Palladium-And Copper-Catalyzed Aryl Halide Amination, Etherification and Thioetherification Reactions in The Synthesis of Aromatic Heterocycles

REVIEW
Palladium- and Copper-Catalyzed Aryl Halide Amination, Etherification and Thioetherification Reactions in the Synthesis of Aromatic Heterocycles
PJessiestSlcredyt-epCdamila adu - n o r Ca l ze H t o y e ynhei E. R. Sadig, Michael C. Willis*
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK Fax +44(1865)285002; E-mail: michael.willis@chem.ox.ac.uk Received 4 August 2010; revised 13 August 2010
1 Introduction 2 CarbonNitrogen Bond Formation 2.1 Indoles 2.2 Carbazoles 2.3 Benzimidazoles and Benzimidazolones 2.4 Indazoles and Indazolones 2.5 Pyrroles 2.6 Pyrazoles 2.7 Oxazoles 2.8 Quinolones 2.9 Quinazolines, Quinazolinones and Quinazolinediones 2.10 Phenazines 2.11 Cinnolines 3 CarbonOxygen Bond Formation 3.1 Benzofurans 3.2 Benzoxazoles 3.3 Isocoumarins 4 CarbonSulfur Bond Formation 4.1 Benzothiophenes 4.2 Benzothiazoles 4.3 Oxathioles 5 Conclusion Key words: palladium catalysis, copper catalysis, aromatic heterocycles, amination, etherification
Introduction
Given the numerous applications of aromatic heterocycles in medicine, agriculture and materials, it is not surprising that a whole host of methods have been developed for their preparation. Prominent amongst these are routes based on transition metal catalyzed transformations.18 Indeed, many transition metal catalyzed processes have been developed with the explicit goal of delivering new synthetic routes to heteroaromatics. This forging of new
SYNTHESIS 2011, No. 1, pp 00010022xx. 201 Advanced online publication: 12.10.2010 DOI: 10.1055/s-0030-1258294; Art ID: E27810SS Georg Thieme Verlag Stuttgart New York
Migita described the palladium-catalyzed coupling of aminostannanes with aryl halides as early as 1983;9 however, it was not until the report of tin-free catalytic amination reactions, by Buchwald10 and Hartwig,11 that the synthetic potential of these processes began to be realized. Copper-based aryl halide amination (and amidation) chemistry has an even longer history, dating back to the original reports by Ullmann12 and Goldberg,13 but again, it was not until the development of mild catalytic variants of these reactions that the majority of applications began to be developed. In recent years both processes have undergone enormous development and now encompass a myriad of different nitrogen nucleophiles and aryl halide (and equivalent) coupling partners. Advances to carbon oxygen and carbonsulfur bond-forming variants have also been achieved. It is beyond the scope of this review to examine the development and mechanistic details of these underpinning catalytic methods, but extensive reviews of both the palladium1417 and copper1823 chemistries exist. The following discussion is divided by the key catalytic bond construction carbonnitrogen, carbon oxygen or carbonsulfur and then by heterocycle type. Where appropriate, individual heterocycles are then subdivided into intermolecular, intramolecular or cascade processes. The review is focused on the formation of aromatic heterocyles, and accordingly we have not included reports of the functionalization of intact heterocyclic cores, nor processes that lead to non-aromatic systems.
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Abstract: This article reviews the use of palladium- and coppercatalyzed aryl halide amination, etherification and thioetherification processes in the synthesis of heteroaromatic molecules. The review is structured by the nature of the key CX bond being formed, and then by heterocycle type. Where applicable individual heterocycles are further divided into syntheses based on intermolecular, intramolecular and cascade processes. In order to limit the length of the article, processes that do not deliver an aromatic heterocycle from the key CX bond-forming event are excluded. Processes for the functionalization of intact heteroaromatics are also not included.
routes, allowing the introduction of new classes of starting materials, or access to alternative substitution patterns, is one of the key advantages offered by transition metal catalysis. The last fifteen years has seen the development of efficient and user-friendly methods, based on both palladium and copper catalysis, for the formation of carbon nitrogen, carbonoxygen and carbonsulfur bonds using aryl halide substrates. Collectively, these processes present almost ideal tools for aromatic heterocycle synthesis, as witnessed by the rapidly increasing number of applications that have been published during this time. For example, reference to the first edition of Li and Gribbles excellent treatise on the use of palladium catalysis in heterocyclic chemistry,1 published in 2000, shows only a handful of examples of palladium-catalyzed aryl amination reactions being employed in the synthesis of aromatic heterocycles. This is certainly not the case today.
J. E. R. Sadig, M. C. Willis
REVIEW
2 2.1
CarbonNitrogen Bond Formation Indoles
Ph 1
N HN
Me Pent
MeO MeO 65% N H 70% N H
Ph Ph Me N H 70% (BINAP used as ligand)
A limitation of the benzophenone hydrazone methodology is the difficulty in removing benzophenone from the final indole products, particularly in large-scale applications. Cho and Lim reported a related procedure, in which N-Boc arylhydrazines were employed in Fischer cyclizations.26 The required N-Boc arylhydrazines were prepared using palladium-catalyzed amination chemistry, but in these cases were isolated before indole formation. The use of intramolecular carbonnitrogen bond formation onto an aryl halide has proved to be a popular method to achieve indole synthesis. In one of the first routes based Biographical Sketches Jessie Sadig received her MChem degree from the University of Oxford in July 2008, where she carried out her final year project under
Me
Me PPh2 O PPh2 PPh2 (rac)-BINAP (3)
PPh2
XantPhos (2)
Scheme 1
the supervision of Dr. Jeremy Robertson. She then joined the Willis group and is currently working towards her DPhil degree. Her
research focuses on palladium- and copper-catalyzed cascade processes for heterocycle synthesis.
Michael Willis received his undergraduate education at Imperial College London, and his PhD from the University of Cambridge working with Prof. Steven V. Ley, FRS. After a postdoctoral stay with Prof. David A. Evans at Harvard University, as a NATO/Royal
Synthesis 2011, No. 1, 122 Thieme Stuttgart New York
Society Research Fellow, he was appointed to a lectureship at the University of Bath in November 1997. In January 2007 he moved to the University of Oxford, where he is a University Lecturer and Fellow of Lincoln College. He was awarded an EPSRC Ad-
vanced Research Fellowship in 2005 and the 2008 AstraZeneca Research Award for Organic Chemistry. His groups research interests are based on the development and application of new catalytic processes for organic synthesis.
A number of new indole syntheses based on aryl halide amination have been developed; however, one of the first heterocycle syntheses to be reported using palladiumcatalyzed amination chemistry was concerned with intercepting reaction intermediates from a very well established route to indoles.24 In 1998 Buchwald demonstrated that a variety of aryl halides could be combined with benzophenone hydrazone using intermolecular palladiumcatalyzed amination reactions to generate the corresponding N-arylhydrazones (1, Scheme 1).25 A palladium(II) acetate/XantPhos (2) catalyst system, in combination with sodium tert-butoxide, was found to be optimal. The Narylhydrazones could either be isolated or, after simple filtration through a silica plug, treated directly with an enolizable ketone under acid hydrolysis conditions. The ensuing Fischer cyclization provided the corresponding indoles in good to excellent yields. Variations to access either N-alkyl- or N-arylindoles were also developed, although in these cases functionalization of the isolated Narylhydrazones was necessary.
on this approach, Watanabe et al. demonstrated that N,Ndimethylhydrazones derived from o-chloroarylacetaldehydes (4) underwent cyclization under the action of palladium catalysis to provide the corresponding N-aminoindoles (Scheme 2).27 Tri(tert-butyl)phosphine and the ferrocene derivative 5 were found to be the optimal ligands. The authors went on to demonstrate that if an appropriately functionalized substrate was employed, then a second palladium-catalyzed transformation could be achieved in the reactions. For example, dichloride 6 could
Br N Ph NH2 + Ph Me i) Pd(OAc)2 (0.1 mol%) XantPhos (0.11 mol%) Me NaOt-Bu, toluene, 80 C ii) TsOH. H2O, EtOH reflux O Me Ph Pent Pent Me N H 79%
REVIEW
Palladium- and Copper-Catalyzed Heterocycle Synthesis
be reacted under the standard conditions but with the addition of phenyl boronic acid, to provide 4-phenylindole 7, resulting from tandem carboncarbon and carbon nitrogen bond formation. In addition to aryl boronic acids being introduced by Suzuki couplings, a range of azoles and amines could also be effectively incorporated via a second carbonnitrogen bond-forming process.
F H Cl N NMe2 F
potassium acetate as base.29 Kondo and co-workers subsequently showed that polymer-supported substrates corresponding to 11 can also be cyclized effectively.30
CO2Et O2N 11 I HN Br
PPh2 Fe
PdCl2(dppf) (5 mol%) KOAc, DMF 90 C O2N 83% Br N
CO2Et
Pd(dba)2 (3 mol%) (4.5 mol%) NaOt-Bu o-xylene, 120 C 5

N
dppf (12)
PPh2
60% NMe2 PhB(OH)2 Pd(dba)2 (5 mol%) (7.5 mol%) Cs2CO3 o-xylene, 120 C 7 5
Ph
Cl H Cl N NMe2
NMe2
, 56%
Fe
NMe2 Pt-Bu2
Scheme 2
Doye and co-workers demonstrated that N-alkyl imines corresponding to hydrazones 4 can also be effectively cyclized under the action of palladium catalysis to provide N-alkylindoles.28 In their approach, the imine substrates were prepared from the corresponding alkynes using a titanium-catalyzed hydroamination process. In this onepot protocol, the imines were then subjected to palladium catalysis to deliver the indole products. Scheme 3 shows an example in which alkyne 8 was converted in a one-pot process into indole 9. N-Heterocyclic carbene (NHC) ligand 10 was most effective. Substrates containing a tethered amine nucleophile could also be included, leading to the formation of NC2 annulated indoles.
Pr MeO + H2N Cl 8 Me Me Me ii) Pd2(dba)3 (5 mol%) (10 mol%) KOt-Bu, dioxane 110 C Me Me Cl
+
i) [Cp2TiMe2] (5 mol%) toluene 110 C, 24 h MeO Pr N , 65% Me Me Me 9 01
Me
Me
N Me
N Me 01
Scheme 3
Isolated dehydrohalophenylalinate derivatives have been converted into indoles using related cyclizations. For example, Brown was the first to report the cyclization of enamines such as 11 (Scheme 4) into the corresponding indole-2-carboxylates. In this report from 2000, a simple dppf-derived catalyst was employed in combination with
In an elegant extension of this chemistry the same group was able to demonstrate that the corresponding pyridinederived substrates could be utilized to access azaindoles.31d The example shown in Scheme 6 illustrates the preparation of a 7-azaindole using reaction conditions almost identical to those for the parent indole series. An important modification from the parent system, needed to achieve high yields, was the use of a nitrogen-protecting group. It was also possible to extend the chemistry to the preparation of 6-azaindoles; however, the synthesis of the
Synthesis 2011, No. 1, 122
Thieme Stuttgart New York
Scheme 4
Lautens and co-workers established gem-dihalovinylanilines as versatile substrates for indole synthesis based on a series of tandem metal-catalyzed processes. The substrates were readily accessed from the relevant o-nitrobenzaldehyde derivatives via Ramirez olefinations followed by reduction of the nitro group. The early chemistry focused on tandem palladium-catalyzed intramolecular amination reactions and intermolecular Suzuki couplings to deliver a series of variously substituted indoles.31a,b For example, reaction of gem-dibromoaniline 13 with thienyl-3-boronic acid delivered the expected indole in 86% yield (Scheme 5). The electron-rich biphenyl-based phosphine SPhos (14), developed by Buchwald, proved to be optimal. Significant variation in the substitution pattern of the substrates and in the type of organoboron coupling partner was possible. For example, it was possible to prepare indoles with individual substituents at positions C2C7; N-aryl substrates could also be employed. Aryl, alkenyl and alkyl boron reagents were all used successfully. For many of the examples it was possible to use palladium loadings of only 1 mol%. Although no reaction intermediates were detected, a brief mechanistic investigation suggested that the intramolecular amination reaction preceded the intermolecular Suzuki coupling. It is interesting to note that the amination reactions took place on alkenyl halides,32 as opposed to the usual aryl halide substrates. To demonstrate the synthetic utility of the method, indole 15, prepared in 86% yield from the corresponding gem-dibromovinylaniline and 2methoxyquinoline boronic acid, was utilized in a short synthesis of KDR kinase inhibitors.31c Bisseret and coworkers also reported a single example of the synthesis of a 2-arylindole using a similar strategy.33
Br Br NH2 + S Me Br Me NH Ph N H 86% NH 73% N Me Me 77% (dichloro substrate) O MeO , 86% (2 mol% Pd) N H N MeO MeO SPhos (14) Cy2P OMe SiMe3 P(p-MeOC6H4)3 (8 mol%) Pd/C (2 mol%) CuI (4 mol%) 61 R Br Pd(OAc)2 (4 mol%) S
REVIEW
CO2t-Bu N 71 81 91 Bn , 79%
Pd(OAc)2 (1 mol%) SPhos (2 mol%) K3PO4.H2O toluene, 90 C N H 86%
t-BuO2C
Me4NCl (100 mol%) K3PO4.H2O, Et3N toluene, reflux PdCl2(PPh3)2 Ph3P (10 mol%) CO (10 atm) DIPEA, THF MeOH, 110 C
(HO)2B
BnO
Scheme 5
Br N NH Bn Br
Pd(OAc)2 (3 mol%) SPhos (14) (6 mol%)

K3PO4.H2O toluene, 100 C N N Bn
+ (HO)2B Ph
Ph
74%
Scheme 6
regioisomeric 5- and 4-azaindoles was more challenging and required the use of N-oxide substrates. Thienopyrroles could also be prepared starting from the corresponding thiophene-derived substrates. The same gem-dihalovinylaniline substrates have been utilized in a number of different tandem processes. For example, as Scheme 7 illustrates, the initial intramolecular amination reactions have been partnered with a number of alternative reactions, including Heck olefinations (16 17),31e carbonylations (16 18)34 and Sonogashira couplings (16 19),31f to deliver acrylate-, ester- and alkynesubstituted indoles, respectively. Bisseret and co-workers used the same substrates in tandem palladium-catalyzed amination/phosphonation sequences to deliver 2-phosphonate-substituted indoles.33 Tethered substrates were used in the Heck chemistry to provide polycyclic products via an intramolecular second step.31e Related tethered substrates, invoking a second intramolecular amination reaction,31g or an intramolecular direct arylation reaction,31h were also developed to access alternative polycyclic scaffolds. It is interesting to note that the double amination processes were achieved using copper catalysis. Lautens and co-workers also demonstrated that the reactivity of gem-dibromovinylanilines can be controlled to allow access to 2-bromoindoles by a single (as opposed to a tandem) palladium-catalyzed intramolecular amination reaction.31i The Willis research group has developed cascade catalytic amination strategies to access a range of indole derivaSynthesis 2011, No. 1, 122 Thieme Stuttgart New York
The Willis research group also demonstrated that similar palladium-catalyzed cascade processes can be achieved using pyridine-derived substrates to provide access to the corresponding azaindole products.35e For example, reaction of dihalopyridine substrate 24 with p-anisidine, using a DPEPhos-derived catalyst, delivered the corresponding
31 51
CO2Me N Bn , 70%
i-Pr2NH, toluene, 100 C
SiMe3 N H , 57%
Scheme 7
tives. They focused on the use of 2-(2-haloalkenyl)aryl halides, together with the corresponding alkenyl triflates, as indole substrates.35a,b Scheme 8 shows examples of both the aryl halide/alkenyl triflate (20) and the aryl halide/alkenyl halide (21) substrates in palladium-catalyzed indole-forming reactions. Both reactions feature an initial intermolecular amination reaction followed by an intramolecular amination as the second step of the cascade, to deliver N-functionalized indole products. The authors noted that it was possible to employ either Z- or E-configured alkene isomers in the process, a consequence of the initial amination reaction taking place at the alkenyl halide and generating a configurationally unstable enamine intermediate. Reactions employing the triflate substrates were best achieved using DPEPhos (22) or XantPhos (2) ligands, while the dihalide substrates delivered best yields with the Buchwald diphenyl ligands, such as SPhos (14). By selecting the appropriate class of substrate it was possible to access a number of indole substitution patterns. Significant variation of the nitrogen coupling partner was possible, with examples of aniline, amine, amide, hydrazine and sulfonamide nucleophiles all being reported. Sterically demanding nitrogen nucleophiles, such as tertbutylamine, could also be introduced;35c the ability to access indoles bearing bulky N-substituents was exploited in a synthesis of the natural product demethylasterriquinone A, in which N-(reverse prenyl)indole 23 was utilized as a key intermediate. A recent extension of the chemistry has seen trihalogenated substrates employed, allowing access to 4-, 5-, 6- and 7-chloroindoles.35d The Li research group has adapted the method to encompass trifluoromethyl-substituted substrates in order to prepare a series of N-aryl-2-trifluoromethyl-substituted indoles.36 A related intramolecular amination reaction between an aniline and an alkenyl triflate was employed by Smith and co-workers in their synthesis of the nodulisporic acids tetracycle.37
REVIEW
Pd2(dba)3 (2.5 mol%) DPEPhos (6 mol%) Cl Br 02 Ph + H2N Ph Pd2(dba)3 (2.5 mol%) SPhos (14) (7.5 mol%) NaOt-Bu toluene, 80 C 94% OTf + H2N Cs2CO3 toluene, 100 C 75% N Cl
Ph
Cl Br , E/Z 2:7
O PPh2 PPh2 DPEPhos (22)
N 71% Ph
N 32 Ph 81% , 77% Me
N Me
Scheme 8
7-azaindole in good yield (Scheme 9). The process was shown to work well for 7-azaindoles; however, access to the remaining regioisomers was less successful.
O OEt OEt N 42 Cl Br
Pd2(dba)3 (5 mol%) DPEPhos (22) (12 mol%) Cs2CO3 toluene, 110 C
O F3C
Hex Pd(OAc)2 (5 mol%) F3C (5 mol%) + H2N Cl 62 Bu CuI (10 mol%) Cl H2N + OMe KOt-Bu toluene, 105 C 69% N K3PO4 toluene, 105 C 72 92 N , 66% Bn Hex
+
OMe
83%
H2N
OMe
Ph
Scheme 9
The 2-(2-haloalkenyl)aryl halide substrates have also been shown to undergo cascade copper-catalyzed amination reactions to deliver N-functionalized indoles.35f An example featuring a carbamate coupling partner is shown in Scheme 10. Although some overlap in scope with the palladium-catalyzed version of the process was established, there were also significant differences in reactivity. In general, the copper-catalyzed variant was more limited, with chloro-substituted substrates performing poorly; however, greater success was achieved with amide nucleophiles, relative to the palladium system.
MeO MeO Br Br
Bu OMe
S N
N Ph N N O F
t-BuO 61%
t-BuO 86% i-Pr i-Pr

Cl N
CuOAc (10 mol%) (20 mol%) Cs2CO3 toluene, 110 C 52
MeO MeO N
, 94%
+
H2N O Ot-Bu
Scheme 10
52
MeN H
NMe H
Scheme 11
92
t-BuO 82%
i-Pr
i-Pr
OMe
Ackermann and co-workers developed efficient indole syntheses based on a cascade amination process starting from o-alkynylhaloarenes.38 In his original report, Ackermann described both palladium- and copper-catalyzed variants of the process (Scheme 11).38a For example, the combination of o-alkynylchloroarene 26 with benzylamine under the action of an NHC-derived palladium catalyst delivered indole 27 in 66% yield. The original copper-catalyzed protocol simply employed copper(I) iodide to combine o-alkynylchoroarenes with anilines furnishing the corresponding N-arylindoles in good yields. The reactions proceed via initial intermolecular N-arylation, followed by cyclization onto the alkyne. The two different metal systems were shown to display differing, and complementary, reactivities; for example, the palladium-catalyzed methods were effective for N-alkyl and Naryl nucleophiles, while the copper system tolerated Naryl and N-acyl substrates.38b The N-acyl systems required the use of diamine ligand 25. Scheme 11 shows several examples of products obtained using the copper methodology, including an N-acyl indole, as well as an azaindole. An indole corresponding to the Chek1/KDR kinase inhibitor pharmacophore was also prepared. The palladiumcatalyzed version of the chemistry was shown to be effective for the preparation of indoles bearing sterically demanding substituents; for example, the adamantylsubstituted indole 28 was obtained in 94% yield.38c,d The Hu39 and Sanz40 research groups have reported related indole-forming chemistries.
82
12
REVIEW
The Hsung research group employed related cascade processes for the synthesis of 2-aminoindoles.41 Scheme 12 shows an example in which ynamide 30 was combined with p-toluamine to deliver indole 31 in 85% yield. An XPhos-derived palladium catalyst was found to be optimal, and a variety of 2-carbamate-substituted indoles were prepared in good yields. The ynamide substrates were prepared, in a separate operation, by a copper-catalyzed amidation of the corresponding bromo-alkynes.
O O N Ph H2N Pd2(dba)3 (2.5 mol%) XPhos (5 mol%) Cs2CO3 toluene, 110 C N N O O
+ Br 03
p-Tol
Cy2P i-Pr
p-Tol
13
Ph , 85%
i-Pr i-Pr XPhos (32)
Scheme 12
OMe Ph N Ph
I Cl Ph
i) Pd(OAc)2 (10 mol%) CuI (10 mol%), (10 mol%) Cs2CO3 toluene, 105 C ii) KOt-Bu H2N p-Tol
Ph
(from Cl/ONf substrate)

Ph N
Scheme 14
+
H
65% p-Tol
2.2
Carbazoles
Cl
Scheme 13
The Barluenga research group developed a successful cascade process, based on palladium-catalyzed aza-enolate a-arylation followed by intramolecular N-arylation, for the synthesis of a variety of indole derivatives.42 The process is outlined in Scheme 14: Initial palladium-catalyzed aza-enolate arylation joins N-phenylimine 33 with 1,2-dibromobenzene, to provide imine 34. Palladium-catalyzed intramolecular amination, presumably via enamine intermediate 35, then delivers the expected indole in an excelSynthesis 2011, No. 1, 122 Thieme Stuttgart New York
Catalytic amination chemistry has a number of applications in carbazole synthesis. Nozaki was one of the first to exploit cascade amination processes for the preparation of a wide range of carbazole architectures.43 An example of the general process developed by the Nozaki research group is shown in Scheme 15; the key heterocycle-forming reaction is a coupling between a nitrogen nucleophile and a doubly activated biphenyl. In this particular example, ditriflate 37 was coupled with tert-butylcarbamate using a XantPhos-derived catalyst to deliver carbazole 38 in 70% yield.43b Deprotection of the Boc group from carbazole 38 revealed the natural product mukinone. The same group has exploited their methodology in the synthesis of heteroacenes,43d,e chiral carbazole variants,43a as well as
73
63
86% Ph 92
, 74%
53
33
43
Ackermann and colleagues were able to extend their original methodology to a three-component system, featuring the in situ formation of the key o-alkynylhaloarenes.38a,e The process involved the initial combination of an ochloroiodobenzene with an alkyne in the presence of a mixed palladium/copper catalyst system (Scheme 13); after two hours the required nitrogen nucleophile was introduced along with additional base, resulting in arylamination followed by a 5-endo ring closure. A variety of 1,2-disubstituted indoles were obtained in good yields. A possible limitation of the method is the poor commercial availability of alternative o-chloroiodobenzene derivatives.
Br
Ph Ph
Pd2(dba)3 (2 mol%) XPhos (32) (4 mol%) NaOt-Bu, dioxane 110 C

N 86% Ph Ph Ph Br Ph HN Ph Cl
+
Br Me
Ph
Br
Ph N Me , 91% Me Me (from I/Cl substrate)
lent 86% yield. The same XPhos-derived catalyst proved optimal for both steps of the cascade. A wide range of imine derivatives could be incorporated. The use of mixed halogen systems, such as 1-bromo-2-iodobenzenes, allowed the regioselective synthesis of substituted indoles by exploiting the greater reactivity of the aryl iodide substituent. The authors were also able to show that mixed halide/sulfonate substrates were efficient reaction components, with both triflate and nonaflate systems being successfully employed. The ability to generate the required sulfonate derivatives from the parent o-chlorophenols significantly widened the scope of the process and allowed unusual substitution patterns to be accessed, such as the 2,4,6-trisubstituted example 36.42b Although an N-aryl or N-alkyl substituent was a requirement of the imine components, the authors demonstrated that N-tert-butylsubstituted indoles could be deprotected under a variety of conditions. For example, the N-H indole derived from Ntert-butylindole 37 was obtained in 97% yield for the indole formation and deprotection (AlCl3) sequence. The group also reported a three-component variant of the methodology, in which an initial palladium-catalyzed alkenyl halide amination was used to prepare the imine reaction components.
REVIEW

Bn F3C NH Cl Br Pd(OAc)2 (4 mol%) t-Bu3P (5 mol%) NaOt-Bu toluene, reflux F3C Me N 69% Bn Me MeO N H 69% clausine P (40) OMe Me
helicenes.43b The second example shown in Scheme 15 was reported by Chida and colleagues, and shows that related strategies developed using dibromobiphenyls are also effective in carbazole synthesis.44a The example shows the preparation of a key intermediate in the synthesis of the natural product murrayazoline.44b In order to achieve an efficient transformation using the sterically demanding amine 39, it was necessary to employ a high catalyst loading (20 mol%). A copper-catalyzed version of these transformations has also been reported.45 The cascade coupling of nitrogen nucleophiles with doubly activated bi-aromatics has proven to be a powerful method for carbazole synthesis and has been exploited by several other groups. For example, Samyn and co-workers utilized dibromo-2,2-bithiophene substrates to prepare dithienopyrroles,46 as did the Barlow research group.47
O MeO OMe OTf 73 OTf + NH2 O MeO2C OMe Pd2(dba)3.CHCl3 (5 mol%) XantPhos (2) (10 mol%) K3PO4 o-xylene, 100 C 70% N-Boc mukonine (38)
+ Me
OMe N H 43%
Scheme 16
N Boc
t-BuO
OMOM Me MOMO Br Br + H2N Pd2(dba)3 (20 mol%) XPhos (32) (60 mol%) Me NaOt-Bu Me toluene, 130 C Me N O 93 O 59% murrayazoline N Ph , 93% 14 N N Ph , 93% 24 N N H MeO murrayafoline A (43) 74% from Br/Cl-Ar 72% from Cl/Cl-Ar CF3 Me N Me + Cl H N O O Cl Pd(OAc)2 (5 mol%) Cy3P (10 mol%) Ph NaOt-Bu NMP, 130 C N Ph 85% Me
Scheme 15
Bedford et al. developed a cascade sequence based on intermolecular aryl-amination followed by intramolecular direct CH arylation as a route to carbazole derivatives; several examples are shown in Scheme 16.48 The process combines o-chloroanilines with aryl bromides using palladium catalysis. Use of the bulky electron-rich tri(tertbutyl)phosphine ligand in combination with palladium(II) acetate was the optimal catalyst system and allowed the preparation of a range of carbazoles in good yields. Significant substitution could be tolerated on the coupling partners, as illustrated by the preparation of the natural product clausine P (40). Ackermann et al. developed a related aryl-amination and direct CH arylation sequence for carbazole synthesis.49 In the Ackermann approach, 1,2-dihaloaromatics were combined with anilines to deliver carbazole products (Scheme 17). A combination of palladium(II) acetate and
Scheme 17
Kan and co-workers reported a palladium-catalyzed cascade route to carbazoles based on initial intermolecular Suzuki coupling followed by an intramolecular aryl amination. A small scoping study was described, although a possible limitation is the availability of suitably functionalized boronic acids.50 Fujii and Ohno have also described a cascade route to carbazoles. In their approach, an intermolecular aryl amination between an aryl triflate and an aniline was used to construct a diphenylamine which then underwent an oxidative coupling to generate a carbazole product. The efficiency of the oxidative step was shown to be dependent on the substitution pattern of the diphenylamine intermediates.51
tricyclohexylphosphine was found to be optimal and allowed a wide range of carbazoles to be prepared. Using this catalyst system it was possible to employ inexpensive 1,2-dichloroarenes as coupling partners, as well as heterocyclic derivatives, illustrated by the preparation of pyrazine and pyridine derivatives 41 and 42. The authors exploited the methodology in a synthesis of the natural product murrayafoline A (43).49b Although less accessible, 1,2-dihaloalkenes could also be employed as substrates, allowing the same cascade sequence to be applied to indole synthesis.
REVIEW
2.3
Benzimidazoles and Benzimidazolones
H2N Me N
N Me N Me Me
N N
Cy2P Oi-Pr Me
88% 05 (from ArCl using ligand )
83% 05 (using ligand )
i-PrO RuPhos (50)
Scheme 19
H N I H2N 44 + O
CF3 CuI (10 mol%)

L-proline (20 mol%)
N CF3 N , 94% 54
K2CO3, DMSO, r.t.
H N I O
O i) CuI (10 mol%)

L-proline (20 mol%)
N N , 73% 64
Buchwald and Zheng also described a complementary copper-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 oiodo-N-alkylaniline 51, followed by base-promoted cyclization, delivered the desired N-alkylbenzimidazole 52 in 87% yield. Alkyl, alkenyl and aryl amides could all be incorporated effectively.
H N F3C I + H2N 15 Pent O Me i) CuI (5 mol%) (20 mol%) Cs2CO3, dioxane, 90 C ii) K3PO4 t-BuOH, 110 C 52 F3C N Pent N , 87% Me 25
+ H2N
K2CO3, DMSO, 40 C ii) AcOH, 140 C
H N I H2N 74 + N O
OMe CuI (10 mol%) L-proline (20 mol%) K2CO3, DMSO 50 C then 130 C , 74%
H N O N 84
Scheme 20
Boc N H H O L-proline
OH
N Boc
Scheme 18
Buchwald and co-workers developed a related palladiumcatalyzed route to aryl-substituted benzimidazoles. For example, the coupling of o-bromacetanilide 49 with otoluamine using an XPhos-derived catalyst provided the corresponding N-arylbenzimidazole in 94% yield
Intramolecular aryl amidation using urea substrates has been achieved using both palladium and copper catalysis and provides a further route to benzimidazolones (Scheme 21). The cyclization of urea 53, using a palladium(II) acetate/XPhos catalyst system, was described by the process group at Merck.55 Chloro-, bromo- and iodoaryl derivatives could all be employed as substrates, as could chloropyridines. Copper-catalyzed variants of similar cyclizations have also been reported,56 including a polymer-supported example;57 the second reaction shown in Scheme 21, reported by SanMartin, Domnguez and co-
94
A host of approaches to benzimidazoles and related derivatives, featuring inter- and intramolecular and cascade reactions, as well as both palladium and copper catalysts, have been reported. Ma and co-workers developed a number of copper-catalyzed routes to these important heterocycles.52 In 2007, they demonstrated that o-haloacetanilides could be combined with primary amines to deliver benzimidazoles (Scheme 18). For example, a copper(I) iodide/proline catalyst system was effective for the union of aryl iodide 44 with allylamine, to furnish benzimidazole 45 in 94% yield.52a When more sterically demanding amines, or less activated aryl units, were employed it was necessary to use either heat or an acid/heat combination to achieve cyclization to the aromatic system; for example, the formation of cyclohexyl-substituted benzimidazole 46 required the addition of acid. A broad range of amines and aryl units, including pyridine derivatives, could be included in the method, delivering benzimidazoles in good to excellent yields. Although Scheme 18 shows only aryl iodide substrates, aryl bromides were also used. When the starting substrates were changed to o-iodoarylcarbamates, the same reaction system was used to access benzimidazolones (47 48).52b Aqueous ammonia could also be employed as the nitrogen nucleophile in both reaction pathways, leading to the corresponding NH derivatives.52c
(Scheme 19).53a A good range of anilines and aryl substrates (both Br and Cl) were described; Scheme 19 also shows an aza-example, derived from the corresponding pyridine substrate, as well as a cyclopropyl-substituted product. Some variation of ligand between XPhos (32) and RuPhos (50) was needed for certain substrates. In 2006, Scott reported a palladium-catalyzed synthesis of imidazopyridinones (aza-benzimadazolones) in a process analogous to the conversion of 47 into 48 shown in Scheme 18.54
Br H N Br O Br Pd2(dba)3 (1 mol%) XPhos (32) (8 mol%) K3PO4 t-BuOH, 110 C Me 94% N Me N Me
Me
Me
REVIEW
PMB N Cl O NH2 PMB
Pd(OAc)2 (1 mol%) XPhos (32) (3 mol%) NaHCO3 i-PrOH, 83 C 92% CuI (8.5 mol%) TMEDA (3.5 equiv) H2O, 120 C
MeO
N O N H Bn
Bn N MeO Br O NH2
prepared in good yields. Szczepankiewicz et al. applied this type of copper-catalyzed cyclization to substrates based on uracil templates to prepare purine and related fused imidazole systems.64 2-Mercaptobenzimidazoles can similarly be accessed using copper-catalyzed cyclization of in situ generated isothioureas.65 The research groups of both Zhang66and Wu67 showed that o-halophenylimidoyl chlorides are effective substrates for copper-catalyzed benzimidazole synthesis. Scheme 24 presents an example from the Zhang group, and shows how imidoyl chloride 55 can be combined with benzylamine using a copper(I) iodide catalyst, to deliver the expected benzimidazole in excellent yield. Both alkyland arylamines could be employed. In both reports it was necessary to include an electron-withdrawing substituent on the imidoyl chloride substrate; for example, the trifluoromethyl substituent on imidoyl chloride 55.
N I Cl CF3
Scheme 21
workers,58 illustrates a copper(I) iodide catalyzed cyclization using water as the solvent. Intramolecular reactions to access benzimidazoles can be achieved using amidines as substrates. An example, reported by Brain et al.,59 is shown in Scheme 22 in which amidine 54 was converted into the corresponding benzimidazole under the action of a Pd2(dba)3/triphenylphosphine catalyst. The authors were also able to show that use of a catch-and-release purification strategy,59b involving Amberlyst resin, allowed the benzimidazoles to be obtained in pure form without recourse to chromatography. Related cyclizations in which the amidine is embedded within a heterocycle have also been described.60,61 De Meijere and Lygin reported that amidines, generated in situ from an isocyanide and a primary amine, can also be cyclized using copper(I) conditions to access N-alkylbenzimidazoles.62
Me N Br 45 Me NHMe Pd2(dba)3, (1.5 mol%) Me Ph3P (12 mol%) NaOH, H2ODME 160 C, MW N Me N 82% Me
CuI (10 mol%) TMEDA (20 mol%) Cs2CO3 toluene, 110 C
N CF3 N
+
H2N Ph
98%
Ph
Scheme 24
Scheme 22
Scheme 25
Me
Me
N Br HN Bn N
Pd(PPh3)4 (10 mol%) Cs2CO3, DME, 80 C or CuI (5 mol%) 1,10-Phen (10 mol%) Cs2CO3, DME, 80 C
N N Bn N
Pd: 66% Cu: 90%
Batey and co-workers described a copper-catalyzed cascade route to benzimidazoles from the combination of a 1,2-dihalobenzene with an amidine, although only a single example was reported.70 Deng et al. reported a related cascade in which amidines were exchanged for guanidines, leading to the synthesis of 2-aminobenzimidazoles (Scheme 26). The majority of examples delivered NH products, although N-substitution could also be introduced.71
Scheme 23
65
Batey and Evindar used related cyclizations employing guanidine substrates to access 2-aminobenzimidazoles.63 Efficient reactions were achieved using either palladium or copper catalysis; Scheme 23 gives an example of the reaction conditions needed for each metal. In general, the copper conditions were found to be superior, providing higher yields and more selective reactions. Both aryl iodides and aryl bromides could be employed as substrates, allowing a broad range of 2-aminobenzimidazoles to be
Maes and co-workers explored a range of cascade amination strategies to access a variety of benzo-fused benzimidazole systems.68 In their lead publication, they were able to combine 2-chloro-3-iodopyridine with 2-picoline to generate dipyridoimidazole 56 in 96% yield (Scheme 25). The example shown employs a palladium(II) acetate/ BINAP catalyst, although XantPhos (2) was also shown to be an effective ligand.68a The chemistry has been extended to the preparation of a number of benzo-fused and aza analogues,68ac,69 and in an interesting application a temperature/halide dependent regioselectivity switch was developed.68d
I
+
N Cl N NH2
Pd(OAc)2 (3 mol%) BINAP (3) (3 mol%) Cs2CO3 toluene, reflux

N
N N
, 96%
55
35
N O N H
92%
10
Me
I Br
REVIEW
CuI (15 mol%) (30 mol%) 52 Cs2CO3 DMA, 165 C
Me
N N N H 53% O
+
HN N H2N O
Scheme 26
Pabba et al., required a two-step one-pot approach in which a ten-minute microwave reaction was used to form the hydrazone before a copper(I)/diamine catalyst was added to the system (62 63).77 Del Olmo and co-workers reported a related copper-catalyzed process which also allowed the use of aryl carboxylic acid substrates to deliver 1-hydroxy-1H-indazoles.78
O PdCl2 (2 mol%) dppp (3 mol%) MeO N MeO , 65% 16 N
2.4
Indazoles and Indazolones
MeO MeO 06
NHMe NHMe
Scheme 28
Guillaumet and co-workers reported an intermolecular copper-catalyzed amination method for the preparation of pyrazolopyridines (azaindazoles).79 3-Cyano-2-chloropyridine was combined with a range of hydrazines using a copper(I) iodide/phenanthroline catalyst to deliver 3-amino-1H-azaindazoles in good yields (Scheme 29). The 3amino products were converted into the corresponding 3iodo derivatives by way of their diazonium salts, and were employed in a range of palladium-catalyzed coupling processes including Stille, Heck and Suzuki reactions.
CN
N Br 75
H N Me
Me Pd(dba)2 (2 mol% DPEPhos (22) (2 mol%) K3PO4 toluene, 110 C Me , 85% 85 N
N Me N
+
Cl
Et
H N
CuI (5 mol%) 1,10-phenanthroline (10 mol%)

NH2
NH2 N N 86% Et
Cs2CO3 DMF, 60 C
MeO
NH HN Br 95
MeO Pd(OAc)2 (5 mol%) dppf (12) (7.5 mol%) NaOt-Bu toluene, 90 C 87%
N N
N N 1,10-phenanthroline
Scheme 29
Scheme 27
There are a number of reports of halo-substituted hydrazones being formed in situ and then cyclized to yield 1Hindazoles; Scheme 28 presents examples using both palladium and copper catalysis. Cho et al. were able to show that o-bromobenzaldehydes could be combined with phenylhydrazine using a palladium(II) chloride/dppp catalyst system to furnish the corresponding indazoles in good yields (60 61).76 The copper example, reported by
The less thermodynamically stable 2H-indazole isomers can also be accessed using amination chemistry. In an approach mirroring their route to the 1H-isomers (see Scheme 27), Song and Yee employed a palladium-catalyzed cyclization of appropriately substituted hydrazines.80 For example, N-alkyl-N-arylhydrazine 65 was converted 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 similar chemistry.81
36
46
46
26
Indazoles have proven to be popular targets for amination chemistry. A number of groups have described the cyclization of appropriately substituted arylhydrazones. Scheme 27 illustrates an intramolecular coupling of bromo-substituted arylhydrazone 57 to deliver 1H-indazole 58 in 85% yield.72 The DPEPhos-derived catalyst system was effective for a wide range of substrates, although aryl chloride substrates performed poorly. Analogous N-tosylhydrazones were also established as effective indazole precursors,73a and were utilized in a synthesis of the natural product nigellicine.73b 3-Amino-1H-indazoles were also prepared by similar palladium-catalyzed cyclizations.74 Song and Yee demonstrated that appropriately substituted hydrazines are also useful indazole precursors. For example, palladium-catalyzed ring closure using hydrazine 59 delivered the corresponding aromatic 1H-indazole directly in 87% yield, following intramolecular amination and spontaneous aromatization.75 The mechanism of aromatization was not established. The authors noted the instability of certain hydrazine substrates to long-term storage, and as alternatives established that the corresponding N-triphenylphosphonium bromide salts provided convenient stable precursors that could be cyclized under identical reaction conditions.
NaOt-Bu + H2N NH toluene, 100 C Br Ph O
i) NMP, 160 C 10 min, MW H + H2N NH ii) CuI (5 mol%) (10 mol%) Br Ph K2CO3, 160 C 10 min, MW
F N N , 84%
REVIEW
MeO Br 56 Ph

Pd(OAc)2 (5 mol%) MeO dppf (12) (7.5 mol%)
N Ph
11
NH2
NaOt-Bu toluene, 90 C 66
, 60%
Scheme 30
Pr Pr
Ot-Bu
Cs2CO3 THF, 80 C
Pr
N Boc , 86%
SiMe3
Me Pr
Pr
Bu
S N SiMe3 N Boc SiMe3 N Boc
Ph
Ph
Cl
+ H2N NH Ph
Cs2CO3 DMF, 110130 C
N Ph N 79% OEt Bu Bu 37 Bu Bu
Ph N Ph N H
CO2t-Bu OEt N Ph N N Ph N 55%
+ I H2N
Ph
Cs2CO3 dioxane, 100 C
93%
Scheme 33
Scheme 31
Indazolones can be prepared by the copper-catalyzed cyclization of o-halobenzohydrazides. For example, treatment of hydrazide 68 with a copper(I) iodide/proline catalyst system delivered indazolone 69 in 60% yield (Scheme 32).83 Iodo substrates delivered the most efficient reactions; the bromo and chloro substrates were also shown to deliver the desired products, albeit in reduced yields.
O N H I 86 O H N
L-proline
Buchwald and colleagues reported a complementary stepwise approach to pyrroles also based on copper-catalyzed alkenylation reactions.86 N,N-Di(Boc)-protected alkenylhydrazides 74, themselves prepared by copper-catalyzed alkenylation reactions, were coupled with a second alkenyl iodide to generate bis(ene)hydrazide 75 (Scheme 34). Thermolysis triggered a [3,3] rearrangement to generate bis-imine 76, cyclization of which provided the pyrrole
Boc Pr N N H Boc I
CuI (10 mol%) (20 mol%) N , 60% 96
NH 47 Pr
(i) CuI (10 mol%) 1,10-phenanthroline (20 mol%) Cs2CO3, DMF 80 C, 30 h ii) o-xylene, 140 C, 30 h iii) p-TsOH, r.t.
Pr
K2CO3, DMSO r.t. to 70 C
Oct
Scheme 32
Pr
Boc
Boc
Boc
N N
[3,3]
Pr Oct Pr
2.5
Pyrroles
Pr 57
Scheme 34
77
67
The Buchwald and Li research groups both reported cascade copper-catalyzed alkenyl amidation routes to pyr-
46
CuI (20 mol%) (20 mol%)

N O 86% Ph
68% Boc
Boc N N Pr Oct
Pr
27
PdCl2 (5 mol%) Pt-Bu3 . HBF4 (10 mol%)
Boc
98%
80%
, 83%
Pr
Oct
Boc N
H NBoc
Oct
+ H2N
17
52
07
Halland, Lindenschmidt and co-workers reported an alternative route to the 2H-indazole isomers employing the same o-alkynylhaloarene substrates used successfully by others to access indoles (see Schemes 11 and 12). The reactions proceeded via an initial regioselective amination reaction using a monosubstituted hydrazine to generate an N,N-disubstituted hydrazine, which then underwent intramolecular hydroamination to form a dihydroindazole intermediate (67, Scheme 31).82 Isomerization from these intermediates to the aromatic 2H-indazoles occurred spontaneously under the reaction conditions of palladium(II) chloride/tri(tert-butyl)phosphine with cesium carbonate in N,N-dimethylformamide. Good functional group tolerance was demonstrated and an extensive range of substituted products was described; three examples are shown in Scheme 31.
roles. The Buchwald group utilized a copper(I) iodide/ diamine 25 catalyst system to combine carbamates (and a limited number of amides) with 1,4-diiodo-1,3-dienes to generate highly substituted pyrrole products (70 71, Scheme 33).84 The methodology displayed excellent functional group tolerance and was applied to the synthesis of a wide range of pyrroles, including tetrasubstituted examples. The method was also applicable to the synthesis of heteroarylpyrroles, such as thienopyrrole 72. The Li approach exploited similar diene substrates in combination with a range of amide coupling partners.45,85 For example, diiododiene 73 was combined with phenylacetamide using a copper(I) iodide/diamine 64 catalyst to deliver the expected pyrrole in 86% yield (Scheme 33).
SiMe3 I O Pr
CuI (5 mol%) (20 mol%)
76
12
REVIEW
via intermediate 77. For certain substrates it was necessary to add acid to achieve complete conversion into the aromatic system. The bis(ene)hydrazides could be isolated, or more conveniently used directly in the next step of the sequence with no purification. The overall method represents a modified PilotyRobinson reaction. The final pyrrole synthesis considered here comprises a copper-catalyzed cascade alkenyl amidation/hydroamination sequence. The process is essentially a pyrroleforming version of the indole synthesis described in Scheme 11. In this approach, described by Buchwald and co-workers, haloenynes such as 78 replace the alkynylhaloarenes used for indole synthesis, and, when combined with tert-butyl carbamate and a copper(I) iodide/diamine catalyst, provide the corresponding pyrroles in good yields (Scheme 35).87 A broad range of di- and trisubstituted pyrroles were prepared, and although the study focused on the use of iodoenynes, it was also possible to employ bromoenynes. A brief mechanistic study established that the reactions likely proceed via initial intermolecular aryl carbonnitrogen bond formation followed by a 5-endo-dig intramolecular hydroamination.
Pent
bromo-enal 80 with phenylhydrazine in the presence of a dppf-derived catalyst yielded pyrazole 81 in 77% (Scheme 37). Both cyclic and acyclic substrates could be employed, although no ketone-derived substrates were reported. Haddad and co-workers developed a pyrazole synthesis in which aryl benzophenone hydrazones, prepared by the palladium-catalyzed coupling of benzophenone hydrazone with aryl halides, were treated with a range of 1,3-bifunctional substrates under acidic conditions.89 1,3Diketones, keto esters and ester/acid chlorides could be combined with the hydrazones to provide a range of substituted pyrazole products.
O H
Pd(OAc)2 (5 mol%) dppf (12) (7.5 mol%) +

H2N NH NaOt-Bu, toluene 125 C Ph N
N Ph
Br 08
, 77%
Scheme 37
2.7
Oxazoles

Pent
OTIPS N Boc 83%
OTIPS
t-BuO
+
O
NH2
Cs2CO3 THF, 80 C
Scheme 35
2.6
Pyrazoles
O H2N Ph
+ Ph
Ph Ph
H N O 28
Ph
Cho and Patel reported a pyrazole synthesis based on the palladium-catalyzed combination of b-bromovinyl aldehydes with hydrazines.88 For example, treatment of
Pent (i) CuI (5 mol%) (20 mol%) I H N + N H Boc OTIPS 52 Cs2CO3 THF, 80 C ii) TFA, CH2Cl2, r.t. Pent N N H , 78% OTIPS
Scheme 38
2.8
Quinolones
Boc
Scheme 36
Manley and Bilodeau used palladium-catalyzed intermolecular aryl halide amidation followed by an in situ aldol condensation to prepare 2-quinolones.91 In this way o-bromobenzaldehydes were combined with a range of enolizable amides to deliver the quinolone products. Scheme 39
52
Buchwald and co-workers utilized haloenyne substrates in a tandem copper-catalyzed pyrazole synthesis.87 For example, combination of iodoenyne 78 with bis(Boc)hydrazine using a copper(I) iodide/diamine catalyst provided pyrazole 79 in 78% yield after Boc-deprotection with trifluoroacetic acid (Scheme 36). As in the related pyrrole syntheses, a good range of di- and trisubstituted aromatics were prepared. The mechanism was again established as proceeding via intermolecular aryl carbonnitrogen bond formation followed by intramolecular hydroamination, although the cyclizations were in this case 5-exo-dig processes.
Buchwald and co-workers utilized copper-catalyzed alkenyl iodide amidation reactions as the key step in a route to oxazoles.90 For example, enamides such as 82 could be treated with iodine and base to provide the expected trisubstituted oxazoles in good yields (Scheme 38). The required enamides were prepared from the corresponding alkenyl bromides using a copper(I) iodide/diamine-catalyzed coupling with the appropriate amide; both aryl and alkyl amides could be used. Depending on the substitution pattern of the oxazole product, certain examples required the addition of p-toluenesulfonic acid to achieve complete conversion into the aromatic molecule. Attempts to prepare mono- and disubstituted oxazoles using this method resulted in complex reaction mixtures, and an alternative process, based on the use of 1,2-dihaloalkene substrates, was developed.
i) CuI (5 mol%) (20 mol%) Ph Cs2CO3, THF, 80 C ii) I2, DBU r.t. to 80 C Ph
Ph
Br
N Ph O 77%
Ph Ph
I N Ph O H
18
97
52
87 87
REVIEW
13
illustrates the combination of the parent aldehyde (83) with phenylacetamide using a XantPhos-derived catalyst in combination with cesium carbonate as base. A variety of substituted amides could be employed, as could ketonebased substrates, allowing the synthesis of 4-substituted products such as quinolone 84. Pyridine derivatives could also be employed, thus providing a route to naphthyridinones. Ester- and nitrile-substituted aryl bromides were also examined and allowed access to hydroxy- and aminosubstituted products, respectively. For a small number of amide coupling partners, the researchers were able to employ a copper(I) iodide/diamine catalyst system.
O O H + H2N Br 38 Ph
sary to isolate the initial amidation products before cyclization.93 A tandem Heck/intramolecular amidation strategy was reported by Cacchi and co-workers as a route to 4-aryl-2quinolones.94 Using molten tetrabutylammonium acetate/ tetrabutylammonium bromide as the reaction medium and a simple palladium(II) acetate catalyst, the combination of o-bromophenylacrylamides (88) and aryl iodides provided the quinolone products in moderate to good yields (Scheme 41). Although only a single acrylamide substrate was employed, a good range of aryl iodide coupling partners could be incorporated. A brief mechanistic investigation supported the Heck followed by intramolecular amidation pathway.
Pd2(dba)3 (1 mol%) XantPhos (2) (3 mol%) Cs2CO3 toluene, 100 C

Ph N H
Ph O
O NH2
N N H 94% O N H , 55%
Ph O
N N H 75%
Ph Br O
+
I
Pd(OAc)2 (5 mol%)
n-Bu4NOAc, n-Bu4NBr 120 C
N H 75%
Scheme 39
Scheme 41
Huang et al. utilized the related o-acetylbromoarenes as substrates in a palladium-catalyzed synthesis of 4-quinolones. The simplest version of the process employed formamide as the nitrogen nucleophile and, when coupled with bromide 85, delivered quinolone product 86 in 77% yield (Scheme 40).92 The reactions proceeded via initial palladium-catalyzed amidation followed by a base-promoted intramolecular condensation step. A XantPhosderived catalyst in combination with cesium carbonate as base was optimal for the amidation step, and the addition of sodium tert-butoxide as a second base was found to be necessary to achieve high yields for the combined process. As can be seen from the examples presented in Scheme 40, a range of substituted amides could be employed, including lactams, which allowed the synthesis of N-fused products such as quinolone 87. The Buchwald research group reported a related process based on coppercatalyzed amidation, although in their case it was necesO O Me MeO O 58
Willis and co-workers exploited 2-(2-haloalkenyl)aryl halide substrates, previously employed in indole syntheses (see Scheme 8), in the preparation of 2-quinolones.95 A cascade palladium-catalyzed carbonylation/intramolecular amidation sequence was employed to access a range of quinolone products. For example, combination of the simple dibromide 89 and p-methoxybenzylamine under a balloon pressure of carbon monoxide delivered quinolone 90 in 80% yield (Scheme 42). Although all of the products shown in Scheme 42 were obtained using a dppp-derived catalyst, the researchers found that ligand variation was needed for particular substrate/amine combinations. In addition, purging the reaction of carbon monoxide was shown to benefit the efficiency of certain amidation reactions. By delaying the introduction of the carbon monoxide and running the reaction in a two-stage process, it was also possible access the regioisomeric isoquinolone products, although in these cases competing indole formation was problematic.
CO (balloon) Pd2(dba)3 (3 mol%) dppp (6 mol%) Br Br
Pd2(dba)3 (1 mol%) XantPhos (2) (2.5 mol%)

H
+ H2N
, 77%
O
O Me
OMe O O MeO N Oct O O N Oct O N N Oct O
N H
N H S
Scheme 40
78
82%
91%
, 85%
69%
65%
Scheme 42
09
98
+ Br
H2N
68
Cs2CO3, dioxane 100 C, 248 h then MeO NaOt-Bu, 100 C
N H
Cs2CO3, toluene 100 C
N PMB , 80%
73%
94%
88
48
14
REVIEW
O OH + H2N Br Me O NH N 69 75% N , 81% NH N 79 O N , 56% O Ph N H + H2N CuI (10 mol%) NH K2CO3 DMF, 80 C 99 N , 77% N Ph 49 39 CuI (20 mol%) NH.HCl Cs2CO3 DMF, r.t. O NH N , 81% Ph N N Me
2.9
Quinazolines, Quinazolinones and Quinazolindiones
I 89
AcOH
O Cl Br 19 OMe O N H NH2
Pd2(dba)3 (2.5 mol%) Cl XantPhos (2) (5 mol%) Cs2CO3 dioxane, 100 C 29

N H , 77%
Bu O
+ Bu
Scheme 43
O O N H CN Br 201 N N N 91% luotonin (103)
Scheme 45
2.10
Phenazines
Li and co-workers reported a cascade process involving in situ amidine formation followed by palladium-catalyzed
The Kamikawa and Beifuss groups have both reported intramolecular palladium-catalyzed aryl-amination routes to phenazines. Both explored the ring-closure of 2-amino2-bromodiphenylamines to access the target systems. Scheme 46 shows an example from Beifuss and co-workers, in which a JohnPhos-derived catalyst was used to convert aniline 104 into phenazine 105 in 76% yield.100 The Kamikawa research group utilized BINAP-derived cata-
101
001
The Fu research group reported a related strategy for the synthesis of quinazolinones and quinazolines. In their original report, they exploited a copper-catalyzed coupling of amidines with o-bromobenzoic acids to access quinazolinones. For example, acid 93 was combined with acetimidamide 94 to provide quinazolinone 95 in 81% yield (Scheme 44).97a The reaction conditions consisted of copper(I) iodide without any added ligand, in N,N-dimethylformamide at room temperature. The ability to use such low-temperature conditions was attributed to the formation of a chelated intermediate involving the oxygen atom of the ortho-positioned carboxylic acid. The reaction was applicable to a broad range of amidines and benzoic acids. The researchers next extended the chemistry to include guanidines as the nitrogen nucleophiles, resulting in the formation of 3-aminoquinazolinone products such as 96.97b The carboxylic acid substrates could also be replaced; the use of the related ketones in combination with guanidines resulted in the synthesis of 3-aminoquinazolines such as 97. Ding and co-workers reported an alternative copper-catalyzed route to quinazolinones based on the use of o-iodobenzamide substrates.98 A typical reaction is shown in Scheme 44: coupling of benzamide 98 with formimidamide, using copper(I) iodide as catalyst, provided quinazolinone 99 in 77% yield. The method was shown to tolerate reasonable variation of both reaction components.
cyclization as an entry into ring-fused quinazolinone derivatives. The key amidine intermediates were generated from intramolecular amide addition to a nitrile; the nitrile group also being introduced by a palladium-catalyzed process.99 Scheme 45 outlines the overall conversion, with aryl iodide 100 being transformed into quinazolinone 101 in 91% yield. A DPEPhos-derived catalyst was effective for both the initial cyanation reaction to generate nitrile 102, and then to achieve the final ring closure from the proposed amidine intermediate to give quinazolinone 101. Using a bromoquinoline-derived substrate, the authors were able to apply the methodology to a synthesis of the natural product luotonin (103).
O NH I Br + KCN Pd(OAc)2 (5 mol%) DPEPhos (22) (10 mol%) dioxane, reflux then dppf (10 mol%) K2CO3 O N N , 91%
Scheme 44
59
In 2006 Willis and co-workers reported the palladiumcatalyzed coupling of o-bromobenzoate esters with monosubstituted ureas as a route to 3-alkylated quinazolinediones.96 The reactions proceeded via initial intermolecular carbonnitrogen bond formation followed by intramolecular, base-promoted, amidation. A XantPhosderived catalyst in combination with cesium carbonate allowed efficient and regioselective processes; for example, bromobenzoate 91 was combined with N-butyl urea to provide quinazolinedione 92 in 77% yield as a single regioisomer (Scheme 43). A variety of substituents were tolerated on both the aryl bromide and urea coupling partners. The observed regiocontrol originates from the initial aryl carbonnitrogen bond formation taking place at the least hindered nitrogen of the urea nucleophile.
REVIEW
NH2
15
H N Br
Pd2(dba)3 (3 mol%) JohnPhos (6 mol%) NaOt-Bu toluene, 100 C MeO P(t-Bu)2 501
N N , 76%
MeO
cyclization to the required benzofurans (109 110, Scheme 48). Yous research group went on to develop a copper-catalyzed version of the hydroxylation reaction and also demonstrated its use in benzofuran synthesis, in this case from an o-iodoarylalkyne to generate benzofuran 112.105
S F3C Cl 901 KOH F3C Pd2(dba)3 (2 mol%) t-BuXPhos (8 mol%) H2O, dioxane 100 C KOH Ph CuI (10 mol%) 1,10-phenathroline (20 mol%) I H2O, DMSO 100 C O , 87% 011
Scheme 46
lysts.101 In both cases the phenazine ring system was isolated directly from the amination reactions.
2.11
Cinnolines
, 86%
t-Bu2P
i-Pr i-Pr
i-Pr t-BuXPhos (111)
Scheme 48
OTBS CO2t-Bu HN Ac N
OTBS
CuI (10 mol%) (10 mol%) 52 Cs2CO3 DMSO, r.t. , 89% 801
N Ac N
CO2t-Bu
Scheme 47
CarbonOxygen Bond Formation
Initially, the development of catalytic carbonoxygen bond-forming processes using aryl halide substrates lagged behind the corresponding carbonnitrogen forming reactions; however, efficient methods, using both palladium and copper catalysts, are now well established.
A greater number of research groups have utilized intramolecular carbonoxygen bond formation as the key step in benzofuran syntheses. In 2004 Willis et al. demonstrated the use of a-(o-haloaryl) ketones as precursors to the required oxygen heterocycles via an enolization/palladium-catalyzed intramolecular O-arylation reaction, with a Pd2(dba)3/DPEPhos catalyst system proving optimum for the process (Scheme 49).106 The starting ketones were themselves formed by a palladium-catalyzed ketone arylation; however, attempts to achieve a one-pot combination of these processes was not straightforward, and after optimization only a single high-yielding example of the cascade could be achieved. Kotschy and co-workers showed that the same cyclization of o-bromobenzyl ketones, which they accessed from aromatic aldehydes and 2-bromobenzyl bromide using dithiane chemistry, is possible using a palladiumNHC catalyst system.107
3.1
Benzofurans
Pd2(dba)3 (2.5 mol%) DPEPhos (22) (6 mol%) Br O Cs2CO3 toluene, 100 C O 95% Me Ph N F O O 74% (NaOt-Bu)
Few examples of benzofuran syntheses that proceed via a metal-catalyzed intermolecular (aryl)carbonoxygen bond-forming reaction exist. In one example, Buchwald and co-workers were able to apply their palladium-catalyzed phenol synthesis to the preparation of benzofurans.103 The chemistry was based on the use of potassium hydroxide as a nucleophile in the palladiumcatalyzed hydroxylation of aryl halides to provide phenols. When applied to benzofuran synthesis, o-chloroarylalkyne substrates reacted with potassium hydroxide in the presence of t-Bu-XPhos as catalyst, to give o-hydroxyalkynylarenes, which, as previously shown,104 undergo
86% (NaOt-Bu)
86% (NaOt-Bu) (chloro substrate)
Scheme 49
211
An intermolecular copper-catalyzed aryl amination was used by Nishida and co-workers to access cinnoline derivatives. In the example shown in Scheme 47, hydrazonesubstituted aryl iodide 107 was converted into N-acyldihydrocinnoline 108 using a copper(I) iodide/diamine catalyst.102 The use of superstoichiometric amounts of catalyst led to mixtures of N-acyl product 108 together with smaller amounts (up to 40%) of the aromatic cinnoline being obtained. Cyclization of hydrazines derived from hydrazone 107 allowed access to 1-aminoindoles.
401 701
JohnPhos (106)
Cl
Cl Ph O
16
REVIEW
Chen and Dormer reported a copper(I) iodide catalyzed, ligand-free modification of this benzofuran synthesis using o-iodo- or o-bromoaromatic ketones.108 A range of substituents at the resulting 2- and 3-positions of the product benzofuran were tolerated, and the first use of an aldehyde substrate was demonstrated, yielding 3benzylbenzo[b]furan 113 in 92% yield (Scheme 50). An on-water variant of this protocol was described by the SanMartin and Domnguez group, with the use of a diamine ligand being required.109 Ackermann and Kaspar also utilized a related copper-catalyzed cyclization in combination with alkyne hydration chemistry to access benzofurans.110
Cl
ners in place of ketones, to give dibenzofuran products (114 115). SanMartin, Domnguez and co-workers reported a similar method for the synthesis of benzofurans;113 in their account they compared the use of homogeneous and heterogeneous polymer-supported palladium catalysis, with the latter affording the heterocycles in slightly inferior yields.
MeO O MeO + Ph Br Br OH Pd(OAc)2 (5 mol%) Ph3P (20 mol%) Cs2CO3 o-xylene, 160 C O 78% Br + Br 411 Pd(OAc)24Ph3P (5 mol%) O Ph OMe OMe
t-Bu
H Br O
CuI (10 mol%) K3PO4 DMF, 105 C

O H
Cl
t-Bu
, 92%
, 66%
Scheme 50
Scheme 52
Willis and co-workers developed a second strategy to access benzofurans, again based on an intramolecular carbonoxygen bond-forming reaction. Scheme 8 highlighted the use of aryl halide/alkenyl triflate substrates in the synthesis of indole derivatives; the research group was able to further demonstrate the utility of these substrates as general heterocycle precursors, through their use in a copper-catalyzed benzofuran synthesis.111 Coupling of the same substrates with potassium hydroxide yielded benzofurans via presumed enolate intermediates. Lautens and co-workers reported an approach to 2-bromobenzofurans using an intramolecular carbonoxygen coupling of gem-dibromovinyl phenols.31i As in the related indole chemistry (see Scheme 5), the dibromovinyl phenol substrates were synthesized using a Ramirez olefination process. As shown in Scheme 51, a ligand-free copper(I) iodide catalyst was found to be effective, providing the benzofurans in excellent yields.
Br Br OH Br Br
Ma and co-workers reported a related copper-catalyzed cascade route to benzofurans. In the optimized system, bketo esters were combined with 1-bromo-2-iodobenzenes to provide benzofurans via initial intermolecular carbon carbon bond formation followed by intramolecular formation of the carbonoxygen bond (Scheme 53).114 Substitution on both the aryl halide and keto ester was well tolerated, providing benzofurans in good yields.
O Ph O OEt I Cl Br CO2Et
CuI (10 mol%) K2CO3 THF, 100 C

Cl O Ph
78%
Scheme 53
3.2
Benzoxazoles
CuI (5 mol%) K3PO4 THF, 80 C

O
Br
96%
Scheme 51
In 1999 Miura and co-workers developed a tandem palladium-catalyzed intermolecular carboncarbon/intramolecular carbonoxygen bond-forming reaction of benzyl phenyl ketones with o-dibromoarenes to yield benzofurans.112 A palladium(II) acetate/triphenylphosphine catalyzed system was found to be optimal, with high reaction temperatures also being used (Scheme 52). The reactions proceeded via initial palladium-catalyzed enolate C-arylation, followed by palladium-catalyzed O-arylation. The protocol was extended to the use of phenol coupling partSynthesis 2011, No. 1, 122 Thieme Stuttgart New York
The use of catalytic intramolecular carbonoxygen bondforming reactions has proved to be a popular route to benzoxazoles. In 2006 Batey and Evindar developed a copper-catalyzed cyclization of o-halobenzanilides to generate a variety of alkyl, aryl, benzyl, alkenyl, dienyl and heterocyclic 2-substituted benzoxazoles (as well as a handful of benzothiazoles see section 4.2). As shown in Scheme 54 the optimal catalyst was a copper(I) iodide/ phenanthroline combination.115 The majority of examples employed aryl bromide substrates, although the iodo derivatives also performed well. A single aryl chloride example was included. SanMartin, Domnguez and coworkers reported a similar copper-catalyzed cyclization to access benzoxazoles. They developed two catalyst systems, using either copper(I) chloride or copper(II) triflate in combination with N,N,N,N-tetramethylethylenediamine (TMEDA), on water, to yield the desired heterocy-
CsCO3 o-xylene, 160 C
511
311
REVIEW

Me NH2 Br + S Cl O MeO O O N O 66% N O Ph Ph F3C N O 85%
17
cles in good yields from either the o-iodo, o-bromo- or ochlorobenzanilides.116 Similar cyclizations have also been reported by Jiang and Ma117 and Kantam and co-workers.118
H N Br O OMe
CuI (10 mol%) 1,10-phenanthroline Me (20 mol%) Cs2CO3, MeCN 210 C, 15 min, MW
N O 91% S
CuI (5 mol%) 1,10-phenanthroline (10 mol%) Cs2CO3 DME, relfux

Cbz
MeO N
99%
N O Ph 89%
N O
Scheme 56
90%
97%
Scheme 54
Br
Br Cl H N N Cl O
H2N
Ph
K2CO3 toluene, 110 C
Scheme 57
N N Cl O 91% N Me N Ph O
K2CO3 toluene, reflux

H N Br O
3.3
Isocoumarins
N Me
CuI (5 mol%) Ph 1,10-phenanthroline (10 mol%) Cs2CO3 THF, reflux
90%
Scheme 55
The Batey research group developed a further synthesis of benzoxazoles involving intramolecular carbonoxygen bond formation. The substrates were again o-halobenzanilides; however, these were formed in situ from the reaction of o-bromoanilines and acyl chlorides.70 A copper(I) iodide/1,10-phenanthroline combination was found to be the optimal catalyst system for this one-pot strategy. In addition, the use of microwave irradiation gave substantially better results than conventional heating. A library of 24 benzoxazoles was prepared, examples of which are shown in Scheme 56. A tandem approach to benzoxazoles was reported by Glorius and Altenhoff, in which reaction of o-dihalobenzenes with amides underwent copper(I) iodide/diamine catalyzed carbonnitrogen followed by carbonoxygen cross-couplings to yield the desired heterocycles.120 Examples of diiodo-, dibromo- and mixed dihalobenzenes, as well as dihalopyridines (Br and Cl) were successfully coupled to benzamide affording 2-phenylbenzoxazoles (Scheme 57). The dibromobenzene substrate was utilized to demonstrate variation of the amide partner, giving aryl,
In 1999 Shen and Wang described the synthesis of isocoumarins from a palladium-catalyzed reaction of gem-dibromovinyl benzoates with an organostannane.121 For example, reaction of benzoate 114 with phenyltrimethylstannane using a trifurylphosphine-derived palladium catalyst delivered isocoumarin 115 in 92% yield (Scheme 58). The tandem process is believed to proceed via an initial Stille reaction of the E bromide with the stannane, which is followed by an intramolecular carbonoxygen bond-forming cyclization and ensuing elimination of methyl bromide. Examples using phenyl, furyl, thienyl and vinyl tin reagents gave the 3-substituted isocoumarins in mostly excellent yields, and both esters and methoxy groups could be tolerated on the aromatic ring. Willis and co-workers reported a palladium-catalyzed carbonylative isocoumarin synthesis, commencing from the same a-(oO OMe Br + PhSnMe3 Br 411 Pd2(dba)3 (2.5 mol%) P(2-furyl)3 (15 mol%) toluene, 100 C , 92% O Ph MeO 81% O O 511 O Ph
O O 85% O 80% O O
Scheme 58
52
N Ph O
90%
In 2009 Sun and co-workers extended this type of cyclization to the synthesis of 2-substituted oxazolopyridines.119 As shown in Scheme 55, a copper(I) iodide/diamine or copper(I) iodide/phenanthroline catalyst system proved to be optimal, yielding the desired heterocycles from the cyclization of o-chloro- or o-bromopyridylamides, respectively.
alkyl, vinyl and heterocyclic 2-substituted benzoxazoles. The use of o-bromochlorobenzenes allowed the regioselective synthesis of substituted benzoxazoles, with the reaction proceeding via initial amidation at the aryl bromide position. Batey and co-workers had previously reported on investigations of related processes, but had not achieved an efficient system.70
52
18
Br SH Br
REVIEW
haloaryl) ketone substrates previously used in benzofuran synthesis (see Scheme 49).122
PdCl2 (3 mol%) SPhos (14) (3 mol%) K3PO4, Et3N dioxane, 110 C

S , 99% S
CarbonSulfur Bond Formation

S
B(OH)2
Relative to the carbonnitrogen and carbonoxygen bond-forming reactions discussed above, there are far fewer examples of catalytic aryl carbonsulfur bondforming processes in the literature. However, reactions are beginning to be developed that exploit the highly nucleophilic character of thiols (and related functional groups) and synthetically useful methods with very low catalyst loadings are being reported.123 The number of applications of these reactions to the synthesis of heterocycles is also growing.
Scheme 60
4.2
Benzothiazoles
SH
O O 911 Me Me
NaOEt, THF, r.t. then TFA, reflux F N Me 021 S , 75%
Pd2(dba)3 (2.5 mol%) DPEPhos (22) (6 mol%)

Br S
Cs2CO3 toluene, 100 C
S 74%
Scheme 59
Scheme 61
In 2009 Lautens and co-workers extended the use of gemdihalovinylanilines in indole synthesis (see Scheme 5) to establish similar thiophenols as precursors for benzothiophenes.124 The combination of a palladium-catalyzed carbonsulfur bond-forming reaction with a second cross-coupling process, such as a SuzukiMiyaura, Heck or Sonogashira reaction, yielded diversely functionalized benzothiophenes. For example, combination of thiophenol 116 with thiophene-3-boronic acid using an SPhos-derived catalyst delivered benzothiophene 117 in 99% yield (Scheme 60). The majority of examples reported involved Suzuki chemistry; a broad range of boronic acids, as well as other boron reagents, were readily included and allowed the introduction of aryl, alkenyl and alkyl C2 substituents. Application of the methodology to a variety of thiophenol backbones afforded the required heterocycles in mostly excellent yields.
Rather than use a thiol surrogate, Ma and co-workers exploited metal sulfides in copper-catalyzed couplings with o-haloanilides to generate benzothiazoles.126 They were able to show that sodium sulfide nonahydrate could be coupled with o-iodoanilides, and following acidic workup, deliver the desired benzothiazole products. For o-bromo substrates, the use of potassium sulfide was optimal. Both systems utilized a ligandless copper(I) iodide catalyst; significant variation of the substrate substituents was possible, delivering benzothiazoles in good to excellent yields (Scheme 62). The use of an intramolecular carbonsulfur bond-forming reaction has proved more popular in the synthesis of benzothiazoles. In 1982, Bowman, Heaney and Smith reported an intramolecular, copper-catalyzed S-arylation in the synthesis of 2-alkyl- and 2-aryl-1,3-benzothiazoles from
121
811
Although a number of metal-catalyzed benzothiophene syntheses exist,1,2 few of these involve a key carbonsulfur bond formation using an aryl halide substrate. As discussed in section 3.1, Willis et al. demonstrated the use of a palladium-catalyzed intramolecular O-enolate arylation in the synthesis of benzofurans (see Scheme 49).106 Similarly, the same group showed that thio ketones, derived from the same a-(o-haloaryl) ketone substrates using phosphorus pentasulfide, could also undergo this enolizationcyclization, again using a DPEPhos catalyst system to afford benzothiophenes.106 Scheme 59 shows an aryl bromide example, although the corresponding aryl chloride also underwent cyclization, albeit in a reduced 44% yield.
H N Br + O
Me Pd2(dba)3 (5 mol%) XantPhos (2) (10 mol%) F
H N S O
Me O OR
i-Pr2NEt, dioxane reflux
4.1
Benzothiophenes
Two research groups have established benzothiazole syntheses based on a key catalytic intermolecular carbonsulfur bond-forming step. In the first approach, Itoh and Mase utilized a palladium-catalyzed thioetherification of o-bromoanilides using a thiol surrogate coupling partner.125 For example, reaction between aryl bromide 118 and thiol 119, an odorless thiol surrogate, using a XantPhos-derived catalyst, ultimately delivered benzothiophene 120 in 75% yield (Scheme 61). The reaction proceeded via intermediate sulfide 121, which was cleaved under basic conditions and then cyclized in the presence of acid to generate the aromatic product. pMethoxybenzylthiol could also be employed as the thiol surrogate, allowing sulfide cleavage under acid conditions.
711
611
REVIEW
H N F I O
19
Me + Na2S . 9H2O
CuI (10 mol%) DMF, 80 C then HCl, r.t.

F
N Me S
75%
H N Br O
Ph +
K2S
CuI (10 mol%) DMF, 140 C then HCl, r.t.
N Ph S
88%
The Wu research group described the synthesis of 2-aminobenzothiazoles by the reaction of o-iodobenzamines with isothiocyanates using a copper(I) iodide/phenanthroline catalyst system (Scheme 65).131 The method was useful as it eliminated the need to generate an ohalobenzothiourea cyclization precursor in a separate step, with the addition/carbonsulfur coupling reaction occurring in one pot. The authors exploited the method in the preparation of an 18-membered library.
CuI (10 mol%) 1,10-phenanthroline (20 mol%) + DABCO toluene, 50 C
F
Scheme 62
NH2
N NH S
H N Br H N Br S S
Me
Me Me
Pd2(dba)3 (5 mol%) JohnPhos (106) (5.5 mol%) Cs2CO3 dioxane, 80 C
N S 88% N
Me Me Me
NMe2
Pd2(dba)3 (5 mol%) P(t-Bu)3 (5.5 mol%) Cs2CO3 dioxane, 80 C
NMe2 S , 92% 321
A number of benzothiazole syntheses that involve tandem processes have also appeared in the literature. Vera and Pelletier utilized tandem palladium-catalyzed carbon sulfur and carbonnitrogen arylation reactions to prepare a series of aminobenzothiazoles.132 For example, the combination of dibromothiobenzamide 124 and isopropylamine, using a JohnPhos catalyst, delivered 4-aminobenzothiazole 125 in 47% yield (Scheme 66). As can be seen from the remainder of the examples in Scheme 66, it was possible to alter the position of the second bromine substituent, to generate 5-, 6-, and 7-amino-substituted products.
Br H N Br 421 S NHi-Pr Ph + H2N(i-Pr) Pd2(dba)3 (10 mol%) JohnPhos (106) (20 mol%) Cs2CO3, NaOt-Bu toluene-dioxane 80 C N Ph S , 47% 521
Scheme 63
Batey and co-workers reported a comparison of the copper- and palladium-catalyzed syntheses of 2-aminobenzothiazoles based on this same cyclization of obromothioureas.129 The use of copper catalysis generally led to higher yields and conversions. Both metals were also shown to catalyze an example of a one-pot thiourea formationcyclization reaction in the same excellent yield. Bateys research group also demonstrated that cyclization of o-bromothioamides under the same copper(I) iodide/1,10-phenanthroline catalyst system afforded benzothiazoles in excellent yields;115 a representative example is shown in Scheme 64. Jiang and Ma reported a related copper-catalyzed cyclization employing oxazolidin-2-one as the ligand; a number of aryl chloride substrates were included in their study, and effectively converted into benzothiazoles.117 Pan and co-workers reported a related preparation of 2-aminobenzothiazoles using a copper(I) iodide/oxazoline catalyst system.130
OMe H N Br S CuI (5 mol%) 1,10-phenanthroline (10 mol%) Cs2CO3, reflux N OMe S 93%
i-PrHN
N Ph S 16%
N Ph
N Ph S NHi-Pr 39%
i-PrHN
50%
Scheme 66
Patel and co-workers showed that 2-arylthiobenzothiazoles can be accessed from cascade intra- and intermolecular carbonsulfur bond-forming reactions using a single catalytic system.133 A combination of o-iodo- or o-bromodithiocarbamates and iodoarenes were subjected to a copper(I) iodide/diamine catalyst system yielding the substituted benzothiazoles in mostly excellent yields (Scheme 67). The methodology was successfully applied to the synthesis of a cathespin-D inhibitor analogue. The same research group developed a cascade protocol for the synthesis of 2-thio- or 2-oxa-benzothiazoles by the copper-catalyzed reaction of o-iodo- or o-bromoarylisothiocyanates with a sulfur or oxygen nucleophile, respectively.134 The required dithiocarbamates or
Scheme 64
o-halothioacetanilides and o-halothiobenzanilides, respectively.127 Castilln and co-workers extended this methodology to a more efficient palladium-catalyzed cyclization of o-bromothioamides (Scheme 63).128 It was also shown that cyclization of o-bromothioureas, prepared from o-bromophenylisothiocyanates and amines, afforded 2-aminobenzothiazoles under similar reaction conditions (122 123).
99%
SCN
Scheme 65
221
20
H N
REVIEW
S HNEt3
Me
+
I
K2CO3 DMSO, 90 C
OMe NH2 NH2
Scheme 67
thiocarbamates, which were formed in situ under basic conditions, readily underwent copper-catalyzed intramolecular carbonsulfur bond formation. Thiophenols and phenols showed the greatest reactivity; however, the corresponding alkyl series could also be employed, albeit to generate the products in reduced yields (Scheme 68).
NCS
CuI (5 mol%) 1,10-phenanthroline (10 mol%) K2CO3 dioxane, 90 C
N SPh S
+ HS Ph
Br
76%
Ph N
N OPh S
N SBn S 69% (iodo substrate) Cl
O S
73%
54%
Scheme 68
4.3
Oxathioles
Bao and co-workers reported a novel one-pot synthesis of 2-iminobenzo-1,3-oxathioles using a cascade addition/ intramolecular carbonsulfur coupling process.135 o-Iodophenols and isothiocyanates were combined using a copper(I) iodide/phenanthroline catalyst system to afford the desired heterocycles in good to excellent yields. A representative example is shown in Scheme 69.
OH I
SCN
CuI (10 mol%) 1,10-phenanthroline (20 mol%) Cs2CO3 toluene, 7090 C
O N S
86%
OMe OMe
Scheme 69
Conclusion
By definition, palladium- and copper-catalyzed aryl amination, aryl etherification and aryl thioetherification reactions are transformations designed to fashion bonds between heteroatoms and aromatic rings. It is perhaps not surprising that these reactions have enjoyed considerable success when applied to the synthesis of aromatic heterocycles. The examples presented above show how these reSynthesis 2011, No. 1, 122 Thieme Stuttgart New York
621
621

Me
N SAr S
72% Ar = 4-MeOC6H4
actions have been exploited towards a wide range of heterocyclic targets. They also show these reactions being used to provide new entries to existing, classic synthetic routes, as well as in the formulation of completely new disconnections. As advances in the underpinning transformations continue to develop new coupling partners, more active catalysts and milder reaction conditions the number of applications will undoubtedly continue to grow. The importance of heteroaromatic molecules virtually assures it.
References
(1) Palladium in Heterocyclic Chemistry, 1st ed.; Li, J. J.; Gribble, G. W., Eds.; Elsevier: Oxford, 2000. (2) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127. (3) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285. (4) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (5) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106, 4644. (6) Palladium in Heterocyclic Chemistry, 2nd ed.; Li, J. J.; Gribble, G. W., Eds.; Elsevier: Oxford, 2007. (7) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395. (8) Willis, M. C. Tetrahedron 2009, 65, 8907. (9) Kosugi, M.; Kameyama, M.; Migita, T. Chem. Lett. 1983, 927. (10) (a) Guram, A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 7901. (b) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem. Int. Ed. 1995, 34, 1348. (c) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1996, 61, 1133. (d) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 7215. (11) (a) Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116, 5969. (b) Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609. (c) Hartwig, J. F.; Richards, S.; Baraano, D.; Paul, F. J. Am. Chem. Soc. 1996, 118, 3626. (d) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 7217. (12) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382. (13) Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691. (14) Hartwig, J. F. In Handbook of Organopalladium Chemistry for Organic Synthesis, Vol. 1; Negishi, E. I., Ed.; WileyInterscience: New York, 2002, 10511096. (15) Jiang, L.; Buchwald, S. L. In Metal-Catalyzed CrossCoupling Reactions, 2nd ed.; de Meijere, A.; Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004. (16) Surry, D. S.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 6338. (17) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534. (18) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003, 42, 5400; Corrigendum: Angew. Chem. Int. Ed. 2004, 43, 1043. (19) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337. (20) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054. (21) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450. (22) Monnier, F.; Taillefer, M. Angew. Chem. Int. Ed. 2009, 48, 6954. (23) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2010, 1, 13. (24) Although the majority of examples described in this approach do not lead directly to an aromatic heterocycle, but to an intermediate, it is included because of its historical relevance to the development of palladium-catalyzed aryl halide amination chemistry in heterocycle synthesis. (25) (a) Wagaw, A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 6621. (b) Wagaw, A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 10251.
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Palladium-And Copper-Catalyzed Aryl Halide Amination, Etherification and Thioetherification Reactions in The Synthesis of Aromatic Heterocycles

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CarbonNitrogen Bond Formation Indoles

MeO MeO 65% N H 70% N H

Ph Ph Me N H 70% (BINAP used as ligand)

Me PPh2 O PPh2 PPh2 (rac)-BINAP (3)

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Palladium- and Copper-Catalyzed Heterocycle Synthesis

PdCl2(dppf) (5 mol%) KOAc, DMF 90 C O2N 83% Br N

Pd(dba)2 (3 mol%) (4.5 mol%) NaOt-Bu o-xylene, 120 C 5

i) [Cp2TiMe2] (5 mol%) toluene 110 C, 24 h MeO Pr N , 65% Me Me Me 9 01

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Pd(OAc)2 (1 mol%) SPhos (2 mol%) K3PO4.H2O toluene, 90 C N H 86%

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

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i-Pr2NH, toluene, 100 C

Palladium- and Copper-Catalyzed Heterocycle Synthesis

O PPh2 PPh2 DPEPhos (22)

Pd2(dba)3 (5 mol%) DPEPhos (22) (12 mol%) Cs2CO3 toluene, 110 C

t-BuO 86% i-Pr i-Pr

CuOAc (10 mol%) (20 mol%) Cs2CO3 toluene, 110 C 52

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i-Pr i-Pr XPhos (32)

(from Cl/ONf substrate)

Pd2(dba)3 (2 mol%) XPhos (32) (4 mol%) NaOt-Bu, dioxane 110 C

Ph N Me , 91% Me Me (from I/Cl substrate)

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Palladium- and Copper-Catalyzed Heterocycle Synthesis

Synthesis 2011, No. 1, 122

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Benzimidazoles and Benzimidazolones

88% 05 (from ArCl using ligand )

83% 05 (using ligand )

i-PrO RuPhos (50)

CF3 CuI (10 mol%)

K2CO3, DMSO, r.t.

O i) CuI (10 mol%)

K2CO3, DMSO, 40 C ii) AcOH, 140 C

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Palladium- and Copper-Catalyzed Heterocycle Synthesis

CuI (10 mol%) TMEDA (20 mol%) Cs2CO3 toluene, 110 C

Pd: 66% Cu: 90%

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Pd(OAc)2 (3 mol%) BINAP (3) (3 mol%) Cs2CO3 toluene, reflux

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CuI (15 mol%) (30 mol%) 52 Cs2CO3 DMA, 165 C

Indazoles and Indazolones

Me Pd(dba)2 (2 mol% DPEPhos (22) (2 mol%) K3PO4 toluene, 110 C Me , 85% 85 N

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

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NaOt-Bu + H2N NH toluene, 100 C Br Ph O

Palladium- and Copper-Catalyzed Heterocycle Synthesis

S N SiMe3 N Boc SiMe3 N Boc

Cs2CO3 DMF, 110130 C

CO2t-Bu OEt N Ph N N Ph N 55%