1-22

REVIEW 1

Palladium- and Copper-Catalyzed Aryl Halide Amination, Etherification and Thioetherification Reactions in the Synthesis of Aromatic HeterocyclesPalladium- and Copper-Catalyzed Heterocycle SynthesisJessie E. R. Sadig, Michael C. Willis*Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UKFax +44(1865)285002; E-mail: [email protected] 4 August 2010; revised 13 August 2010

SYNTHESIS 2011, No. 1, pp 0001–0022xx.xx.2010Advanced online publication: 12.10.2010DOI: 10.1055/s-0030-1258294; Art ID: E27810SS© Georg Thieme Verlag Stuttgart · New York

Abstract: This article reviews the use of palladium- and copper-catalyzed aryl halide amination, etherification and thioetherifica-tion processes in the synthesis of heteroaromatic molecules. The re-view is structured by the nature of the key C–X bond being formed,and then by heterocycle type. Where applicable individual hetero-cycles are further divided into syntheses based on intermolecular,intramolecular and cascade processes. In order to limit the length ofthe article, processes that do not deliver an aromatic heterocyclefrom the key C–X bond-forming event are excluded. Processes forthe functionalization of intact heteroaromatics are also not included.

1 Introduction2 Carbon–Nitrogen Bond Formation 2.1 Indoles2.2 Carbazoles2.3 Benzimidazoles and Benzimidazolones2.4 Indazoles and Indazolones2.5 Pyrroles2.6 Pyrazoles2.7 Oxazoles2.8 Quinolones2.9 Quinazolines, Quinazolinones and Quinazolinediones2.10 Phenazines2.11 Cinnolines3 Carbon–Oxygen Bond Formation3.1 Benzofurans3.2 Benzoxazoles3.3 Isocoumarins4 Carbon–Sulfur Bond Formation4.1 Benzothiophenes4.2 Benzothiazoles4.3 Oxathioles5 Conclusion

Key words: palladium catalysis, copper catalysis, aromatic hetero-cycles, amination, etherification

1 Introduction

Given the numerous applications of aromatic heterocyclesin medicine, agriculture and materials, it is not surprisingthat a whole host of methods have been developed fortheir preparation. Prominent amongst these are routesbased on transition metal catalyzed transformations.1–8 In-deed, many transition metal catalyzed processes havebeen developed with the explicit goal of delivering newsynthetic routes to heteroaromatics. This forging of new

routes, allowing the introduction of new classes of startingmaterials, or access to alternative substitution patterns, isone of the key advantages offered by transition metal ca-talysis. The last fifteen years has seen the development ofefficient and user-friendly methods, based on both palla-dium and copper catalysis, for the formation of carbon–nitrogen, carbon–oxygen and carbon–sulfur bonds usingaryl halide substrates. Collectively, these processespresent almost ideal tools for aromatic heterocycle syn-thesis, as witnessed by the rapidly increasing number ofapplications that have been published during this time.For example, reference to the first edition of Li andGribble’s excellent treatise on the use of palladium catal-ysis in heterocyclic chemistry,1 published in 2000, showsonly a handful of examples of palladium-catalyzed arylamination reactions being employed in the synthesis of ar-omatic heterocycles. This is certainly not the case today.

Migita described the palladium-catalyzed coupling ofaminostannanes with aryl halides as early as 1983;9 how-ever, it was not until the report of tin-free catalytic amina-tion reactions, by Buchwald10 and Hartwig,11 that thesynthetic potential of these processes began to be realized.Copper-based aryl halide amination (and amidation)chemistry has an even longer history, dating back to theoriginal reports by Ullmann12 and Goldberg,13 but again,it was not until the development of mild catalytic variantsof these reactions that the majority of applications beganto be developed. In recent years both processes have un-dergone enormous development and now encompass amyriad of different nitrogen nucleophiles and aryl halide(and equivalent) coupling partners. Advances to carbon–oxygen and carbon–sulfur bond-forming variants havealso been achieved. It is beyond the scope of this reviewto examine the development and mechanistic details ofthese underpinning catalytic methods, but extensive re-views of both the palladium14–17 and copper18–23 chemis-tries exist. The following discussion is divided by the keycatalytic bond construction – carbon–nitrogen, carbon–oxygen or carbon–sulfur – and then by heterocycle type.Where appropriate, individual heterocycles are then sub-divided into intermolecular, intramolecular or cascadeprocesses. The review is focused on the formation of aro-matic heterocyles, and accordingly we have not includedreports of the functionalization of intact heterocycliccores, nor processes that lead to non-aromatic systems.

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2 J. E. R. Sadig, M. C. Willis REVIEW

Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York

2 Carbon–Nitrogen Bond Formation

2.1 Indoles

A number of new indole syntheses based on aryl halideamination have been developed; however, one of the firstheterocycle syntheses to be reported using palladium-catalyzed amination chemistry was concerned with inter-cepting reaction intermediates from a very well estab-lished route to indoles.24 In 1998 Buchwald demonstratedthat a variety of aryl halides could be combined with ben-zophenone hydrazone using intermolecular palladium-catalyzed amination reactions to generate the correspond-ing N-arylhydrazones (1, Scheme 1).25 A palladium(II)acetate/XantPhos (2) catalyst system, in combination withsodium tert-butoxide, was found to be optimal. The N-arylhydrazones could either be isolated or, after simplefiltration through a silica plug, treated directly with anenolizable ketone under acid hydrolysis conditions. Theensuing Fischer cyclization provided the correspondingindoles in good to excellent yields. Variations to access ei-ther N-alkyl- or N-arylindoles were also developed, al-though in these cases functionalization of the isolated N-arylhydrazones was necessary.

A limitation of the benzophenone hydrazone methodolo-gy is the difficulty in removing benzophenone from thefinal indole products, particularly in large-scaleapplications. Cho and Lim reported a related procedure, inwhich N-Boc arylhydrazines were employed in Fischercyclizations.26 The required N-Boc arylhydrazines wereprepared using palladium-catalyzed amination chemistry,but in these cases were isolated before indole formation.

The use of intramolecular carbon–nitrogen bond forma-tion onto an aryl halide has proved to be a popular methodto achieve indole synthesis. In one of the first routes based

on this approach, Watanabe et al. demonstrated that N,N-dimethylhydrazones derived from o-chloroarylacetalde-hydes (4) underwent cyclization under the action of palla-dium catalysis to provide the corresponding N-amino-indoles (Scheme 2).27 Tri(tert-butyl)phosphine and theferrocene derivative 5 were found to be the optimalligands. The authors went on to demonstrate that if an ap-propriately functionalized substrate was employed, then asecond palladium-catalyzed transformation could beachieved in the reactions. For example, dichloride 6 could

Jessie Sadig received herMChem degree from theUniversity of Oxford in July2008, where she carried outher final year project under

the supervision of Dr. Jere-my Robertson. She thenjoined the Willis group andis currently working to-wards her DPhil degree. Her

research focuses on palladi-um- and copper-catalyzedcascade processes for het-erocycle synthesis.

Michael Willis received hisundergraduate education atImperial College London,and his PhD from the Uni-versity of Cambridge work-ing with Prof. Steven V.Ley, FRS. After a postdoc-toral stay with Prof. DavidA. Evans at Harvard Uni-versity, as a NATO/Royal

Society Research Fellow, hewas appointed to a lecture-ship at the University ofBath in November 1997. InJanuary 2007 he moved tothe University of Oxford,where he is a UniversityLecturer and Fellow ofLincoln College. He wasawarded an EPSRC Ad-

vanced Research Fellow-ship in 2005 and the 2008AstraZeneca ResearchAward for Organic Chemis-try. His group’s research in-terests are based on thedevelopment and applica-tion of new catalytic pro-cesses for organic synthesis.

Biographical Sketches

Scheme 1

Ph Ph

NNH2

+

NH

Me

Pent

79%

i) Pd(OAc)2 (0.1 mol%)XantPhos (0.11 mol%)

NaOt-Bu, toluene, 80 °C

Br

Me

Me

O

Pent

Me

HN

N

Ph

Ph Me

NH

65%

MeO

MeO

NH

Ph

NH

Ph

Me

Pent

70% 70%

O

PPh2 PPh2

Me Me

PPh2

PPh2

XantPhos (2) (rac)-BINAP (3)

1

(BINAP used as ligand)

ii) TsOHreflux

H2O, EtOH.

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REVIEW Palladium- and Copper-Catalyzed Heterocycle Synthesis 3


be reacted under the standard conditions but with the ad-dition of phenyl boronic acid, to provide 4-phenylindole7, resulting from tandem carbon–carbon and carbon–nitrogen bond formation. In addition to aryl boronic acidsbeing introduced by Suzuki couplings, a range of azolesand amines could also be effectively incorporated via asecond carbon–nitrogen bond-forming process.

Scheme 2

Doye and co-workers demonstrated that N-alkyl iminescorresponding to hydrazones 4 can also be effectively cy-clized under the action of palladium catalysis to provideN-alkylindoles.28 In their approach, the imine substrateswere prepared from the corresponding alkynes using atitanium-catalyzed hydroamination process. In this one-pot protocol, the imines were then subjected to palladiumcatalysis to deliver the indole products. Scheme 3 showsan example in which alkyne 8 was converted in a one-potprocess into indole 9. N-Heterocyclic carbene (NHC)ligand 10 was most effective. Substrates containing a teth-ered amine nucleophile could also be included, leading tothe formation of N–C2 annulated indoles.

Scheme 3

Isolated dehydrohalophenylalinate derivatives have beenconverted into indoles using related cyclizations. For ex-ample, Brown was the first to report the cyclization ofenamines such as 11 (Scheme 4) into the correspondingindole-2-carboxylates. In this report from 2000, a simpledppf-derived catalyst was employed in combination with

potassium acetate as base.29 Kondo and co-workers subse-quently showed that polymer-supported substrates corre-sponding to 11 can also be cyclized effectively.30

Scheme 4

Lautens and co-workers established gem-dihalovinyl-anilines as versatile substrates for indole synthesis basedon a series of tandem metal-catalyzed processes. The sub-strates were readily accessed from the relevant o-ni-trobenzaldehyde derivatives via Ramirez olefinationsfollowed by reduction of the nitro group. The early chem-istry focused on tandem palladium-catalyzed intramolec-ular amination reactions and intermolecular Suzukicouplings to deliver a series of variously substituted in-doles.31a,b For example, reaction of gem-dibromoaniline13 with thienyl-3-boronic acid delivered the expectedindole in 86% yield (Scheme 5). The electron-richbiphenyl-based phosphine SPhos (14), developed byBuchwald, proved to be optimal. Significant variation inthe substitution pattern of the substrates and in the type oforganoboron coupling partner was possible. For example,it was possible to prepare indoles with individual substit-uents at positions C2–C7; N-aryl substrates could also beemployed. Aryl, alkenyl and alkyl boron reagents were allused successfully. For many of the examples it was possi-ble to use palladium loadings of only 1 mol%. Althoughno reaction intermediates were detected, a brief mechanis-tic investigation suggested that the intramolecular amina-tion reaction preceded the intermolecular Suzukicoupling. It is interesting to note that the amination reac-tions took place on alkenyl halides,32 as opposed to theusual aryl halide substrates. To demonstrate the syntheticutility of the method, indole 15, prepared in 86% yieldfrom the corresponding gem-dibromovinylaniline and 2-methoxyquinoline boronic acid, was utilized in a shortsynthesis of KDR kinase inhibitors.31c Bisseret and co-workers also reported a single example of the synthesis ofa 2-arylindole using a similar strategy.33

In an elegant extension of this chemistry the same groupwas able to demonstrate that the corresponding pyridine-derived substrates could be utilized to access azain-doles.31d The example shown in Scheme 6 illustrates thepreparation of a 7-azaindole using reaction conditions al-most identical to those for the parent indole series. An im-portant modification from the parent system, needed toachieve high yields, was the use of a nitrogen-protectinggroup. It was also possible to extend the chemistry to thepreparation of 6-azaindoles; however, the synthesis of the

NNMe2

H

ClN

NMe2

Pd(dba)2 (3 mol%)5 (4.5 mol%)

NaOt-Buo-xylene, 120 °C

60%

NNMe2

H

Cl N

NMe2

PhB(OH)2Pd(dba)2 (5 mol%)

5 (7.5 mol%)

Cs2CO3o-xylene, 120 °C

7, 56%

Fe

NMe2

Pt-Bu2

F F

4

Cl Ph

6

5

Cl

Pr

NPr

i) [Cp2TiMe2] (5 mol%)toluene

110 °C, 24 h

ii) Pd2(dba)3 (5 mol%)10 (10 mol%)

KOt-Bu, dioxane110 °C

9, 65%

MeO MeO

H2N Me

MeMe

Me Me

Me8

NN

Me

Me MeMe

Me

MeCl–

+

10

+

CO2Et

HNI N

CO2Et

PdCl2(dppf)(5 mol%)

O2NO2N

Br Br

KOAc, DMF90 °C

11

Fe dppf (12)

PPh2

PPh2

83%

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regioisomeric 5- and 4-azaindoles was more challengingand required the use of N-oxide substrates. Thienopyr-roles could also be prepared starting from the correspond-ing thiophene-derived substrates.

The same gem-dihalovinylaniline substrates have beenutilized in a number of different tandem processes. For ex-ample, as Scheme 7 illustrates, the initial intramolecularamination reactions have been partnered with a number ofalternative reactions, including Heck olefinations (16 →17),31e carbonylations (16 → 18)34 and Sonogashira cou-plings (16 → 19),31f to deliver acrylate-, ester- and alkyne-substituted indoles, respectively. Bisseret and co-workersused the same substrates in tandem palladium-catalyzedamination/phosphonation sequences to deliver 2-phos-phonate-substituted indoles.33 Tethered substrates wereused in the Heck chemistry to provide polycyclic productsvia an intramolecular second step.31e Related tethered sub-strates, invoking a second intramolecular amination reac-tion,31g or an intramolecular direct arylation reaction,31h

were also developed to access alternative polycyclic scaf-folds. It is interesting to note that the double aminationprocesses were achieved using copper catalysis. Lautensand co-workers also demonstrated that the reactivity ofgem-dibromovinylanilines can be controlled to allow ac-cess to 2-bromoindoles by a single (as opposed to a tan-dem) palladium-catalyzed intramolecular aminationreaction.31i

The Willis research group has developed cascade catalyticamination strategies to access a range of indole deriva-

tives. They focused on the use of 2-(2-haloalkenyl)arylhalides, together with the corresponding alkenyl triflates,as indole substrates.35a,b Scheme 8 shows examples ofboth the aryl halide/alkenyl triflate (20) and the aryl ha-lide/alkenyl halide (21) substrates in palladium-catalyzedindole-forming reactions. Both reactions feature an initialintermolecular amination reaction followed by an in-tramolecular amination as the second step of the cascade,to deliver N-functionalized indole products. The authorsnoted that it was possible to employ either Z- or E-config-ured alkene isomers in the process, a consequence of theinitial amination reaction taking place at the alkenyl ha-lide and generating a configurationally unstable enamineintermediate. Reactions employing the triflate substrateswere best achieved using DPEPhos (22) or XantPhos (2)ligands, while the dihalide substrates delivered best yieldswith the Buchwald diphenyl ligands, such as SPhos (14).By selecting the appropriate class of substrate it was pos-sible to access a number of indole substitution patterns.Significant variation of the nitrogen coupling partner waspossible, with examples of aniline, amine, amide, hydra-zine and sulfonamide nucleophiles all being reported.Sterically demanding nitrogen nucleophiles, such as tert-butylamine, could also be introduced;35c the ability to ac-cess indoles bearing bulky N-substituents was exploitedin a synthesis of the natural product demethylasterriquino-ne A, in which N-(reverse prenyl)indole 23 was utilized asa key intermediate. A recent extension of the chemistryhas seen trihalogenated substrates employed, allowing ac-cess to 4-, 5-, 6- and 7-chloroindoles.35d The Li researchgroup has adapted the method to encompass trifluoro-methyl-substituted substrates in order to prepare a seriesof N-aryl-2-trifluoromethyl-substituted indoles.36 A relatedintramolecular amination reaction between an aniline andan alkenyl triflate was employed by Smith and co-workersin their synthesis of the nodulisporic acids tetracycle.37

The Willis research group also demonstrated that similarpalladium-catalyzed cascade processes can be achievedusing pyridine-derived substrates to provide access to thecorresponding azaindole products.35e For example, reac-tion of dihalopyridine substrate 24 with p-anisidine, usinga DPEPhos-derived catalyst, delivered the corresponding

Scheme 5

NH

Br

BrNH2

Pd(OAc)2 (1 mol%)SPhos (2 mol%) S

S(HO)2B

N

Me

MeNH

BnO

NH

O

MeO

N

MeO

Cy2P OMe

MeOSPhos (14)

NH

Me

Me

73%86% 77%

15, 86%(2 mol% Pd)

(dichloro substrate)

86%13

Ph

K3PO4toluene, 90 °C

H2O.

+

Scheme 6

N NN

Br

BrNH

Pd(OAc)2 (3 mol%)SPhos (14) (6 mol%)

Ph

74%Bn Bn

(HO)2B PhK3PO4

toluene, 100 °CH2O.+

Scheme 7

N

CO2t-Bu

Bn

Br

BrNH

R

t-BuO2CMe4NCl (100 mol%)K3PO4 toluene, reflux

Pd/C (2 mol%)CuI (4 mol%)

i-Pr2NH, toluene, 100 °C

NCO2Me

Bn

17, 79%

18, 70%

19, 57%N

H

SiMe3

P(p-MeOC6H4)3 (8 mol%)

Pd(OAc)2 (4 mol%)

PdCl2(PPh3)2 Ph3P (10 mol%)

CO (10 atm)

DIPEA, THFMeOH, 110 °C

SiMe3

16

H2O, Et3N.

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7-azaindole in good yield (Scheme 9). The process wasshown to work well for 7-azaindoles; however, access tothe remaining regioisomers was less successful.

Scheme 9

The 2-(2-haloalkenyl)aryl halide substrates have alsobeen shown to undergo cascade copper-catalyzed amina-tion reactions to deliver N-functionalized indoles.35f Anexample featuring a carbamate coupling partner is shownin Scheme 10. Although some overlap in scope with thepalladium-catalyzed version of the process was estab-lished, there were also significant differences in reactivi-ty. In general, the copper-catalyzed variant was morelimited, with chloro-substituted substrates performingpoorly; however, greater success was achieved withamide nucleophiles, relative to the palladium system.

Scheme 10

Ackermann and co-workers developed efficient indolesyntheses based on a cascade amination process startingfrom o-alkynylhaloarenes.38 In his original report,Ackermann described both palladium- and copper-cata-lyzed variants of the process (Scheme 11).38a For exam-ple, the combination of o-alkynylchloroarene 26 withbenzylamine under the action of an NHC-derived palladi-um catalyst delivered indole 27 in 66% yield. The originalcopper-catalyzed protocol simply employed copper(I) io-dide to combine o-alkynylchoroarenes with anilines fur-nishing the corresponding N-arylindoles in good yields.The reactions proceed via initial intermolecular N-aryl-ation, followed by cyclization onto the alkyne. The twodifferent metal systems were shown to display differing,and complementary, reactivities; for example, the palladi-um-catalyzed methods were effective for N-alkyl and N-aryl nucleophiles, while the copper system tolerated N-aryl and N-acyl substrates.38b The N-acyl systems requiredthe use of diamine ligand 25. Scheme 11 shows severalexamples of products obtained using the copper method-ology, including an N-acyl indole, as well as an azaindole.An indole corresponding to the Chek1/KDR kinase inhib-itor pharmacophore was also prepared. The palladium-catalyzed version of the chemistry was shown to be effec-tive for the preparation of indoles bearing sterically de-manding substituents; for example, the adamantyl-substituted indole 28 was obtained in 94% yield.38c,d TheHu39 and Sanz40 research groups have reported relatedindole-forming chemistries.

Scheme 11

Scheme 8

N

BrOTf

Pd2(dba)3 (2.5 mol%)DPEPhos (6 mol%)

BrCl

Ph

Cs2CO3toluene, 100 °C

H2N

Cl

94%

Ph

NCl

75%

PhH2N

Pd2(dba)3 (2.5 mol%)SPhos (14) (7.5 mol%)

NaOt-Butoluene, 80 °C

O

PPh2 PPh2

DPEPhos (22)

21, E/Z 2:7

20

N

Ph71%N

Ph 81%

OMeN

23, 77%Me Me

+

+

N NN Cl

Br

83%

Pd2(dba)3 (5 mol%)DPEPhos (22) (12 mol%)


O

OEt

24

H2N OMe

O

OEt

OMe

+

BrBr

CuOAc (10 mol%)25 (20 mol%)

NCs2CO3

toluene, 110 °C

MeO

MeO MeO

MeO

Ot-BuOH2N

O

Ot-Bu

25

82%MeN NMe

HH

+

NHex

BnCl

HexPd(OAc)2 (5 mol%)

29 (5 mol%)

NN

i-Pr i-Pr

i-Pr i-Pr

F3C

H2N

Ph

K3PO4toluene, 105 °C

F3C

27, 66%26

NBu

Cl

Bu

CuI (10 mol%)

KOt-Butoluene, 105 °C

69%H2N OMe OMe

+

Cl–

29

N

86%

Ot-BuO

N

NPh

Ot-BuO

61%

S

N

28, 94%

F

+

+

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The Hsung research group employed related cascade pro-cesses for the synthesis of 2-aminoindoles.41 Scheme 12shows an example in which ynamide 30 was combinedwith p-toluamine to deliver indole 31 in 85% yield. AnXPhos-derived palladium catalyst was found to be opti-mal, and a variety of 2-carbamate-substituted indoleswere prepared in good yields. The ynamide substrateswere prepared, in a separate operation, by a copper-cata-lyzed amidation of the corresponding bromo-alkynes.

Scheme 12

Ackermann and colleagues were able to extend their orig-inal methodology to a three-component system, featuringthe in situ formation of the key o-alkynylhaloarenes.38a,e

The process involved the initial combination of an o-chloroiodobenzene with an alkyne in the presence of amixed palladium/copper catalyst system (Scheme 13); af-ter two hours the required nitrogen nucleophile was intro-duced along with additional base, resulting in aryl-amination followed by a 5-endo ring closure. A variety of1,2-disubstituted indoles were obtained in good yields. Apossible limitation of the method is the poor commercialavailability of alternative o-chloroiodobenzene deriva-tives.

Scheme 13

The Barluenga research group developed a successful cas-cade process, based on palladium-catalyzed aza-enolatea-arylation followed by intramolecular N-arylation, forthe synthesis of a variety of indole derivatives.42 The pro-cess is outlined in Scheme 14: Initial palladium-catalyzedaza-enolate arylation joins N-phenylimine 33 with 1,2-di-bromobenzene, to provide imine 34. Palladium-catalyzedintramolecular amination, presumably via enamine inter-mediate 35, then delivers the expected indole in an excel-

lent 86% yield. The same XPhos-derived catalyst provedoptimal for both steps of the cascade. A wide range ofimine derivatives could be incorporated. The use of mixedhalogen systems, such as 1-bromo-2-iodobenzenes, al-lowed the regioselective synthesis of substituted indolesby exploiting the greater reactivity of the aryl iodide sub-stituent. The authors were also able to show that mixedhalide/sulfonate substrates were efficient reaction compo-nents, with both triflate and nonaflate systems being suc-cessfully employed. The ability to generate the requiredsulfonate derivatives from the parent o-chlorophenols sig-nificantly widened the scope of the process and allowedunusual substitution patterns to be accessed, such as the2,4,6-trisubstituted example 36.42b Although an N-aryl orN-alkyl substituent was a requirement of the imine com-ponents, the authors demonstrated that N-tert-butyl-substituted indoles could be deprotected under a variety ofconditions. For example, the N-H indole derived from N-tert-butylindole 37 was obtained in 97% yield for the in-dole formation and deprotection (AlCl3) sequence. Thegroup also reported a three-component variant of themethodology, in which an initial palladium-catalyzed alk-enyl halide amination was used to prepare the imine reac-tion components.

Scheme 14

2.2 Carbazoles

Catalytic amination chemistry has a number of applica-tions in carbazole synthesis. Nozaki was one of the first toexploit cascade amination processes for the preparation ofa wide range of carbazole architectures.43 An example ofthe general process developed by the Nozaki researchgroup is shown in Scheme 15; the key heterocycle-form-ing reaction is a coupling between a nitrogen nucleophileand a doubly activated biphenyl. In this particular exam-ple, ditriflate 37 was coupled with tert-butylcarbamate us-ing a XantPhos-derived catalyst to deliver carbazole 38 in70% yield.43b Deprotection of the Boc group from carba-zole 38 revealed the natural product mukinone. The samegroup has exploited their methodology in the synthesis ofheteroacenes,43d,e chiral carbazole variants,43a as well as

Br

N

+N

p-Tol

Pd2(dba)3 (2.5 mol%)XPhos (5 mol%)


O

O

Ph

H2N p-Tol

ON

O

Ph

31, 85%30Cy2P i-Pr

i-PrXPhos (32)

i-Pr

I

Cl

H Ph

i) Pd(OAc)2 (10 mol%)CuI (10 mol%), 29 (10 mol%)


ii) KOt-Bu NPh

p-Tol

Cl

Ph

H2N p-Tol 65%

+

NPh

Ph

Br

Br

N

Me Ph

Ph

+

Pd2(dba)3 (2 mol%)XPhos (32) (4 mol%)

NaOt-Bu, dioxane 110 °C

N

Ph

PhBrHN

Ph

PhBr

33 86%

N

Ph86%N

Ph

Ph

OMe

36, 74%

NPh

Cl

Me Me

Me37, 91%

(from Cl/ONf substrate) (from I/Cl substrate)

34 35

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helicenes.43b The second example shown in Scheme 15

was reported by Chida and colleagues, and shows that re-lated strategies developed using dibromobiphenyls arealso effective in carbazole synthesis.44a The exampleshows the preparation of a key intermediate in the synthe-sis of the natural product murrayazoline.44b In order toachieve an efficient transformation using the sterically de-manding amine 39, it was necessary to employ a high cat-alyst loading (20 mol%). A copper-catalyzed version ofthese transformations has also been reported.45 The cas-cade coupling of nitrogen nucleophiles with doubly acti-vated bi-aromatics has proven to be a powerful method forcarbazole synthesis and has been exploited by several oth-er groups. For example, Samyn and co-workers utilizeddibromo-2,2¢-bithiophene substrates to preparedithienopyrroles,46 as did the Barlow research group.47

Scheme 15

Bedford et al. developed a cascade sequence based on in-termolecular aryl-amination followed by intramoleculardirect C–H arylation as a route to carbazole derivatives;several examples are shown in Scheme 16.48 The processcombines o-chloroanilines with aryl bromides using pal-ladium catalysis. Use of the bulky electron-rich tri(tert-butyl)phosphine ligand in combination with palladium(II)acetate was the optimal catalyst system and allowed thepreparation of a range of carbazoles in good yields. Sig-nificant substitution could be tolerated on the couplingpartners, as illustrated by the preparation of the naturalproduct clausine P (40).

Ackermann et al. developed a related aryl-amination anddirect C–H arylation sequence for carbazole synthesis.49

In the Ackermann approach, 1,2-dihaloaromatics werecombined with anilines to deliver carbazole products(Scheme 17). A combination of palladium(II) acetate and

tricyclohexylphosphine was found to be optimal and al-lowed a wide range of carbazoles to be prepared. Usingthis catalyst system it was possible to employ inexpensive1,2-dichloroarenes as coupling partners, as well as hetero-cyclic derivatives, illustrated by the preparation of pyra-zine and pyridine derivatives 41 and 42. The authorsexploited the methodology in a synthesis of the naturalproduct murrayafoline A (43).49b Although less accessi-ble, 1,2-dihaloalkenes could also be employed as sub-strates, allowing the same cascade sequence to be appliedto indole synthesis.

Scheme 17

Kan and co-workers reported a palladium-catalyzed cas-cade route to carbazoles based on initial intermolecularSuzuki coupling followed by an intramolecular aryl ami-nation. A small scoping study was described, although apossible limitation is the availability of suitably function-alized boronic acids.50 Fujii and Ohno have also describeda cascade route to carbazoles. In their approach, an inter-molecular aryl amination between an aryl triflate and ananiline was used to construct a diphenylamine which thenunderwent an oxidative coupling to generate a carbazoleproduct. The efficiency of the oxidative step was shown tobe dependent on the substitution pattern of the diphenyl-amine intermediates.51

OTf

OTfN

K3PO4o-xylene, 100 °C

Br

BrNaOt-Bu

toluene, 130 °C

O

MeOOMe

Pd2(dba)3.CHCl3 (5 mol%)

XantPhos (2) (10 mol%)Boc

OMeMeO2C

N-Boc mukonine (38)70%

Me

OMOM

NMe

Me

O O

H2NMe

Me

OO

Me

MOMOPd2(dba)3 (20 mol%)

XPhos (32) (60 mol%)

59%

murrayazoline

37

39

NH2

Ot-BuO

+

+

Scheme 16

NH

Cl

N

Bn

Pd(OAc)2 (4 mol%)t-Bu3P (5 mol%)

Br

Bn

F3C

Me

F3C

MeNaOt-Butoluene, reflux

NH

Me

Me

69%

MeO

OMe69%

clausine P (40)

NH

OMe

43%

+

HN

Cl

Cl

N NaOt-BuNMP, 130 °C

Ph

Pd(OAc)2 (5 mol%)Cy3P (10 mol%)

Ph85%

NN

Ph42, 93%

CF3

NH

murrayafoline A (43)MeO

Me

74% from Br/Cl-Ar

NN

N

Ph41, 93%

+

72% from Cl/Cl-Ar

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2.3 Benzimidazoles and Benzimidazolones

A host of approaches to benzimidazoles and related deriv-atives, featuring inter- and intramolecular and cascade re-actions, as well as both palladium and copper catalysts,have been reported. Ma and co-workers developed a num-ber of copper-catalyzed routes to these important hetero-cycles.52 In 2007, they demonstrated that o-haloacetanil-ides could be combined with primary amines to deliverbenzimidazoles (Scheme 18). For example, a copper(I)iodide/proline catalyst system was effective for the unionof aryl iodide 44 with allylamine, to furnish benzimida-zole 45 in 94% yield.52a When more sterically demandingamines, or less activated aryl units, were employed it wasnecessary to use either heat or an acid/heat combination toachieve cyclization to the aromatic system; for example,the formation of cyclohexyl-substituted benzimidazole 46required the addition of acid. A broad range of amines andaryl units, including pyridine derivatives, could be includ-ed in the method, delivering benzimidazoles in good toexcellent yields. Although Scheme 18 shows only aryl io-dide substrates, aryl bromides were also used. When thestarting substrates were changed to o-iodoarylcarbamates,the same reaction system was used to access benzimida-zolones (47 → 48).52b Aqueous ammonia could also beemployed as the nitrogen nucleophile in both reactionpathways, leading to the corresponding N–H deriva-tives.52c

Scheme 18

Buchwald and co-workers developed a related palladium-catalyzed route to aryl-substituted benzimidazoles. Forexample, the coupling of o-bromacetanilide 49 with o-toluamine using an XPhos-derived catalyst provided thecorresponding N-arylbenzimidazole in 94% yield

(Scheme 19).53a A good range of anilines and aryl sub-strates (both Br and Cl) were described; Scheme 19 alsoshows an aza-example, derived from the correspondingpyridine substrate, as well as a cyclopropyl-substitutedproduct. Some variation of ligand between XPhos (32)and RuPhos (50) was needed for certain substrates. In2006, Scott reported a palladium-catalyzed synthesis ofimidazopyridinones (aza-benzimadazolones) in a processanalogous to the conversion of 47 into 48 shown inScheme 18.54

Scheme 19

Buchwald and Zheng also described a complementarycopper-catalyzed protocol, based on aryl halide amidation(as opposed to amination), for benzimidazole synthesis.53b

The basic process is shown in Scheme 20; copper(I)iodide/diamine-catalyzed coupling of hexamide with o-iodo-N-alkylaniline 51, followed by base-promoted cy-clization, delivered the desired N-alkylbenzimidazole 52in 87% yield. Alkyl, alkenyl and aryl amides could all beincorporated effectively.

Scheme 20

Intramolecular aryl amidation using urea substrates hasbeen achieved using both palladium and copper catalysisand provides a further route to benzimidazolones(Scheme 21). The cyclization of urea 53, using a palladi-um(II) acetate/XPhos catalyst system, was described bythe process group at Merck.55 Chloro-, bromo- and iodo-aryl derivatives could all be employed as substrates, ascould chloropyridines. Copper-catalyzed variants of sim-ilar cyclizations have also been reported,56 including apolymer-supported example;57 the second reaction shownin Scheme 21, reported by SanMartin, Domínguez and co-

HN

IN

NCF3

CuI (10 mol%)L-proline (20 mol%)O

CF3

H2N

K2CO3, DMSO, r.t.

45, 94%

HN

IN

Ni) CuI (10 mol%)

L-proline (20 mol%)O

H2NK2CO3, DMSO, 40 °C

46, 73%

O

O

ii) AcOH, 140 °C

HN

IN

HN

O

CuI (10 mol%)L-proline (20 mol%)O

OMe

K2CO3, DMSO50 °C then 130 °C 48, 74%H2N

NBoc N

Boc

44

47

NH

O

OH

H

L-proline

+

+

+

HN

Br N

NMeO

Me

H2N 94%

Me

Br

MeMe

Br

Pd2(dba)3 (1 mol%)XPhos (32) (8 mol%)

K3PO4t-BuOH, 110 °C

N

N

NMe

(from ArCl using ligand 50)

88%

Cy2P Oi-Pr

i-PrORuPhos (50)

N

N

Me

Me MeMe

83%

(using ligand 50)

49+

HN

I

N

Ni) CuI (5 mol%)25 (20 mol%)

H2NCs2CO3, dioxane, 90 °C

52, 87%

Me

Pent

O

PentMe

ii) K3PO4t-BuOH, 110 °C

F3CF3C

51+

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workers,58 illustrates a copper(I) iodide catalyzed cycliza-tion using water as the solvent.

Intramolecular reactions to access benzimidazoles can beachieved using amidines as substrates. An example, re-ported by Brain et al.,59 is shown in Scheme 22 in whichamidine 54 was converted into the corresponding benzim-idazole under the action of a Pd2(dba)3/triphenylphos-phine catalyst. The authors were also able to show that useof a ‘catch-and-release’ purification strategy,59b involvingAmberlyst resin, allowed the benzimidazoles to be ob-tained in pure form without recourse to chromatography.Related cyclizations in which the amidine is embeddedwithin a heterocycle have also been described.60,61

De Meijere and Lygin reported that amidines, generatedin situ from an isocyanide and a primary amine, can alsobe cyclized using copper(I) conditions to access N-alkyl-benzimidazoles.62

Scheme 22

Batey and Evindar used related cyclizations employingguanidine substrates to access 2-aminobenzimidazoles.63

Efficient reactions were achieved using either palladiumor copper catalysis; Scheme 23 gives an example of thereaction conditions needed for each metal. In general, thecopper conditions were found to be superior, providinghigher yields and more selective reactions. Both aryl io-dides and aryl bromides could be employed as substrates,allowing a broad range of 2-aminobenzimidazoles to be

prepared in good yields. Szczepankiewicz et al. appliedthis type of copper-catalyzed cyclization to substratesbased on uracil templates to prepare purine and relatedfused imidazole systems.64 2-Mercaptobenzimidazolescan similarly be accessed using copper-catalyzed cycliza-tion of in situ generated isothioureas.65

The research groups of both Zhang66and Wu67 showedthat o-halophenylimidoyl chlorides are effective sub-strates for copper-catalyzed benzimidazole synthesis.Scheme 24 presents an example from the Zhang group,and shows how imidoyl chloride 55 can be combined withbenzylamine using a copper(I) iodide catalyst, to deliverthe expected benzimidazole in excellent yield. Both alkyl-and arylamines could be employed. In both reports it wasnecessary to include an electron-withdrawing substituenton the imidoyl chloride substrate; for example, the tri-fluoromethyl substituent on imidoyl chloride 55.

Scheme 24

Maes and co-workers explored a range of cascade amina-tion strategies to access a variety of benzo-fused benzim-idazole systems.68 In their lead publication, they were ableto combine 2-chloro-3-iodopyridine with 2-picoline togenerate dipyridoimidazole 56 in 96% yield (Scheme 25).The example shown employs a palladium(II) acetate/BINAP catalyst, although XantPhos (2) was also shown tobe an effective ligand.68a The chemistry has been extendedto the preparation of a number of benzo-fused and aza an-alogues,68a–c,69 and in an interesting application a tempera-ture/halide dependent regioselectivity switch wasdeveloped.68d

Scheme 25

Batey and co-workers described a copper-catalyzed cas-cade route to benzimidazoles from the combination of a1,2-dihalobenzene with an amidine, although only a sin-gle example was reported.70 Deng et al. reported a relatedcascade in which amidines were exchanged forguanidines, leading to the synthesis of 2-aminobenzimi-dazoles (Scheme 26). The majority of examples deliveredN–H products, although N-substitution could also be in-troduced.71

Scheme 21

NH

NO

N

NH2

O

Cl

PMB PMBPd(OAc)2 (1 mol%)

XPhos (32) (3 mol%)

CuI (8.5 mol%)TMEDA (3.5 equiv)

NaHCO3i-PrOH, 83 °C

NH

NO

N

NH2

O

Br

BnBn

H2O, 120 °CMeO

MeO

92%

92%

53

N

N

Me

Me

N Me

NHMeBr

NaOH, H2O–DME160 °C, MW

Me MePd2(dba)3, (1.5 mol%)

Ph3P (12 mol%)

82%54

Scheme 23

Cs2CO3, DME, 80 °C

N

NHNBr

Me

Pd: 66%

Bn

NN

Bn N

Me

Pd(PPh3)4 (10 mol%)

CuI (5 mol%)1,10-Phen (10 mol%)

Cs2CO3, DME, 80 °Cor

Cu: 90%

N

NCF3

N

Cl

CF3

ICuI (10 mol%)

TMEDA (20 mol%)

H2N Ph


Ph98%

55

+

N

I

Cl N NH2N N

NPd(OAc)2 (3 mol%)BINAP (3) (3 mol%)

Cs2CO3toluene, reflux

+

56, 96%

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Scheme 26

2.4 Indazoles and Indazolones

Indazoles have proven to be popular targets for aminationchemistry. A number of groups have described the cy-clization of appropriately substituted arylhydrazones.Scheme 27 illustrates an intramolecular coupling of bro-mo-substituted arylhydrazone 57 to deliver 1H-indazole58 in 85% yield.72 The DPEPhos-derived catalyst systemwas effective for a wide range of substrates, although arylchloride substrates performed poorly. Analogous N-tosyl-hydrazones were also established as effective indazoleprecursors,73a and were utilized in a synthesis of the natu-ral product nigellicine.73b 3-Amino-1H-indazoles werealso prepared by similar palladium-catalyzed cycliza-tions.74 Song and Yee demonstrated that appropriatelysubstituted hydrazines are also useful indazole precursors.For example, palladium-catalyzed ring closure using hy-drazine 59 delivered the corresponding aromatic 1H-inda-zole directly in 87% yield, following intramolecularamination and spontaneous aromatization.75 The mecha-nism of aromatization was not established. The authorsnoted the instability of certain hydrazine substrates tolong-term storage, and as alternatives established that thecorresponding N-triphenylphosphonium bromide saltsprovided convenient stable precursors that could be cy-clized under identical reaction conditions.

Scheme 27

There are a number of reports of halo-substituted hydra-zones being formed in situ and then cyclized to yield 1H-indazoles; Scheme 28 presents examples using both palla-dium and copper catalysis. Cho et al. were able to showthat o-bromobenzaldehydes could be combined with phe-nylhydrazine using a palladium(II) chloride/dppp catalystsystem to furnish the corresponding indazoles in goodyields (60 → 61).76 The copper example, reported by

Pabba et al., required a two-step one-pot approach inwhich a ten-minute microwave reaction was used to formthe hydrazone before a copper(I)/diamine catalyst wasadded to the system (62 → 63).77 Del Olmo and co-work-ers reported a related copper-catalyzed process which alsoallowed the use of aryl carboxylic acid substrates to deliv-er 1-hydroxy-1H-indazoles.78

Scheme 28

Guillaumet and co-workers reported an intermolecularcopper-catalyzed amination method for the preparation ofpyrazolopyridines (azaindazoles).79 3-Cyano-2-chloropy-ridine was combined with a range of hydrazines using acopper(I) iodide/phenanthroline catalyst to deliver 3-ami-no-1H-azaindazoles in good yields (Scheme 29). The 3-amino products were converted into the corresponding 3-iodo derivatives by way of their diazonium salts, and wereemployed in a range of palladium-catalyzed coupling pro-cesses including Stille, Heck and Suzuki reactions.

Scheme 29

The less thermodynamically stable 2H-indazole isomerscan also be accessed using amination chemistry. In an ap-proach mirroring their route to the 1H-isomers (seeScheme 27), Song and Yee employed a palladium-cata-lyzed cyclization of appropriately substituted hydra-zines.80 For example, N-alkyl-N-arylhydrazine 65 wasconverted into 2-aryl-2H-indazole 66 in 60% yield(Scheme 30). Katayama and co-workers showed that N2–C3-fused examples can also be prepared using similarchemistry.81

I

Br

N

H2N

HN

O

Cs2CO3DMA, 165 °C N

H

NN O

CuI (15 mol%)25 (30 mol%)

Me

Me

53%

+

Br

N

HN N

N

K3PO4toluene, 110 °CMe

MePd(dba)2 (2 mol%

DPEPhos (22) (2 mol%) Me

Me

58, 85%

NNNH

BrHN

Pd(OAc)2 (5 mol%)dppf (12) (7.5 mol%)


MeO

59 87%

57

MeO

NN

O

H

Br Ph

NH

O

H

Br


ii) CuI (5 mol%)64 (10 mol%)

K2CO3, 160 °C10 min, MW

NHMe

NHMe

MeO

MeO

PdCl2 (2 mol%) dppp (3 mol%)

MeO

MeO

F i) NMP, 160 °C 10 min, MW

NN

F

63, 84%

61, 65%

64

60

62

H2N

Ph

NHH2N

+

+

N

CN

ClEt

HN

NH2N N

N

NH2

Et

CuI (5 mol%)1,10-phenanthroline

(10 mol%)

Cs2CO3DMF, 60 °C

86%

NN1,10-phenanthroline

+

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Scheme 30

Halland, Lindenschmidt and co-workers reported an alter-native route to the 2H-indazole isomers employing thesame o-alkynylhaloarene substrates used successfully byothers to access indoles (see Schemes 11 and 12). The re-actions proceeded via an initial regioselective aminationreaction using a monosubstituted hydrazine to generate anN,N¢-disubstituted hydrazine, which then underwent in-tramolecular hydroamination to form a dihydroindazoleintermediate (67, Scheme 31).82 Isomerization from theseintermediates to the aromatic 2H-indazoles occurredspontaneously under the reaction conditions of palladi-um(II) chloride/tri(tert-butyl)phosphine with cesium car-bonate in N,N-dimethylformamide. Good functionalgroup tolerance was demonstrated and an extensive rangeof substituted products was described; three examples areshown in Scheme 31.

Scheme 31

Indazolones can be prepared by the copper-catalyzed cy-clization of o-halobenzohydrazides. For example, treat-ment of hydrazide 68 with a copper(I) iodide/prolinecatalyst system delivered indazolone 69 in 60% yield(Scheme 32).83 Iodo substrates delivered the most effi-cient reactions; the bromo and chloro substrates were alsoshown to deliver the desired products, albeit in reducedyields.

Scheme 32

2.5 Pyrroles

The Buchwald and Li research groups both reported cas-cade copper-catalyzed alkenyl amidation routes to pyr-

roles. The Buchwald group utilized a copper(I) iodide/diamine 25 catalyst system to combine carbamates (and alimited number of amides) with 1,4-diiodo-1,3-dienes togenerate highly substituted pyrrole products (70 → 71,Scheme 33).84 The methodology displayed excellentfunctional group tolerance and was applied to the synthe-sis of a wide range of pyrroles, including tetrasubstitutedexamples. The method was also applicable to the synthe-sis of heteroarylpyrroles, such as thienopyrrole 72. The Liapproach exploited similar diene substrates in combina-tion with a range of amide coupling partners.45,85 For ex-ample, diiododiene 73 was combined with phenyl-acetamide using a copper(I) iodide/diamine 64 catalyst todeliver the expected pyrrole in 86% yield (Scheme 33).

Scheme 33

Buchwald and colleagues reported a complementary step-wise approach to pyrroles also based on copper-catalyzedalkenylation reactions.86 N,N¢-Di(Boc)-protected alkenyl-hydrazides 74, themselves prepared by copper-catalyzedalkenylation reactions, were coupled with a second alke-nyl iodide to generate bis(ene)hydrazide 75 (Scheme 34).Thermolysis triggered a [3,3] rearrangement to generatebis-imine 76, cyclization of which provided the pyrrole

NPh

NH2Br N

N Ph



MeO MeO

66, 60%65

Ph

Cl NN Ph

Ph

HBF4 (10 mol%)

Cs2CO3DMF, 110–130 °C

NH

Ph

NH

N Ph

Ph

79%

NN Ph

CO2t-Bu

93%N

N Ph

55%

OEt

OEt

67

+ H2N

PdCl2 (5 mol%)Pt-Bu3

.

NH

O

I

HN

NNH

O

CuI (10 mol%)L-proline (20 mol%)

K2CO3, DMSOr.t. to 70 °C

68 69, 60%

I

Pr

Pr

SiMe3

I

NPr

Pr

SiMe3

Boc

H2N

Cs2CO3dioxane, 100 °C

Cs2CO3THF, 80 °C

O

Ot-Bu

CuI (20 mol%)64 (20 mol%)

CuI (5 mol%)25 (20 mol%)

NPr

Pr

SiMe3

Boc

Bu71, 86%

80%98% 72, 83%

N SiMe3

Boc

Me

S

N

Boc

S

IBu

IN

Bu

H2N

O

86%

70

73

Bu

Ph

Bu

O

Ph

+

+

Scheme 34

NPr

Boc

NH

Boc

I

Oct

Cs2CO3, DMF80 °C, 30 h

ii) o-xylene, 140 °C, 30 hiii) p-TsOH, r.t.

Pr

(i) CuI (10 mol%)1,10-phenanthroline

(20 mol%)

NPr

Pr Oct

Boc

N N

BocBoc

Pr

Pr Oct

NPr

Pr Oct

Boc

NBoc

H[3,3]

74

75 76 77

68%

NNPr

Pr Oct

BocBoc

+

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via intermediate 77. For certain substrates it was neces-sary to add acid to achieve complete conversion into thearomatic system. The bis(ene)hydrazides could be isolat-ed, or more conveniently used directly in the next step ofthe sequence with no purification. The overall methodrepresents a modified Piloty–Robinson reaction.

The final pyrrole synthesis considered here comprises acopper-catalyzed cascade alkenyl amidation/hydroamina-tion sequence. The process is essentially a pyrrole-forming version of the indole synthesis described inScheme 11. In this approach, described by Buchwald andco-workers, haloenynes such as 78 replace the alkynylha-loarenes used for indole synthesis, and, when combinedwith tert-butyl carbamate and a copper(I) iodide/diaminecatalyst, provide the corresponding pyrroles in goodyields (Scheme 35).87 A broad range of di- and trisubsti-tuted pyrroles were prepared, and although the study fo-cused on the use of iodoenynes, it was also possible toemploy bromoenynes. A brief mechanistic study estab-lished that the reactions likely proceed via initial intermo-lecular aryl carbon–nitrogen bond formation followed bya 5-endo-dig intramolecular hydroamination.

Scheme 35

2.6 Pyrazoles

Buchwald and co-workers utilized haloenyne substratesin a tandem copper-catalyzed pyrazole synthesis.87 Forexample, combination of iodoenyne 78 with bis(Boc)hy-drazine using a copper(I) iodide/diamine catalyst provid-ed pyrazole 79 in 78% yield after Boc-deprotection withtrifluoroacetic acid (Scheme 36). As in the related pyrrolesyntheses, a good range of di- and trisubstituted aromaticswere prepared. The mechanism was again established asproceeding via intermolecular aryl carbon–nitrogen bondformation followed by intramolecular hydroamination, al-though the cyclizations were in this case 5-exo-dig pro-cesses.

Cho and Patel reported a pyrazole synthesis based on thepalladium-catalyzed combination of b-bromovinyl alde-hydes with hydrazines.88 For example, treatment of

bromo-enal 80 with phenylhydrazine in the presence of adppf-derived catalyst yielded pyrazole 81 in 77%(Scheme 37). Both cyclic and acyclic substrates could beemployed, although no ketone-derived substrates were re-ported. Haddad and co-workers developed a pyrazole syn-thesis in which aryl benzophenone hydrazones, preparedby the palladium-catalyzed coupling of benzophenone hy-drazone with aryl halides, were treated with a range of1,3-bifunctional substrates under acidic conditions.89 1,3-Diketones, keto esters and ester/acid chlorides could becombined with the hydrazones to provide a range of sub-stituted pyrazole products.

Scheme 37

2.7 Oxazoles

Buchwald and co-workers utilized copper-catalyzed alke-nyl iodide amidation reactions as the key step in a route tooxazoles.90 For example, enamides such as 82 could betreated with iodine and base to provide the expectedtrisubstituted oxazoles in good yields (Scheme 38). Therequired enamides were prepared from the correspondingalkenyl bromides using a copper(I) iodide/diamine-cata-lyzed coupling with the appropriate amide; both aryl andalkyl amides could be used. Depending on the substitutionpattern of the oxazole product, certain examples requiredthe addition of p-toluenesulfonic acid to achieve completeconversion into the aromatic molecule. Attempts to pre-pare mono- and disubstituted oxazoles using this methodresulted in complex reaction mixtures, and an alternativeprocess, based on the use of 1,2-dihaloalkene substrates,was developed.

Scheme 38

2.8 Quinolones

Manley and Bilodeau used palladium-catalyzed intermo-lecular aryl halide amidation followed by an in situ aldolcondensation to prepare 2-quinolones.91 In this way o-bro-mobenzaldehydes were combined with a range of enoliz-able amides to deliver the quinolone products. Scheme 39

I

Pent

Cs2CO3THF, 80 °C

NOTIPS

NH2

O

t-BuO

CuI (5 mol%)25 (20 mol%) OTIPS

Pent78

83%

Boc+

Scheme 36

ii) TFA, CH2Cl2, r.t.HN

NH

BocBoc

I

Pent

Cs2CO3THF, 80 °C

NNH

OTIPS

(i) CuI (5 mol%)25 (20 mol%)

OTIPS78

79, 78%

Pent

+


NaOt-Bu, toluene125 °CBr

O

HH2N NH

PhN

N

Ph80 81, 77%

+

H2N Ph

O

i) CuI (5 mol%)25 (20 mol%)

Cs2CO3, THF, 80 °C

ii) I2, DBUr.t. to 80 °CPh

Ph Br

Ph

PhHN

O

Ph

Ph

Ph

O

NPh

I

H

Ph

Ph

O

NPh

77%

82

+

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illustrates the combination of the parent aldehyde (83)with phenylacetamide using a XantPhos-derived catalystin combination with cesium carbonate as base. A varietyof substituted amides could be employed, as could ketone-based substrates, allowing the synthesis of 4-substitutedproducts such as quinolone 84. Pyridine derivatives couldalso be employed, thus providing a route to naphthyridi-nones. Ester- and nitrile-substituted aryl bromides werealso examined and allowed access to hydroxy- and amino-substituted products, respectively. For a small number ofamide coupling partners, the researchers were able to em-ploy a copper(I) iodide/diamine catalyst system.

Scheme 39

Huang et al. utilized the related o-acetylbromoarenes assubstrates in a palladium-catalyzed synthesis of 4-quino-lones. The simplest version of the process employed for-mamide as the nitrogen nucleophile and, when coupledwith bromide 85, delivered quinolone product 86 in 77%yield (Scheme 40).92 The reactions proceeded via initialpalladium-catalyzed amidation followed by a base-pro-moted intramolecular condensation step. A XantPhos-derived catalyst in combination with cesium carbonate asbase was optimal for the amidation step, and the additionof sodium tert-butoxide as a second base was found to benecessary to achieve high yields for the combined pro-cess. As can be seen from the examples presented inScheme 40, a range of substituted amides could be em-ployed, including lactams, which allowed the synthesis ofN-fused products such as quinolone 87. The Buchwald re-search group reported a related process based on copper-catalyzed amidation, although in their case it was neces-

sary to isolate the initial amidation products before cy-clization.93

A tandem Heck/intramolecular amidation strategy was re-ported by Cacchi and co-workers as a route to 4-aryl-2-quinolones.94 Using molten tetrabutylammonium acetate/tetrabutylammonium bromide as the reaction medium anda simple palladium(II) acetate catalyst, the combination ofo-bromophenylacrylamides (88) and aryl iodides provid-ed the quinolone products in moderate to good yields(Scheme 41). Although only a single acrylamide substratewas employed, a good range of aryl iodide coupling part-ners could be incorporated. A brief mechanistic investiga-tion supported the Heck followed by intramolecularamidation pathway.

Scheme 41

Willis and co-workers exploited 2-(2-haloalkenyl)aryl ha-lide substrates, previously employed in indole syntheses(see Scheme 8), in the preparation of 2-quinolones.95 Acascade palladium-catalyzed carbonylation/intramolecu-lar amidation sequence was employed to access a range ofquinolone products. For example, combination of the sim-ple dibromide 89 and p-methoxybenzylamine under a bal-loon pressure of carbon monoxide delivered quinolone 90in 80% yield (Scheme 42). Although all of the productsshown in Scheme 42 were obtained using a dppp-derivedcatalyst, the researchers found that ligand variation wasneeded for particular substrate/amine combinations. Inaddition, purging the reaction of carbon monoxide wasshown to benefit the efficiency of certain amidation reac-tions. By delaying the introduction of the carbon monox-ide and running the reaction in a two-stage process, it wasalso possible access the regioisomeric isoquinolone prod-ucts, although in these cases competing indole formationwas problematic.

Scheme 42

NH

O

Ph

Br

H

O

H2NPh

O


Pd2(dba)3 (1 mol%)XantPhos (2) (3 mol%)

94%83

N

NH

O

Ph

75%

NH

O

Ph

84, 55%

Ph

NH

O

94%

N

+

Scheme 40

NH

OO

Me

BrH2N H

OPd2(dba)3 (1 mol%)

XantPhos (2) (2.5 mol%)

Cs2CO3, dioxane100 °C, 2–48 h then

NaOt-Bu, 100 °CMeO

NH

O

N

O

NH

O

S

Me

86, 77%

82% 91% 87, 85%

85MeO

+

NH2

O

Br I

NH

O

Pd(OAc)2 (5 mol%)

n-Bu4NOAc, n-Bu4NBr120 °C

75%

88

+

N OPMB

BrBr

H2N

CO (balloon)

Cs2CO3, toluene100 °C

Pd2(dba)3 (3 mol%)dppp (6 mol%)

OMe

N O

Oct

O

O N O

OctO

MeON N O

Oct

90, 80%

69% 65% 73%

89

+

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2.9 Quinazolines, Quinazolinones and Quinazolindiones

In 2006 Willis and co-workers reported the palladium-catalyzed coupling of o-bromobenzoate esters withmonosubstituted ureas as a route to 3-alkylated quinazo-linediones.96 The reactions proceeded via initial intermo-lecular carbon–nitrogen bond formation followed byintramolecular, base-promoted, amidation. A XantPhos-derived catalyst in combination with cesium carbonate al-lowed efficient and regioselective processes; for example,bromobenzoate 91 was combined with N-butyl urea toprovide quinazolinedione 92 in 77% yield as a single re-gioisomer (Scheme 43). A variety of substituents weretolerated on both the aryl bromide and urea coupling part-ners. The observed regiocontrol originates from the initialaryl carbon–nitrogen bond formation taking place at theleast hindered nitrogen of the urea nucleophile.

Scheme 43

The Fu research group reported a related strategy for thesynthesis of quinazolinones and quinazolines. In theiroriginal report, they exploited a copper-catalyzed cou-pling of amidines with o-bromobenzoic acids to accessquinazolinones. For example, acid 93 was combined withacetimidamide 94 to provide quinazolinone 95 in 81%yield (Scheme 44).97a The reaction conditions consisted ofcopper(I) iodide without any added ligand, in N,N-di-methylformamide at room temperature. The ability to usesuch low-temperature conditions was attributed to the for-mation of a chelated intermediate involving the oxygenatom of the ortho-positioned carboxylic acid. The reactionwas applicable to a broad range of amidines and benzoicacids. The researchers next extended the chemistry to in-clude guanidines as the nitrogen nucleophiles, resulting inthe formation of 3-aminoquinazolinone products such as96.97b The carboxylic acid substrates could also be re-placed; the use of the related ketones in combination withguanidines resulted in the synthesis of 3-aminoquinazo-lines such as 97. Ding and co-workers reported an alterna-tive copper-catalyzed route to quinazolinones based onthe use of o-iodobenzamide substrates.98 A typical reac-tion is shown in Scheme 44: coupling of benzamide 98with formimidamide, using copper(I) iodide as catalyst,provided quinazolinone 99 in 77% yield. The method wasshown to tolerate reasonable variation of both reactioncomponents.

Li and co-workers reported a cascade process involving insitu amidine formation followed by palladium-catalyzed

cyclization as an entry into ring-fused quinazolinone de-rivatives. The key amidine intermediates were generatedfrom intramolecular amide addition to a nitrile; the nitrilegroup also being introduced by a palladium-catalyzedprocess.99 Scheme 45 outlines the overall conversion,with aryl iodide 100 being transformed into quinazolinone101 in 91% yield. A DPEPhos-derived catalyst was effec-tive for both the initial cyanation reaction to generate ni-trile 102, and then to achieve the final ring closure fromthe proposed amidine intermediate to give quinazolinone101. Using a bromoquinoline-derived substrate, the au-thors were able to apply the methodology to a synthesis ofthe natural product luotonin (103).

Scheme 45

2.10 Phenazines

The Kamikawa and Beifuss groups have both reported in-tramolecular palladium-catalyzed aryl-amination routesto phenazines. Both explored the ring-closure of 2-amino-2¢-bromodiphenylamines to access the target systems.Scheme 46 shows an example from Beifuss and co-work-ers, in which a JohnPhos-derived catalyst was used to con-vert aniline 104 into phenazine 105 in 76% yield.100 TheKamikawa research group utilized BINAP-derived cata-

NH

N

O

O

BuOMe

O

Br

NH

NH2

O

Bu

Pd2(dba)3 (2.5 mol%)XantPhos (2) (5 mol%)

Cl

Cs2CO3dioxane, 100 °C

Cl

91 92, 77%+

Scheme 44

N

N

O

NH

O

I

Ph

NHH2N

AcOH

OH

O

BrNH.HClH2N

Me

K2CO3DMF, 80 °C

CuI (20 mol%)

Cs2CO3DMF, r.t. N

NH

O

Me

93 95, 81%

N

NH

O

75%

N

NH

O

N

96, 81% O

N

N

Ph

N

97, 56%

CuI (10 mol%)Ph

98 99, 77%

94

+

+

NH

O

CN Br N

N

N

O

NH

O

I

Br N

N

O

KCN

Pd(OAc)2 (5 mol%)DPEPhos (22) (10 mol%)

dioxane, reflux

then dppf (10 mol%)K2CO3

100 101, 91%

102

+

91%luotonin (103) D

ownl

oade

d by

: A.E

.Fav

orsk

y Ir

kuts

k In

stitu

te o

f Che

mis

try

SB

RA

S. C

opyr

ight

ed m

ater

ial.



lysts.101 In both cases the phenazine ring system was iso-lated directly from the amination reactions.

2.11 Cinnolines

An intermolecular copper-catalyzed aryl amination wasused by Nishida and co-workers to access cinnoline deriv-atives. In the example shown in Scheme 47, hydrazone-substituted aryl iodide 107 was converted into N-acyl-dihydrocinnoline 108 using a copper(I) iodide/diaminecatalyst.102 The use of superstoichiometric amounts of cat-alyst led to mixtures of N-acyl product 108 together withsmaller amounts (up to 40%) of the aromatic cinnoline be-ing obtained. Cyclization of hydrazines derived from hy-drazone 107 allowed access to 1-aminoindoles.

Scheme 47

3 Carbon–Oxygen Bond Formation

Initially, the development of catalytic carbon–oxygenbond-forming processes using aryl halide substrateslagged behind the corresponding carbon–nitrogen form-ing reactions; however, efficient methods, using both pal-ladium and copper catalysts, are now well established.

3.1 Benzofurans

Few examples of benzofuran syntheses that proceed via ametal-catalyzed intermolecular (aryl)carbon–oxygenbond-forming reaction exist. In one example, Buchwaldand co-workers were able to apply their palladium-cata-lyzed phenol synthesis to the preparation of benzo-furans.103 The chemistry was based on the use ofpotassium hydroxide as a nucleophile in the palladium-catalyzed hydroxylation of aryl halides to provide phe-nols. When applied to benzofuran synthesis, o-chloroaryl-alkyne substrates reacted with potassium hydroxide in thepresence of t-Bu-XPhos as catalyst, to give o-hydroxy-alkynylarenes, which, as previously shown,104 undergo

cyclization to the required benzofurans (109 → 110,Scheme 48). You’s research group went on to develop acopper-catalyzed version of the hydroxylation reactionand also demonstrated its use in benzofuran synthesis, inthis case from an o-iodoarylalkyne to generate benzofuran112.105

Scheme 48

A greater number of research groups have utilized in-tramolecular carbon–oxygen bond formation as the keystep in benzofuran syntheses. In 2004 Willis et al. demon-strated the use of a-(o-haloaryl) ketones as precursors tothe required oxygen heterocycles via an enolization/palla-dium-catalyzed intramolecular O-arylation reaction, witha Pd2(dba)3/DPEPhos catalyst system proving optimumfor the process (Scheme 49).106 The starting ketones werethemselves formed by a palladium-catalyzed ketone ary-lation; however, attempts to achieve a one-pot combina-tion of these processes was not straightforward, and afteroptimization only a single high-yielding example of thecascade could be achieved. Kotschy and co-workersshowed that the same cyclization of o-bromobenzyl ke-tones, which they accessed from aromatic aldehydes and2-bromobenzyl bromide using dithiane chemistry, is pos-sible using a palladium–NHC catalyst system.107

Scheme 49

Scheme 46

N

NHN

MeONaOt-Bu

toluene, 100 °C MeO

Pd2(dba)3 (3 mol%)JohnPhos (6 mol%)

104105, 76%

P(t-Bu)2

JohnPhos (106)

NH2

Br

CO2t-Bu

N

OTBS

NN

OTBS

CO2t-Bu

Ac

CuI (10 mol%)25 (10 mol%)

Cs2CO3DMSO, r.t.

108, 89%107

I

HNAc

OCl

Ph

I

Cl

H2O, dioxane100 °C

H2O, DMSO100 °C

F3C

S

F3C

S

KOHPd2(dba)3 (2 mol%)t-BuXPhos (8 mol%)

110, 87%

KOHCuI (10 mol%)

1,10-phenathroline(20 mol%)

OPh

Cl

112, 86%

109

t-Bu2P i-Pr

i-Prt-BuXPhos (111)

i-Pr

BrCs2CO3

toluene, 100 °CO

Pd2(dba)3 (2.5 mol%)DPEPhos (22) (6 mol%)

O

95%

OPh

86%(NaOt-Bu)

Me

N O

86%(NaOt-Bu)

(chloro substrate)

O

74%(NaOt-Bu)

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Chen and Dormer reported a copper(I) iodide catalyzed,ligand-free modification of this benzofuran synthesis us-ing o-iodo- or o-bromoaromatic ketones.108 A range ofsubstituents at the resulting 2- and 3-positions of the prod-uct benzofuran were tolerated, and the first use of an alde-hyde substrate was demonstrated, yielding 3-benzylbenzo[b]furan 113 in 92% yield (Scheme 50). Anon-water variant of this protocol was described by theSanMartin and Domínguez group, with the use of a di-amine ligand being required.109 Ackermann and Kasparalso utilized a related copper-catalyzed cyclization incombination with alkyne hydration chemistry to accessbenzofurans.110

Scheme 50

Willis and co-workers developed a second strategy toaccess benzofurans, again based on an intramolecularcarbon–oxygen bond-forming reaction. Scheme 8 high-lighted the use of aryl halide/alkenyl triflate substrates inthe synthesis of indole derivatives; the research group wasable to further demonstrate the utility of these substratesas general heterocycle precursors, through their use in acopper-catalyzed benzofuran synthesis.111 Coupling of thesame substrates with potassium hydroxide yielded benzo-furans via presumed enolate intermediates.

Lautens and co-workers reported an approach to 2-bro-mobenzofurans using an intramolecular carbon–oxygencoupling of gem-dibromovinyl phenols.31i As in the relat-ed indole chemistry (see Scheme 5), the dibromovinylphenol substrates were synthesized using a Ramirez olefi-nation process. As shown in Scheme 51, a ligand-freecopper(I) iodide catalyst was found to be effective, pro-viding the benzofurans in excellent yields.

Scheme 51

In 1999 Miura and co-workers developed a tandem palla-dium-catalyzed intermolecular carbon–carbon/intramo-lecular carbon–oxygen bond-forming reaction of benzylphenyl ketones with o-dibromoarenes to yield benzo-furans.112 A palladium(II) acetate/triphenylphosphine cat-alyzed system was found to be optimal, with high reactiontemperatures also being used (Scheme 52). The reactionsproceeded via initial palladium-catalyzed enolate C-aryla-tion, followed by palladium-catalyzed O-arylation. Theprotocol was extended to the use of phenol coupling part-

ners in place of ketones, to give dibenzofuran products(114 → 115). SanMartin, Domínguez and co-workers re-ported a similar method for the synthesis of benzo-furans;113 in their account they compared the use ofhomogeneous and heterogeneous polymer-supported pal-ladium catalysis, with the latter affording the heterocyclesin slightly inferior yields.

Scheme 52

Ma and co-workers reported a related copper-catalyzedcascade route to benzofurans. In the optimized system, b-keto esters were combined with 1-bromo-2-iodobenzenesto provide benzofurans via initial intermolecular carbon–carbon bond formation followed by intramolecular forma-tion of the carbon–oxygen bond (Scheme 53).114 Substitu-tion on both the aryl halide and keto ester was welltolerated, providing benzofurans in good yields.

Scheme 53

3.2 Benzoxazoles

The use of catalytic intramolecular carbon–oxygen bond-forming reactions has proved to be a popular route tobenzoxazoles. In 2006 Batey and Evindar developed acopper-catalyzed cyclization of o-halobenzanilides togenerate a variety of alkyl, aryl, benzyl, alkenyl, dienyland heterocyclic 2-substituted benzoxazoles (as well as ahandful of benzothiazoles – see section 4.2). As shown inScheme 54 the optimal catalyst was a copper(I) iodide/phenanthroline combination.115 The majority of examplesemployed aryl bromide substrates, although the iodo de-rivatives also performed well. A single aryl chloride ex-ample was included. SanMartin, Domínguez and co-workers reported a similar copper-catalyzed cyclization toaccess benzoxazoles. They developed two catalyst sys-tems, using either copper(I) chloride or copper(II) triflatein combination with N,N,N¢,N¢-tetramethylethylenedi-amine (TMEDA), on water, to yield the desired heterocy-

H

OBr

CuI (10 mol%)

Cl

O H

113, 92%

Cl

K3PO4DMF, 105 °C

BrOH

Br

OBr

CuI (5 mol%)

K3PO4THF, 80 °C

96%

BrBr

Ph

O

Br

Br

Pd(OAc)2 (5 mol%)Ph3P (20 mol%)

OH

t-Bu Br

Br Ot-Bu

Pd(OAc)2–4Ph3P (5 mol%)

CsCO3o-xylene, 160 °C

115, 66%

MeO

MeO

OPh

78%

Cs2CO3o-xylene, 160 °C

114

+

+

OMe

OMe

I

Br

O

OEt

O

O

CO2Et

K2CO3THF, 100 °C

CuI (10 mol%)

Cl

Cl Ph

78%

Ph+

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cles in good yields from either the o-iodo, o-bromo- or o-chlorobenzanilides.116 Similar cyclizations have also beenreported by Jiang and Ma117 and Kantam and co-work-ers.118

Scheme 54

In 2009 Sun and co-workers extended this type of cycliza-tion to the synthesis of 2-substituted oxazolopyridines.119

As shown in Scheme 55, a copper(I) iodide/diamine orcopper(I) iodide/phenanthroline catalyst system proved tobe optimal, yielding the desired heterocycles from the cy-clization of o-chloro- or o-bromopyridylamides, respec-tively.

Scheme 55

The Batey research group developed a further synthesis ofbenzoxazoles involving intramolecular carbon–oxygenbond formation. The substrates were again o-halobenza-nilides; however, these were formed in situ from the reac-tion of o-bromoanilines and acyl chlorides.70 A copper(I)iodide/1,10-phenanthroline combination was found to bethe optimal catalyst system for this one-pot strategy. Inaddition, the use of microwave irradiation gave substan-tially better results than conventional heating. A library of24 benzoxazoles was prepared, examples of which areshown in Scheme 56.

A tandem approach to benzoxazoles was reported byGlorius and Altenhoff, in which reaction of o-dihaloben-zenes with amides underwent copper(I) iodide/diaminecatalyzed carbon–nitrogen followed by carbon–oxygencross-couplings to yield the desired heterocycles.120 Ex-amples of diiodo-, dibromo- and mixed dihalobenzenes,as well as dihalopyridines (Br and Cl) were successfullycoupled to benzamide affording 2-phenylbenzoxazoles(Scheme 57). The dibromobenzene substrate was utilizedto demonstrate variation of the amide partner, giving aryl,

alkyl, vinyl and heterocyclic 2-substituted benzoxazoles.The use of o-bromochlorobenzenes allowed the regiose-lective synthesis of substituted benzoxazoles, with the re-action proceeding via initial amidation at the aryl bromideposition. Batey and co-workers had previously reportedon investigations of related processes, but had notachieved an efficient system.70

Scheme 57

3.3 Isocoumarins

In 1999 Shen and Wang described the synthesis of isocou-marins from a palladium-catalyzed reaction of gem-dibro-movinyl benzoates with an organostannane.121 Forexample, reaction of benzoate 114 with phenyltrimethyl-stannane using a trifurylphosphine-derived palladium cat-alyst delivered isocoumarin 115 in 92% yield (Scheme58). The tandem process is believed to proceed via an ini-tial Stille reaction of the ‘E’ bromide with the stannane,which is followed by an intramolecular carbon–oxygenbond-forming cyclization and ensuing elimination of me-thyl bromide. Examples using phenyl, furyl, thienyl andvinyl tin reagents gave the 3-substituted isocoumarins inmostly excellent yields, and both esters and methoxygroups could be tolerated on the aromatic ring. Willis andco-workers reported a palladium-catalyzed carbonylativeisocoumarin synthesis, commencing from the same a-(o-

O

NHN

Br


(10 mol%)

O OMe Cs2CO3DME, relfux

MeO

99%

O

N

Ph89%

O

N N

Cbz

90%

O

N

Ph

97%

N

HN

Cl N O

NCuI (5 mol%)25 (10 mol%)

K2CO3toluene, reflux

NHN

Br

N

O

NPh


(10 mol%)

Cs2CO3THF, reflux

O

Me

Ph

OMe

Cl

Cl

91%

90%

Scheme 56

NH2

Br

Cl

O

O

N


(20 mol%)

Cs2CO3, MeCN210 °C, 15 min, MWS

Me

Me

S

91%

O

N

66%Ph

O

O O

N

85%F3C

MeO

+

Br

BrH2N Ph

O CuI (5 mol%)25 (10 mol%)

K2CO3 toluene, 110 °C

O

NPh

90%

+

Scheme 58

Pd2(dba)3 (2.5 mol%)P(2-furyl)3 (15 mol%)

toluene, 100 °C O

Ph

O

PhSnMe3

115, 92%

O

O85%

O

O

O80%

S

O

Ph

O81%

MeO

114

Br

Br

O OMe

+

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haloaryl) ketone substrates previously used in benzofuransynthesis (see Scheme 49).122

4 Carbon–Sulfur Bond Formation

Relative to the carbon–nitrogen and carbon–oxygenbond-forming reactions discussed above, there are farfewer examples of catalytic aryl carbon–sulfur bond-forming processes in the literature. However, reactionsare beginning to be developed that exploit the highly nu-cleophilic character of thiols (and related functionalgroups) and synthetically useful methods with very lowcatalyst loadings are being reported.123 The number of ap-plications of these reactions to the synthesis of heterocy-cles is also growing.

4.1 Benzothiophenes

Although a number of metal-catalyzed benzothiophenesyntheses exist,1,2 few of these involve a key carbon–sul-fur bond formation using an aryl halide substrate. As dis-cussed in section 3.1, Willis et al. demonstrated the use ofa palladium-catalyzed intramolecular O-enolate arylationin the synthesis of benzofurans (see Scheme 49).106 Simi-larly, the same group showed that thio ketones, derivedfrom the same a-(o-haloaryl) ketone substrates usingphosphorus pentasulfide, could also undergo this enoliza-tion–cyclization, again using a DPEPhos catalyst systemto afford benzothiophenes.106 Scheme 59 shows an arylbromide example, although the corresponding aryl chlo-ride also underwent cyclization, albeit in a reduced 44%yield.

Scheme 59

In 2009 Lautens and co-workers extended the use of gem-dihalovinylanilines in indole synthesis (see Scheme 5) toestablish similar thiophenols as precursors for ben-zothiophenes.124 The combination of a palladium-cata-lyzed carbon–sulfur bond-forming reaction with a secondcross-coupling process, such as a Suzuki–Miyaura, Heckor Sonogashira reaction, yielded diversely functionalizedbenzothiophenes. For example, combination of thiophe-nol 116 with thiophene-3-boronic acid using an SPhos-de-rived catalyst delivered benzothiophene 117 in 99% yield(Scheme 60). The majority of examples reported involvedSuzuki chemistry; a broad range of boronic acids, as wellas other boron reagents, were readily included and al-lowed the introduction of aryl, alkenyl and alkyl C2 sub-stituents. Application of the methodology to a variety ofthiophenol backbones afforded the required heterocyclesin mostly excellent yields.

Scheme 60

4.2 Benzothiazoles

Two research groups have established benzothiazole syn-theses based on a key catalytic intermolecular carbon–sul-fur bond-forming step. In the first approach, Itoh andMase utilized a palladium-catalyzed thioetherification ofo-bromoanilides using a thiol surrogate coupling part-ner.125 For example, reaction between aryl bromide 118and thiol 119, an odorless thiol surrogate, using aXantPhos-derived catalyst, ultimately delivered ben-zothiophene 120 in 75% yield (Scheme 61). The reactionproceeded via intermediate sulfide 121, which wascleaved under basic conditions and then cyclized in thepresence of acid to generate the aromatic product. p-Methoxybenzylthiol could also be employed as the thiolsurrogate, allowing sulfide cleavage under acid condi-tions.

Scheme 61

Rather than use a thiol surrogate, Ma and co-workers ex-ploited metal sulfides in copper-catalyzed couplings witho-haloanilides to generate benzothiazoles.126 They wereable to show that sodium sulfide nonahydrate could becoupled with o-iodoanilides, and following acidic work-up, deliver the desired benzothiazole products. For o-bro-mo substrates, the use of potassium sulfide was optimal.Both systems utilized a ligandless copper(I) iodide cata-lyst; significant variation of the substrate substituents waspossible, delivering benzothiazoles in good to excellentyields (Scheme 62).

The use of an intramolecular carbon–sulfur bond-formingreaction has proved more popular in the synthesis of ben-zothiazoles. In 1982, Bowman, Heaney and Smith report-ed an intramolecular, copper-catalyzed S-arylation in thesynthesis of 2-alkyl- and 2-aryl-1,3-benzothiazoles from

BrS

S

Pd2(dba)3 (2.5 mol%)DPEPhos (22) (6 mol%)

Cs2CO3toluene, 100 °C 74%

Br

BrSH

S

PdCl2 (3 mol%)SPhos (14) (3 mol%)

K3PO4, Et3Ndioxane, 110 °C

S

B(OH)2117, 99%

S116+

HN Me

OBr

HN Me

OS

Pd2(dba)3 (5 mol%)XantPhos (2) (10 mol%)

S

NMe

NaOEt, THF, r.t.then TFA, reflux

i-Pr2NEt, dioxanereflux

FF

F

120, 75%

SH O

O

Me

Me

119

118121

+ O

OR

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o-halothioacetanilides and o-halothiobenzanilides, re-spectively.127 Castillón and co-workers extended thismethodology to a more efficient palladium-catalyzed cy-clization of o-bromothioamides (Scheme 63).128 It wasalso shown that cyclization of o-bromothioureas, preparedfrom o-bromophenylisothiocyanates and amines, afforded2-aminobenzothiazoles under similar reaction conditions(122 → 123).

Scheme 63

Batey and co-workers reported a comparison of the cop-per- and palladium-catalyzed syntheses of 2-aminoben-zothiazoles based on this same cyclization of o-bromothioureas.129 The use of copper catalysis generallyled to higher yields and conversions. Both metals werealso shown to catalyze an example of a one-pot thioureaformation–cyclization reaction in the same excellentyield. Batey’s research group also demonstrated that cy-clization of o-bromothioamides under the same copper(I)iodide/1,10-phenanthroline catalyst system afforded ben-zothiazoles in excellent yields;115 a representative exam-ple is shown in Scheme 64. Jiang and Ma reported arelated copper-catalyzed cyclization employing oxazoli-din-2-one as the ligand; a number of aryl chloride sub-strates were included in their study, and effectivelyconverted into benzothiazoles.117 Pan and co-workers re-ported a related preparation of 2-aminobenzothiazoles us-ing a copper(I) iodide/oxazoline catalyst system.130

Scheme 64

The Wu research group described the synthesis of 2-ami-nobenzothiazoles by the reaction of o-iodobenzamineswith isothiocyanates using a copper(I) iodide/phenanthro-line catalyst system (Scheme 65).131 The method was use-ful as it eliminated the need to generate an o-halobenzothiourea cyclization precursor in a separatestep, with the addition/carbon–sulfur coupling reactionoccurring in one pot. The authors exploited the method inthe preparation of an 18-membered library.

Scheme 65

A number of benzothiazole syntheses that involve tandemprocesses have also appeared in the literature. Vera andPelletier utilized tandem palladium-catalyzed carbon–sulfur and carbon–nitrogen arylation reactions to preparea series of aminobenzothiazoles.132 For example, thecombination of dibromothiobenzamide 124 and isopropyl-amine, using a JohnPhos catalyst, delivered 4-aminoben-zothiazole 125 in 47% yield (Scheme 66). As can be seenfrom the remainder of the examples in Scheme 66, it waspossible to alter the position of the second bromine sub-stituent, to generate 5-, 6-, and 7-amino-substituted prod-ucts.

Scheme 66

Patel and co-workers showed that 2-arylthiobenzothiaz-oles can be accessed from cascade intra- and intermolec-ular carbon–sulfur bond-forming reactions using a singlecatalytic system.133 A combination of o-iodo- or o-bro-modithiocarbamates and iodoarenes were subjected to acopper(I) iodide/diamine catalyst system yielding the sub-stituted benzothiazoles in mostly excellent yields(Scheme 67). The methodology was successfully appliedto the synthesis of a cathespin-D inhibitor analogue.

The same research group developed a cascade protocol forthe synthesis of 2-thio- or 2-oxa-benzothiazoles by thecopper-catalyzed reaction of o-iodo- or o-bromoaryl-isothiocyanates with a sulfur or oxygen nucleophile, re-spectively.134 The required dithiocarbamates or

Scheme 62

HN Me

OI S

NMe

CuI (10 mol%)

DMF, 80 °Cthen HCl, r.t.

HN Ph

OBr S

NPh

CuI (10 mol%)

DMF, 140 °Cthen HCl, r.t.

K2S

F F75%

88%

Na2S.9H2O+

+

HN

SBr

Me

MeMe Pd2(dba)3 (5 mol%)

JohnPhos (106)(5.5 mol%)

Cs2CO3 dioxane, 80 °C

S

N Me

Me

Me

88%

HN NMe2

SBr

Pd2(dba)3 (5 mol%)P(t-Bu)3 (5.5 mol%)

Cs2CO3 dioxane, 80 °C

S

NNMe2

123, 92%122

HN

SBr

OMe

S

NOMe

93%

CuI (5 mol%) 1,10-phenanthroline

(10 mol%)

Cs2CO3, reflux

NH2

I S

NNH


(20 mol%)

DABCOtoluene, 50 °C

SCN

99%F F+

HN Ph

SBr S

NPh

Pd2(dba)3 (10 mol%)JohnPhos (106) (20 mol%)

Cs2CO3, NaOt-Butoluene-dioxane

80 °C

H2N(i-Pr)

Br NHi-Pr

S

NPh

125, 47%

i-PrHN

16%

S

NPh

50%i-PrHN S

NPh

NHi-Pr 39%

124

+

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thiocarbamates, which were formed in situ under basicconditions, readily underwent copper-catalyzed intramo-lecular carbon–sulfur bond formation. Thiophenols andphenols showed the greatest reactivity; however, the cor-responding alkyl series could also be employed, albeit togenerate the products in reduced yields (Scheme 68).

Scheme 68

4.3 Oxathioles

Bao and co-workers reported a novel one-pot synthesis of2-iminobenzo-1,3-oxathioles using a cascade addition/intramolecular carbon–sulfur coupling process.135 o-Io-dophenols and isothiocyanates were combined using acopper(I) iodide/phenanthroline catalyst system to affordthe desired heterocycles in good to excellent yields. Arepresentative example is shown in Scheme 69.

Scheme 69

5 Conclusion

By definition, palladium- and copper-catalyzed aryl ami-nation, aryl etherification and aryl thioetherification reac-tions are transformations designed to fashion bondsbetween heteroatoms and aromatic rings. It is perhaps notsurprising that these reactions have enjoyed considerablesuccess when applied to the synthesis of aromatic hetero-cycles. The examples presented above show how these re-

actions have been exploited towards a wide range ofheterocyclic targets. They also show these reactions beingused to provide new entries to existing, classic syntheticroutes, as well as in the formulation of completely newdisconnections. As advances in the underpinning transfor-mations continue to develop – new coupling partners,more active catalysts and milder reaction conditions – thenumber of applications will undoubtedly continue togrow. The importance of heteroaromatic molecules virtu-ally assures it.

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Scheme 67

HN

I

S

S

I

S

NSAr

K2CO3DMSO, 90 °C

NH2

NH2

Me

OMe

Me72%

HNEt3

126

Ar = 4-MeOC6H4

CuI (5 mol%)126 (10 mol%)

+

NCS

Br S

NSPh


(10 mol%)

K2CO3dioxane, 90 °C

76%

S

NOPh

S

NSBn

69%(iodo substrate)

S

NO

54%

Ph

73%

Cl

HS Ph+

OH

I

SCN S

OCuI (10 mol%)

1,10-phenanthroline (20 mol%)

Cs2CO3toluene, 70–90 °C

OMe

N

OMe86%

+

Dow

nloa

ded

by: A

.E.F

avor

sky

Irku

tsk

Inst

itute

of C

hem

istr

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B R

AS

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Documents

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