been utilized for domino Heck in-termolecular direct arylations to furnish a variety of dihy-drobenzofurans, indolines, and oxindoles (Scheme 8).24
The methodology is applicable over a wide variety of arylbromides 26 and heterocyclic coupling partners 27. Underoptimized reaction conditions, the Heck coupling prod-ucts 28 were obtained in 47–99% yields and in good regi-oselectivity. Kim and co-workers25 conducted palladium-mediated reductive Heck-type cyclizations to produce di-hydroindole derivatives starting with Baylis–Hillmanadducts having a 2-bromoaniline moiety at the primaryposition. The same starting materials were also used forthe synthesis of indole derivatives under slightly differentconditions via concomitant d-carbon elimination and de-carboxylation processes.26
Scheme 8
A palladium-catalyzed domino reaction that involved aC–H activation27 process was reported by Jia et al.28 intheir synthesis of diverse carbo- and heterocyclic skele-tons from aryl iodides 30. Five-membered palladacycles31 could be regioselectively trapped by Heck as well asSuzuki cross-coupling or cyanation to give migration ‘off’products 33 or migration ‘on’ products 32 in 60–95% and47–95% yields, respectively, by manipulating the reactionconditions (Scheme 9). Moreover, the conditions avoided
the use of expensive bases, which are usually employed inC–H activation reactions.
We have reported29 a variety of substituted isoquinolonederivatives 35a–g, obtained through the implementationof the intramolecular Heck reaction sequence underligand-free conditions in excellent yields from the corre-sponding Heck precursors 34a–g. The reaction proceededon the unactivated allylic system without the necessity ofusing any ligand (Scheme 10).
Scheme 10
Recently, we have also utilized palladium catalysis in thedevelopment of a mild and efficient route for the construc-tion of a new class of benz-annulated pyrido[2,3-d]pyrim-idines 37 as well as pyrimido[5,4-c]isoquinoline-2,4,6-(1H,3H,5H)-triones 39 in 81–91% and 90–96% yields, re-spectively. The palladium-catalyzed intramolecular aryla-tion of the pyrimidine C–H bond was carried out underligand-free conditions using palladium(II) acetate, potas-sium acetate and tetrabutylammonium bromide in N,N-dimethylformamide (Scheme 11).30
A new route to the asymmetric synthesis of ergotalkaloid31 (+)-lysergic acid methyl ester was reported byFukuyama and co-workers,32 who constructed the tetracy-clic ergoline skeleton by utilizing a palladium(0)-mediat-ed double-cyclization strategy consisting of anintramolecular aromatic amination33 and a Heck reaction
Scheme 6
R1CHO
R2NC
NH2
Y
Y
OH
X
I
Y
Y
N
I
R1
OR2HN
X
CF3COOH (0.2 equiv) then Pd(OAc)2
(10 mol%)
Y
Y
NR1
OR2HN
X
Ph3P (20 mol%)Et3N (1.6 equiv)toluene, 80 °C
51–75%
+NH4Cl
toluene–H2O
18
2223
R1 = Et, i-BuR2 = Bn, 4-ClC6H4CH2, Cy, MeOC6H4CH2
X = H, Cl, i-Pr, NO2
Y = N, CH
19
20
21
Scheme 7
N
MeO
MeO
O
IOMe
OMe
N
MeO
MeO
O
OMe
OMe
24 25
Pd(OAc)2, K2CO3 TBAB
110 °C, 7 h91%
YX
Br
+
(1.0 equiv) (4.0 equiv)
Pd(OAc)2 (5 mol%)X-Phos (5 mol%)
PivOH (30 mol%)K2CO3 (2.0 equiv)DMA, 110 °C, 16 h
XY
S
R1
26a–g27a–f
28
X = O, NTs, NPMBY = CH2, C=O
i-Pr
P(Cy)2
i-Pr
i-Pr X-Phos
heterocycle
heterocycle:
SR1
N
SR1 = Cl, n-Pri-Bu
S
47–99%
29
Scheme 9
XY
I
1. K4[Fe(CN)6]⋅3H2O (0.22 equiv) or olefin or R1B(OR2)2
DMF, 60 °C
XY
Nu
2. Pd(OAc)2 Na2CO3, TBAC
DMF–H2O (95:5)
XY
30
32
60–95% 33
47–95%
Nu
60 °C
XY
Pd
Nu
31X = CH2, O, NMsY = CH2, C(CO2Et)2, O, NBoc
R1N
O
I
N
O
R2
R1
Pd(OAc)2, KOAc
DMF, N2, TBAB, 80 °C
34a–g 35a–g70–95%
R1 = Ph, C6H4Cl, C10H7, 6-aminocoumarin, N-methyl-6-aminoquinolone
R2 = H, Me
R2
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REVIEW Palladium-Catalyzed Formation of Fused Heterocycles 821
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in one pot.34 The double-cyclization strategy was carriedout in the presence of palladium(II) acetate (3 mol%), ce-sium carbonate (1.5 equiv), triphenylphosphine, triethyl-amine in refluxing propionitrile (Scheme 12). Thetetracyclic product 41 was obtained in 70% yield as a mix-ture of diastereomers and with the transfer of a chiral cen-tre. After twelve more steps, the synthesis of the targetmolecule (+)-lysergic acid was achieved.
Scheme 12
2.3 Intramolecular Heck Cyclizations of Aryl Triflates
a-(3-Arylidene-2-oxindol-1-yl)carboxamides 43a–g weresynthesized in 52–77% yields via the intramolecular Heckreactions of aryl triflates 42a–g catalyzed by palladi-um(II) acetate–BINAP (3–5 mol%) in acetonitrile undermicrowave heating at 180 °C for 30–60 minutes. The aryltriflates 42 were themselves prepared by the Ugi four-component reaction of 2-aminophenols, trans-cinnamicacids, aromatic aldehydes and isocyanides in methanol(50 °C, 48 h) to give the linear a-[N-(2-hydroxyphenyl)-substituted amido]carboxamides followed by triflate pro-tection (Scheme 13).35
A catalytic sequence consisting of an asymmetric Heckreaction and iminium ion cyclizationwas developed36 togive the differentially protected carbazole derivative 46 ingood yield. Microwave heating was used to accelerate thecatalytic asymmetric Heck cyclization of dienyl aryl tri-flate 44. Even though the reaction temperature reached
170 °C under microwave heating, the dihydrocarbazole46 was obtained in 99% ee. The tricyclic carbazole 46 led,in a few reaction steps, to the final product (+)-min-fiensine (Scheme 14).
Scheme 14
2.4 Intramolecular Hydroxylations of Alkenes
Alonso et al.37 developed a new route for the synthesis of2-substituted perhydrofuro[2,3-b]furans38 based on theultrasound-promoted generation of the dianion of iso-pentenyl alcohol followed by palladium-catalyzed in-tramolecular acetalization under Wacker-type reactionconditions39 (PdCl2, CuCl2, H2O2). The methodology hasbeen applied both to ketones and aldehydes. Pang andChen40 reported the synthesis of 2-(2¢-hydroxyphe-nyl)benzoxazole derivatives using the palladium-mediat-ed oxidative cyclization of 2-hydroxyaniline and (2-hydroxyaryl)aldehydes.
Spiroketals such as 1,6-dioxaspiro[4.5]decane, 1,7-dioxa-spiro[5.5]undecane and 1,6-dioxaspiro[4.4]nonane occurwidely as substructures of natural products41 from manysources, including insects, microbes, plants, fungi andmarine organisms. Recently, spiro C-arylglycoribosidewas synthesized in 21 steps, starting from cis-2-butene-1,4-diol, including the palladium-catalyzed spirocycliza-tion of hemiketal 47 as the key step. The spirocyclizationwas carried out with bis(benzonitrile)dichloropalladi-um(II) [PdCl2(PhCN)2] in dilute tetrahydrofuran solution
Scheme 11
N
N
O
O
NR1
R1
R3
Br
R2
Pd(OAc)2 (10 mol%)
KOAc (2.5 equiv)TBAB (1.2 equiv), DMF
90 °C, 24 h81–91%
N
N
O
O
NR1
R1
R3
Br
R2
N
N
O
O
NR1
R2
R3
I
Pd(OAc)2 (10 mol%)KOAc (2.5 equiv)
TBAB (1.2 equiv), DMF140 °C, 24 h
90–96%
N
N
O
O
NR1
R2
R3
O O
36a–d 37a–d
38a–f 39a–f
N
BrNHBoc
H
HBr
CO2MeOTBDPS
HN
NBoc
H
H
CO2MeOTBDPS
H
Pd(OAc)2 (cat.)Ph3P, Cs2CO3
Et3N, EtCNreflux, 70%
4041
NH
NMeO2C
H Me
H
(+)-lysergic acid
12 steps
Scheme 13
N
OTf
O
O
HNR5
R1
R2
R3
R4
N
O
O
HNR5
R1
R2
R3
R4
H
Pd(OAc)2 (5 mol%)rac-BINAP (5 mol%) Et3N (4 equiv)
MeCN, MW180 °C, 30–60 min≤ 77% combined
E/Z = 91:9
42a–g 43a–g
R1 = R4 = H, MeR2 = H, Me, t-BuR3 = H, Cl, MeOR5 = Cy, Bn
N
CO2MeOTf
BocHN
Pd(OAc)2 (20 mol%), ligands 45, PMPtoluene, 100 °C, 70 h
orPd(OAc)2 (10 mol%), ligand 45b
PMP, toluene, MW, 170 °C30–45 min, 75–87%, 99% ee
N
BocHN
CO2Me44
46
N
O
PPh2
R45a R = i-Pr45b R = t-Bu
N
MeO2CN
OH
(+)-minfiensine
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(0.01 M) to give the 1,6-dioxaspiro[4.4]nonane skeletonin high yield but as a mixture of three enantiomers(Scheme 15).42
Scheme 15 Spirocyclization reaction conditions
2.5 Intramolecular Aminations of Alkenes
Wang and co-workers43 reported a facile and efficientsynthesis of substituted pyrroles 50 and 52 starting fromreadily available amino acids, using PdCl2(PhCN)2 as cat-alyst and copper(II) triflate as oxidant in ethanol at 30 °Cin 62–92% and 26–76% yields, respectively (Scheme 16).
This method is an aza-Wacker oxidative cyclization cata-lyzed by palladium(II) and copper(II). It was found thatPdCl2(PhCN)2 and bis(acetonitrile)dichloropalladium(II)[PdCl2(MeCN)2] exhibit a higher catalytic activity in thisreaction than do palladium(II) chloride and palladium(II)acetate.
Scheme 16
Recently, we reported44 the cyclization of 5-allyl-6-ami-nocoumarins and 5-allyl-6-aminoquinolones by palladi-um-catalyzed oxidative amination of alkenes to give anumber of 2-methylpyrrolocoumarin and 2-methylpyr-roloquinolone derivatives (54a–e) in excellent yields (85–97%). Although both sets of reaction conditions A and Bshown afforded the desired products, conditions B gavebetter results (Scheme 17). For example, the substrate 53a(X = NMe, R = Et) gave product 54a in 71% and 95%yields under conditions A and B, respectively.
A similar type of palladium-catalyzed amination ap-proach was developed by Yang and co-workers45 to fur-nish structurally versatile indoline derivatives with fusedtetracyclic rings in good yields. Excellent diastereoselec-tivities were achieved in the palladium-catalyzed oxida-tive cascade cyclization utilizing quinoline or isoquinoineas ligand to form the carbon–carbon and carbon–nitrogenbonds simultaneously in a single step (Scheme 18). Theyields and diastereomeric ratios of the products were af-fected by the choice of ligands. The yields of indolines 56,with R = H, X = H, F, OMe and n = 1, were quite satisfac-tory under the palladium(II) acetate and isoquinoline sys-tem as this lowered the yields of olefin-isomerizedproduct 57. The other precursors also gave correspondingfused-spiro products depending upon the ligand basicitiesand nature of substitution on the nitrogen.
PdCl2(PhCN)2 THF, r.t.
OO
O O
48
14
1
2
3
4
5
10
10
10
2
20
0.1
0.05
0.01
0.01
0.01
60
60
60
60
15
60
77
83
51
91
7.7:2.2:1
13.2:4.4:1
11.5:3.4:1
16.8:1.8:1
12.6:4.6:1
Entry Pd(II)(mol%)
Concn(mol/L)
Time(min)
Yield (%)
Ratio (1R,4R/1R,4S/1S,4R)
OTHPO
O O
HO
47hemiketal
91%
spiro-C-arylglycoriboside
OO
HO OH
HO
Scheme 17
XO
NHR
XO
NR
53a–e 54a–e
X = NMe, OR = H, Me, Et
NMe
O
NEt
54a, 71%
anhyd DMF100 °C, 10 h
conditions APd(OAc)2 (10 mol%)
Na2CO3 (3 equiv)
Na2CO3 (3 equiv)anhyd DMF
70 °C, 1.5 h, 85–97%
conditions BPd(OAc)2 (10 mol%)
IBX (1 equiv)
Scheme 18
NH
O
Pd(OAc)2 (10 mol%)ligand (40 mol%) N
O
Htoluene, O2 (1 atm)70 °C
N
O
H55
56 33–81% 57, when R = H
+X X
X
X = H, F, OMe
5–29%(quinoline as ligand)
(isoquinoline as ligand)
nn
n
R
RR
n = 0, 1 when R = Hn = 1, 2, 3 when R = Ph
BocHN
OHR PdCl2(PhCN)2 (10 mol%)
NR
Boc
BocHN
OHRPdCl2(PhCN)2 (10 mol%)
NR
Boc
R = H, Me, i-Pr, MeSCH2CH2, BocN(CH2)4, Bz, 4-HOC6H4
49 50
5152
Cu(OTf)2 (1 equiv)EtOH, 30 °C, 24 h
62–92%
Cu(OTf)2 (1 equiv)EtOH, 30 °C, 24 h
26–76%
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REVIEW Palladium-Catalyzed Formation of Fused Heterocycles 823
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Another example of a palladium-catalyzed amination re-action is the reductive N-heterocyclization of nitro-substi-tuted heteroaromatic46 compounds 58 having an alkeneadjacent to the nitro group. A library of pyrrolo-fusedaromatic and heteroaromatic compounds were prepared in32–94% yields by the use of bis(dibenzylideneacetone)palladium(0), 1,3-bis(diphenylphosphino)propane(dppp), carbon monoxide (6 atm) and 1,10-phenanthro-line as the catalytic system where carbon monoxide actsas a reducing agent and is itself converted into carbon di-oxide (Scheme 19).46c
Scheme 19
A palladium-catalyzed reductive N-heteroannulation ofenamines 60, derived from 2-nitroanilines, was reportedto give a mixture of 1,2-dihydroquinoxalines 61 and 3,4-dihydroquinoxalin-2-ones 62. The reactions were per-formed using bis(dibenzylideneacetone) palladium(0),1,3-bis(diphenylphosphino)propane and 1,10-phenan-throline in N,N-dimethylformamide under carbon monox-ide (6 atm) at 70 °C to give the products 62 in greaterratios (Scheme 20).47
Scheme 20
2.6 Intramolecular Annulations of Alkenes via Double C–H Activations
Arai and co-workers demonstrated a dicyanating [4+2]cycloaddition of dienyne derivatives that is triggered bycyanopalladation.48 This new protocol includes the forma-tion of four carbon–carbon bonds and gives highly func-tionalized cyclohexenes in only one operation. Treatment
of 63 under the optimized conditions [Pd(CN)2 (10 mol%)and TMSCN (2.5 equiv) in propionitrile under O2 (1 atm),at 80 °C], gave separable mixtures of the cis- and trans-fused cyclohexene derivatives 64 in 41–78% yield. Thereaction rate was influenced by the presence of a bulky R3
substituent (Scheme 21).
The palladium-catalyzed simultaneous double C–H bond-activitation procedure has been utilized for the synthesesof diperoxyoxindoles 68 starting from N-phenylacryl-amides 65, palladium(II) acetate (5 mol%) and tert-butylhydroperoxide (10 equiv) in acetic acid. The diperoxyox-indoles 68 were reduced with palladium-on-carbon togive a series of 3-hydroxyoxindole derivatives of biologi-cal importance (Scheme 22).49
Fagnou and Liegault50 also reported an arene–alkane cou-pling reaction between an azole ring and an unactivatedalkane by way of a palladium(II)-catalyzed double C–Hactivation strategy employing air as terminal oxidant.
Broggini and co-workers51 reported the cyclization ofN-allyl-N-carboethoxy-substituted aminothiophenes andfurans by intramolecular palladium(II)-catalyzed oxida-tive coupling reaction. The conditions required werebis(acetonitrile)dichloropalladium(II) [PdCl2(MeCN)2] ascatalyst, copper(II) chloride as co-catalyst and an environ-ment-friendly reoxidant such as molecular oxygen to pro-mote the catalytic cycle. The coupling reactions of thecorresponding furan analogues led to furo[2,3-b]pyrrolesin lower yields than thiophene substrates (Scheme 23).
Ph
NO2
Ar/het
Ar/het
NH
PhPd(dba)2, dppp
1,10-phenanthrolineCO (6 atm), DMF
120 °C≤ 94%
5859
NO2
HN
RNH
N
R
NH
HN
R
OPd(dba)2, dppp1,10-phenanthroline
CO, DMF70 °C
25–88%
+
60 61 62yields up to 88% up to 45%
R = 4-Me, 6-Me, 4-OMe, 4-Cl, 5-Cl, 4-COPh, 4-CO2Me, 4-NO2
Scheme 21
TsN
R3R2
R1 Pd(CN)2 (10 mol%)TMSCN (2.5 equiv)
EtCN O2, 80 °C41–78%
TsN
H
HCN
CN
R3
R1
R2
64a–h
TsNTsN
CN
H
H
H
X
Pd(CN)2 (10 mol%)TMSCN (2.5 equiv)
EtCN (0.1 M)O2, 80 °C13–65%
63i 64ia X = CN64ib X = H
63a–h
R1 = R3 = H, Me, Ph; R2 = H, Me
Scheme 22
HN
O
Pd(OAc)2 (5 mol%)t-BuOOH (10 equiv)
AcOH, 80 °C46–96%
HN
O
OOt-Bu
OOt-BuHN
O
OOt-Bu
OOt-Bu
Pd
X
HN
OOt-Bu
OOt-Bu
O t-BuO
OH
PdX2
HX
6566
67
68
RRR
R
R = 2-Me, 3-Me, 4-Me, 2-Br, 3-Br, 2-Cl, 5-Cl, 2-OMe, 4-OMe
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Scheme 23
A strategy involving palladium-catalyzed aromatic C–Hfunctionalization and intramolecular alkenylation pro-vides a convenient and direct synthetic approach, and thuseasy access, to 3-alkylideneoxindoles52 in up to 80%yields. In the presence of bis(acetonitrile)dichloropalladi-um(II) (5 mol%) and silver trifluoroacetate (2 equiv) inchlorobenzene at 100 °C for three hours, a wide variety ofN-cinnamoylanilines 71 gave 3-alkylideneoxindoles 72 inmoderate to good yields and diastereoselectivity. For N-aryl or N-alkyl anilides (R2 = Me, Ph) the reaction condi-tions were altered slightly and 10 mol% of the palladiumcatalyst was used at 110 °C for 12 hours (Scheme 24).53
Scheme 24
Neuville, Zhu and co-workers54 also reported a palladium-catalyzed oxidative carbo- and hetero-functionalization ofanilide derivatives 73 with concomitant direct C–Hfunctionalization55 and formation of one carbon–carbonand one carbon–nitrogen bond.56 With appropriately teth-ered nucleophiles at the a-position of acrylamides, it wasobserved that either carboacetoxylation or carboamina-tion can occur, leading to 3,3¢-disubstituted oxindoles 74or spiroxindoles 75 from the same starting precursors bychanging the catalyst and solvent (Scheme 25).54b
2.7 Intermolecular Annulations of Alkenes
The palladium-catalyzed annulations of 1,3-dienes 77with o-iodoaryl acetates 76 provides an efficient approach
to biologically interesting dihydrobenzofurans 78 in 40–98% yields in the presence of bis(dibenzylideneacetone)palladium(0) (5 mol%), 1,2-bis(diphenylphosphino)eth-ane (dppe; 5 mol%), silver carbonate (2 equiv) in a 4:1mixture of 1,4-dioxane and water at 100 °C. The annula-tion is supposed to proceed via oxidative addition, syn-ad-dition, intramolecular coordination, and hydrolysis of theacetyl group and reductive elimination of palladium(0)which regenerates the catalyst. The reaction tolerates avariety of terminal, cyclic and internal 1,3-dienes as wellas electron-rich and electron-deficient o-iodoaryl acetates(Scheme 26).57
A novel, convergent, and stereoselective technique for thesynthesis of trans-dihydrobenzofurans 81 from commer-cially available o-aminophenols 79 and arylpropenes 80was developed via diazotization and palladium-catalyzedoxyarylation in a one-pot process.58 Many biologically ac-tive, naturally occurring 8,5¢-neolignans and several syn-thetic derivatives possess this structural motif. Withelectron-donating (chloro) or electron-withdrawinggroups (carboxylic acids, esters) para to the hydroxygroup, acceptable yields (18–85%) of the correspondingoxyarylation products were obtained (Scheme 27). Thebest results were achieved with zinc carbonate and calci-um glycerophosphate as bases (85 and 77%), though zinccarbonate provided 81 with better trans-diastereoselectiv-ity.
Fullerene-tethered compounds are in demand because oftheir potential applications in materials science59 and bio-medical sciences.60 Wang and Zhu61 reported the palladi-um-catalyzed heteroannulation of [60]fullerene withvarious o-iodoaniline derivatives to give C60-fused indo-line derivatives. o-Iodoanilines with a substituent on thephenyl ring or on the nitrogen atom were well tolerated,and they all gave good yields of the desired C60-fusedindoline62 derivatives 85a–g, ranging from 30–42% (83–95% based on consumed C60). Wang and Zhu further
X
PdCl2(MeCN)2 (15 mol%)
CuCl2 (15 mol%)O2, DMF, 23–62%
R1
R2
N
CO2Et
X N
R1
R2
CO2Et69a–d 70a–d
R1 = H, Me, (CH=CH)2
R2 = H, (CH=CH)2
X = O, S
N O
R4
R3
R1PdCl2(MeCN)2 (5–10 mol%)
AgOCOCF3 (2 equiv)PhCl, 100–110 °C, 3–12 h N O
R4
R3
R1
71 7228–80%
E/Z ≤ 6.8:1E/Z ≤ 6.3:1 (R2 = H)
R1 = 4-Me, 4-F, 4-Cl, 4-OEt
R2
R2
R2 = H, Me, Ph R3 = Me, Ph R4 = H, Me
Scheme 25
N
NHTs
O
R2
R1
H
R1
N
NTs
O
R2
PdCl2 (0.1 equiv) PhI(OAc)2 (2.0 equiv)
MeCN, 80 °C
R3 R3
Pd(OAc)2 (0.1 equiv)PhI(OAc)2 (2.0 equiv)
AcOH, 100 °CR1
N
NHTs
O
R2
R3
OAc
737475
38–85% 37–58%
R1 = 4-Me, 4-OMe, 4-Cl, 4-CN, 6-Me
R2 = Me, Bn, SEM R3 = H, Ph, i-Pr
Scheme 26
I
OAc R4
R2
R3
R5 R6
+
Pd(dba)2 (5 mol%) dppe (5 mol%)
Ag2CO3 (2 equiv) 1,4-dioxane–H2O
100 °C, 24 h
O
R6
R5
R4R3
R2
R1 = OMe, CHO, COMe, OAc, NO2, COOMeR2
= R3 = H, Me, Ph R4 = R5 = R6 = H, Me
76 77 78
40–98%
R1
R1
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REVIEW Palladium-Catalyzed Formation of Fused Heterocycles 825
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improved63 the reaction conditions to avoid the use of o-iodoanilines as starting precursors, as these are expensiveas well as difficult to prepare. The C60 was treated withreadily available anilides 86a–i, using a palladium-cata-lyzed oxidative annulation approach, through carbon–car-bon coupling initiated by C–H bond activation and thencarbon–nitrogen coupling to furnish the cyclized products85 in 20–53% yields (Scheme 28).
Biologically important64 pyrazino[1,2-a]indole deriva-tives were prepared in moderate to good yields via the pal-ladium-catalyzed double allylic alkylation65 of indole-2-hydroxamates. The reaction was carried out by the treat-ment of substrates 87 with dicarbonate 88 in the presenceof tris(dibenzylideneacetone)dipalladium(0)–chloroformcomplex (5 mol%) and triisopropyl phosphite (30 mol%)as ligand in dichloroethane at room temperature(Scheme 29).66 Electron-donating, electron-withdrawing,and conjugating groups were all tolerated at various posi-tions.
Regioselective product formation was observed when 2-aminophenylmalonates 90 were treated with (Z)-1,4-diace-toxybut-2-ene (91) in the presence of tris(dibenzylidene-acetone)dipalladium(0)–chloroform complex (5 mol%),ligand (20 mol%) and potassium carbonate in tetrahydro-furan under reflux for two hours. The product 3-vinyltet-rahydroquinolines 92a,b were obtained in 86 and 92%yields when tosyl was used as protecting group and 2-vi-nyltetrahydroquinolines were obtained in 71 and 85%yields from the starting materials with Boc as protectinggroup (Scheme 30).67 This is due to the variation in the
Scheme 27
NH2
OH
NO+ X–
R3
R2
79 802) base (1 equiv) Pd2(dba)3 (10 mol%), r.t., 20 h
O
R3
N2+
OH
+ R2
Pd-catalyzedoxyarylation
alkene (80)
81
1) NOBF4 (1 equiv) MeCN, 0 °C, 30 min
+
18–85%
R1
R1
R1
R1 = 4-Cl, 5-NO2, 5-CO2H, 5-CO2Me
R2 = Me, OMe
R3 = H, Me82
X–
Scheme 28
R1
R2
I
HN
R3
+
N
R3
R1
R2
Pd(OAc)2 (20 mol%)DPPE (10 mol%)
DABCO⋅H2O (2 equiv)PhCl, 130 °C
84a–g
85a–gR1 = R2 = Me, CO2Me R3 = COMe, CO2Et
30–42%
H
N
H
+
N
Pd(OAc)2 (10 mol%)PTSA (1 equiv)
86a–i
85R1 = Me, OMe, Cl, COMe R2 = Me, Ph
R2
OR1
O R2
R1K2S2O8 (5 equiv)
1,2-Cl2C6H4–MeCN130 °C, 24 h
20–53%
83
83
Scheme 30
NH
CO2Me
CO2Me
R2 OAc
OAc
conditions A: Pd2(dba)3⋅CHCl3 (5 mol%), DPPP (20 mol%), K2CO3, THF, reflux, 2 h
R1
+
NR1
Ts
MeO2C CO2Me
NR1
Boc
MeO2C CO2Me90
9192a R1 = Me; 86%92b R1 = OMe; 92%
92c R1 = Me; 71%92d R1 = OMe; 85%
conditions Aconditions B
R2 = Boc R2 = Ts
conditions B: Pd2(dba)3⋅CHCl3 (5 mol%), BINAP (20 mol%), K2CO3, THF, reflux, 2 h
Scheme 29
NH
R1
R2
HN
O
Ot-Bu
+
OBoc
OBocPd2(dba)3⋅CHCl3
(5 mol%)
(Oi-Pr)3P (30 mol%)
DCE, r.t., 55–88%
N N
O
Ot-Bu
R2
R1
87 88
89
R1 = H, Me, F, Cl, OMe, Br, CO2EtR2 = H, Me
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electron-withdrawing capacity of the nitrogen substituentwhich controls the acidity of the N–H proton.
Ishar and co-workers68 developed an easy route to ben-zoindolizine derivatives 95 that involved the cycloaddi-tion of azadienes with a silyl enol ether69 followed by apalladium(0)-catalyzed Heck coupling reaction. The insitu generated azadienes 96 (X = H, Me, Cl) underwentcycloaddition reactions with ethyl 3-trimethylsiloxy-2-butenoate (94; 1:1.2 mole ratio) followed by intramolecu-lar Heck coupling reaction using a catalytic amount ofpalladium(II) acetate (5–10 mol%) in anhydrous tolueneat 90 o C in the presence of a slight excess of triethylamineas a base (Scheme 31).68
3 Synthesis of Heterocycles via Alkyne Cycliza-tions
Heterocyclization by way of alkyne–nucleophile annula-tion has proven to be a very useful method in modern syn-thetic organic chemistry. Firstly, the alkyne bond isactivated by a palladium species, and this then leads theattack of the nucleophilic centre to the triple-bonded car-bon. Both endo and exo cyclization products can be ob-tained, depending on the number of atoms between thetriple bond and the nucleophilic center (i.e., depending onthe stability of the newly formed ring).
3.1 Intramolecular Cyclizations of Internal Alkynes
One of the major research directions in the pharmaceuticaland fine chemicals industries is to adapt homogeneouscatalytic reactions to heterogeneous versions through im-mobilization of homogeneous catalysts on polymer or in-organic supports.70,71 Somorjai and co-workers72 reporteda heterogeneous palladium nanoparticle based catalystthat exhibited superior catalytic activity for p-bond reac-tions, as well as its application in a continuous flow reac-tor.73 This palladium-mediated cyclization methodology
was utilized for the synthesis of benzofuran derivatives74
in excellent yield at room temperature. The reaction con-ditions comprised simply the 40-atom palladium nanopar-ticles (Pd40)
75 supported on high-surface-area mesoporoussilica (SBA-15),76 along with toluene as solvent and(dichloroiodo)benzene as oxidant (Scheme 32).
A series of isatin derivatives were synthesized regiospe-cifically in 47–70% yields via the treatment of 1-(2¢-iodo-ethynyl)-2-nitrobenzenes 102 in the presence of dichloro-bis(triphenylphosphine)palladium(II) [PdCl2(PPh3)2; 5mol%] in acetone at ambient temperature or at 60 °C(Scheme 33).77 The reaction was carried out without anyadded oxidant. Both electron-withdrawing and electron-donating groups were tolerated on the aromatic ring. Ster-ically more hindered substrates adjacent to the iodoalkyneor the nitro group did not interfere with the reaction. How-ever, the cyclizations of the corresponding pyridine ana-logues failed.
Scheme 33
Cacchi et al.78 developed an efficient approach for thesynthesis of free N–H 2,3-disubstituted indoles79 106 ingood to excellent yields (50–96%) from arenediazoniumtetrafluoroborates 105 and 2-alkynyltrifluoroacetanilides104 using tetrakis(triphenylphosphine)palladium(0), tet-
Scheme 31
O
CHO
O
X
I
H2N
OEt
Me3SiO O
+ +
N
OX
HO
CO2EtPd(OAc)2, Et3N
toluene, 90 °C
93X = H, Me, Cl
O
O
X
I
96
N
84 94
95
aza-Diels–Alder O
O
X
I
97
N
EtO2C OSiMe3
base
– Me3SiOH
O
O
X
I
98
N
EtO2C
Pd(OAc)2
Et3N, tolueneO
O
X
99
N
EtO2C H
95
25–34%
94
Scheme 32
OH
Ph
OPh
Pd40 on SBA-15
100 101
PhICl2, toluene95%
NO2
R
I
Pd(PPh3)2Cl2 (5 mol%)
acetone, r.t. or 60 °C47–70%
R
NH
O
O
102 103
R = 3-Me, 4-Me, 6-Me, 4-OMe, 4-Cl, 4-NO2
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REVIEW Palladium-Catalyzed Formation of Fused Heterocycles 827
© Thieme Stuttgart · New York Synthesis 2012, 44, 817–847
rabutylammonium iodide (TBAI) and potassium carbon-ate in anhydrous acetonitrile at 60 °C. This methodtolerates a variety of useful functional groups, includingbromo and chloro substituents, nitro, cyano, keto, ester,and ether groups, on both the alkyne and the arenediazo-nium salt (Scheme 34).78
Scheme 34
The palladium-catalyzed halo–alkyne coupling80 method-ology has become a valuable tool for the synthesis of bio-logically active81 fluoroalkylindole derivatives. Recently,Wu, Gong and co-workers82 synthesized (2-trifluorometh-yl)indole derivatives 108a–n in up to 86% yield via in-tramolecular annulation of N-(o-iodoaryl)alkynylimines107. The best reaction conditions were established as be-ing bis(triphenylphosphine)palladium(II) dichloride (10mol%), water (1 equiv), and potassium phosphate (2equiv) in 1,2-dimethoxyethane at 60 °C under a nitrogenatmosphere (Scheme 35).
Scheme 35
A cationic palladium complex83 was used in the synthesisof substituted (3-hydroxymethyl)indoles 109. The methodinvolved Pd(bpy)(H2O)2(OTf)2 as catalyst, and was thefirst example of a tandem reaction initiated by the amino-palladation of an alkyne followed by addition of the car-bon–palladium bond to the carbonyl group in thequenching step. This regenerates the palladium(II) specieswithout the necessity of a redox system (Scheme 36).84
Scheme 36
Polysubstituted indolizinones were synthesized by Kimand Kim85 from readily available tertiary propargylic al-cohols in a one-pot procedure by employing a palladium-catalyzed domino cyclization reaction.14 In this protocol,aminopalladation and reductive elimination were success-fully coupled with 1,2-rearrangement. The methodologyis mild and has a broad functional-group tolerance. Thearylpalladium species, formed in situ by oxidative addi-tion of palladium(0) to R3I, activates the alkyne moiety,thereby inducing 5-endo-dig cyclization by the neighbor-ing pyridine group. The resulting indolizinium salts 113undergo reductive elimination to give 114.12a,d,86 Finally,1,2-migration87 occurs to furnish the desired indolizino-nes 111 (Scheme 37).
Gevorgyan and co-workers88 also used the coupling andcyclization of propargyl esters 115 with aryl iodides underJeffery’s two-phase protocol89 [Pd(PPh3)2Cl2 (5 mol%),Ph3P (40 mol%), TBAI (1 equiv), K2CO3 (2 equiv) inDMF]. The cyclized products, indolizines 116, were ob-tained in up to 96% yield (Scheme 38). This method iscomplementary to the previously developed approaches90
towards the syntheses of mono- and disubstituted N-fusedpyrroloheterocycles.
Scheme 38
An excellent temperature-dependent cyclization reactionwas observed during the stereoselective synthesis of (E)-and (Z)-3-(monosubstituted methylene)oxindoles 118 byway of a 5-exo-dig hydroarylation of N-arylpropiolamides117 with palladium(II) acetate and 1,1¢-bis(diphenylphos-phino)ferrocene (dppf) as the catalytic system(Scheme 39).91 The stereoselectivity of the products wasthermodynamically controlled, providing the (E)-oxin-
NHCOCF3
R1R2
ArN2BF4–+
Pd(PPh3)4 (5 mol%) TBAI (4 equiv)
K2CO3 (2 equiv) MeCN, 60 °C
50–96%
NH
R1
R2
Ar
R1 = F, Me, Ac, ClR2 = Ph, 4-MeC6H4, 4-MeOC6H4, 4-AcC6H4, 2-BrC6H4, n-C5H11
Ar = Ph, 4-FC6H4, 4-MeOC6H4, 4-AcC6H4, 4-O2NC6H4, 4-ClC6H4
104105
106
+
I
N
F3C
R2
R1Pd(PPh3)2Cl2 (10 mol%)
K3PO4 (2 equiv), H2O (1 equiv)DME, 60 °C
NH
R1
O
R2
CF3
107a–n
108a–n13–86%
R1 = H, 4-Me, 4-F, 4-OMe, 4-CF3
R2 = t-Bu, Ph, 2-thienyl, 2-naphthyl, 4-MeC6H4, 4-MeOC6H4
NHTs
R1
R2
CHO
R3+
Pd(bpy)(H2O)2(OTf)2 (2 mol%)
1,4-dioxane, 60 °C
NTs
R2
HO
R1
R3
10420
109R1 = H, 4-Me, 4-F, 4-Cl, 5-Cl
R2 = Ph, 4-MeC6H4, 4-BrC6H4, n-hexyl, MeOCH2
R3 = 4-NO2, 3-NO2, 5-Cl-4-NO2, 4-Ac, 4-CN
overnight, 49–93%
Scheme 37
N R2
R1 OH
N R2
R1 OH R3PdI
Pd(0)R3I
N
R2
PdR3
R1 OH
I
N
R2
R3
N
R2
R3
R1 OH
I
base
R1 O
Pd(PPh3)4 (5 mol%)
K2CO3 (2.5 equiv) R3I (1.5 equiv)MeCN, 90 °C
45–100%
R1 = Me, PhR2 = n-Bu, t-Bu, 3-thienyl, Ph, 4-MeC6H4
R3 = Ph, pyridinyl, thienyl, 4-NCC6H4, 4-ClC6H4
110 111
112 113 114
N
OR1
R2N
OR1ArI (1.5 equiv)
Pd(PPh3)2Cl2 (5 mol%)Ph3P (40 mol%)
TBAI (1 equiv)K2CO3 (2 equiv)
DMF, 120 °C, 1–6 h
Ar
R2
115
116
R1 = Ac, PivR2 = n-Bu, n-Hex, n-Oct, t-Bu, CH2CH2Ph, 4-Tol
Ar = Ph, 4-MeO2CC6H4, 4-MeC6H4, 4-MeOC6H4, 4-O2NC6H4
50–96%D
ownl
oade
d by
: Uni
vers
ity o
f Oxf
ord.
Cop
yrig
hted
mat
eria
l.
828 K. C. Majumdar et al. REVIEW
Synthesis 2012, 44, 817–847 © Thieme Stuttgart · New York
dole in 59–86% yields under conditions B (i.e., at highertemperature). The nature of the substituents showed nosignificant effect on the stereoselectivity. This methodol-ogy could be an attractive route to the conversion of Z-ole-fins into E-olefins in organic syntheses.
2H-Chromene derivatives, comprising a key structuralunit of a variety of biologically important92 and pharma-ceutically significant compounds, have been synthesizedfrom aryl propargyl ethers 119 in the presence of a cata-lytic amount of palladium(II) along with a stoichiometricamount of copper(II) bromide. It was postulated that theactivation of the alkyne would occur by coordination topalladium(II) followed by a rapid intramolecular nucleo-philic attack by the arene and subsequent halogen transferassisted by copper(II) bromide to furnish the corresponding3-bromo-2H-chromene derivatives 120a–i (Scheme 40).93
Scheme 40
The reaction did not proceed in the absence of either pal-ladium(II) acetate or copper(II) bromide, thereby illustrat-ing their significant roles in the reaction, and with lithiumbromide present, the reaction was clean and proceeded tocompletion in a shorter reaction time.
Pyrimidine and its derivatives are very important owingto their high biological activities.94,95 A number of pyrim-idine- and uracil-based molecules,96 active against cancerand AIDS viruses,97 have already been synthesized. Re-cently, we reported the synthesis of pyrano[3,2-b]pyrimi-
dine derivatives via an unusual, palladium-catalyzed[1,3]-aryloxy shift followed by a 6-endo-dig cyclizationand [1,3]-prototropic shift. The cyclization and isomeriza-tion reactions of 1,3-dimethyl-5-(1-aryloxybut-2-ynyl-oxy)uracils 121a–f were carried out in the presence ofpalladium(II) acetate and triethylamine in N,N-dimethyl-formamide under a nitrogen atmosphere to give the pyra-nopyrimidine derivatives 122a–f in up to quantitativeyields (Scheme 41).98
Larock’s research group99 reported the first solution-phase synthesis of combinatorial libraries of isoquinolinesusing palladium- and copper-catalyzed alkyne annula-tions as the key step. The presence of the isoquinolinescaffold in numerous biologically active compoundsserved a justification for the generation of such a library.99
The palladium-catalyzed cyclization of the iminoalkynesubstrates 127 in the presence of commercially availablearyl iodides furnished the targeted isoquinolines(Scheme 42).100
Ohno et al. reported that the palladium-catalyzed dominocyclizations of propargyl bromides 130, possessing twonucleophilic functional groups, with catalytic tet-rakis(triphenylphosphine)palladium(0) in the presence ofsodium hydride in methanol gave 2,7-diazabicyc-lo[4.3.0]non-5-enes 132 in good yields (Scheme 43).101
The regioselectivity of the reaction was entirely con-trolled by the relative reactivity of the amine functionalgroups, irrespective of the position of the nucleophiles.
Scheme 39
R1
N O
R2
R3
NO
R2
R1
HR3
NO
R2
R1
R3H
+
conditions A (80 °C)
117(Z)-118 (E)-118
20–88% 22–65%
conditions B (140 °C) 8–30% 59–86%
R1 = Me, OMe, F, CF3, Cl, Ac, n-C5H11
R2 = H, Me, Ac, BnR3 = Ph, 4-MeC6H4, 4-MeOC6H4, 4-AcC6H4, 4-F3CC6H4, 2-furyl
Pd(OAc)2 dppf, toluene
O
R
Pd(OAc)2 (5 mol%) LiBr (1 equiv)
CuBr2 (2.5 equiv)AcOH
63–75%
O
R
Br
119a–i 120a–i
R = Me, Et, OMe, Pr, C5H11
Scheme 41
N
N
O
O
O
Me
Me
OAr
N
N
O
O
O
Me
Me
OAr
121a–f 122a–f
Pd(OAc)2
N
N
O
O
O
Me
Me
OAr123
[Pd]
N
N
O
O
O
Me
Me
OAr
N
N
O
O
O
Me
Me
OAr
[Pd]6-endo-dig
[Pd]124 125
N
N
O
O
O
Me
Me
126
OAr
[1,3]-H+ shiftN
N
O
O
O
Me
Me
OAr
122
protonolysis
Pd(OAc)2 (10 mol%)
DMF, Et3N, N2
92–100%
Ar = Ph, 4-MeOC6H4, 4-MeC6H4, 2,6-Me2C6H3 4-t-BuC6H4, 1-naphthyl
Scheme 42
RR
Ph
NN
Ar
Ph ArI, 100 °C
Pd(PPh3)4 (cat.)K2CO3, DMF
RN
Ph
ArO100 °CArI, CO
127128129
Pd(PPh3)4 (cat.)Bu3N, DMF
26–71%11–87%
R = OMe, F, -OCH2O-
Ar = 4-FC6H5, 4-NCC6H5, 4-O2NC6H5, 4-F3CC6H5, 4-BnOC6H5
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Scheme 43
Lautens and co-workers reported102 a one-pot procedurecombining the copper-catalyzed Huisgen cycloadditionsof alkynes and azides (CuAAC)103 and palladium-cata-lyzed direct annulation by C–H bond activation104 for thesynthesis of structurally unique polycyclic frameworks134 in good to excellent yields (62–97%) from differentheterocycle-substituted aryliodoacetylenes 133. The moreeffective protocol for the combination of the [3+2] cy-cloaddition with palladium-catalyzed cyclization was toadd palladium(II) acetate, triphenylphosphine, base, andtetrabutylammonium bromide as a solid to the completedCuAAC reaction and allow the annulation to proceed. Theyields of the one-pot process were similar to those of thetwo step procedure (Scheme 44).
An efficient palladium-catalyzed intramolecular carbo-palladation and cyclization reaction towards the synthesisof tetracyclic N-fused heterocycles uses palladium(II)acetate (5 mol%), potassium carbonate (2 equiv) in N,N-dimethylacetamide or N,N-dimethylformamide as sol-vent. This transformation proceeds via the palladium-catalyzed coupling of aryl bromides with internal propar-gylic esters or ethers (137) followed by the 5-endo-dig cy-clization leading to polycyclic pyrroloheterocycles 138and 139 in moderate to excellent yields (Scheme 45).105
The palladium-catalyzed alkyne cyclization protocol hasbeen used for the synthesis of benzo[a]carbazole deriva-tives with a large variety of substitution patterns in goodto excellent yields staring from N,N-dimethyl-2-[2-(2-ethynylphenyl)ethynyl]anilines. The optimized reactionconditions include palladium(II) chloride (10 mol%) ascatalyst and copper(II) chloride (2 equiv) as hydrocycliza-tion agent in refluxing tetrahydrofuran for one hour. How-ever, under these optimized reaction conditions,cyclization of 140n (R1 = R2 = H, R3 = t-Bu) producedonly the monocyclization product 142n in 95% yield(Scheme 46).106 Compound 142n was then dissolved intetrahydrofuran and refluxed with palladium(II) chloride(10 mol%) and copper(II) chloride (2 equiv) for a pro-longed time of 72 hours to give benzo[a]carbazole 141nin 40% yield, with a significant amount (50%) of 142n re-maining unchanged in the reaction mixture.
Scheme 46
Br
NHR
RHNPd(PPh3)4 (5 mol%)
NaH, MeOH
N
R
Pd BrN
N
R
R131
13238–91%
NHR130
R = Ts, Ns
Scheme 44
Y
Z
XI
Y
Z
X
NN
NR2
I
b) Pd(OAc)2 (10 mol%) Ph3P (20 mol%) TBAB (1 equiv) K2CO3 (1 euiv) THF, 80 °C, 62–97%
Y
Z
X
NN
N
R2
133
135
134
a) CuI (5 mol%) TBTA (5 mol%) R2N3 (1.0 equiv)
CuI, R2N3
R1
TBTA, THF
Pd(OAc)2 Ph3P, TBAB
K2CO3, DMF, 140 °C or THF, 80 °C
R1
R1
R1 = F, Cl, CN, NO2, CO2Me
R2 = Bn, PMB, PNB, Hex, TMS, PMP
N NN Bn
N
3
TBTA (136)
X = C, O
Y = C, N
Z = C, S
Scheme 45
Pd(OAc)2 (5 mol%)K2CO3 (2 equiv)
DMA, 100–130 °C3–20 h, 58–91%
N
O
O
R1A
X
R1
Pd(OAc)2 (5 mol%)K2CO3 (2 equiv)
A
R1
Br
R3
TBAC (1 equiv)DMF, 120 °C
138a–m137a–m 139a–m
XR3
A = CH, N
26–83%R2
R3R2
R1 = c-Pr, n-Bu, n-Hex, Bn, CH2CH2PhR2 = Me, OMeR3 = Me, F, Cl, CN, OMeX = OC(O)
A = N
R1 = n-Bu, PhR2 = HR3 = F, Cl, CN, OMe, CO2MeX = O, OSi(i-Pr)2O
R3
R1
R2
NMe
Me
140a–n
N
ClR3
MeR1
R2
141a–n
R3 = n-Pr, i-Bu, t-Bu, Ph, 4-MeOC6H4, 2-MeC6H4, 4-ClC6H4, 4-BrC6H4, 4-F3CC6H4, 4-O2NC6H4
N
Me
Cl
t-Bu
142n (95%)
PdCl2 (10 mol%) CuCl2 (2 equiv)
THF, reflux, 1 h75–96%
R1 = H, MeR2 = H, Me, CO2Me
PdCl2 (10 mol%)CuCl2 (2 equiv)
THF, reflux, 72 h
40%
PdCl2 (10 mol%) CuCl2 (2 equiv)
THF, reflux, 1 h
95%
not for R3 = t-Bu
R1 = R2 = HR3 = t-Bu
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3.2 Intramolecular Cyclizations of Terminal Alkynes
The importance of benzofurans107 justifies the continuousefforts directed towards the development of new, selec-tive, and efficient syntheses of furan heterocycles. Gabrieleand co-workers108 developed an efficient route for thesynthesis of 2-methylene-2,3-dihydrobenzofuran-3-ols144 based on the palladium-catalyzed cycloisomerizationof 2-(1-hydroxyprop-2-ynyl)phenols 143 under basic con-ditions and obtained the desired products in yields up to98% (Scheme 47). An equimolar amount of morpholinewas needed in order to obtain the higher yields.
Saikawa and Nakata et al.109 used a palladium-catalyzedcyclization and methoxycarbonylation as the major step inthe synthesis of the highly biologically active naturalproduct lactonamycin model aglycon.110 The cyclizationprecursor 145 was synthesized from the trihalogenatedbenzene derivative via carbon elongations, an oxidativedemethylation, a cycloaddition reaction with the diene de-rived from homophthalic anhydride, and a dihydroxyla-tion. When ethynyltetraol 145 was treated in methanolwith a catalytic amount of palladium(II) chloride and 1,4-benzoquinone under atmospheric pressure of carbon mon-oxide (balloon) at room temperature, 146 was obtained in62% yield as a single stereoisomer (Scheme 48).109
The palladium(0) and copper iodide catalyzed Sonogashiracross-coupling of 2-aryl-3-iodo-4 (phenylamino)quino-lines 147 with terminal alkynes111 afforded a series of1,2,4-trisubstituted 1H-pyrrolo[3,2-c]quinolines 149 in asingle-step operation in yields of up to 75%. The reaction
was carried out with dichlorobis(triphenylphosphine)pal-ladium(II) and copper(I) iodide as catalysts and triethyl-amine as base in a mixed solvent of 1,4-dioxane andwater. Conversely, the 4-(N-allyl-N-phenylamino)-2-aryl-3-iodoquinoline derivatives 150 were found to undergodichlorobis(triphenylphosphine)palladium(II) and cop-per(I) iodide catalyzed112 intramolecular Heck reaction toyield the corresponding 1,3,4-trisubstituted 1H-pyrro-lo[3,2-c]quinolines 151 in good yields (Scheme 49).113
The biaryl coupling reaction with the N-phenyl moietywas not observed.
Benzoxazine derivatives were found to display widerange of biological activities such as anticancer,114a anti-hypertensive,114b antirheumatic,114c serotonin-3(5-HT3)receptor antagonist,114d neuroprotective antioxidant114e
and other114f,g activities. Chowdhury et al. developed anew, one-pot palladium-catalyzed reaction for the generalsynthesis of (E)-3-arylidene-3,4-dihydro-2H-1,4-benzox-azines at room temperature utilizing a catalytic systemcomprising palladium(II) acetate, triphenylphosphine, po-tassium carbonate and tetrabutylammonium bromide(Scheme 50).115 The reaction procedure tolerates variousfunctional groups, and the method is characterized byregio- and stereoselectivity, operational simplicity, mildreaction conditions, and short reaction times.
Scheme 47
OH
R3
R2R1 OH palladium catalyst
morpholine
MeOH, 40 °C, 2 hR3
R2
O
OHR1
143144
80–98%
PdX2 + 2KX
R1 = H, Me, Ph R2 = H, Cl, OMe R3 = H, OMe
Scheme 48
O
O
OH H
OH
OH
OH PdCl2 (cat.)1,4-benzoquinone
CO, MeOH, 62%
O
O
OH
OH
OH
O
MeO2C
E
145 146
O
O
OH
OH
O
O
O
OMeE
F
DCB
model aglycon
O
O
OH
OR
O
O
O
OMeE
F
DCB
lactonamycin
N
O
Me
A
O
OHR =
Scheme 49
N
NHPh
I
C6H4R1 N
NHPh
C6H4R1
R2
N C6H4R1
PhN
R2
R2
Pd(PPh3)2Cl2
CuI, Et3Ndioxane–H2O
80 °C, 4 h, 53–75%147
148149
N
PhN
I
C6H4R1
150N C6H4R1
PhN
151N C6H4R1
N
152
+
Pd(PPh3)2Cl2
CuI, Et3N, DMF
80 °C, 4 h, 74–81%not formed
R1 = H, 4-F, 4-Cl, 4-OMeR2 = CH(OH)Me, Ph, SiMe3
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Scheme 50
3.3 Intermolecular Annulations of Alkynes
The palladium-catalyzed reaction of propargylic carbon-ates 155a–e with 2-substituted cyclohexane-1,3-diones156a–d, reported by Yoshida et al.,116 produced tetrahy-drobenzofuranones 157 with a quaternary carbon stereo-center. The process yielded the tetrahydrobenzofuranonesin a highly diastereoselective manner (Scheme 51). Thismethodology may be useful for the synthesis of naturalproducts having similar tetrahydrobenzofuranone struc-tures.117
Jiao and co-workers118 disclosed a unique, direct approachfor constructing indoles from simple and readily availableanilines and alkynes by C–H activation.27 Just 10 mol%palladium(II) acetate as catalyst and molecular oxygen (1atm) as the oxidant were used in a mixture of N,N-di-methylacetamide as solvent and an acid in this catalyticcycle. The reaction conditions are mild and do not requirethe addition of a ligand or base. Applying this methodol-ogy, both N-unsubstituted and N-monoalkyl-substitutedanilines were successfully transformed into the corre-sponding indoles in 20–99% yields (Scheme 52).
Scheme 52
Palladium-catalyzed annulations119 of 1-alkynyl-phos-phine sulfides 165 with 2-iodoanilines 84 have been re-ported to take place in the presence of palladium(II)acetylacetonate (10 mol%) and potassium carbonate (2equiv) in DMSO at 90 °C in one hour to afford indole-based phosphines120 166 in moderate to excellent yields(Scheme 53).121 The choice of palladium source wasimportant: catalysts such as palladium(II) acetate, palladi-um(II) chloride and tris(dibenzylideneacetone)dipalladi-um(0) led to lower yields. The substituent adjacent to thethiophosphinyl group, in cooperation with a substituenton the nitrogen atom, creates a sterically congested envi-ronment around the phosphorus in 166.
Scheme 53
Products 166 can be easily reduced to the correspondingtrivalent phosphines. 1-Alkynylphosphine oxides werealso used instead of the 1-alkynylphosphine sulfides. In-terestingly, the use of 1-alkynylphosphine oxides as sub-strates expanded the scope of accessible 2-indolylphosphines in this reaction.
Palladium catalysts have also been used for the coupling–cyclization reactions between aryl halides carrying an ap-propriate functional group at the ortho position and termi-nal alkynes to afford 3-alkylideneisobenzofuran-1(3H)-ylidene derivatives122 in up to 82% yields. A variety of ter-minal alkynes were satisfactorily examined in this reac-tion.
A variety of substituted isoquinoline derivatives123 can besynthesized in moderate yield by palladium-catalyzed,microwave-assisted, multicomponent reactions startingfrom o-bromoarylaldehydes, terminal alkynes, and aque-ous ammonia. The reaction conditions included (0.01mol%) bis(triphenylphosphine)palladium(II) dichloride,copper(I) iodide (0.02 mol%), and aqueous ammonia (2.5M) in tetrahydrofuran at 130 °C (Scheme 54).124
Scheme 54
O
NH
TsArI, Pd(OAc)2 (5 mol%)
Ph3P (20 mol%)
K2CO3 (4 equiv), TBAB (10 mol%)
DMF, r.t., 38–78%
O
N
Ts
Ar
H
153 154a–j
Ar = Ph, 4-MeC6H4, 4-F3CC6H4, 1-naphthyl, 3-pyridinyl, 2-thienyl
Scheme 51
OCO2Me
R1
O
O
R2
+Pd2(dba)3⋅CHCl3 (5 mol%)
ligand (20 mol%)DMSO, 120 °C,
5–30 min, 43–83%
O
OR2
R1
155a–e 156a–d 157
R1 = 1- and 2-naphthyl, 3-furyl, C5H11, Ph
R2 = Me, Pr, Bn
NH2
R2 R3+
O2 (1 atm)Pd(OAc)2 (10 mol%)
DMA–PivOH 120 °C, 12 h, 20–99% N
R3
R2
H
NH2
+
TMS
TfO NH
NH
+ CO2MeMeO2C N
MeO2C CO2Me
158159
160
158a 161 162
163159a
164
similar conditions
similar conditions
46%
60%
R1 = F, Me, OH, OMe, i-PrR2 = R3 = CO2Me, CO2Et, CO2i-Pr
R1 R1
NH
R2 I
R1
R3
PPh2S
+
Pd(acac)2 (10 mol%)K2CO3 (2.0 equiv)
DMSO, 90 °C, 11 h35–91%
NPPh2
R3
R1
R2
S
84165
166
R1 = Me, Ph, t-Bu, n-C6H13, 4-AcC6H4, 4-MeO2CC6H4, 4-MeOC6H4, 2-thienyl R2 = Me, Et, Bn, i-PrR3 = H, Me, Cl, Br, Ph, t-Bu, Ph2P(O)
X
R1
Br
H
O
+
R2 Pd(PPh3)2Cl2 (0.01 mol%)CuI (0.02 mol%)
NH3 (2.5 M aq)THF, MW, 130 °C
32–64%
X
N
R2
R1167 168
X = CH, N
R1 = H, F, OMe
R2 = Ph, 2-MeOC6H4, 4-MeOC6H4, 4-MeO-2-MeC6H3, (EtO)2CH, 3-F3CC6H4, 3-FC6H4, C5H11, SiMe3, 4-MeC6H4
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Under microwave irradiation at the same temperature, thesame product yield was obtained but in half the time re-quired for conventional heating. The concentration of am-monia solution was found to be critical in the couplingreaction:125 both higher and lower concentrations of am-monia gave poor results.
Liang and co-workers126 reported a mild and efficientdomino approach for the synthesis of substituted quino-lines via palladium-catalyzed reaction of imidoyl chlo-rides 169 with 1,6-enynes 170 under Sonogashiracoupling conditions. This palladium-catalyzed reactionwas simple, and the reaction proceeded smoothly in mod-erate to good yields. The optimal conditions for this reac-tion were bis(triphenylphosphine)palladium(II)dichloride (5 mol%) and copper(I) iodide (2.5 mol%) inanhydrous triethylamine at 80 °C for seven days (Scheme55). Other catalysts [Pd2(dba)3, PdCl2, and Pd(PPh3)4] andother common bases (Et2NH, Cs2CO3, NaOAc, Na2CO3,and K3PO4) were found to be less effective in this reac-tion.
Liang, Li and co-workers127 developed a useful methodfor the synthesis of 6H-benzo[c]chromenes 176 by palla-dium-catalyzed annulation of 2-(2-iodophenoxy)-1-sub-stituted ethanones with arynes 161. This new route usedpalladium(II) acetate, triphenylphosphine and cesium fluo-ride in a mixed solvent system (acetonitrile and toluene),and allowed for the one-pot formation of two carbon–carbon bonds through an sp3-carbon functionalization(Scheme 56). In two cases [R1 = H, R2 = Ph, R3 = 4-Meand R1 = H, R2 = Ph, R3 = 2,4-(t-Bu)2], two regioisomerswere obtained in ratios of 1.2:1 and 1.1:1, respectively.Many substituents, either electron-donating or electron-withdrawing, on the 2-iodophenoxy moiety were uni-formly tolerated.
A multicomponent reaction was carried out by the treat-ment of pent-4-yn-1-ols 177, salicyl aldehydes 178, andamines 179 with [Pd(MeCN)4](BF4)2 (5 mol%) in aceto-nitrile at room temperature to form spiroacetals 180. Theproducts were obtained in 71– 90% yields as 1:1 diastereo-meric mixtures (1:1), which seems to be the main draw-back of this method. The crude mixture of 180a and its
diastereomer 180a was further treated with magnesiumperchlorate (5 equiv) and of perchloric acid (1.6 equiv) indichloromethane and acetonitrile (10:1).128 Under theseconditions, clean and complete conversion of one of thediastereomers into the other was observed, thus providinga single diastereomer. For the synthesis of oxygen-substi-tuted chroman spiroacetal using alkoxymethanes 181,only [Pd(MeCN)4](BF4)2 in acetonitrile at room tempera-ture led to the formation of the desired products in highyields and as single diastereoisomers (Scheme 57).129
Here, the relative configuration of the carbon atom carry-ing the alkoxy group is opposite that of the nitrogen ana-
Scheme 55
N
ClR2O
R3
+
N
O R3
R2
169170
174
Pd(PPh3)2Cl2
CuI, Et3N
80 °C, 62–90%
R1
R1
N R2
R1
O R3
N R2
R1
O R3
base
N
R3O
R2
H
R1
6π-electrocyclizationR1 = H, Me, OMe, Cl R2 = Ph, 4-MeC6H4, 4-ClC6H4
R3 = Ph, 4-MeC6H4, 4-ClC6H4, 4-MeOC6H4
171 172
173
Scheme 56
I
OR2
O
R1TfO
TMS
R3+
Pd(OAc)2 (10 mol%) Ph3P (20 mol%)
CsF (4 equiv) MeCN–toluene (1:1)
45 °C, 30 h
OR2
O
R1
R3
175 161 176
R1 = Me, Cl, NO2
R2 = Ph, 4-MeC6H4, 4-MeOC6H4, 4-FC6H4, 4-ClC6H4
R3 = Me, t-Bu
30–86%
Scheme 57
OH
R1
+
OH
H
O
R2
R3NH2
177 178
179
1) [Pd(MeCN)4](BF4)2 (5 mol%) MeCN, r.t.
2) Mg(ClO4)2 ( 5 equiv) HClO4 (1.6 equiv) CH2Cl2–MeCN, r.t.
OOR2
R1
NHR3180
OH
R1
+
OH
H
O
R2
HC(OR3)3
177 178
[Pd(MeCN)4](BF4)2
(5 mol%)
MeCN, r.t.
OOR2
R1
OR3180
71–90%
70–96%
OO
HN
MeO
R1 = R2 = HR3 = o-anisidine
180 diast-180a+
(1:1)
OO
HN180a
MeO
step 1
step 2
R1 = Me, Ph, c-C5H9, CyR2 = F, BrR3 = 4-MeC6H4, 2-MeOC6H4, 4-FC6H4, 4-BrC6H4, 4-t-BuC6H4
181
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logue and the single diastereomers were obtained directlyin one step, thereby negating the necessity for furtherisomerization (i.e., step 2).
Zhu and co-workers130 reported a palladium-catalyzedthree-component synthesis of unsymmetrically substitut-ed 3-(diarylmethylene)indolin-2-ones 184 in yields of upto 67% starting from aryl bromides, alkyl propiolamidesand aryl iodides. The reaction involved a sequence of N-arylation, carbopalladation, C–H activation, and carbon–carbon bond formation, and the oxindoles were producedas both E- and Z-isomers with up to 1:4 (E/Z) regioselec-tivity (Scheme 58).
Scheme 58
4 Synthesis of Heterocycles via Allene Cycliza-tions
Ma and co-workers131 developed a palladium(II)-cata-lyzed tandem double-cyclization reaction of 1,w-bisalle-nols 185 to form 2,5-dihydrofuran-fused bicyclicskeletons 186 in the presence of palladium(II) halide (5mol%). Two catalytic combinations were used to achievesatisfactory yields of the products. The substrates withX = NTs afforded good results in the presence of palladi-um(II) chloride at 25 °C (conditions A, Scheme 59). Onthe other hand, substrates with X = CH2, O, or SO2 gave57–81% yields in the presence of palladium(II) chlorideand sodium iodide (0.5 equiv) (conditions B, Scheme 59).With ‘unsymmetric’ substrates, the reaction was realizedby converting one of the hydroxy groups into acetate. Op-tically active bicyclic products 188 were easily preparedby a Novozym-435 catalyzed kinetic resolution and tan-dem double cyclization of the optically active substrates187.
Dixon and Li132 developed a mild, efficient, and diastere-oselective cyclization methodology for the synthesis of arange of stereo-defined arylated spirolactam compoundsby the treatment of pro-nucleophile-linked allenes 189with aryl and heteroaryl halides in the presence oftris(dibenzylideneacetone)dipalladium(0) (5 mol%), 1,2-bis(diphenylphosphino)ethane (10 mol%) and potassiumcarbonate (2.0 equiv) as shown in Scheme 60. As it is op-erationally simple and tolerates multiple points of diversi-ty, this reaction should be of use in complex naturalproduct synthesis, as well as compound library synthesis.
Broggini and co-workers133 developed an effective palla-dium-catalyzed protocol for the intramolecular carboami-nation or hydroamination reactions of indole allenamidesthat proceed differently, giving either a-styryl- or simplyvinylimidazo[1,5-a]indoles. Under the optimal conditions[ArI (1.5 equiv), Pd(PPh3)4 (5 mol%), K2CO3 (4.0 equiv)],the cyclization occurred to give a-styrylimidazo[1,5-a]in-dole derivatives 193 in 68–88% yields (Scheme 61, pathA). Despite well-established palladium-catalyzedcarbonylations134 and their application to allene deriva-tives,135 the rarity of this kind of carboamination reactionon allenes in carbonylative conditions prompted Kang andKim136 to carry out the domino heterocyclization of 191 inthe presence of carbon monoxide (Scheme 61, path B).
Under the same reaction conditions as used in path A,compound 191 (when R = 2-iodobenzyl) gave the penta-cyclic imidazolinone derivative 197, which can be as-cribed to intramolecular carbopalladation of the allenegroup to form the p-allylpalladium complex 196 followedby intramolecular amination by the indole nitrogen.
Imidazolidine derivatives show interesting biologicalactivities137 and are used successfully as organocata-lysts.138 Recently, Broggini and co-workers139 reportedthe synthesis of 2-vinylimidazolidin-4-ones from a-aminoacid derived a-amino allenamides via a palladium-cata-lyzed domino carbopalladation and 5-exo-allylic amina-tion process. Use of tetrakis(triphenylphosphine)palla-dium(0) (0.02 equiv), iodobenzene (1.2 equiv), and potas-sium carbonate (4 equiv) in N,N-dimethylformamide gave
R1
Br
+
Ph
R2HN O
(1) Pd(OAc)2 (5 mol%) Xantphos (3 mol%)
Cs2CO3 (3 equiv)1,4-dioxane , 100 °C
182183 (2) ArI, DMF, 110 °C
NO
ArPh
R1
R2184
R1 = NO2, CN, CHO, CO2Me, COPh
R2 = Me, Bn
Ar = 2-O2NC6H4, 4-MeOC6H4
up to 1:4 (E/Z) regioselectivity
N O
Ph
R2
R1
117
32–67%
ArI
Scheme 59
X
OY
R OH
R
conditions B
X
OR
H
R
185 186Y = HX = O, SO2, NTs, (CH2)2R, R = Et, Et; i-Pr, i-Pr; Et, n-Bu
Novozym-435
vinyl acetate
60 °C
OY
R OH
R
OR
H
R
41%, 99% ee
Cond. B
conditions A
76–80% 99% ee
nn
n
n = 1, 2
n = 1
X = CH2, Y = Ac187
188
or
conditions A: PdCl2 (5 mol%), DMF, 25 °Cconditions B: PdCl2 (5 mol%), NaI (0.5 equiv), DMF, 80 °C
51–81%
Scheme 60
R
N
O O
ArX+
Pd2(dba)3 (5 mol%)dppe (10 mol%)
K2CO3 (2.0 equiv)DMSO, 70 °C
50–86%dr 3:1 to 47:1
NO
R
HArO
189
(±)-190R = Me, Et, Pr, Bn, allyl
Ar = 4-MeOC6H4, 3,5-Me2C6H3, 4-MeO2CC6H4, 4-BrC6H4, 3-O2NC6H4, 2-iodothiophenyl, 2-bromopyridinyl
X = Br, I
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the products 199a–e and 200a–e in 2.5:1 to 5.5:1 diastereo-isomeric ratios through an exo-cyclization of the p-allylintermediate (Scheme 62). Under atmospheric pressure ofcarbon monoxide, the reaction gave the enoyl imidazolid-inones 201a–e as single diastereomers. Only the substratewith isopropyl substitution, 198b, afforded two products(201b and 202b) as a diastereomeric mixture in a 6:1 ra-tio. Carbopalladation and amination of 198f–h using tet-rakis(triphenylphosphine)palladium(0) as catalyst andpotassium carbonate as a base gave the expected tricyclicproducts 203f (51%), 203g,h and 203j,k in a 6.5:1 ratioand in 54–59% yields (Scheme 62).
Highly biologically active140 ergot alkaloids have beenprepared by the palladium-catalyzed domino cyclizationof amino allenes bearing a bromoindolyl group. With thisbis-cyclization as the key step, the total syntheses of (±)-
lysergic acid, (±)-lysergol, and (±)-isolysergol wereachieved. To study the domino cyclization, diastereomer-ically pure 204a and 204b (obtained by Mitsunobu reac-tion) were subjected to the reaction conditions [Pd(PPh3)4
(5 mol%), K2CO3 (3.0 equiv), DMF, 120 °C, 3.5 h]. Dom-ino cyclization of the major isomer 204a gave an 83:17 di-astereomeric mixture of 205a and 205b in 78% yield(Scheme 63).141 In contrast, the reaction of the minor iso-mer 204b favored the other diastereomer (205a/205b = 21:79), with an overall yield of 67%.
5 Intramolecular Biaryl-Coupling Reactions
5.1 Biaryl Couplings via C–X Functionalizations
Benzo[4,5]furo[3,2-c]pyridines are common structuralmotifs in medicinal chemistry and are often linked to im-portant biological activity.142A convenient approach forthe synthesis of benzo[4,5]furo[3,2-c]pyridines bearingseveral substituents on both rings involves the palladium-mediated biaryl-coupling reaction. The optimal condi-tions for this intramolecular coupling reaction to give theproducts in up to 95% yields are the following: palladi-um(II) acetate (5 mol%), 1,3-bis-(2,6-diisopropylphe-nyl)imidazolium chloride (IPr-HCl; 10 mol%) as ligand,and potassium carbonate (2 equiv) as base in 1,2-dimethoxyethane at 130 °C (Scheme 64).143
Scheme 61
NH
N
O
R
path APd(PPh3)4(5 mol%)
ArI, K2CO3MeCN, reflux
NH
O
N Me
ArPdI
191
192
NN
O
Me
Ar
path BPd(PPh3)4(5 mol%)
ArI, K2CO3CO (1 atm)MeCN, reflux
NH
O
N Me
PdI
194
NN
O
Me
193
O
ArAr
O
195
Pd(PPh3)4(5 mol%)
ArI, K2CO3MeCN, reflux
2 h, 68–88%
2 h, 80%
NH
O
NPd
I
196
NN
O
197
Ar = Ph, 4-MeOC6H4, 4-MeOCC6H4, 4-EtO2CC6H4, 4-O2NC6H4
28–45%
R = Me
R = 2-iodobenzyl
R = Me
Scheme 62
BocHN
N
O
MeR
NN
O
MeR
Boc Ph
NN
O
MeR
Boc Ph
Pd(PPh3)4(2 mol%)
PhI, K2CO3DMF
100 °C, 2 h
+
NN
O
Me
R
Boc O
Ph
N
N OMe
Boc
OPh
+
Pd(PPh3)4(2 mol%)
CO (1 atm)
PhI, K2CO3 DMF, 100 °C2 h
198
199a–e
200a–e 12–20%
201a–e
202b 7%
BocHN
N
O
R1
I
Pd(PPh3)4(2 mol%)
DMF100 °C, 2 h
N
N
O
Boc
R1N
N
O
Boc
R1
203f 51%203g 54%203h 59%
203j 8%203k 6%
198f–h
+
50–65%
R = Me, i-Pr, i-Bu, Bn, Ph
PhI, K2CO3
38–67%
R1 = Me, i-Pr, i-Bu
Scheme 63
NTs
H
H
NHNs
OTIPSBr
Pd(PPh3)4 (5 mol%)
K2CO3 (3.0 equiv)DMF, 120 °C, 3.5 h
78%NTs
NNsH
OTIPS
NTs
NNsH
OTIPS
+
205a 205b
NTs
H
NHNs
OTIPSBr H Pd(PPh3)4 (5 mol%)
K2CO3 (3.0 equiv)DMF, 120 °C, 3.5 h
67%
205a/205b = 83:17
205a/205b = 21:79
NTs
NH
R Me
lysergic acid (R = CO2H)
lysergol (R = CH2OH)
isolysergol
NTs
NH
MeHO
(±)-204a
(±)-204b
Scheme 64
N
O
Br R2
R1
Pd(OAc)2 (5 mol%) IPr-HCl (10 mol%)
K2CO3 (2 equiv)DME, 130 °Csealed tube
N
O
R2
R1
206a–i 207a–i5–95%
R1 = NO2, MeNHCO
R2 = F, Cl, OMe, NO2, CO2Et
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Ila and co-workers developed an efficient synthetic proto-col for the construction of two classes of heterocyclicframeworks – pyrazolo[3,4-b]indoles 209 and pyrazo-lo[1,5-a]benzimidazoles 210 – from a common heterocy-clic precursor, 208, employing palladium-catalyzedintramolecular carbon–carbon or carbon–nitrogen bondformation as the key step, respectively (Scheme 65).144
The 1,3-substituted 5-(2-bromoarylamino)pyrazoles re-acted under Jeffery’s conditions145 to give the carbon–car-bon-coupled products 209 in 52–97% yields. However,attempts to obtain pyrazolo[1,5-a]benzimidazole 210 in asynthetically useful yield was not successful: the productwas isolated in only 35% yield, along with the unreactedstarting material.
Imidazo[2,1-a]phthalazines were synthesized146 in onestep from the reaction of N-aminoimidazoles and 2-bro-mobenzaldehydes utilizing palladium(II) acetate, triphe-nylphosphine, copper(I) iodide, cesium carbonate in N,N-dimethylformamide at 140 °C. The imine formation andthe Heck arylation were found to occur simultaneously.Both electron-donating and electron-withdrawing groupswere equally tolerated.
Increasing interest in carbazole alkaloids can be attributedto the useful biological activities found in this class of nat-ural products.147 Carbazole derivatives were obtained bythe palladium-catalyzed dealkylative cyclization of N-(2-halophenyl)-2,6-diisopropylanilines 211a–f in the pres-ence of palladium(II) acetate (5 mol%), 1,3-bis(2,6-diiso-propylphenyl)imidazolinium chloride (SIPr·HCl; 10mol%) and sodium tert-butoxide (3 equiv) in toluene. Thereaction involves intramolecular carbon–carbon bond for-mation, coupled with the simultaneous cleavage of a car-bon–halogen and carbon–carbon bond. The reaction isproposed to proceed through the formation of a dearoma-tized intermediate which readily aromatizes via dealkyla-tion, if the alkyl carbocation is stable. In the case ofdiethyl-substituted aniline 211g, the carbazole derivative213g thus produced subsequently dimerized to the isolat-ed product 214g (Scheme 66).148
Scheme 66
Ethyl oxanilate 215 (R1 = R2 = H, R3 = Et) underwent anintramolecular direct arylation in the presence of palladi-um(II) acetate and 1,1¢-bis(diphenylphosphino)ferrocene,furnishing the 5,6-dihydrophenanthridine derivative 216.On the other hand, the corresponding phenyl oxanilates215 (R3 = Ph) were transformed into N-arylisoindolin-1-ones 217 under similar reaction conditions. This is due tothe fact that the ethyl oxanilates were quite stable underpalladium catalysis and thus gave direct arylation product.But the phenyl oxanilates decomposed upon exposure topotassium carbonate in N,N-dimethylacetamide at 120 °Cand were transformed into N-arylisoindolin-1-ones viapalladium(II) acetate catalyzed intramolecular decarbon-ylative coupling (Scheme 67).149
A palladium-catalyzed intramolecular direct arylationprotocol was utilized for the synthesis of 1-dearyllamel-larin D, which is a potent inhibitor of topoisomerase I.150
Intramolecular direct arylation of 218 in the presence oftetrakis(triphenylphosphine)palladium(0) (5 mol%) andpotassium carbonate in N,N-dimethylacetamide (DMA) at125 °C afforded 219 in 89% yield (Scheme 68).151 Final-ly, dehydrogenation followed by selective deprotectionafforded the desired 1-dearyllamellarin D in 66% yield.
Scheme 65
NH
N
N
R3
R1
R2
Br
NH
R2
NN
R1
R3
Pd(OAc)2 (10 mol%)
n-Bu4NBr (1 equiv)K2CO3 (2.5 equiv)
DMF, 140 °C2–23 h, 52–97%
208209
Pd(OAc)2 (6 mol%)
XPhos (12 mol%) NaOt-Bu (2.5 equiv)
PhMe, reflux 70 h, 35%
N
NH
N
210
Ph
R1 = arylR2 = F, i-Pr, MeOR3 = Me, MeO, aryl
R1 = R2 = HR3 = Ph
HN
X HN
R
HN
BrN
Pd(OAc)2 (5 mol%) SIPr⋅HCl (10 mol%)
Pd(OAc)2 (5 mol%) SIPr⋅HCl (10 mol%)
N
N
HH
211a–f212a–f
211g 213g214g
NaOt-Bu (3 equiv)toluene, 110 °C, 20 h
14–73%
isopropyl carbocation (stable)
ethyl carbocation (unstable)
R
X = Cl, Br
R = H, Me, OMe, CF3
NaOt-Bu (3 equiv)toluene, 110 °C, 24 h
60%
Scheme 67
NO
EtO
O
NO
O
O
Br
N
R2
O Pd(OAc)2 (10 mol%)
dppf (10 mol%)
K2CO3 (2 equiv) DMA, 120 °C
2 h, 71%
Pd(OAc)2 (10 mol%) dppf (10 mol%)
K2CO3 (2 equiv) DMA, 120 °C, 2 h
215 216
217R2
R1
R3
R1 = R2 = HR3 = Et
R1 = H, Me, Cl, OMe, NO2, PhR2 = H, MeR3 = Ph
R1
27–80%
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Scheme 68
The synthesis of piperidin-2-one derivatives152 has beenachieved efficiently via the palladium-catalyzed intramo-lecular Heck (aryl–aryl coupling) cyclization of amide de-rivatives 220a–f. We synthesized coumarin-annulatedpiperidinones 221a–f in yields of up to 91% by employingpalladium(II) acetate, potassium acetate, and tetrabutyl-ammonium bromide in N,N-dimethylformamide at120 °C for 10 hour (Scheme 69).152a The yields of theHeck cyclization products are lower for precursors with afree N–H group.
Recently, a new synthetic protocol was developed by ourgroup153 through the implementation of the palladium-cat-alyzed benzylic C–H activation followed by a tethered in-tramolecular arylation strategy to give linearly fused andunusually oxidized pyridocoumarin derivatives. When7-[(N-alkyl)(2-bromobenzyl)amino]-4-methylcoumarins
222 were subjected to a typical Heck-type reaction proto-col [Pd(OAc)2, KOAc, TBAB in DMF at 140 °C], in mostof the cases, the benzylic methylene was oxidized to a car-bonyl group in the expected biaryl coupling reaction prod-ucts. Only the substrates with methyl as the nitrogenprotecting group gave the usual products, 223, in 45 and50% yields. The unusual reaction is supposed to proceedby an initial coordination of the nitrogen lone pair to pal-ladium(0) followed by a metal insertion into the adjacentcarbon–hydrogen bond to form 225154 and a rapid equilib-rium with the iminium ion 226.155 The intermediates 227may be formed from 226 by reaction with potassium ace-tate present in the reaction medium. A second oxidationfollowed by hydrolysis may give the final oxidized prod-ucts 229. Alternatively, as shown in path b, an oxidationpathway may follow the normal intramolecular arylationto afford the products 229 (Scheme 70).
Recently, we also developed a new efficient syntheticroute to polycyclic sultones156 via ligand-free palladium-catalyzed intramolecular coupling reactions. When the in-tramolecular coupling reaction was carried out on sub-strate 230 using the concept of Jeffery’s two-phaseprotocol89 at 100 °C for one hour under a nitrogen atmo-sphere, the starting materials underwent total decomposi-tion. Therefore, the catalytic system was modified and, inthe end, gave 88 and 78% yields of the substituted aromat-
N
OMeO
O
Oi-PrMeO
Pd(PPh3)4 (5 mol%)
K2CO3, DMA125 °C, 20 h
89%
N
O
O
Oi-PrMeO
MeO
i-PrO
Br
i-PrO
218219
N
O
O
Oi-PrMeO
MeO
HO
1-dearyllamellarin D
Scheme 69
OO
N
I
R2
O
Pd(OAc)2 (10 mol%)KOAc (2.75 equiv)
TBAB (1.2 equiv) DMF, 120 °C, 10 h
OO
N
O
R2
220a–f 221a–f
R1 R1
R1 = H, MeR2 = H, Me, Et
59–91%
Scheme 70
OO N
Me223, 45–50%
found only when R1 = Me
OO N
Br
OO NR1
normal intramolecular
cyclization
224222
OO N
R1Pd
225
OO N
R1226
OO N
Br
R1
O
may follow suggested oxidation pathway as in path a
228
OO N
R1
O
second oxidation
normal intramolecularcyclization
229
R1Pd
H
Pd H–
OO N
R1227
KOAc
H
H
OAc
Pd(OAc)2 (10 mol%) KOAc (2.75 equiv)
TBAB (1.2 equiv) DMF, 140 °C when R1 = Et,
Pr, C5H11
R2R2
R2
R2
R2
R2R2
R2
R2 = H, OMe
path a
path b
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ic sultones 231 and 233, respectively, under the optimizedreaction conditions [Pd(PPh3)4, KOAc, TBAB, DMF,100 °C] as shown in Scheme 71.157
Palladium-catalyzed intramolecular arylation reactions158
occurred when helicenes 234a,b were treated with palla-dium(II) acetate (10 mol%) and tricyclohexylphosphinetetrafluoroborate (20 mol%) in N,N-dimethylacetamide at130 °C for 12 hours (Scheme 72).159 The bis-arylated he-licenes 235, containing phenyl groups fused with the new-ly formed pyran rings, were isolated in yields of up to95%. In the case of the substrate with a nitro substituent,an inseparable product mixture was obtained, despite thefact that intramolecular arylation of nitro-containing sub-strates was previously reported.160 The reaction condi-tions were changed slightly, to include palladium(II)acetate (10 mol%), tricyclohexylphosphine tetrafluorobo-rate (10 mol%) and pivalic acid (60 mol%), for the heli-cene with a naphthyl group (234c) to give the mono-arylated product 236 in 37% yield and the correspondingbis-arylated product was also found in 20% yield.
A useful synthetic protocol for the biaryl- and triaryl-cou-pling reactions under palladium catalysis in the absence ofany phosphine ligand was demonstrated by our group.161
When substrates 237 and 239 were subjected to palladi-um-catalyzed reactions, biaryl-coupling products 238 and
240 were obtained in 75–80% and 70% yields, respective-ly. Similarly, treatment of substrates 241 under the samereaction conditions, except at 120 °C instead of 100 °C,afforded the corresponding products 242 in 75 and 85%yields (Scheme 73).
Scheme 73
5.2 Biaryl Couplings via Double C–H Activa-tions
Glorius and co-workers162 developed a novel protocol forthe highly selective palladium-catalyzed intramoleculardirect arylation of benzoic acids by tandem decarboxyla-tion and double C–H activation.163 Substituted 2-phenoxy-benzoic acids 243a–n, with both electron-donating andelectron-withdrawing substituents, afforded the corre-sponding biaryl-coupling products 244a–n in good isolat-ed yields. Methyl, tert-butyl, fluoro, chloro and evenbromo groups were tolerated in this process. The reactionafforded excellent control over the competing proto-decarboxylation process (Scheme 74).
Scheme 71
O
SO
OBr
O
SO
O
OS O
O
BrO
S
BrO
O
OS O
O
OS
O
O
Pd(PPh3)4 (10 mol%) KOAc (2.5 equiv)
TBAB (1.2 equiv) DMF, 100 °C, 1 h
88%
similarconditions
1.5 h78%
233
231230
232
Scheme 72
O O
ClCl
Pd(OAc)2 (10 mol%) Cy3PHBF4 (20 mol%)
DMA, 130 °C, 12 hR1R1
R2R2
O O
OC7H15
1
3
234
236c 37%
O O
235
Cl234a R1 = H 234b R1 = NO2
benzyl-substituted
234c R2 = OC7H15 naphthyl-substituted
95%
OC7H15
Pd(OAc)2 (10 mol%) Cy3PHBF4 (20 mol%)
PivOH (60 mol%)DMA, 130 °C, 12 h
XO
R
Br
R
Br
XO
RR
237 238
Pd(OAc)2, KOAc
DMF, TBAB
OO
Br
Br
OOPd(OAc)2, KOAc
DMF, TBAB
239240 70%
O
Br
RO O
Br
R
Br
R O
O O
R
R R
241a R = H241b R = OMe
242a,b
Pd(OAc)2, KOAc
DMF, TBAB
100 °C, 75–80%
120 °C
100 °C, 70%
X = O, NH; R = H, OMe
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Scheme 74
A protocol using palladium(II)-catalyzed cyclization bydouble C–H bond activation147,164 was also employed inthe highly efficient synthesis of carbazole alkaloids fromN-phenylaniline derivatives 246. The reaction, using pal-ladium(II) acetate (30 mol%), copper(II) acetate (2.5equiv), and pivalic acid as solvent,165 provided 63% yieldof 247 along with 26% yield of recovered 246 and pro-ceeded faster (Scheme 75).166 Oxidation of 247 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) led quan-titatively to glycosinine. Similarly, other alkaloids –clausine, mukonidine and isomukonidine – were obtainedfrom 247.
Very recently, Huang and co-workers167 reported a varietyof functionalized N-alkyl carbazolones168 which were pre-pared via N-alkylation of 3-(arylamino)cyclohex-2-enones followed by an intramolecular palladium(II) ace-tate mediated oxidative coupling reaction under an oxy-gen atmosphere.
Intramolecular dehydrogenative direct arylation of 1,2,3-triazoles169 248 was carried out in the presence of palladi-um(II) acetate (5 mol%) and copper(II) acetate (1.0 equiv)in a mixed solvent system (toluene–pivalic acid) at 140 °Cunder ambient pressure of air for 20 hours (Scheme 76).170
The reaction was further applied to a modular synthesis ofhetero-annulated phenanthrenes through a reaction se-quence involving two distinct C–H bond arylations. Nota-bly, this multicatalytic approach to p-conjugatedheteroarenes tolerated a variety of valuable functionalgroups, such as (enolizable) ketones or esters, and the di-rect use of molecular oxygen171 was not necessary.
6 Heterocycles via Carbonylative Cyclization
Palladium-catalyzed domino processes that involve theinsertion of unsaturated molecules, such as carbon mon-oxide, alkynes, and alkenes, into a carbon–metal bond arean important step toward the formation of both carbon–carbon and carbon–heteroatom bonds in a single step.Carbon monoxide insertion into the aryl–palladium bondto form an acylpalladium complex is a ubiquitous processin organic synthesis.11a,c,172 Recently, Larock andWorlikar173 employed a palladium-catalyzed amino-carbonylation174 process for easy access to 2-substitutedisoindole-1,3-diones175 in 25–92% yields with a largevariation of substitution on nitrogen. 2-Bromobenzalde-hyde (167) underwent carbonylative cyclization with aro-matic and aliphatic primary amines 179 under carbonmonoxide pressure in the presence of a palladium catalystto give isoindolin-1-ones 250 in 30–86% isolated yields(Scheme 77).176
Scheme 77
A series of a-(o-bromoaryl)-substituted ketones 251 wereexposed to palladium-catalyzed carbonylation177 condi-tions, leading to the formation of the correspondingisocoumarins178,179 252 in good to excellent yields.Tris(dibenzylideneacetone)dipalladium(0) (3 mol%),DPEphos (6 mol%), cesium carbonate (3 equiv) and bal-loon pressure of carbon monoxide180 were sufficient toachieve high yields of the products, and both cyclic andacyclic ketones were efficient substrates for the reaction(Scheme 78).181 This methology was also utilized for ashort synthesis of natural product thunberginol A througha comparatively simpler route than the earlier publishedreports.182
Scheme 78
A wide variety of substituted quinazolin-4(3H)-ones 254were prepared in 63–91% yields by the palladium-cata-lyzed cyclocarbonylation of o-iodoanilines with imidoyl
O
COOH R2R1 Pd(tfa)2 (15 mol%)Ag2CO3
DMSO–1,4-dioxane150 °C, 14 h
O
R2R1
243a–n244a–n
39–85%
R2 = Me, OMe, F, Cl, Br, t-Bu, fused benzene
O
R2R1
H
+
245
244/245 ≤ 99:1R1 = H, F
Scheme 75
N
H
Pd(OAc)2 (30 mol%)Cu(OAc)2 (2.5 equiv)
PivOH, 90 °C3 h, 63–78%
N
H246
247
R2
R1 R1
R2
glycosinine (R1 = CHO, R2 = OMe)clausine L (R1 = CO2Me, R2 = OMe)mukonidine (R1 = CO2Me, R2 = OH)isomukonidine (R1 = CO2H, R2 = OMe)
Scheme 76
NN
N O
R1
R2
Pd(OAc)2 (5.0 mol%)Cu(OAc)2 (1.0 equiv)
PhMe–PivOH140 °C, 20 h, air
NN
N O
R1
R2248 24957–93%
R1 = Bu, C5H11, C6H13, C8H17 R2 = 4-F, 2,4-Me2, 2-Cl, C5H11
CHO
Br
+ H2NRPdCl2(PhCN)2 (2 mol%)
CO (10 atm), DMF, 100 °C24 h, 30–86%
N R
O167
179250
R = Ph, 2-MeC6H4, 2-MeOC6H4, 4-s-BuC6H4, 4-ClC6H4, 1-naphthyl, 3-pyridyl
BrO
R1
R2
R3 Pd2(dba)3 (3 mol%) DPEphos (6 mol%)
O
O
R2
R1
R3
251252
O
O OH
HO
HOthunberginol A
Cs2CO3 (3.0 equiv)
CO (balloon)PhMe, 110 °C, 69–98%
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REVIEW Palladium-Catalyzed Formation of Fused Heterocycles 839
© Thieme Stuttgart · New York Synthesis 2012, 44, 817–847
chlorides and carbon monoxide. When equimolaramounts of o-iodoanilines 84 and imidoyl chlorides 169were treated with palladium(II) acetate, triphenylphos-phine and triethylamine in tetrahydrofuran under carbonmonoxide (500 psi) at 140 °C, the correspondingquinazolinone derivatives 254 were formed(Scheme 79).183The reaction is believed to proceed via insitu formation of an amidine, followed by oxidative addi-tion, carbon monoxide insertion, and intramolecular cy-clization to give the substituted quinazolin-4(3H)-ones.
Scheme 79
Another approach to cyclocarbonylation was realized inthe palladium-catalyzed one-pot reaction of diethyl(2-io-dophenyl) malonates 255 and imidoyl chlorides 169 usingpalladium(II) acetate, tri(2,6-dimethoxyphenyl)phos-phine (TDMPP) and diisopropylethylamine in tetrahydro-furan under carbon monoxide (400 psi) at 120 °C for 48hours. The desired products, the highly substituted iso-quinolin-1(2H)-ones 256, were obtained in a single step in33–70% yields with variable substituents (Scheme 80).184
The Alper research group185 very recently reported thepalladium-catalyzed couplings of N,N¢-di(o-iodophe-nyl)carbodiimides 257a-d with different alkyl or arylamines under carbon monoxide (balloon) as a route toquinazolino[3,2-a]quinazolinones 258, forming five newbonds in a single step. The best suited reaction conditionsfor the regioselective formation of quinazolinone deriva-tives 258a–p in up to 89% yields were palladium(II) ace-tate (4 mol%), triphenylphosphine (8 mol%) andpotassium carbonate (3.0 equiv) in tetrahydrofuran undercarbon monoxide (500 psi). The reaction was not depen-dent on the electronic nature of the substituents of the aryl
moiety. The yield of the tetracyclic product decreased asthe bulkiness of the R3 group increased (Scheme 81).
Scheme 81
The same research group186 also developed a highly regi-oselective palladium-catalyzed carbonylation reactionstrategy for the synthesis of 3,4-dihydro-2H-1,3-benzothi-azin-2-one derivatives 260 from 2-substituted 2,3-dihy-dro-1,2-benzisothiazoles 259 using tetrakis(triphenyl-phosphine)palladium(0) (5 mol%) in anhydrous pyridineunder carbon monoxide (300 psi) at 80 °C (Scheme 82).The yield of the reaction was strongly dependent on thesubstituent attached to nitrogen and decreased as the sterichindrance of the R group increased.
Similarly, 2-aryl- and benzyl-amino-substituted 4H-1,3-benzothiazine derivatives were synthesized by Orain etal.,187 who used an unprecedented intramolecular palladi-um cyclization to form the sulfur–aryl bond.
7 Synthesis of Heterocycles from Alkane Sub-strates
N-(1¢-Alkoxy)cyclopropyl-2-haloanilines 264 were trans-formed into 3,4-dihydro-2(1H)-quinolinones 266 via pal-ladium-catalyzed cyclopropane ring expansion and C–Xbond functionalization reactions (Scheme 83).188 The re-action tolerated a variety of functional groups such as es-ter, nitro, nitrile, ether, and keto groups. Bromo- andiodoaniline derivatives gave better yields with a shorterreaction period than the corresponding chloroaniline de-rivatives.
I
NH2
N
R3Cl
R2
+Pd(OAc)2 /PPh3
N
N
R3
R2
N
HNI
R3
R2
O
84 169 253
254
Et3N, THFCO (500 psi)
63–91%R1 R1
R1
COR1 = H, Me, Cl, CN
R2 = i-Pr, n-Bu, Ph, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4
R3 = t-Bu, Ph, 4-MeC6H4, 4-ClC6H4, 2-furyl
Scheme 80
I
CO2Et
CO2Et
NR2
R3Cl
+
N
O
CO2Et
R3
R2Pd(OAc)2, TDMPP
i-Pr2NEt, THF
255a R1 = H255b R1 = 4,5-(MeO)2
169256
R2 = Ph, i-Pr, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4
R3 = Ph, t-Bu, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4
33–70%
CO (400 psi)120 °C, 48 h
R1R1
I
CN
N
I
R1
R2
R3NH2+
257a R1 = R2 = H257b R1 = R2 = Me257c R1 = R2 = Cl257d R1 = Me, R2 = H
Pd(OAc)2 (4 mol%)Ph3P (8 mol%)
K2CO3 (3.0 equiv)
CO (500 psi), THF120 °C, 15 h
N
N
N
R1
OR2
O
R3
179
258
38–89%
R3 = i-Pr, t-Bu, n-Hex, allyl, Ph, Cy, MeC6H4CH2
Scheme 82
NS
RPd(PPh3)4 (5 mol%)
CO (300 psi), pyridine80 °C
259a–g
N
S O
R
N
PdL2S
R N
PdL2S
R
ON
PdL2
S
R
O
orCO
260 56–95%
261 262 263
R = i-Pr, Bu, i-Bu, Cy, Bn, PMB, naphthylmethyl
Dow
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840 K. C. Majumdar et al. REVIEW
Synthesis 2012, 44, 817–847 © Thieme Stuttgart · New York
Scheme 83
When 1,1-dianilinocyclopropane 269 was treated undersimilar palladium-catalysis conditions, 5,6-dihydrobenz-imidazo[1,2-a]quinoline 270 was obtained in 37% yieldalong with 271 and 272 in 28% combined yield(Scheme 84).188 The reaction can easily be rationalized bythe cyclopropane ring expansion of 269 followed by pal-ladium-catalyzed intramolecular N-arylation.189 No directN-arylation product (i.e., 273) was isolated from the reac-tion mixture.
Rapid microwave-promoted palladium-catalyzed in-tramolecular enolate arylations of o-haloanilides werecarried out in the synthesis of medicinally relevant 3-alkoxy-3-aryloxindoles.190 The results highlighted the tol-erance of the arylation protocol towards heteroatom sub-stituents on the enolate. Only a single prior example191
existed. The convergent nature of the synthesis (startingfrom readily available 2-bromoanilines and mandelic acidderivatives), together with the potential for asymmetricvariants, makes this an attractive, convenient approach tothis important class of molecules (Scheme 85).192
Scheme 85
Similarly, Neuville, Zhu and Salcedo193 reported the syn-thesis of benzoxazolyl isoindolinones 277 via two sequen-tial intramolecular O- and C-arylation reactions (by C–Hactivation), using two different metal-catalyzed reactionsteps (Scheme 86). The salient feature of the work is thedifferentiation of two tethered aryl iodides for the con-struction of two different types of heterocycles. Bothbenzoxazole and isoindolinone are considered to be priv-ileged structures in medicinal chemistry.
Scheme 86
8 Miscellaneous
A palladium(II)-catalyzed intramolecular addition of aryl-boronic acids to ketones was developed for the synthesisof 2-hydroxydehydrobenzofurans and higher homo-logues.194 Compared to palladium(II) acetate, a cationicpalladium complex with 1,3-bis(diphenylphosphino)pro-pane as the ligand has higher catalytic activity and greaterefficiency for a broader scope of substrates. Highly opti-cally active cyclic tertiary alcohols (up to 96% ee) wereobtained with the chiral cationic palladium complex ascatalyst (Scheme 87).
Felpin and co-workers195 exploited the dual reactivity ofpalladium catalysts in one pot196 for the synthesis of C3-benzylated oxindoles by a sequential tandem Heck–reduction–cyclization (HRC) using aryl diazonium saltsas ‘super’ electrophiles. When methyl 2-(2-nitrophe-nyl)acrylates 281 and benzenediazonium tetrafluorobo-rates 105 were coupled under Heck reaction conditions,the arylated products 282 were obtained as an inseparablemixture of diastereomers. The reaction progress was indi-cated by the evolution of nitrogen gas (~30 min) and thereaction mixture was futher stirred under an atmosphereof hydrogen for 24 hours, leading to oxindole derivatives284 in good yields (Scheme 88).195a The electronic effects
X
NH
OR2
R1
Pd2(dba)3 (1.5 mol%)X-Phos (7.5 mol%)
K2CO3 (1.5 equiv) DMF, 95 °C
NH
O
R1
264 266 41–88%
X = Cl, Br, I
R1 = H, 4-F, 6-Me, 4-NC, 4-F3C, 4-MeO, 4-O2N, 4-MeO2C
R2 = Me, Et, i-Pr
PdXLn
NH
OR2
R1
267 N
Pd
OR2
Lnbase
HX base268
N OR2
R1
265 70–90%
H+
R1
Scheme 84
HN
Br
Br
NH
Pd2(dba)3 (3.0 mol%) X-Phos (15.0 mol%)
K2CO3 (2.0 equiv) DMF, 95 °C, 30 h
N N
269
270
N
Br
NH
NH
Br
N
271
272
+
+
37%
NH
N
Br
273
N
OBr
OR3R2
R1
R4 Pd(OAc)2 (10 mol%)HPCy3BF4 (10 mol%)
NaOt-Bu (3 equiv), tolueneMW, 100 °C, 10 min
R1
R4
NO
R3O
R2
R1 = 4-Me, 3-F, 3-CF3 R2 = Me, Bn, Cbz R3 = H, Me, Bn, THP R4 = 4-OMe, 2-Cl, 4-CF3
274a–o 275a–o56–86%
NH
R1
N
R2
O
IO
H
N
O
R2
R1O
N
1) CuI (5 mol%), thiophene- 2-carboxylic acid (5 mol%) K2CO3, DMSO, 120 °C
2) Pd(OAc)2 (10 mol%) XPhos (30 mol%) NaOt-Bu (1.5 equiv) DMSO, 90 °C, 23–87%
276 277I
Scheme 87
R2
O
B(OH)2
O
R1 nconditions A
conditions A: [Pd(dppp)(H2O)2](OTf)2 (5 mol%), K3PO4, H2O (2 equiv), 1,4-dioxane, 80 °C, 66–94%
O
HO R2
n
R1
conditions B
conditions B: [Pd(dppp)(H2O)2](OTf)2 (5 mol%), 1,4-dioxane, 80 °C, 53–99%
R1
n = 0, 1
278 279
n = 1, 2
R1 = Me, Cl, OMe, benzo-fusedR2 = Ph, 4-ClC6H4, 2-MeOC6H4, 4-MeOC6H4, 4-F3CC6H4
280O
R2
n
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ater
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REVIEW Palladium-Catalyzed Formation of Fused Heterocycles 841
© Thieme Stuttgart · New York Synthesis 2012, 44, 817–847
of the substituents on the diazonium salts had only a minorimpact on the tandem process. Indeed, diazonium saltshaving electron-withdrawing substituents reacted morerapidly with the corresponding acrylate in the Heck cross-coupling than did those with electron-donating substitu-ents.
Scheme 88
Tryptamine and tryptamine homologues197 were synthe-sized in a straightforward manner by the palladium-catalyzed coupling of o-iodoanilines with different alde-hydes.198 The reaction of 84 (when R = H) with 285(n = 1, PG = Boc) in the presence of palladium(II) acetate(5 mol%) and 1,4-diazabicyclo[2.2.2]octane (DABCO) inN,N-dimethylformamide at 85 °C for 12 hours, followedby the addition of palladium(II) acetate (5 mol%) and con-tinuation of the reaction for 12 more hours at the sametemperature, afforded the desired tryptamine in 56% yield(Scheme 89).199 The reaction worked well for o-iodo-aniline with both electron-donating and electron-with-drawing groups.
Kuriyama et al.200 reported the synthesis of 3-arylphtha-lides 289 via the arylation of methyl 2-formylbenzoates287 with organoboronic acids (Scheme 90). The reactionproceeded smoothly using allylpalladium(II) chloridedimer (1 mol%) as catalyst, imidazolinium chloride thio-ether 290 as ligand (1 mol%), and cesium fluoride (2equiv) as base in toluene at 80 °C for one hour. This pro-
tocol was tolerant of a diverse range of substrates, and ledto a variety of 3-substituted phthalides in good to excel-lent yields (52–99%).
Scheme 90
Xanthones were synthesized by way of a palladium-cata-lyzed annulation of dibromoarenes 291 and salicylalde-hydes 178 in moderate to good yields. The reaction wascarried out by stirring the dibromoarene (2 equiv) with thesalicylaldehyde (1 equiv) in N,N-dimethylformamide at130 °C in the presence of dichlorobis(triphenylphos-phine)palladium(II) (5 mol%) as catalyst and potassiumcarbonate (2 equiv) as base (Scheme 91).201 Both methyland methoxy groups were tolerated on the salicylalde-hyde, furnishing the desired xanthones in good yields(52–63%). However, when a strong electron-donatinggroup, such as diethylamino, was introduced, the yieldwas lower (38%). It also seems that the reaction was muchinfluenced by the electron density on the dibromoben-zene. For example, when two methoxy groups were at-tached to the aromatic ring, its reactions withsalicylaldehyde and its methyl-substituted analogue onlygave the desired xanthones in 36% and 33% yields, re-spectively.
Scheme 91
Phenanthridine derivatives were synthesized in yields ofup to 48% by the treatment of imidoyl phenyl selenides293 (as precursors) with tetrakis(triphenylphosphine)pal-ladium(0) in refluxing toluene in the presence of a base.The insertion of palladium into the carbon–seleniumbond, followed by cyclization onto a phenyl ring and sub-sequent aromatization by elimination of HPdSePh, led tofinal products 294 (Scheme 92).202
NO2
CO2Me
R1
R2
N2BF4 Pd(OAc)2(5 mol%)
charcoal, MeOH40 °C
61–87%
+
NO2
CO2Me
R1
R2
NH2
CO2Me
R1
R2
reduction'H2, Pd'
cyclization
R1
NH
O
R2
281 105
282
283
284
R1 = OMe, CO2Me, Ph
R2 = Me, OMe, CF3, i-Pr, CO2Me, NEt2, 4-MeOC6H4
Scheme 89
I
NH2
+ ONPG2
n
84 PG2 = Boc2 or Phth
Pd(OAc)2 (5 mol%)
DABCO (3 equiv)DMF, 85 °C
16–79%NH
NPG2
n
285 n = 1 or 2
286≤ 79% (PG = Boc)≤ 77% (PG2 = Phth)
R = Me, MeO, F, NO2
RR
OMe
O
CHO
+ (HO)2BR2
287a R1 = H287b R1 = 5,6-(MeO)2
288
N N
i-Pr
i-Pr PhS
Cl
ligand 290
290 (1 mol%)[Pd(allyl)Cl]2 (1 mol%)
CsF (2 equiv)toluene, 80 °C, 1 h
52–99%
O
O
R2289
R2 = 2-FC6H4, 3-ClC6H4, 4-MeOC6H4, 3-AcC6H4, 3-EtO2CC6H4, 4-PhC6H4
R1 R1
CHO
OH
Br
Br
R1 R2+
Pd(PPh3)2Cl2(5 mol%)
K2CO3 (2 equiv)DMF, 130 °C, 12 h
95% conversionO
O
R1 R2
178 291 292
R1 = H, Me, OMe, NEt2
R2 = H, Me, OMe
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842 K. C. Majumdar et al. REVIEW
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Scheme 92
9 Conclusion
This review has presented numerous useful methodolo-gies, published in the years 2008 through 2010, involvingpalladium-catalyzed cyclizations or annulations for thesynthesis of regular-size fused heterocycles. Most of thereactions proceed under relatively mild reaction condi-tions and tolerate a wide variety of functional groups togive different heterocycle-fused compounds that are ei-ther themselves biologically important, or can easily betransformed into natural product moieties via syntheticmanipulation. Most palladium-based methodologies pro-ceed stereo- and regioselectively in excellent yields. Asthis is still an emerging area, we hope this article will in-spire synthetic organic chemists to develop many newprotocols for the synthesis of application-oriented, new,and complex heterocyclic compounds.
Acknowledgement
We thank CSIR (New Delhi) and DST (New Delhi) for financial as-sistance. Two of us (S.S. and B.S.) are grateful to CSIR (New Delhi)for their research fellowships.
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N
SePhPh
R N
R
Pd(PPh3)4
Et3N, toluenereflux, 48 h, 22–48%
N
PdPh
R
Pd(PPh3)4
SePh
N
R
PdSePh
– HPdSePh
293
294
295 296
R = H, Me, OMe, t-Bu, Cl, NMe2, CF3
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