Metal-Catalyzed Cross-Coupling Reactions for Indoles

Abstract

Metal-catalyzed cross-coupling reactions for indoles are reviewed. Palladium-catalyzed cross-coupling reactions are the most widely explored and applied of all metal-catalyzed cross-coupling reactions. Applications of Kumada coupling, Negishi coupling, Suzuki coupling, Stille coupling, Sonogashira reaction, the Heck reaction, carbonylation, and C–N bond formation reactions in indoles are summarized. In addition, other transition metal-catalyzed cross-coupling reactions using copper, rhodium, iron, and nickel in indole synthesis are also discussed.

1 Introduction

Metal-catalyzed cross-coupling reactions have emerged as an important advancement in organic chemistry during the last few decades. Meanwhile, due to the importance of indoles in medicinal chemistry and many other fields, metal-catalyzed cross-coupling reactions have been extensively applied in the field of indole synthesis. While many books and reviews [1–3] have been published in the field, a book by the authors is solely dedicated to Palladium in Heterocyclic Chemistry [4]. In this chapter, we will cover applications of palladium- and other transition metal-catalyzed cross-coupling reactions in indole synthesis and reactions.

2 Palladium-Catalyzed Cross-Coupling Reactions

2.1 Mori–Ban Indole Synthesis

The Mori–Ban indole synthesis [5–12], the intramolecular version of the Heck reaction as applied to the synthesis of indoles, is not a cross-coupling reaction per se, but it is covered here due to its importance in assembling the indole core.

The cyclization of o-halo-N-allylanilines to indoles is a general and efficient methodology. For example [5], the conversion of 1 and 2 can be performed at low temperature, shorter reaction times, and with less catalyst to give 3-methylindole (2) in 87% yield.

Larock’s improved method [13–18], which has been widely adopted, involves catalytic (2%) Pd(OAc)₂, n-Bu₄NCl, DMF, base (usually Na₂CO₃), 25°C, and 24 h (also known as the “Jeffrey’s conditions”). Larock extended his work in several ways, particularly with regard to Pd-catalyzed cross-coupling of o-allylic and o-vinylic anilides with vinyl halides and triflates to produce 2-vinylindoles. The related “Larock indole synthesis” is discussed separately in the next section. In a program to synthesize CC-1065 analogs, Sundberg prepared indole 4 from o-bromo-N-allylaniline 3 in excellent yield [19] using the Jeffrey’s conditions. Silver carbonate and sodium carbonate were less effective than triethylamine. One of the present authors (JJL) took advantage of the Mori–Ban indole synthesis using the Jeffrey’s conditions to prepare a series of quinoxalinyl-pyrrole derivatives such as 6 from chloro-allylamino-quinoxalines such as 5 [20].

Macor also exploited the Mori–Ban indole synthesis to synthesize several antimigraine analogs of Sumatriptan and homotryptamines as potent and selective serotonin reuptake inhibitors [21, 22]. Noticeably, the presence of the second bromine (the bromine “passenger”) on substrate 7 was not significantly deleterious to the reaction although a small amount of the 7-bromoindole 8 might be sacrificed at the end of the reaction to consume the active palladium catalyst. The approach to 7-bromoindole 8 could provide a general method accessing 7-bromoindoles (a rare class of indole derivatives), which then could be further adapted to the synthesis of more complex 7-substituted indoles.

Recently, Cook’s group described their Mori–Ban indole synthesis of substrate 10, easily assembled from 9 [23]. The intramolecular cyclization gave a 1:1 mixture of indole 11 and exo-3-methylene-indoline 12, which was readily converted to 11 upon treatment with acid. By changing the base from K₂CO₃ to Ag₂CO₃, the Mori–Ban reaction gave exo-3-methylene-indoline 12 exclusively in 90% yield.

2.2 Larock Indole Synthesis

Larock and coworkers described the one-step Pd-catalyzed reaction of o-haloanilines with internal alkynes to give indoles [24, 25]. This excellent reaction, which is shown for the synthesis of indoles 13, involves oxidative addition of the aryl halide (usually iodide) to Pd(0), syn-insertion of the alkyne into the ArPd bond, nitrogen displacement of the Pd in the resulting vinyl-Pd intermediate, and final reductive elimination of Pd(0).

The reaction can be regioselective with unsymmetrical alkynes, and this is particularly true with silylated alkynes wherein the silyl group always resides at the C-2 indole position in the product. This is noteworthy because silyl-substituted indoles are valuable substrates for other chemistry (halogenation, Heck coupling). Gronowitz used the appropriate silylated alkynes with o-iodoanilines to fashion substituted tryptophans following desilylation with AlCl₃ [26]. Similarly, a series of 5-, 6-, and 7-azaindoles was prepared by Ujjainwalla and Warner from o-aminoiodopyridines and silylated (and other internal) alkynes using PdCl₂dppf [27, 28]. Yum and coworkers also used a Larock indole synthesis to prepare 7-azaindoles 14 [29, 30] and, from 4-amino-3-iodoquinolines, pyrrolo[3,2-c]quinolines 15, which have a wide spectrum of biological activity [30].

The Larock synthesis was used by Chen and coworkers to synthesize the 5-(triazolylmethyl)tryptamine MK-0462, a potent 5-HT_1D receptor agonist, as well as a metabolite [31, 32]. The reaction was carried out on a 25-kg scale. Larock employed his methodology to prepare tetrahydroindoles [33], and Maassarani used this method for the synthesis of N-(2-pyridyl)indoles [34]. The latter study features the isolation of cyclopalladated N-phenyl-2-pyridylamines. Rosso and coworkers have employed this method for the industrial scale synthesis of an antimigraine drug candidate 16. In this paper, removal of spent palladium was best effected by trimercaptotriazine (17), although many techniques were explored [35].

Larock found that allenes (1,2-dienes) undergo Pd-catalyzed reactions with o-iodoanilines to afford 3-alkylidene indolines, including examples using cyclic dienes, e.g., to give 18 [36], and ones leading to asymmetric induction, e.g., to give 19 [37, 38]. The highest enantioselectivities ever reported for any Pd-catalyzed intramolecular allylic substitution reactions were observed in this study. Mérour modified this reaction for the synthesis of 7-azaindolinones, following ozonolysis of the initially formed exo-methylene-indoline [39].

Prior to his work with internal alkynes, Larock found that o-thallated acetanilide undergoes Pd-catalyzed reactions with vinyl bromide and allyl chloride to give N-acetylindole and N-acetyl-2-methylindole each in 45% yield [40]. In an extension to reactions of internal alkynes with imines of o-iodoaniline, Larock reported a concise synthesis of isoindolo[2,1-a]indoles 20 and 21 [41, 42]. The regioselectivity was excellent with unsymmetrical alkynes.

In 2009, Djakovitch et al. described the first heterogeneous ligand- and salt-free Larock indole synthesis [43]. For instance, indole 22 was assembled in high yield under these conditions compared to the traditional homogeneous Larock indole synthesis conditions.

2.3 Oxidative Coupling

Most of the early applications of palladium to indole chemistry involved oxidative coupling or cyclization using stoichiometric Pd(II). Åkermark first reported the efficient oxidative coupling of diphenylamines to carbazoles 23 with Pd(OAc)₂ in refluxing acetic acid [44]. The reaction is applicable to several ring-substituted carbazoles (Br, Cl, OMe, Me, NO₂), and 20 years later Åkermark and colleagues made this reaction catalytic in the conversion of arylaminoquinones 24 to carbazole-1,4-quinones 25 with tert-butylhydroperoxide or oxygen as the oxidant [45]. This oxidative cyclization is particularly useful for the synthesis of benzocarbazole-6,11-quinones (e.g., 26).

Stoltz has reported the first oxidative indole annulations that are catalytic in palladium, and two examples are illustrated below [46]. The ligand is ethyl nicotinate.

A similar Pd-catalyzed cyclization–carboalkoxylation of several alkenyl indoles has been described by Widenhoefer, one of which is shown [47].

In a series of papers, Itahara established the utility of Pd(OAc)₂ in the oxidative cyclization of C- and N-benzoylindoles, and two examples are shown [48–50]. Itahara also found that the cyclization of 3-benzoyl-1,2-dimethylindole proceeds to the C-4 position (31% yield) [48]. Under similar conditions, both 1-acetylindole and 1-acetyl-3-methylindole are surprisingly intermolecularly arylated at the C-2 position by benzene and xylene (22–48% yield) [51, 52].

Hill described the Pd(OAc)₂-oxidative cyclization of bisindolylmaleimides (e.g., 27) to indolo[2,3-a]pyrrolo[3,4-c]carbazoles (e.g., 28) [53], which is the core ring system in numerous natural products, many of which have potent protein kinase activity [54]. Other workers employed this Pd-induced reaction to prepare additional examples of this ring system [55, 56]. Ohkubo found that PdCl₂/DMF was necessary to prevent acid-induced decomposition of benzene-ring-substituted benzyloxy analogs of 27, and the yields of cyclized products under these conditions are 85–100% [55].

Intermolecular Pd oxidative couplings with indoles are well established, although initial results were unpromising. For example, Billups found that indole reacts with allyl acetate (Pd(acac)/Ph₃P/HOAc) to give a mixture of 3-allyl-(54%), 1-allyl-(7%), and 1,3-diallylindole (11%) [57]. Allyl alcohol also is successful in this reaction but most other allylic alcohols fail. Likewise, methyl acrylate reacts with N-acetylindole (Pd(OAc)₂/HOAc) to give only a 20% yield of methyl (E)-3-(1-acetyl-3-indolyl)acrylate and a 9% yield of N-acetyl-2,3-bis-(carbomethoxy)carbazole [58]. Itahara improved these oxidative couplings by employing both N-(2,6-dibenzoyl)indoles (e.g., 29, 30) and N-(phenylsulfonyl)-indole as substrates [59]. Reaction occurs at C-3 unless this position is blocked. The coupling can be made catalytic using AgOAc or other reoxidants [59]. Some examples are shown below and E-stereochemistry is the major or exclusive isomer. Acrylonitrile also reacts with 29 under these conditions (52%; E/Z=3/1) [59], and methyl vinyl ketone, ethyl (E)-crotonate, and ethyl α-methyl acrylate react with N-(phenylsulfonyl)indole under these oxidative conditions [60]. Interestingly, an N-indole 2-pyridylmethyl substituent leads to C-2 alkenylation with methyl acrylate, acrylonitrile, and phenyl vinyl sulfone under typical conditions (Pd(OAc)₂, Cu(OAc)₂, HOAc, dioxane, 70°C) [61].

Hegedus found that 4-bromo-1-(4-toluenesulfonyl)indole (31) reacts with methyl acrylate to form the C-3 product in low yield under stoichiometric conditions [62]. Yokoyama, Murakami and coworkers also utilized 31 in total syntheses of clavicipitic acid and costaclavine, one key step of which is the oxidative coupling of 31 with 32 to give dehydrotryptophan derivative 33 [63, 64]. The use of chloranil as a reoxidant to recycle Pd(O) to Pd(II) greatly improves the coupling over earlier conditions [65, 66]. For example, chloranil was more effective than DDQ, MnO₂, Ag₂CO₃, Co(salen)₂/O₂, and Cu(OAc)₂. In the absence of chloranil the yield of 33 is 31%.

The palladium-catalyzed C-3 alkylation of indoles via nucleophilic allylic substitution on allylic carbonates and acetates has been described [67, 68]. Two clever indole ring syntheses involving oxidative cyclization are illustrated below [69, 70].

In 2007, Fagnou reported a remarkable catalytic cross-coupling of unactivated arenes onto indoles via oxidative oxidation [71]. Using Cu(OAc)₂ as the oxidant and 3-nitropyridine as the additive, C–H activation was accomplished via the S_EAr mechanism. As a consequence, 3-acylindole was phenylated predominantly at the C-3 position although small amount of C-2 phenylated was observed as well.

2.4 Kumada Coupling

Of all the palladium-catalyzed coupling reactions, the Kumada coupling has been applied least often in indole chemistry. However, this Grignard-Pd cross-coupling methodology has been used to couple 1-methyl-2-indolylmagnesium bromide with iodobenzene and α-bromovinyltrimethylsilane to form 1-methyl-2-phenylindole and 1-methyl-2-(1-trimethyl-silyl)vinylindole in 79% and 87% yields, respectively [72, 73]. Kumada constructed the tri-heterocycle 34 using a tandem version of his methodology [74].

Kondo employed the Kumada coupling using the Grignard reagents derived from 2- and 3-iodo-1-(phenylsulfonyl)indole to prepare the corresponding phenyl derivatives in 50% yield [75]. Widdowson expanded the scope of the Kumada coupling and provided some insight into the mechanism [76].

2.5 Negishi Coupling

Although the Negishi coupling has been less frequently used in indole synthetic manipulations than either Suzuki or Stille couplings, we will see in this chapter that Negishi chemistry is often far superior to other Pd-catalyzed cross-coupling reactions involving indoles. One of the first such examples is Pichart’s coupling of 1-methyl-2-indolylzinc chloride (35) with iodopyrimidine 36 to give 37 [77].

Danieli extended the Pd-catalyzed coupling of 2-indolylzinc chlorides to a series of halopyridin-2-ones and halopyran-2-ones [78]. This Negishi coupling is more efficient than a Suzuki approach but not as good as a Stille coupling. An example of the latter will be shown in Sect. 2.7. These workers also generated zinc reagents from 5-iodopyridin-2-one and 5-bromopyran-2-one but Negishi couplings were sluggish. Since direct alkylation of a 2-lithioindole failed, Fisher and coworkers utilized a Negishi protocol to synthesize 2-benzylindole 38 as well as the novel CNS agent 39 [79].

Cheng and Cheung also employed a 2-indolylzinc chloride 41 to couple with indole 40 in a synthesis of “inverto-yuehchukene” 42 [80]. Other Pd catalysts were no better in this low-yielding process.

Negishi methodology can also be used to achieve the 3-acylation of indoles. Thus, Faul used this tactic to prepare a series of 3-acylindoles 44 from indole 43 [81]. Indole 43 could also be iodinated cleanly at C-3 with N-iodosuccinimide (78%).

Grigg employed organozinc chemistry to construct 3-alkylidenedihydroindoles such as 45 via a tandem Pd-catalyzed cyclization-cross-coupling sequence [82]. A similar route to such compounds was reported by Luo and Wang; e.g., 46 [83].

Karoyan et al. accomplished an asymmetric synthesis of prolino-homotryptophan 50 via amino-zinc-ene-enolate cyclization of 47 followed by transmetalation of the cyclic zinc intermediate 48 with indolyliodide 49 [84]. The use of a Pd catalyst derived from Fu’s [t-Bu₃PH]-BF₄ was required to avoid the undesired β-hydride elimination. Proline chimeras such as 50 are useful tools for medicinal chemistry and/or biological applications.

2.6 Suzuki Coupling

Two reviews were published in 2001 and 2002, respectively, on the Suzuki coupling of indoles by Ishikura [85, 86].

Although the first report of an indoleboronic acid was by Conway and Gribble in 1990, this compound (51) was not employed in Suzuki coupling, but rather it was utilized en route to 3-indolyl triflate [87].

In the intervening years, indoleboronic acids substituted at all indole carbon positions have found use in synthesis. For example, Claridge and coworkers employed 51 in a synthesis of isoquinoline 52 under standard Suzuki conditions in high yield [88]. Compound 52 was subsequently converted to the new Pd-ligand 1-methyl-2-diphenylphosphino-3-(1′-iso-quinolyl)indole.

Several groups have reported the synthesis and Suzuki reactions of a N-methylindolyl-3-carboxamido-2-boronic acid for the synthesis of benzo[a]carbazoles [89], a N-Boc-5-sulfonamidoindolyl-2-boronic acid for the synthesis of novel KDR kinase inhibitors [90, 91], indolyl-4-boronic acid in a new synthesis of lysergic acid [92], and 5-, 6-, and 7-indolylboronic acids for the synthesis of aryl-substituted indoles [93, 94]. Carbazole-2,7-bis (boronates) have been employed to construct diindolocarbazoles [95].

The medicinal importance of 2-aryltryptamines led Chu and coworkers to develop an efficient route to these compounds (55) via a Pd-catalyzed cross-coupling of protected 2-bromotryptamines 53 with arylboronic acids 54 [96]. Several Suzuki conditions were explored and only a partial listing of the arylboronic acids is shown here. In addition, boronic acids derived from naphthalene, isoquinoline, and indole were successfully coupled with 53. The C-2 bromination of the protected tryptamines was conveniently performed using pyridinium hydrobromide perbromide (70–100%). Other groups have employed 2- and 5-halotryptamines (and homotryptamines) in Suzuki coupling to prepare novel inhibitors of 15-lipoxygenase [97] and selective 5-HT receptor agonists [98]. 2-Phenyl-5- (and 7-) azaindoles have been prepared via a Suzuki coupling of the corresponding 2-iodoazaindoles [99].

Carini et al. converted 8-bromobenzo[c]carbazole to the corresponding aryl derivatives 56, which are selective inhibitors of cyclin dependent kinase 4 [100], and Nicolaou employed a 4-bromoindole to craft 57 in a model study towards the synthesis of diazonamide A [101].

Abell utilized a Suzuki cross-coupling reaction on resin 58. Subsequent acid treatment effected cyclization to indole 59, which was readily cleaved with amines and alcohols to form potential libraries of amides and esters, respectively [102].

A group of process chemists at GSK optimized the Suzuki coupling of indolylbromide 60 with boronic acid 61 to afford a drug intermediate 62 [103]. They performed a screen to choose optimal ligand, solvent and base. In order to remove the residual palladium in isolated product, they treated the reaction mixture with toluene and 20% aqueous NaHSO₃ at elevated temperature. The palladium content was lowered from ∼8,000 to 100 ppm or less on a 20 L scale.

2.7 Stille Coupling

Despite the well-documented toxicity of organotin compounds, the use of these reagents in Pd-catalyzed cross-coupling reactions continues unabated, following the pioneering work of Stille. Indolylstannanes are usually prepared either by treating the appropriate lithioindole with a trialkyltin halide or by halogen-tin exchange with, for example, hexamethylditin. Typical procedures for the generation of (1-(4-toluenesulfonyl)indol-2-yl)trimethylstannane (63) and (1-(4-toluenesulfonyl)indol-3-yl)trimethylstannane (64) are illustrated [104, 105]. Bosch described an excellent route to the N-TBS-3-trimethylstannylindole [106].

The indolyltributylstannanes, which are more robust than their trimethylstannyl counterparts, are prepared similarly [107, 108]. Labadie and Teng synthesized the N-Me, N-Boc, and N-SEM (indol-2-yl)tributylstannanes [108], and Beak prepared the N-Boc trimethyl- and tributyltin derivatives in high yield [107]. Caddick and Joshi found that tributylstannyl radical reacts with 2-tosylindoles to give the corresponding indole tin compounds as illustrated [109].

Fukuyama devised a novel tin-mediated indole ring synthesis leading directly to 2-stannylindoles that can capture aryl and alkyl halides in a Pd-catalyzed cross-coupling termination reaction [110–112]. The presumed pathway is illustrated and involves initial tributylstannyl radical addition to the isonitrile 65, cyclization, and final formation of stannylindole 66.

Moreover, the in situ reaction of 67 under Stille conditions affords a variety of coupled products 68, which have been employed in a synthesis of (−)-vindoline [113].

The potential power of Fukuyama’s method is illustrated by the synthesis of biindolyl 70 which was used in a synthesis of indolocarbazoles [111, 112]. The isonitriles (e.g., 69) are generally prepared by dehydration of the corresponding formamides with POCl₃.

Murakami generated 3-tributylstannylindoles in situ (but also isolable) using 3-bromoindole 71, allylic acetates and carbonates, and hexamethyl tin [114, 115]. A typical procedure is illustrated for the synthesis of 72. The corresponding 5-bromo analog is allylated to the extent of 59%. 3-Stannylindoles couple smoothly in tandem fashion with 2,3-dibromo-5,6-dimethylbenzoquinone under Stille conditions [116].

Halonitropyridines were particularly attractive as coupling partners with tributyl-2-ethoxyvinyltin and precursors to azaindoles. Although the (Z)-isomer of 73 is obtained initially, it isomerizes to the (E)-isomer which is the thermodynamic product. This strategy represents a powerful method for the synthesis of all four azaindoles (1H-pyrrolopyridines) [117]. In fact, this method, starting with 2,6-dibromoaniline, is one of the best ways to synthesize 7-bromoindole (96% overall yield) [118].

Mérour synthesized novel 5-azaindolocarbazoles as cytotoxic agents and Chk1 inhibitors [119]. Therefore, the Stille coupling between monobromoindolylmaleimide 74 and trimethylstannyl-1-Boc-5-azaindole 75 gave adduct 76 in 92% yield. When the corresponding less toxic 3-tributylstannyl-1-Boc-5-azaindole instead of 75 was used, only 36% yield was obtained.

2.8 Sonogashira Coupling

The Sonogashira coupling is the Pd-catalyzed coupling of aryl halides and terminal alkynes [120], which, in the appropriate cases, can be followed by the spontaneous, or easily induced, cyclization to an indole ring. It is a sequel to the Castro acetylene coupling and subsequent cyclization to indoles in the presence of copper [121–124]. For example, Castro and coworkers found that copper acetylides react with o-iodoaniline to form 2-substituted indoles often in high yield. In the intervening years, the Pd-catalyzed cyclization of o-alkynylanilines to indoles has become a powerful indole ring construction.

Yamanaka and coworkers were the first to apply the Sonogashira coupling reaction to an indole synthesis when they coupled trimethylsilylacetylene with o-bromonitrobenzene [PdCl₂(Ph₃P)₂/Et₃N]. Treatment with NaOEt/EtOH gives o-(2,2-diethoxyethyl)nitrobenzene (39% overall), and hydrogenation and acid treatment affords indole (87%, two steps) [125–127]. The method is applicable to a variety of ring-substituted indoles and, particularly, to the synthesis of 4- and 6-azaindoles (pyrrolopyridines) from halonitropyridines. Taylor coupled thallated anilides 77 with copper(I) phenylacetylide to afford the corresponding o-alkynylanilides 78. In the same pot, catalytic PdCl₂ is then used to effect cyclization to N-acylindoles 79 [128]. Hydrolysis to the indoles 80 was achieved by base.

Tischler and Lanza effected coupling of several substituted o-chloro- and o-bromo-nitrobenzenes with trimethylsilylacetylene to give the o-alkynylnitro-benzenes 81 [129]. Further manipulation affords the corresponding indoles 82 in good to excellent yield.

The combination of Pd-catalyzed coupling of terminal acetylenes with o-alkynylanilines or o-alkynylnitrobenzenes followed by base or CuI cyclization to an indole has been used in many situations with great success. Arcadi employed this methodology to prepare a series of 2-vinyl-, 2-aryl-, and 2-heteroarylindoles from 2-aminophenylacetylene and a subsequent elaboration of the acetylenic terminus. A final Pd-catalyzed cyclization completes the scheme [130].

A new, water soluble palladium catalyst was used in the Sonogashira reaction (Pd(OAc)₂ triphenylphosphine–trisulfonate sodium salt) [131], and several groups adapted the Sonogashira coupling and subsequent cyclization to the solid-phase synthesis of indoles. Bedeschi and coworkers used this method to prepare a series of 2-substituted-5-indolecarboxylic acids [132]. Collini and Ellingboe extended the technique to 1,2,3-trisubstituted-6-indolecarboxylic acids [133]. Zhang and coworkers used the solid phase to prepare a series of 2-substituted-3-aminomethyl-5-indolecarboxamides, and, by manipulation of the resin-bound Mannich reaction intermediates, to synthesize 3-cyanomethyl-5-indole-carboxamide and other products of nucleophilic substitution [134]. This research team also employed a sulfonyl linker, as summarized below, to provide a series of substituted indoles [135, 136]. The advantages of this particular approach are that the sulfonyl linker is “traceless”, since it disappears from the final indole product, and the polystyrene sulfonyl chloride resin is commercially available.

Pirrung carried out a Sonogashira coupling between phenyliodide 83 and alkyne 84 [137]. With N-methanesulfonyl protection, the coupling product spontaneously cyclized to the indole and 85 was obtained in 70% yield.

2.9 Heck Coupling

The incredibly powerful and versatile Heck coupling reaction has found enormous utility in indole ring synthesis and in the elaboration of this important heterocycle. Due to the enormity of this topic the section is divided into Heck reactions of indoles; the synthesis of the indole ring as developed by Hegedus, Mori–Ban, and Heck; and the Larock indole ring synthesis.

Both inter- and intramolecular Heck reactions of indoles have been pursued and these will be considered in turn. Appropriately, Heck and coworkers were the first to use Pd-catalyzed vinyl substitution reactions with haloindoles [138]. Thus, 1-acetyl-3-bromoindole (86) gave a 50% yield of 3-indolylacrylate 87. A similar reaction with 5-bromoindole yielded (E)-methyl 3-(5-indolyl)acrylate (53% yield), but 3-bromoindole gave no identifiable product.

Somei carried out the Heck reactions of haloindoles with allylic alcohols. For example, reaction of 4-iodo-3-indolecarboxaldehyde with 2-methyl-3-buten-2-ol afforded alcohol 88 in high yield [139]. This could be subsequently transformed to (±)-6,7-secoagroclavine. Interestingly, the one-pot thallation–palladation protocol failed in this case.

Mérour and Gribble have independently explored the Heck reactions of indolyl triflates with allylic alcohols and other substrates [140–142]. For example, reaction of triflate 89 with allyl alcohol gives the rearranged allylic alcohol 90 [140].

The intramolecular Heck reaction as applied to indoles has led to several spectacular synthetic achievements. Both Hegedus and Murakami exploited intramolecular Heck reactions to synthesize ergot alkaloids. In model studies, Hegedus noted that 3-allyl-4-bromo-1-tosylindole (91) cyclizes to 92 in good yield [62, 143, 144], and Murakami’s group observed that, for example, 93 cyclizes to 94 [145]. Roberts effected similar cyclizations leading to 7- and 8-membered ring tryptophan surrogates [146, 147], and Snieckus used similar intramolecular Heck reactions to prepare seco-C/D ring analogs of Ergot alkaloids [148].

In his synthetic approaches to iboga alkaloids, Sundberg pursued several Heck cyclization strategies but found the best one to be 95 and 96 [149].

Kraus found that a Pd-catalyzed cyclization is superior to those involving tin-initiated radical cyclizations in the construction of pyrrolo[1,2-a] indoles such as 98 [106]. The bromide corresponding to 97 cyclizes in 48% yield, and N-(2-bromo-1-cyclohexenecarbonyl)indole-3-carboxaldehyde cyclizes in 60% yield. In contrast, the corresponding radical reactions afford these products in 35–53% yields. Substrate 99 failed to cyclize under these Heck conditions, as did 100 as reported by Srinivasan [107]. However, radical cyclization of 100 did afford the desired 3,4-benzocarbolines.

Rawal applied the Heck cyclization in elegant fashion to the construction of indole alkaloids. His route to geissoschizine alkaloids features a novel ring D formation, 101, 102, and 103 [150]. Whereas classical Heck conditions favor the isogeissoschizal (103) product, the “ligand-free” modification of Jeffrey favors the geissoschizal (102) stereochemistry.

Following the application of a Heck cyclization to a concise synthesis of the Strychnos alkaloid dehydrotubifoline [151, 152], and earlier model studies [153], Rawal employed a similar strategy to achieve a remarkably efficient synthesis of strychnine [154]. Thus, pentacycle 104 is smoothly cyclized and deprotected to isostrychnine (105) in 71% overall yield.

Enamine 106 underwent an intramolecular Heck reaction using palladium on charcoal to afford benzoyl indole 107 in 74% yield after crystallization from heptane/EtOAc [155]. Benzoyl indole 107 is an intermediate for a Merck PPARγ modulator.

2.10 Carbonylation

The insertion of carbon monoxide into σ-alkylpalladium(II) complexes followed by attack by either alcohols or amines is a powerful acylation method. This carbonylation reaction has been applied in several different ways to the reactions and syntheses of indoles. Hegedus and coworkers converted o-allylanilines to indoline esters 108 in yields up to 75% [156]. In most of the examples in this section, CO at atmospheric pressure was employed.

Edstrom expanded his studies on the carbonylation of pyrroles to the methoxy-carbonylation of 5-azaindolones leading to 109 [157, 158].

Herbert and McNeil have shown that the appropriate 2-iodoindole can be carbonylated in the presence of primary and secondary amines to afford the corresponding 2-indolecarboxamides in 33–97% yield. Further application of this protocol leads to amide 110, which is a CCK-A antagonist (Lintitript) [159].

Fukuyama employed a vinyltin derivative in the carbonylation of 3-carbomethoxymethyl-2-iodoindole to afford 111 [111]. Buchwald effected the carbonylation of 4-iodoindole 112 to give lactam 113 [160].

Ishikura has adapted his Pd-catalyzed cross-coupling methodology involving indolylborates to include carbonylation reactions. For example, 114 was treated with enol triflates in the presence of CO and Pd to give 2-acylindoles such as 115 [161].

In 2008, Beller and coworkers reported catalytic and stoichiometric synthesis of novel 3-aminocarbonyl-,3-alkoxycarbonyl-, and 3-amino-4-indolyl-maleimides [162]. For instance, t-butyl ester 117 was prepared in 29% yield from 3-bromo-4-indolyl-maleimide 116 under the palladium-catalyzed carbonylation conditions using t-butanol as the solvent and TMEDA as the base.

A 2009 paper described a palladium-catalyzed domino-C,N-coupling/carbonylation/Suzuki coupling reaction was used provide an efficient synthesis of 2-aroyl-/heteroaroylindoles [163]. For instance, 2-gem-dibromovinylaniline 118 and 3-furyl-boronic acid under carbon monoxide afforded 3-furylindole 119 in 67% yield.

2.11 C–N Bond Formation

Hegedus conducted the Pd-induced amination of alkenes [164] to an intramolecular version leading to indoles from o-allylanilines and o-vinylanilines [165, 166]. One of the original examples from the work of Hegedus are shown below. The Hegedus indole synthesis can be stoichiometric or catalytic and a range of indoles was synthesized from the respective o-allylanilines in modest to very good yields (31–89%) [167].

Boger and coworkers were the first to report the intramolecular amination of aryl halides in their synthesis of lavendamycin [168–170]. Thus, biaryl 122 is smoothly cyclized under the action of palladium to β-carboline 123, which comprises the CDE rings of lavendamycin.

Similarly, carbazoles can be synthesized via a double N-arylation of primary amines [171, 172], and comparable tactics lead to indoles, as shown for 124 and 125 [173].

Buchwald parlayed the powerful Hartwig–Buchwald aryl amination technology [174–186] into a simple and versatile indoline synthesis [187]. For example, indole 126, which has been employed in total syntheses of the marine alkaloids makaluvamine C and damirones A and B, was readily forged via the Pd-mediated cyclization shown below [187]. This intramolecular amination is applicable to the synthesis of N-substituted optically active indolines [188, 189]. and o-bromobenzylic bromides can be utilized in this methodology, as illustrated for the preparation of 127 [190, 191].

Snieckus and coworkers applied the Hartwig–Buchwald amination to the synthesis of o-carboxamido diarylamines, which can be elaborated to oxindoles [192]. Dobb synthesized α-carboline 128 via an intramolecular amination protocol [193]. These α-carbolines (pyrido[2,3-b]indoles) have been found to be modulators of the GABA_A receptor, and this ring system is found in several natural products (grossularines, mescengricin). Snider achieved a similar cyclization of a 2-iodoindole leading to syntheses of (−)-asperlicin and (−)-asperlicin C as illustrated for the model reaction giving 129 [194]. The requisite 2-iodoindole was readily synthesized by a mercuration sequence [Hg(OCOCF₃)₂, KI/I₂/82%].

Recently, Lautens engineered a silver-promoted domino Hartwig–Buchwald amination/direct arylation: access to polycyclic heteroaromatics [195]. From substrate 130, a unique a hetero-pentacycle 131 was assembled with a seven-membered ring as its core.

The Buchwald–Hartwig aryl amination methodology cited above in this section was engaged by Hartwig and others to synthesize N-arylindoles 132 [196, 197]. Carbazole can be N-arylated under these same conditions with p-cyanobromobenzene (97% yield). Aryl chlorides also function in this reaction. The power of this amination method is seen by the facile synthesis of tris-carbazole 133 [198].

2.12 Direct Arylation

Although palladium-catalyzed cross-coupling reactions provide an efficient entry to C-arylated indoles, these reactions require the preparation of functionalized heteroarenes such as boronates and halides. Therefore, C-arylation reactions of azole and related heteroarenes via direct C–H bond functionalization of the parent heteroarenes would be much more favorable. In 2004, Sames reported a selective palladium-catalyzed C2-arylation of N-substituted indoles via direct C–H bond arylation [199]. Use CsOAc as the base and low concentration of the substrates proved to be critical for the success of this methodology.

One year later, Sames and coworkers described formation of indole magnesium salts by treatment with either Grignard reagents or Mg(HMDS)2 as a strategy for C-arylation of indoles [200]. As shown in the example below, a 26:1 ratio of C-3/C2 selectivity was achieved using Mg(HMDS)2 to generate the indole magnesium intermediate. It is possible that the bulky trimethyl-silyl group offers the steric shielding from the C-2 position thus resulting in selective C-3 arylation.

Also in 2007, Sames and coworkers reported that protection of the NH group using N-Mg, N-Zn, or N-SEM could be eliminated when substrate concentration was increased and phosphine ligands removed. Indeed, phosphine ligands inhibit the reaction. Therefore, 3-methylindole (5.0 M) was arylated at C-3 with methyl 4-bromobenzoate in 64% yield when CsOAc was used as the base without the phosphine ligand [201].

At the end of Sect. 2.3 on Oxidative Cyclization, we briefly mentioned Fagnou’s remarkable catalytic cross-coupling of unactivated arenes onto indoles via oxidative oxidation using Cu(OAc)₂ [71]. Bellina and Rossi described a regioselective direct C-2 arylation free NH of indoles using Pd and Cu catalysts [202]. Unfortunately, the yields were only moderate, ranging from 10 to 53% for different aryl iodides. On the other hand, their direct palladium-catalyzed C-3 arylation had higher yields (53–97%) for free NH indoles with aryl bromides under ligandless conditions [203].

Recently, Zhang and coworkers reported a direct palladium-catalyzed C-2 arylation of indoles with potassium aryltrifluoroborate salts [204]. Remarkably, the direct arylation took place at room temperature when acetic acid was used as the solvent.

3 Copper-Catalyzed Cross-Coupling Reactions

An excellent review by Djakovitch on transition metal-catalyzed, direct and site-selective N1, C2-, or C3-arylation of indole nucleus was published in 2009 [205].

3.1 Selective N1-Arylation

Selective N1-arylation via copper-catalyzed cross-coupling reaction may be achieved under ligand-free conditions or ligand-promoted conditions.

Using a simple ligand-free procedure, Wang et al. prepared the N1-phenylation product 135 from indole 134 using CuSO₄ as the catalyst and K₂CO₃ as the base [206].

Also under ligand-free conditions, a series of 5-HT₂ antagonists was synthesized using CuI as the catalyst, ZnO as the cocatalyst, and K₂CO₃ as the base [207, 208]. One example is shown below. A remarkable selectivity was achieved for the N1-arylation for the indole NH versus the urea NH of the imidazolidin-2-one moiety.

After Buchwald’s report of copper-catalyzed N1 arylation of indoles using trans-1,2-cyclohexanediamine (CHDA) as the ligand [209], many diamine and related dinitrogen ligands have been developed. For instance, trans-N,N′-dimethyl-1,2-cyclohexanediamine was a better ligand than CHDA for phenylating indole 136 and 137 [210].

Additional ligands to promote copper-catalyzed N1-arylation of indoles include hydrazones such as 138 [211], Schiff base such as 139 [211], and salicyladoxime 140 [212]. N-Hydroxyphthalimide [213] and L-proline [214] were also used as ligands for copper-catalyzed N1-arylation of indoles.

3.2 Selective C2-Arylation

Direct and site-selective C2-arylation of indole nucleus is more challenging than the corresponding N1-arylation. Nonetheless, Gaunt’s group achieved such a feat for N-acylindoles with aryliodonium salts using Cu(OTf)₂ as the catalyst [215]. The mild reaction conditions tolerate a variety of functional groups (dtbpy=2,6-di-tert-butylpyridine).

3.3 Selective C3-Arylation

By extenuating the reaction temperatures, Gaunt et al. was able to selectively phenylate C3-position of indole nucleus using aryliodonium salts [215]. At temperatures below 60°C, Cu(OTf)₂-catalyzed C3-arylation took place selectively between N-acylindoles with aryliodonium salts using dtbpy as the agent to prevent indole dimerization.

4 Rhodium-Catalyzed Cross-Coupling Reactions

4.1 Selective C2-Arylation

Although there is no report on rhodium-catalyzed selective N1-arylation, Sames described a direct C2-arylation of indoles catalyzed by rhodium complexes [216]. When the rhodium catalyst was mixed with an electron-deficient phosphine ligand, a weak base, and an aryl iodide, a highly electrophilic and reactive Ar–Rh(III) species was generated in situ. The catalyst then promotes the C–H bond activation at the C2 position and arylation would take place selectively at C2 as demonstrated by the transformation of 141 and 142.

4.2 Selective C3-Arylation

Rhodium-catalyzed selective C3-arylation of indoles was reported by Itami et al. in 2006 [217]. Using a rhodium complex bearing a strong p-accepting phosphine ligand, they achieved a moderate selectivity of 2.4:1 for C3/C2 arylations as shown below.

5 Iron-Catalyzed Cross-Coupling Reactions

Iron catalysis is experiencing a renaissance. In 2007, Bolm described a selective N1-arylation using FeCl₃ as the catalyst and K₃PO₄ as the base [218]. The coupling reaction was facilitated by the addition of 20 mol% of DMEDA as a chelating agent.

6 Nickel-Catalyzed Cross-Coupling Reactions

Using nickel-2,2′-bipyridine complex as the catalyst, electroreductive coupling of 5-bromoindole gave rise to the bis-indole shown using NaBr as the electrolyte and iron and the sacrificial electrode [219].

A trace amount of nickel metal was able to catalyze the alkylation of indole at the C3-position in the presence of tert-butyl peroxide [220]. Mechanistically, the mixture of Ni(0)/t-BuOOH was likely to be responsible for oxidizing the primary alcohol to the corresponding aldehyde, which was then added to the C3-position of the indole ring. The resulting alcohol was reduced in situ to give the 3-alkylindole shown below.