Top Heterocycl Chem (2010) 26: 141191 DOI: 10.

1007/7081_2010_56 # Springer-Verlag Berlin Heidelberg 2010 Published online: 25 August 2010

Metalation of Indole
Erin T. Pelkey

Abstract Metalation reactions involving indoles (and indolines) is reviewed (through 2009). The most common mode of metalation is lithiation. Other metals that have been used, either through direct metalation of indole or through transmetalation, include magnesium, zinc, tin, and boron. This monograph is divided into three sections: metalation directed by a nitrogen functionality, directed ortho metalation by substituents not located at nitrogen, and halogenmetal exchange. All of the sections are organized by the location of the metalation event. The review will have a primary focus on the seminal papers that contributed to the development of metalation reactions and a secondary focus on applications of metalation reactions used in the synthesis of complex indoles including indole natural products. Keywords Directed ortho metalation Halogenmetal exchange Indole Lithiation

Contents
1 2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142 Metalation Directed by Nitrogen Functionality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144 2.1 C2-Lithiation of N-Methylindoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145 2.2 C2-Lithiation of N-(Arylsulfonyl)indoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 2.3 C2-Lithiation of N-(Carboalkoxy)indoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 2.4 C2-Lithiation of Indole-1-Carboxylic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 2.5 C2-Lithiation of Other N-(Substituted)indoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 2.6 C2 Metalation with Other Metals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 2.7 C3-Lithiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162

E.T. Pelkey Department of Chemistry, Hobart and William Smith Colleges, 300 Pulteney St, Geneva, NY 14456, USA e-mail: [email protected]

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E.T. Pelkey

2.8 C7-Lithiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 2.9 Lateral Lithiation to a Side-Chain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166 3 Directed Ortho Metalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 3.1 Directed Ortho Lithiation to C2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168 3.2 Directed Ortho Lithiation to C3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 3.3 Directed Ortho Lithiation to C4 from C3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172 3.4 Directed Ortho Lithiation in Benzenoid Ring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 4 HalogenMetal Exchange . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 4.1 HalogenLithium Exchange at C2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 4.2 HalogenLithium Exchange at C3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177 4.3 HalogenLithium Exchange in Benzenoid Ring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 4.4 Indolyl Grignard Reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 4.5 HalogenMetal Exchange with Other Metals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

1 Introduction
Metalation reactions, either by direct proton abstraction (usually protons directly adjacent to heteroatoms), directed ortho metalation (DOM), or halogenmetal exchange, are extremely useful for the conversion of simple indole starting materials into complex indole products. The indole ring system is prevalent in biochemical systems (e.g., tryptophan, melatonin, and serotonin), medicinal chemistry in the form of drugs (e.g., tadalal, sumatriptan, uvastatin, vincristine, and indomethacin) and biologically active molecules (e.g., staurosporine and ellipticine), and complex targets that helped inspire major advances in synthetic chemistry (e.g., strychnine, reserpine, and ibogamine). Due to the ubiquitous nature of the indole ring system, it is not surprising that a signicant portion of the seminal work in the eld of metalation reactions has been accomplished in the context of indoles. The research groups that have signicantly advanced the eld of indole metalation include Sundberg, Gribble, Snieckus, Katritzky, Iwao, Kondo, Sakamoto, Amat, Bosch, and Bergman; their work, along with many others, will be presented throughout the monograph. DOM methodology (including indoles) has been reviewed by Beak and Snieckus [13], while the use of metalated heterocycles (including indoles) was reviewed recently by Chinchilla and colleagues [4]. Katritzky and Rewcastle reviewed the generation of carbanions in heterocyclic nitrogen systems and this included a signicant section on indoles [5]. A timeline that describes some of the major advancements in indole metalation chemistry appears below (Fig. 1). Gilman reported perhaps the earliest metalation of an indole-containing ring system in the literature in 1936, and this work involved the selective lithiation of carbazole and N-ethylcarbazole (1) at C4 [6]. In 1953, Shirley demonstrated that the treatment of N-methylindole (2) with n-butyllithium led to selective metalation at C2 [7], adjacent to the nitrogen heteroatom as observed previously in other ve-membered ring heterocycles [8]. In the search for a removable N-protecting group, which would allow for the preparation of 2-substituted N-unsubstituted indoles, Sundberg surveyed lithiation reactions of

Metalation of Indole
3

143

N Me 2

N Boc 4

N O

OLi

N R1 9a R1 = TIPS 9b R1 = DEB Iwao 2001

N PO(t-Bu)2

Shirley 1953

Fowler and Levy 1981

5 Katritzky 1985

10 Snieckus 2003

1940

1950

1960

1970

1980

1990

2000

1936 Gilman

1973 Sundberg

1982 Gribble
3

halogen-metal exchange

1986 Rapoport
4

1993 Iwao

NMe2

I Br N H 7

N Et 1

N SO2Ph 3

N SO2Ph 6

N TIPS 8

Fig. 1 Timeline of selected advances in indole metalation

simple indoles containing different N-protecting groups [9, 10]. They found that N-(phenylsulfonyl)indole (3) led to selective C2-lithiation and overall was the best substrate. Consequently, the phenylsulfonyl protecting group has become the most common indole-protecting group for selective C2 metalation of indole. In the search for an acid-labile N-protecting group capable of directing lithiation, Fowler and Levy found that N-(tert-butoxycarbonyl)indole (4) was also selectively lithiated at C2 [11]. Katritzky used CO2 as a temporary N-protecting group in the synthesis of 2-substituted indoles [12, 13]; this method has subsequently found wide applicability. Gribble demonstrated the rst example of metalation at C3 using a halogenmetal exchange reaction with 3-iodo-1-(phenylsulfonyl)indole (6) [14]. They also investigated the generation of a 2,3-dilithioindole intermediate via a double halogenmetal exchange reaction with a 2,3-diiodoindole. Rapoport reported the use of halogenmetal exchange reactions of bromoindoles 7 for the functionalization of the benzene part of the indole ring system [15]. Iwao demonstrated the rst C4-selective lithiation of the indole ring by treating gramine derivative 8 with t-BuLi [16]. Iwao also found N-protecting groups, triisopropylsilyl (TIPS) [17] and 2,2-diethylbutanoyl (DEB) [18], that promoted the direct C3lithiation of indoles 9. Finally, Snieckus discovered a nitrogen-protecting group, ditert-butylphosphinoyl, which promoted the selective C7-lithiation of indole 10 [19]. Metalated indoles are extremely useful intermediates in synthesis. Either by choice of different N-protecting groups, by the use of directed ortho metalating groups, or by halogenmetal exchange reactions, metalation is possible at every position within the indole framework. To name just a few reaction manifolds, metalated indoles can undergo electrophilic substitution, transmetalation, and/ or cross-coupling reactions allowing for the synthesis of a variety of highly

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E.T. Pelkey

N H N Me CO2Me N H

Me N H Me N H

H H N H

minovine Ziegler 1970

ellipticine Kano 1981 Potier 1975 Joule 1979 Gribble 1982 Snieckus 1980

aristoteline Gribble 1985

H N

COOH N O N H O O hippadine Snieckus 2003

sempervirine Gribble 1988

clavicipitic acid Iwao 1997

Fig. 2 Selected indole natural products

functionalized indoles including indole natural products. Examples of natural products that have been prepared using indole metalation chemistry appear below (Fig. 2). Completed targets include minovine [20, 21], ellipticine [2230], aristoteline [31], sempervirine [32], clavicipitic acid [33, 34], and hippadine [19]; the location of the CC bonds formed via metalated indole intermediates is indicated by the arrows. This monograph will discuss the two major methods for indole metalation: (1) hydrogenmetal exchange (deprotonation) facilitated by nitrogen-based groups and carbon-based groups; and (2) halogenmetal exchange. Each section will discuss the key contributions that drove methodology development forward and will provide examples of important applications including those related to the total synthesis of natural products.

2 Metalation Directed by Nitrogen Functionality

Treatment of N-substituted indoles with strong bases can lead to selective deprotonation at C2, C3, or C7 depending on the nature of the nitrogen-protecting group. Most substitution patterns give selective metalation at C2. In fact, lithiation of N-(substituted)indoles is one of the premiere methods for preparing 2-substituted indoles. This section is organized by both the location of the metalation and also by the type of group substituted at nitrogen.

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145

2.1

C2-Lithiation of N-Methylindoles

The C2-lithiation of simple indoles was rst investigated by Shirley and Roussell in 1953 [7]. An attempted lithiation of N-lithioindole (double lithiation of indole) failed to yield any C-substituted products. On the other hand, treatment of N-methylindole (2) with n-butyllithium gave 2-lithioindole 11 as evidenced by quenching with CO2, which gave indole-2-carboxylic acid 12 (Scheme 1). The methyl group serves as a non-removable nitrogen substituent. This reaction worked with a variety of electrophiles including p-chlorobenzaldehyde, benzophenone, a-naphthyl isocyanate, quinoline, and methyl tosylate. In addition, treatment of N-phenylindole with a large excess of n-butyllithium followed by CO2 led to products arising from metalation at both 2-position of the indole ring along with 20 -position of the phenyl ring. Since this rst report, groups have mostly followed the original reaction conditions (n-BuLi in ether) to generate 11 for use as a nucleophile and no systematic study has been undertaken. In a series of papers regarding the generation of indolyl2-borates, Ishikura used tert-butyllithium as a base to form 11 [3543]. In addition, Caixach showed that N-methylindole (2) was not lithiated by treatment with lithiocyclohexylisopropylamide [44]. This result might not be too surprising after Fraser and co-workers measured the pKa of 2 in THF to be 38.1 using 13C spectroscopy [45]. Recently, Mulvey studied the direct magnesiation of 2 with (TMEDA)2Na2MgBu4; a similar reagent was used in the direct zincation of 2 [46]. Over the years, 11 has been treated with many different electrophiles leading to the formation of N-methyl-2-substituted indoles (Scheme 2); the electrophiles studied include: acetylpyridines [47], ketones [48], 1-chloro-2-(N,N-dimethylamino)ethane [49], pyridinecarboxaldehydes [50], iodine [51], amidines (e.g., 13 giving 2-ketoindole 15a) [52], N-methoxyurea 14 (followed by methyllithium giving 2-acetylindole 15b) [53], furanoses [54], nitrilimines [55], enaminoketones [56], sulfur (giving pentathiepino[6,7-b]indole 16) [57], bis-epoxides [58], and bicyclic aminals [59]. Some indole natural products contain an N-methyl group, and thus 11 can serve as a viable building block in total synthesis. For example, Ziegler and Spitzner generated 11 at the outset of their total synthesis of minovine (Fig. 2) [20, 21]. An inverse addition of 11 to an ethereal solution containing a large excess of dimethyl oxalate provided the corresponding indole-2-glyoxylate 17. Lithioindole 11 and structurally related derivatives have been transmetalated with a variety of metals. Bergman treated 11 with copper(I) bromide which gave the

n-BuLi, ether, N Me 2 11 N Me Li

1. CO2 2. HCl (78%) 12 N Me CO2H

Scheme 1 C2-lithiation of N-methylindole

146

E.T. Pelkey
S S S S S

Ts N O N Me

S8
(22%
11

13 N Me R O 1. Me or O N N Me Me 14 OMe

16

dim e

15a R = cyclopentyl (31%) 15b R = Me (79%)

thyl oxa late (59 %)

N Me 17 CO2Me O

2. MeLi

Scheme 2 Treatment of 11 with selected electrophiles

stable indolyl copper 18a [51]. Treatment of 18a with iodobenzene gave N-methyl2-phenylindole 19. Modifying the reaction conditions led to homocoupled products, 2,20 -biindoles (see also [60]), and cyclotrimerization products, trisindolobenzenes. Kumada formed the indolyl Grignard reagent 18b by treating 11 with magnesium bromide. Palladium-catalyzed cross-coupling of 18b with iodobenzene also gave N-methyl-2-phenylindole 19 [61]. Labadie converted 11 into stannane 18c by treatment with tributyltin chloride [62] (see also the work of Liebeskind [63, 64]). Labadie studied the palladium-catalyzed cross-coupling (Stille reaction) of 18c with a variety of electrophiles including 4-iodotoluene, which gave the corresponding 2-arylindole 19 (R Me) in good yield. Similarly generated 18d was used by Quintard to study ipso nitration reactions [65], by Arnswald to study FriedelCrafts amidations [66], and by Widdowson to study ipso uorination reactions [67]. Levy and later Ishikura explored the generation and reactions of a number of 2-indolylborates (e.g., 18e). Indolylborates can be converted into a variety of functionalized indoles including 2-alkylindoles [68], 2-allylindoles [69], 2-vinylindoles [70], 2,3-disubstituted indoles [38, 71], 2-arylindoles (e.g., 19) via palladium-catalyzed cross-coupling [3537], fused indoles [39, 40], and 2-ketopyrroles [41]. Iwasawa treated 11 with triethylborate, which presumably led to boronic acid intermediate 18f [72]. Subsequent treatment with 2,2-dimethyl-1,3-propanediol followed by a rhodium catalyst and carbon dioxide led to the corresponding indole-2-carboxylic acid. As is the case with many heteroarylboronic acids, 18f is now commercially available. Nicolaou prepared 6,7-dimethyl-N-methylindol-2-yl boronic acid as a building block in a total synthesis of aspidophytine [73]. Kaufmann generated an N-methylindol-2yldiarylborane from 11 for study as uorescent dyes [74]. Maas generated indolyl zincate 18g and transformed it into 2-vinylindoles via a palladium-catalyzed crosscoupling reaction [75]. Bisagni and co-workers studied the lithiation of N-methyl-5-azaindoles. They found that treatment of the latter with t-butyllithium led to selective C2-lithiation [76]. Lithiation reactions involving N-methyl-3-substituted indoles are sometimes useful for introducing electrophiles regioselectively to C2. Comins [77] and Adam [78] reported regioselective C2-lithiations of indole substrates containing

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147

MeO MeO N Me 20 N Me 21 MeO N OMe Me 22

regioselective

Fig. 3 Methoxy-substituted N-methylindoles

3-chloro and 3-vinyl substituents, respectively. On the other hand, lithiation of N-methylindoles containing methoxy groups in the benzenoid ring has proven to be unselective (Fig. 3). Lithiation of 6-methoxy-1-methylindole (20) led to a mixture of 2-substituted and 7-substituted products [79], while lithiation of 5methoxy-1-methylindole (21) led to a mixture of 2-substituted, 4-substituted, and 6-substituted products [10]. The lack of selectivity is due to the directing effect of the methoxy group [80], whereas the N-methyl group is not much more than just a blocking group. Regarding the latter, Sundberg found that using the benzenesulfonyl nitrogen-protecting group led to regioselective lithiation at the C2 position of the indole ring containing a 5-methoxy group [10]. More recently, Nicolaou reported the regioselective C2-lithiation of 6,7-dimethoxy-N-methylindole (22) for the preparation of the corresponding boronic acid [73]. In that case, the Nmethyl group was desirable as it was contained in the ultimate natural product target, aspidophytine.

2.2

C2-Lithiation of N-(Arylsulfonyl)indoles

To prepare 2-substituted N-unsubstituted indoles, Sundberg examined lithiation reactions for several indoles containing different removable N-protecting groups [9] as the N-methyl group is not readily removable. They assessed six different leaving groups by treating indole substrates 3 and 23 with t-butyllithium, quenching with D2O, and measuring deuterium incorporation at C-2 (Table 1) in the form of 25; both the methoxymethyl (entry 1) and benzenesulfonyl (entry 4) substrates were successfully lithiated. The benzyloxymethyl (entry 2) and benzyl (entry 3) substrates suffered from lithiation in the methylene portion of the benzyl moiety. Lithiation of the silyl-protected indoles (entries 56) led to 2-silylindoles via a rearrangement. The benzenesulfonyl group proved to be the protecting group of choice as it can readily be removed by treatment with mild base; consequently, benzenesulfonyl-protecting group has become the most common indole-protecting group for selective C2 metalation of indole. The use of metalated sulfonamides (including indoles) in synthesis has been reviewed by Familoni [81].

148 Table 1 Transmetalation of lithioindole 11

11 electrophile N Me 18 M ArI, Pd catalyst N Me 19

E.T. Pelkey

(R = H: 60% from 18a) (R = H: 79% from 18b) (R = Me: 82% from 18c) (R = H; 80% from 18d)

Entry 1 2 3 4 5 6 7

Base (to generate 11) t-BuLi t-BuLi n-BuLi n-BuLi n-BuLi or t-BuLi n-BuLi t-BuLi

Electrophile CuBr MgBr2 Bu3SnCl Me3SnCl Et3B B(OEt)3 ZnCl2

M Cu MgBr SnBu3 SnMe3 Et3BLi B(OH)2 ZnCl

Product 18a 18b 18c 18d 18e 18f 18g

Ref. [51] [61] [6264] [6567] [3538, 6871] [72] [75]

MeO N SO2Ph 26

1. t-BuLi, THF, 0 C 2. pyridine-2-carboxaldehyde (59%)

MeO N PhO2S 27 N OH

Scheme 3 Regioselective lithiation of methoxy-substituted indole

An advantage of the benzenesulfonyl group is that it allows for the regioselective generation of 2-lithioindole derivatives containing methoxy groups and other potential directing groups in the benzenoid ring. For example, Sundberg treated 5-methoxyindole 26 with tert-butyllithium followed by pyridine-2-carboxaldehyde which gave 27 in moderate yield (with no trace of products derived from lithiaton of the benzene ring as had been observed with the corresponding N-methylindole substrate) (Scheme 3) [10]. Others have observed regioselective transformations in similar systems containing methoxy groups [30, 79, 8290], benzyloxy groups [9195], halides [82, 9699], and a cyano group [100]. Sundberg reported the dilithiation of 3 when treated with 2.2 equivalents of tertbutyllithium at 5 C. Trapping with trimethylsilyl chloride gave a product containing two silyl groups [101]. Kondo reported a problem with lithiation in the arylsulfonyl ring upon treatment of 3 with tert-butyllithium, but this could be alleviated using LDA [102]; later, Kondo reported that the dilithiation reaction could also be suppressed using mesityllithium as the base [103]. As the benzenesulfonyl group is electron-withdrawing, there is a wide range of bases that can be used to generate lithio intermediate 24. Shortly after Sundbergs publication in 1973 [9], Grethe [104] and Joule [105] used n-BuLi, while Kano

Metalation of Indole

149

[106] and Gribble [14] used LDA. Other bases that have been used to generate 24 and structurally related analogs include sec-butyllithium [107109], phenyllithium [27], lithium hexamethyldisilazane (LiHMDS) [110], lithium tetramethylpiperidide (LiTMP) [86, 88], and lithium cyclohexylisopropylamide [44]. LDA has become the base of choice for the generation of 24. One advantage that LDA offers over alkyllithium bases is functional group tolerance. For example, Gribble treated with 3-iodoindole 6 with LDA followed by iodine which gave 2,3-diiodoindole 28 (Scheme 4) [14]. A wide range of electrophiles have been introduced to the C2 position of the indole ring system via lithio intermediate 24. Electrophiles that have been added include the following (selected examples shown in Table 2): iodine [111, 112] (entry 1), BrCN [112] (entry 2), benzenesulfonyl chloride [112] (entry 3), DMF [14] (entry 4), trimethylsilyl chloride [113] (entry 5), oxirane [114] (entry 6), ketoesters [115, 116] (entry 7), allylic halides [117] (entry 8), acyclic anhydrides [106, 109] (entry 9), dinitrogen tetroxide [118] (entry 10), heterocylic carboxaldehydes [82, 119, 120], heterocylic carbonyl chlorides [92, 94], hetero cyclic
1. LDA, THF, 78C 2. I2 (98%) N PhO2S 28

I N SO2Ph 6

I I

Scheme 4 Selective C2-lithiation of 3-iodo-(N)-benzenesulfonylindole 6 with LDA

Table 2 Generation and reactions of 2-lithio-N-(phenylsulfonyl)indole 24

base N SO2Ph 3 N Li SO2Ph 24 electrophile N E SO2Ph 29

Entry Base Electrophile E Product Yield (%) I 29a 80 1 LDA I2 2 LDA BrCN Br 29b 85 Cl 29c 82 3 LDA PhSO2Cl 4 LDA DMF CHO 29d 50 5 t-BuLi TMS-Cl TMS 29e 75 29f 69 6 LDA Oxirane CH2CH2OH CH2(OH)CO2Et 29g 64 7 t-BuLi CHOCO2Et 29h 74 8 n-BuLi Allyl bromide CH2CH=CH2 Ac 29i 76a 9 s-BuLi Ac2O NO2 29j 67 10 t-BuLi N2O4 a Yield with anhydride improved by inverse addition procedure in many cases

Ref. [111, 112] [112] [112] [14] [113] [114] [116] [117] [109] [118]

150

E.T. Pelkey

ketones [22, 121, 122], 4,4-dimethoxy-2,5-cyclohexadienones [123], phthalic anhydride [124], pyridine-fused anhydrides [26, 30, 89], ethoxymethylidene Meldrums acid [125], t-butyl isocyanate [32], 1-benzoylpyrrolidin-2-one, sulnyl aldimines [126], toluenesulnates [127], tosyl uoride [128], lactones [25, 129, 130], lactams [131], ketones [132, 133], aldehydes [104, 134, 135], halopyridines [9, 44], oxalates [136], and iodomethane [14, 29]. Gribble reported that 3-lithio-N-(phenylsulfonyl)indole, generated via halogenmetal exchange (vide supra) at 100 C, rearranges to form 24 upon warming to room temperature [14]. Lithioindole 24 and structurally related derivatives have been transmetalated with a variety of metals to give important metalated intermediates 30 including indol-2-yl triethylborate 30a [36, 37, 41, 68, 71], 5-azaindol-2-yl boronic acid [137] related to 30b, indol-2-yl stannanes 30c [138, 139] and 30d [91], other indol-2-yl stannanes [67, 91, 137, 140145], indol-2-yl coppers [51, 146148], indol-2-yl zincate 30e [102, 149151], and other indol-2-yl zincates [84, 141] (Table 3). Heterocyclic boronic acids tend to be unstable; Burke has developed a method for generating 30b in situ through use of the corresponding MIDA (Nmethyliminodiacetic acid) boronate ester [152]. These metalated intermediates 30 are valuable in synthesis since they can be further transformed into 2-substituted indoles and [b]-fused indoles via palladium-mediated cross-coupling reactions among other reactions. Caddick has developed an alternate route to indol-2-yl stannanes (e.g., 30d) using an interesting ipso stannylation/detosylation reaction [128, 153]. Joule discovered a novel route to [b]-fused indoles via an interesting sequence that involved C2-lithiation of indole, quenching with either lactam [154] or lactone electrophiles [105, 155, 156], and subsequent intramolecular cyclization reactions with consequent loss of the benzenesulfonyl group. Their synthesis of oxepinofused indole 33 is instructive (Scheme 5) [155]. Treatment of 24 with phthalide (31)

Table 3 Transmetalation of 2-lithio-N-(phenylsulfonyl)indole 24

electrophile N Li SO2Ph 24 M N SO2Ph 30

Entry Base (to generate 24) Electrophile M Product Yield (%) Ref. BEt3Li 30a a [36, 37, 41, 68, 71] 1 n-BuLi BEt3 b 2 B(OH)2 30b SnMe3 30c 83 [138] 4 LDA Me3SnCl SnMe3 30c 43 [139] 4 t-BuLi Me3SnCl SnBu3 30d 85 [91] 5 LDA Bu3SnCl ZnCl 30e a [102, 149151] 6 LDA ZnCl2 a Not isolated; used directly in subsequent reactions b Commercially available; no published syntheses found in the primary literature

Metalation of Indole

151

gave keto alcohol 32. Mixing 32 with sodium hydroxide gave 33 via an intramolecular cyclization and loss of the benzenesulnate group. Outside of the prevalent benzenesulfonyl group, the use of other arylsulfonyl groups has been investigated in indole C2-lithiation reactions. Thus, treatment of N-arylsulfonylindoles 34 with various lithium bases (as noted) led to 2-lithioindoles 35 and subsequently to 2-substituted indoles 36. Illustrative examples are shown below (Table 4). Additional studies have also been reported with 34a [96, 148, 157, 158], the 3-bromo analog of 34a [159], 34b [48, 145, 160, 161], a 3methyl analog of 34b [162], and an ergot alkaloid derivative of 34c [163]. In the search for a scalable lithiation procedure, Wu and co-workers found that 34b could be lithiated with LDA at 25 C in the presence of bis(N,N-dimethylaminoethyl) ether [96]. Kondo and co-workers studied the use of uorous-tagged N(arylsulfonyl)indole derivatives [103]. They found mesityllithium to be the best base for the selective a-lithiation of these substrates. The selective C2-lithiation of 3-substituted-1-(phenylsulfonyl)indoles 37 is a common strategy for the synthesis of 2,3-disubstituted indoles 39. The bases that have been used to prepare 3-alkyl-2-lithio-N-(phenylsulfonyl) indoles 38 include LDA, n-butyllithium, sec-butyllithium, and phenyllithium
OH 24 + NaOH, EtOH O O 31 N PhO2S 32 O N H O 33 O

Scheme 5 Joules synthesis of [b]-fused indoles Table 4 Generation and reactions of 2-lithio-N-(arylsulfonyl)indoles 35
base N O S O R1 34 N Li O S O R1 35 electrophile N R2 O S O R1 36

Entry R1 SM Base Electrophile DMF 1 p-OMeC6H4 34a LDA 2 p-OMeC6H4 34a n-BuLi NISa 34b LDA Me3SnCl 3 p-MeC6H4 34b t-BuLi Me3SnCl 4 p-MeC6H4 34b t-BuLi BtCNc 5 p-MeC6H4 34c LDA lactone 6 NMe2 a NIS N-iodosuccinimide b Yield not given; 36c used without purication c BtCN 1-cyanobenzotriazole

R2 CHO I SnMe3 SnMe3 CN lactol

Product 36a 36b 36c 36c 36d 36e

Yield (%) 90 60 79 b 43 91

Ref. [164] [141] [144] [143] [165] [130]

152

E.T. Pelkey

(not tert-butyllithium). Some straightforward examples are illustrated below (Table 5); Ito contributed additional examples in their preparation of 2-mannosyltryptophans [166, 167]. Much of this work has focused on the preparation of 2,3-disubstituted indoles, substrates that can be transformed into fused indoles [168, 169] including natural product targets such as ellipticine (from 39g) [27, 29], iboga alkaloids [140], and b-carbolines [170, 171]. Intramolecular cyclizations of 2-lithio-3-substituted indole intermediates have been explored to give [b]-fused indoles; the base of choice for the generation of the lithio intermediate is LiHMDS [110, 172, 173]. Gribble has reported many examples that involved the generation of lithio intermediate of type 38 that eventually were converted into fused indoles including pyrrolo[3,4-b]indoles [107, 108] and furo[3,4-b]indoles [27, 29, 176179]; this work has been reviewed [180]. In some cases, the substituent at C3 was a hydroxyalkyl group or an acetal group; the oxygen heteroatoms in these groups can also participate in stabilizing the lithiated intermediate. A second generation synthesis of furo[3,4-b]indole 42 is instructive (Scheme 6) [176]. Treatment of indole 40 with sec-butyllithium followed by formaldehyde gave 2,3-disubstituted indole 41.
Table 5 Generation and reactions of 3-alkyl-2-lithio-N-(phenylsulfonyl)indoles 38
R1 base N O S O Ph 37a R1 = Me 37b R1 = Et N Li O S O Ph 38a R1 = Me 38b R1 = Et R1 electrophile N R2 O S O Ph 39 R1

Entry SM Base Electrophile R2 Product Yield (%) Ref. PhCO 39a 50 [24] 1 37a LDA (PhCO)2O 2 37a n-BuLi MeS(=O)Cl S(=O)Me 39b 80 [174] Ac 39c 81 [109] 3 37a sec-BuLi Ac2O C(=O)CO2Et 39d 31 [107] 4 37a sec-BuLi ClC(=O)CO2Et 5 37a LDA t-BuNCO CONHt-Bu 39e 68 [175] COPh 39f 75a [24] 6 37b LDA (PhCO)2O CH(OH)CH3 39g 73 [27] 7 37b PhLi CH3CHO 8 37b sec-BuLi PhCHO CH(OH)Ph 39h 63 [108] a Yield of this transformation with the pyridine analog, isonicotinic anhydride, was also 75%

O O N O S O Ph 40

1. sec-BuLi THF, 78 C 2. HCHO N O S O Ph 41

O O OH

BF3 Et2O, THF hydroquinone (52% from 41) O N O S O Ph 42

Scheme 6 Synthesis of furo[3,4-b]indole 42

Metalation of Indole

153

Exposure of 41 to boron triuoride etherate led to 42 in 52% yield from 40. Bergman and Janosik lithiated 40 by treatment with LDA in their synthesis of sulfur- and selenium-substituted indoles [181, 182]. As noted earlier (Scheme 4), 3-iodo-N-(phenylsulfonyl)indole 6 was lithiated selectively at C2 (thus avoiding halogenmetal exchange) by treatment with LDA [14, 183185]. This selectivity has also been observed with 3-bromoindole 43 [159, 183, 184, 186], functionalized 3-bromoindoles (not shown) [159, 187], and 3-cyanoindole 44 [103, 188]. Examples of the C2-lithiation of these substrates in the synthesis of 2,3-disubstituted indoles 39 are shown below (Table 6). Merour [137, 190, 191], Dormoy [86], Mahboobi [85], and Bisagni [76] have reported the selective C2-lithiation of various N-(phenylsulfonyl)azaindoles using LDA and n-butyllithium. The following example with 5-azaindole 45 is illustrative (Scheme 7) [137]. With a 7-azaindole substrate, lithiation also occurred in the arylsulfonyl ring [190]. The C2-lithation of N-(arylsulfonyl)indoles has proven to be an important strategy that helped enable the total synthesis of several indole natural products (Figs. 2 and 4). Targets prepared from N-(phenylsulfonyl)indole (3) include
Table 6 Generation and reactions of 3-halo-2-lithioindoles and 3-cyano-2-lithioindoles
R1 LDA N O S O Ph 6, 43, 44 N Li O S O Ph 38 R1 electrophile N R2 O S O Ph 39 R1

Entry R1 SM Electrophile 1 I 6 (PhCO)2O 2 I 6 BrCN 3 Br 43 PhSSPh 4 Br 43 BrCN 5 CN 44 ICH2CH2I 6 CN 44 TsCN a Utilized mesityllithium as the base

R2 COPh Br SPh Br I CN

Product 39i 39j 39k 39l 39m 39n

Yield (%) 79 80 61 73 65a 77

Ref. [189] [184] [159] [184] [103] [188]

N N O S O Ph 45

1. LDA/TMEDA THF, 20 C 2. acetophenone (79%)

Me Ph N O S O OH Ph 46

Scheme 7 Selective C2-lithiation of 5-azaindole

154

E.T. Pelkey

apparacine [146, 147], aspidofractinine [117], cinchonamine [104], desethylcatharanthine [115, 116], ellipticine [22, 25, 26, 30, 89, 122], hyellazole [30, 106, 133], olivacine [121, 122], and sempervirine [32]. Ellipticine has also been prepared from 3-ethyl-N-(phenylsulfonyl)indole (37b) [24, 29].

2.3

C2-Lithiation of N-(Carboalkoxy)indoles

The second most used protecting group utilized for preparing 2-substituted N-unsubstituted indoles via lithiation chemistry is the acid-labile Boc (tertbutoxycarbonyl) group. Fowler and Levy rst reported the use of Boc in the generation and reactions of 2-lithiated indoles [11] (Scheme 8). Lithio intermediate 47 was generated by treating Boc-indole 4 with tert-butyllithium. Careful quenching with dimethyl oxalate gave 2-methoxalylindole 48a in 66% yield. The Boc group could be removed by treatment with triuoroacetic acid or sodium methoxide. Compound 47 has been generated and used in the synthesis of a variety of 2-substituted indoles 48. Unlike lithiation of N-(phenylsulfonyl)indole 3 [9, 14], lithiation reactions of 4 have not been studied systematically. Nonetheless, selected examples including the corresponding reaction conditions used are given below (Table 7). Silanol 48g has been generated and exploited by Denmark in cross-coupling reactions [192, 193]. Kline used this chemistry to prepare 48b en route to a synthesis of 2-iodotryptamine [194]. Additional electrophiles used in reactions with 47 include epoxides (carbohydrates) [166], allylic pivalates [195], and chlorodialkylphosphines [196].

Me N N H apparacine N H OMe Me Ph N H N

Me

hyellazole

olivacine

Fig. 4 Additional indole natural product targets synthesized via lithiated indole intermediates

O MeO t-BuLi, THF, 78 C N t Bu-O 4 O t Bu-O 47 N O Li O (66%) t Bu-O N O 48a O CO2Me OMe

Scheme 8 Selective C2-lithiation of N-(tert-butoxycarbonyl)indole 4

Metalation of Indole Table 7 Generation and reactions of 2-lithio-N-(BOC)indole 47

base, temperature N tBu-O 4 O t Bu-O 47 N O Li t Bu-O 48 electrophile N

155

E O

Entry Base 1 t-BuLi 2 t-BuLi 3 t-BuLi 4 n-BuLi 5 n-BuLi 6 LDA a Not reported

Temp 78 C 78 C 120 C 78 C 65 C 0 C

Electrophile I2 ClCO2Et N2O4 SO2Cl2 ClPOMeN(iPr)2 SiMe2Cl2

E I CO2Et NO2 SO2Cl P(=O)HOMe SiMe2OH

Product 48b 48c 48d 48e 48f 48g

Yield (%) 67 75 78 a 45 91

Ref. [111] [197] [118] [198] [199] [200]

Table 8 Transmetalation of 2-lithio-N-(BOC)indole 47

base, temperature N t Bu-O 4 O t Bu-O 47 N O Li tBu-O 48 electrophile N O E

Entry Base Temp Electrophile E Product B(O-iPr)3 B(OH)2 48h 1 LiTMP 78 C B(O-iPr)3 B(OH)2 48h 2 LiTMP 78 C B(O-iPr)3 B(OH)2 48h 3 LDA 0 C B(OMe)3 B(OH)2 48h 4 t-BuLi 78 C BEt3 BEt3Li 48i 5 t-BuLi 78 C Bu3SnCl SnBu3 48j 6 sec-BuLi b Bu3SnCl SnBu3 48j 7 n-BuLi 78 C Bu3SnCl SnBu3 48j 8 LDA 78 C Me3SnCl SnMe3 48k 9 n-BuLi 78 C Me3SnCl SnMe3 48k 10 LDA 78 C ZnCl2 ZnCl 48l 11 t-BuLi 78 C a Generated and used directly in a wide variety of reactions b Reported in microche c Generated and used directly in Pd-catalyzed cross-coupling reactions

Yield (%) 65 94 96 69 a b 40 91 37 76 c

Ref. [223] [205] [200] [224] [208] [225] [62] [226] [65] [145] [102]

Lithioindole 47 and structurally related derivatives have been transmetalated with a variety of metals to give important metalated intermediates 48hl. Examples with the reaction conditions used to generate 47 are given below (Table 8). Vazquez reported a signicant advance in the metalation of 4 using LDA under noncryogenic

156

E.T. Pelkey

conditions (0 C) [200], and higher yields for the preparation of metalated intermediates seemed to be obtained using LDA. Boronic acid 48h and functionalized derivatives have been further transformed into the corresponding triuoroborate salts by treatment with KHF2 [201205]. The latter tend to be more stable and useful than boronic acids in palladium-catalyzed cross-coupling reactions. Ishikura and co-workers have explored the chemistry of triethylborate 48i in great detail [37, 43, 70, 206, 207]; 48i proved useful in total syntheses of ellipticine [208], yuehchukene [209], and tubifoline [210]. A number of functionalized N-(Boc) indole-2-boronic acids [201, 211215], 2-stannanes [216, 217], 2-zincates [218220], and a 2-cuprate [221] have been prepared using lithiation chemistry. Dari and co-workers generated N-(methoxycarbonyl)indole-2-boronic acid and used it in a process-quality synthesis of anticancer drug candidate, obatoclax [222]. Sestelo and Sarandeses generated tris(indol-2-yl)indium 49 for use in palladiumcatalyzed cross-coupling reactions (Scheme 9) [227]. Lithiation of 4 with n-butyllithium followed by treatment with indium trichloride gave 49 which was used directly in palladium-catalyzed cross-coupling reactions leading to 2-arylindoles 50. These same authors exploited this chemistry to prepare indole-substituted maleimides [228]. The BOC group has enabled the selective C2-functionalization of a wide range of benzenoid-substituted and/or 3-substituted indoles [166, 167, 229234] [235]. An early example was reported by Castagnoli for the preparation of ethyl 5,6-dimethoxy-3-methylindole-2-carboxylate [236]. Marino lithiated 5-benzyloxyindole 51 with sec-butyllithium and quenched the 2-lithio intermediate with dimethyl sulde giving indol-2-yl sulde 52 (Scheme 10) [162]. The latter proved to be a useful intermediate in a total synthesis of physostigmine. Cook introduced an isopropenyl group to the 2-position of an N-(Boc)indole derivative in a sequence that resulted in the total synthesis of tryprostatin A [237]; others have

1. n-BuLi, THF, 78 C 2. InCl3 N Boc 49 In

3

3 ArX, Pd(dppf)Cl2 THF, (70-93%) tBu-O N 50 O Ar

Scheme 9 Preparation of novel tris(indol-2-yl)indium intermediate 49

BnO N t Bu-O 51 O

Me

1. sec-BuLi THF, 78 C 2. MeSSMe (85%)

BnO N t Bu-O 52 O

Me SMe

MeHN O

Me

N Me

N Me

physostigmine

Scheme 10 Selective C2-lithiation of functionalized N-(Boc)indole 51

Metalation of Indole

157

prepared tryprostatin analogs using lithiation chemistry [221, 229]. Selective C2lithiation of N-Boc-substituted 5-azaindoles [86] and 7-azaindoles [217] has also been reported. Several protecting groups similar in structure to Boc, other N-(carboxy)indoles and N-(carbamoyl)indoles, have been investigated in C2-lithiation reactions. Examples of the protecting groups, bases, and electrophiles that have been used appear below (Table 9). As mentioned throughout the text, the C2-lithation of N-(Boc)indoles has proven to be an important strategy that helped enable the total synthesis of several indole natural products including: physostigmine [162] (Scheme 10) arcyriacyanin A [145], ellipticine [208] (Fig. 2), yuehchukene [209], tubifoline [210], and tryprostatin [237]. Approaches to the Strychnos [233] and indolocarbazole alkaloids [203, 204] have also been reported.

2.4

C2-Lithiation of Indole-1-Carboxylic Acids

Although the early attempts at the double lithiation of the parent indole ring system failed to produce 2-substituted indoles [7], in 1985, Katritzky invented a sequence that basically accomplished this goal [12]. They used carboxylate as a temporary nitrogen-protecting group, which allowed for the selective C2-lithiation of the indole ring system (Scheme 11). Indole (56) is treated with n-butyllithium followed by carbon dioxide, which generates lithium indole-1-carboxylate 5. Subsequent treatment of 5 with tert-butyllithium then gave the 2-lithioindole intermediate 57; quenching the latter with an electrophile (e.g., benzoyl chloride) and work-up then gave 2-substituted indoles (e.g., 58) after loss of the carboxylate group. This method is advantageous because it does not require extra steps for the introduction
Table 9 C2-lithiation of N-(carboxy)indoles and N-(carbamoyl)indoles
base N X 53 O X 54 N O Li X 55 electrophile N O E

Entry X Base Electrophile E Product B(OH)2 55a 1 OMe LDA B(O-iPr)3 sec-BuLia ClCO2Et CO2Et 55b 2 CEt3 Me3SiCl SiMe3 55c 3 NHt-Bu t-BuLib t-BuLi Me3SiCl SiMe3 55d 4 NEt2 BuLi PCy2Cl PCy 55e 5 N(iPr)2 a t-BuOK was also added; otherwise, lithiation primarily occurred at C3 b 2.2 equivalents of t-BuLi

Yield (%) 70 90 95 97 70

Ref. [222] [18] [238] [19] [196]

158
1. n-BuLi THF, 70 C 2. CO2 N H 56 LiO 5 N O LiO 57 O Cl t-BuLi N O Li (59%)

E.T. Pelkey

N H 58

Ph O

Scheme 11 Katritzky method for preparing 2-substituted indoles

56

1. n-BuLi THF 70 C 2. CO2 3. t-BuLi

H O 59 57 (71-84%) N H 60 HN yuehchukene OH 4 steps N H

Scheme 12 Using Katritzky method in total synthesis of yuehchukene

OMe

1. n-BuLi THF 70 C 2. CO2 3. t-BuLi N H 61

O OMe H 63 N LiO 62 N O (43%) N N H 64 NPhth OMe NPhth N OH N OH N

NH2 N

H2N N variolin B

Scheme 13 Using Katritzky method in total synthesis of variolin B

and removal of indole-protecting groups. Katritzky has also written a review on indole-1-carboxylic acids [239]. The above reaction sequence (Scheme 11), sometimes called the Katritzky method, has been exploited by a number of research groups for the preparation of 2-substituted N-unsubstituted indoles [83, 102, 130, 218, 240245]. Gribble and Bergman used this chemistry to prepare 2-bromoindole and 2-iodoindole [246248]. Bergman and Janosik further explored this sequence to prepare indol2-yl suldes and selenides [57, 249, 250]. Hudkins has used this chemistry to prepare 2-hydroxyalkylindoles en route to indolocarbazole derivatives [251, 252]. The rst step in Bergmans short total synthesis of yuehchukene used the Katritzky method and aldehyde 59, which gave 2-(hydroxyalkyl)indole 60 (Scheme 12) [253, 254]. The Katritzky method has also proven useful in the functionalization of azaindoles. Alvarez and co-workers have used the Katritzky method to synthesize variolin B starting with 7-azaindole 61 (Scheme 13) [255257].

Metalation of Indole

159

2.5

C2-Lithiation of Other N-(Substituted)indoles

The most common indole nitrogen-protecting groups used in C2-lithiation reaction sequences are benzenesulfonyl and tert-butoxycarbonyl (Boc). Additional protecting groups that have been examined, some of which have already been mentioned, include benzyl (Table 10, entry 3), p-methoxyphenyl (PMP) [258], trimethylsilylethoxymethyl (SEM) [36, 62, 259261], methoxymethyl (MOM) [9, 102, 170172, 262265] (Table 10, entry 1), diethylbutanoyl (DEB) (Table 9, entry 2), carbamoyl derivatives (Table 9, entries 35), diethoxymethyl (DEM) [266268], (dimethylamino)methyl (isogramine) [269271], methoxy [272], methoxymethoxy [273], and 2-oxazolinyl [274]. Examples of the C2-lithiation of indole substrates not mentioned prior are given below (Table 11). Sundberg found that N-benzyl-substituted indoles are not suitable substrates for C2 metalation due to competitive metalation at the benzyl methylene [9]. On the other hand, metalation at C2 is possible with N-benzylindoles with the presence of an additional directing group at C3 (vide infra) [23]. Additionally, Snieckus reported a tandem DOM/cyclization sequence involving an N-benzylindole substrate, which gave tetracyclic indole derivatives [23]. More recently, Sanz reported a tandem halogenmetal exchange/C2-lithiation of N-benzylindole 68 (Scheme 14) [276]. Trapping dilithio intermediate 69 with ethyl benzoate gave tetracyclic indolo[1,2-b]isoquinoline 70. Very few examples of C2-lithiation reactions involving N-arylindoles are known [258]. In the search for new indolyl phosphine ligands (e.g., 72) for palladiumcatalyzed amination reactions, mono-lithiation and di-lithiation reactions involving N-arylindoles have been used (Scheme 15). Beller reported the synthesis of indolyl ligand 72a using a mono-lithiation of N-phenylindole (71a) [277], whereas Nifantev used a dilithiation of 71b under much colder conditions to give bis (phosphine)indole 72b [278].
Table 10 Lithiation of different N-substituted indoles
t-BuLi N R 3, 23 N R Li D2O N R 25 D

24 (R = SO2Ph)

Entry Substrate R 1 23a CH2OCH3 2 23b CH2OCH2Ph 3 23c CH2Ph 4 3 SO2Ph 5 23d Si(CH3)3 6 23e Sit-Bu(CH3) 2 a TMEDA tetramethylenediamine

Solvent Ether Ether THF THF TMEDAa THF

D incorporation at C2 (%) 95 30 15 86 0 0

160 Table 11 C2-lithiation of various N-(substituted)indoles

base N R 65 N R 66 Li electrophile

E.T. Pelkey

N R 67

Entry R 1 SEM 2 MOMa 3 DEM 4 CH2NMe2 5 OMe 6 OCH2OMe 7 2-(oxazolinyl) a Starting material = 23a

Base n-BuLi t-BuLi t-BuLi n-BuLi n-BuLi n-BuLi n-BuLi

Electrophile Bu3SnCl PhNMeCHO Me3SiCl Ph2CO I2 Me2NCHO MeI

E SnBu3 CHO SiMe3 CHOHPh2 CHO CHO Me

Product 67a 67b 67c 67d 67e 67f 67g

Yield (%) 77 53 82 85 73 96 31

Ref. [62] [275] [267] [270] [272] [273] [274]

t-BuLi, TMEDA ether, 78 C to rt N Br N Li

PhCO2Et (62%) N

OH Ph

Li 68 69 70

Scheme 14 Tandem halogenmetal exchange/C2-lithiation

t Bu P t Bu

1. n-BuLi (1 equiv) TMEDA toluene, 100 C 2. (t-Bu)2PCl (50%) N

1. n-BuLi (2.2 equiv) TMEDA ether, 70 C 2. Ph2PCl (60%) Ph2P N PPh2

72a

R 71a R = H 71b R = Me

Me 72b

Scheme 15 Lithiation reactions involving N-(aryl)indoles 71

Ruhland reported a novel solid-phase C2-lithiation of the indole ring [279] using a linker that resembled the MOM-protecting group (Scheme 16). Lithiation of resin-bound indole 73 was accomplished by treatment with tert-butyllithium in toluene followed by quenching with benzonitrile. Reductive cleavage of 74 then gave amine 75 in an overall yield of 2%, proof of principle that this type of transformation is possible.

Metalation of Indole
1. t-BuLi, toluene 2. PhCN, ether N O 73 O N Ph 74

161

AlH3, ether NH (2% from indole) N H 75 Ph NH2

Scheme 16 C2-lithiation of a resin-bound indole derivative

2.6

C2 Metalation with Other Metals

Thus far, all of the metalation reactions of indole discussed have involved lithiumhydrogen exchange (lithiation) using organolithium and bulky lithium amide bases. In recent years, there has been an increase in interest in nding milder, non-lithium bases to effect the metalation of aromatics and heteroaromatics; this topic was reviewed by Mulvey in 2009 [280]. In 1996, Kondo and Sakamoto reported one of the rst metalations (metalhydrogen exchange) of the indole ring that involved a non-lithium base [281]. They achieved the C2-metalation of indole using magnesium bases. For example, they treated N-(phenylsulfonyl)indole (3) with magnesium diisopropylamide (generated from diisopropylamine and an alkyl Grignard reagent) which gave indol-2-yl Grignard reagent 76; quenching with iodine then gave 2-iodoindole 29a (Scheme 17). Following the precedent of Dinsmore in the magnesiation of pyrroles [282], de Koning prepared 29a (in an improved 79% yield) using a catalytic amount of amine and a stoichiometric amount of the Grignard reagent to generate the magnesium amide base. Additional metals that have been used in novel, direct metalation reactions of indole include aluminum [283, 284], copper [285], and zinc [220]. To compare the different conditions that have been explored, different syntheses of N-(tertbutoxycarbonyl)-2-iodoindole (48b) are compared below (Table 12). From 4, 48b was prepared using different direct metalation methods followed by quenching with iodine; the highest yielding conditions involved the cupration chemistry. Given the importance of arylboronic acids and arylboronates, Ishiyama and co-workers developed a direct C2-borylation of indole using iridium catalysis [286289]. Treatment of indole (56) with pinacolborane (78), iridium catalyst 79, and 4,40 -di-tert-butylpyridine (80) in hexane gave indol-2-ylborane 79 in 73% yield (Scheme 18) [288]. Nishida published a similar method using an iridium catalyst and an imine complex [290]. Multiple groups have reported that the iridiumcatalyzed borylation with 2-(substituted)indoles led to C7-borylation [291, 292]. Maleczka and Smith reported that the iridium-catalyzed borylation of 4 gave the corresponding indol-3-ylborane [293]; whereas Ishiyama and co-workers also observed 3-borylation with an N-(trialkylsilyl)indole substrate [289]. Finally, Snieckus reported an ipso-borylation/desilylation produced indol-2-ylboranes [294, 295].

162

E.T. Pelkey

NiPr2MgBr, THF, rt N SO2Ph 3 N MgBr SO2Ph 76

I2 (60%) I N SO2Ph 29a

Scheme 17 Direct magnesiation of N-(phenylsulfonyl)indole 3

Table 12 Comparison of different direct metalation reactions

base, conditions N tBu-O 4 O N M t Bu-O 48b I2 N O I

tBu-O O 47, 48l, 77

Metalated Yield Ref. indole (%) Li 47 67 [111] 1 t-BuLi THF, 78 C THF, rt Mga 77a 52 [281] 2 (NiPr2)2Mg ZnCl 48l 67 [220] 3 LiTMP, ZnCl2 TMEDA THF, rt THF, 78 C Al(i-Bu)3Li 77b 64 [283] 4 (i-Bu)3Al(TMP)Li THF, 40 C Cu(Me)(CN)Li2 77c 88 [285] 5 MeCu(TMP)(CN)Li2 a Presumably, di-indol-2-ylmagnesium intermediate is generated by treatment of 4 with (NiPr2) 2Mg
l

Entry

Base

Conditions

1/ [Ir(OMe)(COD)] 2 2

N 80 (73%)

, hexane, rt B O O

O + N H 56 O 78 BH

79

N H 81

Scheme 18 Direct borylation of indole

2.7

C3-Lithiation

The direct C3-lithiation of the indole ring has been observed with N-(trialkylsilyl) indoles although it took some time for this to be realized. In their original 1973 paper, Sundberg reported that the attempted C2-lithiation of N-(trialkylsilyl)indoles 23d and 23e failed and instead led to products where the silyl group had migrated [9]. Klingebiel later reported that the treatment of 1-(di-tert-butyluorosilyl)indole

Metalation of Indole

163

with tert-butyllithium led to C3-lithiation as ascertained by the 1,3-disilylindoles obtained upon quenching with uorotrialkylsilanes [296]. This result was explored further by Iwao using N-(triisopropylsilyl)indole (9a) [17]. Treatment of 9a with tert-butyllithium in the presence of TMEDA, followed by quenching with electrophiles, led to the formation of 3-(substituted)indoles 83 (Table 13, entries 14) in good yields. Although C2 is more acidic than C3 in N-(substituted)indoles (by approximately 4 pKa units as measured for indole 2 [297]), the triisopropylsilylprotecting group blocks reactivity at C2 and also itself is not subjected to transfer. This C3-selectivity was later exploited by Satoh in reactions between N-(silyl) indoles and alkylidene carbenoids [258]. Iwao also observed direct lithiation at C3 with N-(2,2-diethylbutanoyl)indole 9b (Table 13, entries 58) [18]. The yields obtained with the DEB-protecting group were somewhat lower than those obtained with the TIPS-protecting group. The optimal reaction conditions included hexane as the solvent; much lower yields were obtained when the reactions were run in ether. When superbase was used (secBuLi t-BuOK), lithiation of 9b occurred preferentially at C2.

2.8

C7-Lithiation

Although most N-(substituted)indoles are selectively lithiated at C2, a few protecting groups have been found to selectively direct lithiation at C7 even in the absence of groups at C2. Iwao found that the DEB (2,2-diethylbutanoyl) group directed lithiation to C7 [18]. This reaction was synthetically useful for 3-(substituted)indole

Table 13 Direct C3-lithiation of N-(triisopropylsilyl)indole 9a and N-(2,2-diethylbutanoyl)indole 9b

t-BuLi, conditions N R 9 N R 82 Li electrophile N R 83 E

Entry R SM Electrophile Si(iPr)3 9a Me2NCHO 1a Si(iPr)3 9a CO2 2a Si(iPr)3 9a BrF2CCF2Br 3a Si(iPr)3 9a Me3SiCl 4a C(=O)CEt3 9b Me2NCHO 5b C(=O)CEt3 9b CO2 6b C(=O)CEt3 9b BrF2CCF2Br 7b C(=O)CEt3 9b Me3SiCl 8b a Conditions: hexane, TMEDA, 0 C b Conditions: hexane, PMDTA, 78 C

E CHO CO2H Br SiMe3 CHO CO2H Br SiMe3

Product 83a 83b 83c 83d 83e 83f 83g 83h

Yield (%) 78 88 92 84 49 51 59 58

Ref. [17] [17] [17] [17] [18] [18] [18] [18]

164

E.T. Pelkey

substrates. For example, treatment of 84 with sec-butyllithium in the presence of TMEDA under kinetically controlled conditions followed by quenching with various electrophiles gave 7-(substituted)indoles 86 (Table 14). The regioselectivity of the reaction is likely due to the conformation that is preferred for the amide group thus allowing the carbonyl oxygen to directed lithiation to C7. Sakagami used this strategy to prepare 7-geranyl-substituted tryptophan derivatives [221]. Snieckus identied a second protecting/directing group which allowed for the selective C7-lithiation of indole substrates [19]. Interestingly, the regioselectivity of the lithiation was dependent on the base. Thus, treatment of N-(di-tertbutylphosphinoyl)indole (10) with LDA at 0 C followed by trimethylsilyl chloride gave 2-silylindole 87. On the other hand, the same reaction with n-butyllithium gave the corresponding 7-silylindole 88a. The scope of this reaction was explored with a few substrates (Table 15). Notably, this C7-lithiation reaction worked in the absence of substituents at both C2 and C3.
Table 14 C7-lithiation of N-(2,2-diethylbutanoyl)indole 84
Me N this amide conformation favored due to sterics O Et Et 84 Li O Et Et 85 sec-BuLi, TMEDA ether, 78 C N E O Et Et 86 Me electrophile N Me

Entry 1 2 3 4 5 6

Electrophile Me2NCHO CO2 BrF2CCF2Br Me3SiCl ClCO2Et PhSSPh

E CHO CO2H Br SiMe3 CO2Et SPh

Product 86a 86b 86c 86d 86e 86f

Yield (%) 17 65 67 75 77 73

Table 15 Selective lithiation reactions of N-(di-tert-butylphosphinoyl)indole 10

1. LDA, THF, 0 C 2. SiMe3Cl N SiMe3 P t Bu O t Bu 87 (82%) N P tBu O t Bu 10 1. n-BuLi, THF, 40 C 2. electrophile N P tBu O t Bu 88

Entry 1 2 3 4 5 6

Electrophile Me3SiCl MeI BrCH2CH=CMe2 Me2NCHO ClPPh2 I2

E SiMe3 Me CH2=CMe2 CHO PPh2 I

Product 88a 88b 88c 88d 88e 88f

Yield (%) 72 93 87 53 44 78

Metalation of Indole

165

Another method for achieving C7-lithiation involves blocking the C2 position with a removable group such as trimethylsilyl. After surveying several protecting groups, Snieckus achieved an acceptable yield with the C7-lithiation of N-(diethylcarbamoyl)-2-trimethylsilylindole 89; some of the electrophiles explored are shown below [19] (Table 16). Perhaps the most common strategy for C7-lithiation of the indole ring involves using N-(tert-butoxycarbonyl)indoline (91). Iwao reported the rst lithiation reactions involving 91 in 1992 [298, 299]. Treatment of 91 with sec-butyllithium and TMEDA followed by various electrophiles gave 7-(substituted)indolines 92 (Table 17). Additional examples of this reaction have appeared in the literature
Table 16 Selective lithiation of N-(diethylcarbamoyl)-2-(trimethylsilyl)indole 89
1. sec-BuLi, TMEDA THF, 78 C 2. electrophile N O 89 SiMe3 NEt2 E O 90 N SiMe3 NEt2

Entry 1 2 3 4 5 6

Electrophile Me3SiCl MeI BrCH2CH=CMe2 Me2NCHO Bu3SnCl I2

E SiMe3 Me CH2=CMe2 CHO SnBu3 I

Product 90a 90b 90c 90d 90e 90f

Yield (%) 82 81 66 40 33 75

Table 17 Lithiation of N-(tert-butoxycarbonyl)indoline 91

1. sec-BuLi, TMEDA, 78 C 2. electrophile N O 91 O E O 92 N O

Entry Electrophile E Product Yield (%) I 92a 59 1 I2 2 MeI Me 92b 91 CHO 92c 64 3 Me2NCHO SiMe3 92d 83 4 Me3SiCl SnBu3 92e 87 5 Bu3SnCl ZnCl 92f a 6 ZnCl2 a 92f generated and used directly in Pd-catalyzed cross-coupling reactions

Ref. [298] [298] [299] [298] [302] [303]

166

E.T. Pelkey

[225, 300303]. Indolines 92 can be converted into the corresponding indoles by oxidation with Mn(OAc)3 [112]. Meyers [304] and Flippin [305] used the indoline C7-lithiation strategy during their respective total syntheses of the pyrrolophenanthridine natural product, oxoassoanine. Overman has used the indoline C7-lithiation strategy with C3functionalized indolines to prepare a number of complex, indole natural products including: asperazine [306], idiospermuline [307, 308], hodgkinsine [309], quadrigemine C [310], and phenserine [311]. In contrast to the C7-lithiation chemistry, Beak reported that the lithiation of 91 occurred at the 2-position when the reaction conditions included the chiral auxiliary ()-sparteine [312]. Earlier, Meyers [300] and Albrecht [313] reported the selective C2-lithiation of indoline using aminal and dithiocarbamoyl proecting groups, respectively. As mentioned in a previous section, the iridium-catalyzed borylation of 2(substituted)indoles gave 7-(borylated)indoles [291].

2.9

Lateral Lithiation to a Side-Chain

Methyl groups located at the 2-position of indole can be lithiated in the presence of certain nitrogen-protecting groups. This process, known as lateral lithiation, has most often been accomplished using the Katritzky method (in situ protection of the indole nitrogen with carbon dioxide). Katritzky converted 2-methylindole (93) into 2-(substituted)indoles 95 via lithio intermediate 94 (Table 18) [13]. The mechanism of this reaction has been studied by Snaith [314]. Amat and Bosch used this chemistry in developing a new approach to the Strychnos alkaloids [315]. Bergman

Table 18 Lateral lithiation of 2-methylindole 93

1. n-BuLi, THF, 70 C 2. CO2 3. t-BuLi N H 93 Me LiO 94 N O Li electrophile N H 95 E

Entry 1 2 3 4 5

Electrophile MeI C6H13I Ph2CO t-BuNCO CO2

E Me C6H13 C(OH)Ph2 CONHt-Bu CO2H

Product 95a 95b 95c 95d 95e

Yield (%) 52 93 67 61 70

Metalation of Indole Table 19 De novo generation of 3-lithiomethylindoles 97

Br N R 96 Br t-BuLi TMEDA ether Li N R 97 Li Li N R 98 electrophile N R 99

167

Entry 1 2 3 4 5

R CH2Ph CH2Ph Me Me Me

SM 96a 96a 96b 96b 96b

Electrophile Me3SiCl (PhCH2S)2 Me3SiCl p-ClC6H4CHO PhNCO

E SiMe3 SCH2Ph SiMe3 p-ClC6H4CH(OH) NH(C=O)Ph

Product 99a 99b 99c 99d 99e

Yield (%) 65 63 68 71 67

[316] and Junjappa [317] each adapted this chemistry to prepare functionalized carbazoles. Terashima explored the use of an oxazolinyl group for the lateral lithation of 2 methylindoles [274]. Merour used a phenylsulfonyl group to direct a lateral lithiation within a 2-methyl-7-azaindole system [191]. Inagaki explored the use of superbase (n-butyllithium + t-BuOK) to generate the dianion of 2-methylindoles [318] (and other 2,3-dialkylindoles [319, 320]). This provided another method for the functionalization of the 2-methyl group of the indole ring system. Finally, Barluenga developed a de novo synthesis approach to 3-lithiomethylindole intermediates 97 [321, 322]. Double halogenmetal exchange of dibromoaniline 96 leads to lithio intermediate 98, which upon quenching with electrophiles gives 3-(substituted)indoles 99 (Table 19).

3 Directed Ortho Metalation

Another method for achieving metalation, via lithiumhydrogen exchange, involves the use of directed metalation groups (DMGs). Substituents such as ethers, alkoxides, halogens, carboxylates, carboxamides, sulfonamides, pyridines, and oxazolines direct metalation (metalhydrogen exchange) to ortho positions within aromatic systems in a process known as DOM. The DOM reaction has been reviewed by Beak and Snieckus [13] and earlier by Gschwend and Rodriguez [8]. The selective C2-, C3-, and C7-lithiation of N-(substituted)indoles was covered in the previous section. This section deals with the use of carbon-based substituents to direct metalation throughout the indole ring system.

168

E.T. Pelkey

3.1

Directed Ortho Lithiation to C2

The C2-lithiation of indole has been investigated using a number of C3-based DMGs including dimethylaminomethyl (gramine), a-aminoalkoxides, carboxylic acids, carboxamides, a-alkoxyalkyl, and acetals (Scheme 19). Nitrogen-protecting groups are still used in these reactions, and the structure of the protecting group can sometimes alter the regiochemical outcome (C2 vs. C4) of the lithiation reaction. As observed earlier, N-(arylsulfonyl)indoles undergo selective lithiation at C2. In an extension, Gribble explored the selective C2-lithiation of 3-hydroxymethylN-(phenylsulfonyl)indole 100 and related derivatives [27, 29, 177, 178]. In this case, the deprotonated alcohol can be considered a DMG, which helps facilitate lithiation at C2. Treatment of 100 with 2.2 equivalents of LDA followed by methyl formate gave indole-2-carboxaldehyde 102 presumably via dianion intermediate 101 (Scheme 20). Methyl formate was found to give more reliable yields than DMF [29]. This sequence was used by Gribble to prepare a wide range of furo[3,4-b] indoles. These types of substrates have also been prepared using acetals [176] (see also [181, 182]) and silyl enol ether groups [179] located at C3. Comins used their aminoalkoxide methodology [323] to direct C2-lithiation with an indole-3-carboxaldehyde substrate [324]. Kitagaki and Mukai later used the Comins strategy to prepare a 2-iodoindole-3-carboxaldehyde, a precursor to a 2,3-bis(alkynyl)indole [325]. This strategy was also applied by Comins to direct lateral lithiation onto an N-methyl group from an aminoalkoxide generated at C2 [77]. Knight explored the C2-lithiation of indole-3-carboxylic acids [326, 327]. Similar to the reaction with alcohol 100, two equivalents of LDA were used to generate dianion intermediates which upon quenching with electrophiles gave 2-(substituted)indole-3-carboxylic acids. This strategy was later used by Fisher

DMG N R

RLi N R

DMG Li

electrophile N R

DMG E

Scheme 19 General strategy for directed metalation to C2 from C3-based DMG

O OH N SO2Ph 100 LDA, THF 70 C Li N SO2Ph 101 OLi H OMe (82%) OH N CHO SO2Ph 102

Scheme 20 Directed ortho metalation (DOM) by 3-hydroxymethyl group

Metalation of Indole

169

and Clark to prepare large quantities of an indole-3-carboxylic acid substrate that showed CNS activity [328]. In the same series of papers, Knight also investigated the selective C2-lithiation of indole-3-carboxamides [326, 327]. In this case, n-butyllithium (slight excess) was used as the base instead of LDA. Treatment of indole-3-carboxamides 103 with n-butyllithium followed by electrophiles gave 2,3-(disubstituted)indoles 104. A portion of the results obtained are shown below (Table 20). Snieckus used a directed lithiation of 103c to prepare the corresponding indole-2-boronic acid, a useful building block for the synthesis of indolocarbazoles [329]. Iwao [16] and Somei [330] investigated the lithiation of gramine derivatives 105 (Scheme 21). Depending on the nitrogen substituent, lithiation can occur at either C2 or C4. With N-methylgramine 105a and N-methoxygramine 105b, lithiation occurs at C2 giving 106a and 106b upon quenching with trimethylsilylchloride. On the other hand, with N-(triisopropylsilyl)gramine 8, lithiation occurs preferentially at C4 giving 107. Trimethylsilyl group also can serve as a block group; lithiation of 106 also gave C4-substituted products via a selective C4-lithiation.

Table 20 Directed ortho metalation (DOM) by 3-carboxamide group

O NEt2 N R 103 1. n-BuLi, THF, 70 C 2. electrophile N R 104 E O NEt2

Entry R SM Electrophile 103a MeI 1 CH2OMe 103a PhCHO 2 CH2OMe 103a PhCOMe 3 CH2OMe 103b MeI 4 SO2Ph 103b PhCHO 5 SO2Ph 103b PhCOMe 6 SO2Ph Me 103c B(OMe)3 7a a Utilized sec-BuLi/TMEDA for deprotonation

E Me CH(OH)Ph CMe(OH)Ph Me CH(OH)Ph CMe(OH)Ph B(OH)2

Product 104a 104b 104c 104d 104e 104f 104g

Yield (%) 91 86 26 75 70 0 59

Ref. [327] [327] [327] [327] [327] [327] [329]

SiMe3 NMe2 N Si(iPr)3 107

1. t-BuLi ether, 0 C 2. Me3SiCl (82%) N R

NMe2

1. 105a: t-BuLi, ether, 78 C 105b: n-BuLi, ether, 18 C 2. Me3SiCl N R

NMe2 SiMe3

105a R = Me 105b R = OMe 8 R = Si(iPr)3

106a R = Me (80%) 106b R = OMe (91%)

Scheme 21 Regioselective lithiation of gramines

170

E.T. Pelkey

Snieckus has investigated the directed remote lithiation of indoles at C2 in the context of preparing fused heterocycles [23, 224]. The synthesis of indolo[2,3-c] benzo[e]pyran-6-one 110 is illustrative (Scheme 22) [224]. Treatment of 108 with LDA led to the formation of 110 via cyclization of lithio intermediate 109. Bisagni used a similar sequence to prepare benzo[f]indolo-6,11-quinones [331].

3.2

Directed Ortho Lithiation to C3

The C3-lithiation of indole has been investigated using a number of C2-based DMGs including pyridyl, a-aminoalkoxides, carboxylic acids, and carboxamides (Scheme 23). In some cases, the 3-lithio intermediates give products derived from ring opening reactions rather than 3-substitution; this is dependent upon electronic factors regarding the nitrogen substituent and the DMG. Gribble was the rst to investigate the use of a C2-based DMG (pyridyl) to direct lithiation to the C3 position of the indole ring [332]. Treatment of 2-pyridylindole 111 with n-butyllithium followed by quenching with electrophiles gave 2-pyridyl3-(substituted)indoles 113 in moderate yields via lithio intermediate 112 (Table 21); 112 proved to be unexpectedly stable and only underwent ring fragmentation upon heating to 50 C. Gribble used this strategy in the synthesis of the zwitterionic natural products avopereirine [333] and sempervirine [32]. More recently, Lipinskia followed this strategy to prepare sempervirine analogs [334].

N Boc 108

O O

LDA OMe THF, 78C NEt2

N Li Boc 109

O O

OMe NEt2

OMe (80%) N Boc O 110 O

Scheme 22 Directed remote C2-lithiation leading to fused indoles

tro elec
RLi N R DMG N R Li DMG

phile

N R

DMG

DMG

NH R ring-opened by-product

Scheme 23 General strategy for directed metalation to C3 from C2-based DMG

Metalation of Indole Table 21 Directed ortho metalation (DOM) by a C2-pyridyl substituent

n -BuLi, THF, 78 C N PhO2S 111 N N PhO2S 112 Li N electrophile N PhO2S 113 E

171

Entry 1 2 3 4 5

Electrophile MeI CO2 Me3SiCl MeCHO ClCO2Et

E Me CO2H SiMe3 CH(OH)Me CO2Et

Product 113a 113b 113c 113d 113e

Yield (%) 74 58 51 68 55

O NHt Bu n-BuLi, THF, 78 C (30%) N R NHt Bu O

1. sec-BuLi TMEDA, 78 C 2. MeCHO (60%)

OH Me NHt Bu

NH SO2Ph 115

114a R = SO2Ph 114b R = Me

N Me O 116a

Scheme 24 Lithiation of indole-2-carboxamides 114

Gribble also explored the lithiation of indole-2-carboxamides [332] (Scheme 24). In this case, the nature of the protecting group altered the reaction outcome. With N-(phenylsulfonyl)indole-2-carboxamide 114a, treatment with n-butyllithium led to alkyne 115. Replacing the phenylsulfonyl group with a methyl group averted the ring fragmentation. Treatment of (N)-methylindole-2-carboxamide 114b with secbutyllithium and TMEDA (n-butyllithium failed to generate C3-anion) followed by acetaldehyde gave 2,3-di(substituted)indole 116a. Rubiralta also reported a ring fragmentation with an N-(phenylsulfonyl)indole containing a dithianyl side-chain at C2 [113]. Pujol has examined carboxylic acids (Table 22, entry 5) [335], carboxamides (Table 22, entries 23) [335], and hydrazinecarbonyls (Table 22, entry 4) [336] as directing groups for the selective C3-lithiation of indole. The different protecting groups (including the one result from Gribble) are compared below. The best result was obtained using an N-ethylcarboxamido group. Interestingly, lithation of indole-2-carboxylic acid failed to yield any product. On the other hand, lithiation of N-(methoxymethyl)indole-2-carboxylic acid with secbutyllithium in the presence of HMPA successfully gave C3-substituted indoles [337].

172 Table 22 Comparing C2-DMGs

1. base, conditions 2. MeCHO N Me 114 R O N Me 116 O OH

E.T. Pelkey

Entry 1 2 3 4 5

R NHtBu NHEt NEt2 NHNMe2 OH

SM 114b 114c 114d 114e 114f

Base, conditions sec-BuLi, TMEDA t-BuLi, TMEDA t-BuLi, TMEDA t-BuLi, TMEDA t-BuLi, TMEDA

Product 116a 116b 116c 116d 116e

Yield (%) 60 100 70 78 0

Ref. [332] [335] [335] [336] [335]

O CONEt2 N Boc 117 LiTMP THF, 0 C N Boc 118 Li CONEt2 (78%) N Boc 119

Scheme 25 Directed remote C3-lithiation leading to fused indoles

Snieckus reported a directed remote lithiation at C3 of the indole ring system [295]. Treatment of 2-arylindole 117 with LiTMP led to fused indole 119 via 3lithioindole intermediate 118 (Scheme 25).

3.3

Directed Ortho Lithiation to C4 from C3

Directed lithiation of gramine derivatives is one of the best methods for preparing 4-(substituted)indoles. Iwao has investigated the selective C4-lithiation of gramine derivatives in great detail. The most common substrate for C4-lithiation is N-(triisopropylsilyl)gramine 8 [16]; the triisopropylsilyl group serves to block C2-lithiation. Lithiation at C2 can also be blocked using removable trimethylsilyl-protecting groups (e.g., 106) [16, 330]. A survey of the electrophiles introduced to C4 using this chemistry appears below (Table 23). Gramines 120 can be transformed into many interesting indole products. The dimethylamino group can be replaced in two steps by quaternization with methyl iodide followed by treatment with uoride in the presence of nucleophiles (eliminationaddition) [342]. Waldmann converted 120e and 120f into the

Metalation of Indole Table 23 Selective C4-lithiation of gramine

1. t -BuLi, ether, 0 C 2. electrophile E NMe2 N Si(i Pr)3 120

173

NMe2 N Si(i Pr)3 8

Entry Electrophile E Product Yield (%) Ref. SnBu3 120a 78 [16] 1 Bu3SnCl 2 PhSSPh SPh 120b 70 [16] I 120c 58 [16] 3 I2 CHO 120d 57 [16] 4 Me2NCHO 5 MeI Me 120e 69 [338] 6 EtI Et 120f 62 [338] ZnCl 120g a [102] 7 ZnCl2 CH(OH)=CMe2 120h 82 [33] 8 Me2C=CHCHO OH 120i 64 [339] 9 (SiMe3)2O Cl 120j 66 [339] 10 Cl3CCl3 Br 120k 56 [339] 11 BrCH2CH2Br Br 120k 60 [340] 12 CBr4 13 MeCHO CH(OH)Me 120l 70 [340] CH(OH)=CH2 120m 80 [340] 14 H2C=CHCHO NH2 120n 79 [341] 15 Me3SiCH2N3 a Zincate 120g was generated and used directly in Pd-catalyzed cross-coupling reactions leading to 4-arylindoles

corresponding tryptophan derivatives [338]. Iwao prepared 120h en route in a total synthesis of clavicipitic acids [33, 34]. Iwao also used this C4-lithiation methodology with 6-methoxy-N-(triisopropylsilyl)gramine during a total synthesis of the makaluvamines [343] and also veiutamine [344]. Kirk used the methodology to prepare 4-uoroserotonin and 4-uoromelatonin [345]. Perez-Castells found that treatment of N-(triisopropylsilyl)-3-methoxymethylindole also gave 4-(substituted)indoles although the yields tended to be lower than the corresponding gramine derivatives [340].

3.4

Directed Ortho Lithiation in Benzenoid Ring

Carboxamides, carbamates, and halogens have served as DMGs for lithiation in the benzenoid portion of the indole ring. In an extension of the C4-lithiation chemistry, Iwao transformed 4-aminogramine 120n into carbamate 121, which then underwent selective lithiation at C5 (Table 24) [341]. Treatment of 121 with three equivalents of t-butyllithium followed by various electrophiles gave 3,4,5(trisubstituted)indoles 123 via dianion 122. This chemistry was also investigated

174 Table 24 Synthesis of 3,4,5-(trisubstituted)indoles 122

Ot Bu NHR NMe2 N Si(i Pr)3 120n R = H Boc2O 121 R = Boc t -BuLi, ether 78 C to 0 C O Li NLi NMe2 N Si(i Pr)3 122 electrophile E

E.T. Pelkey

NHBoc NMe2 N Si(i Pr)3 123

Entry 1 2 3 4 5 6

Electrophile MeI Cl3CCCl3 BrF2CCBrF2 Me2NCHO PhCHO t-BuNCO

E Me Cl Br CHO CH(OH)Ph C(=O)NHtBu

Product 123a 123b 123c 123d 123e 123f

Yield (%) 91 83 81 82 81 65

Table 25 Selective C4-lithiation of indole 5-O-carbamates 124

Et 2N O O N TBS 124 1. sec -BuLi, TMEDA, THF, 70 C 2. electrophile E Et2N O O N TBS 125

Entry 1 2 3 4 5

Electrophile MeI Me2NCHO ClCO2Et I2 Cl3CCCl3

E Me CHO CO2Et I Cl

Product 125a 125b 125c 125d 125e

Yield (%) 99 96 43 79 90

with the corresponding 6-methoxyindole derivatives [341] and fused indole derivatives [346]. Snieckus reported the selective C4-lithiation of indole 5-O-carbamate 124 [3, 347, 348]. Treatment of 124 with sec-butyllithium and TMEDA followed by electrophiles gave 4,5-(disubstituted)indoles 125 (Table 25) [347]. Unexpectedly, the lithiation of 3-substituted derivatives of 124 led to C6-lithiation as demonstrated by formylation at C6 upon quenching with DMF. Dodd explored the metalation of N-sulfonamidoindole-5-carboxamides [349]. Metalation at the 2-position was blocked by incorporation of a trimethylsilyl group (or by utilizing the corresponding indoline derivative). Treatment of protected

Metalation of Indole

175

indole-5-carboxamide with sec-butyllithium followed by electrophiles gave products derived from C4-lithiation. Tois investigated the solid-phase lithiation of resin-bound indole-5carboxamides. The reactions led to the mixtures of products derived from C4and C6-lithiation [350]. Schlosser investigated the use of halogens (uorine and chlorine) as DMGs in the benzenoid portion of indole rings [351, 352]. This chemistry was used to introduce halogens at all possible positions C4 through C7.

4 HalogenMetal Exchange
The nal method for generating metalated indoles that will be covered in this monograph involves halogenmetal exchange processes. Halogenmetal exchange, most often halogenlithium exchange, is an excellent method for controlling the regiochemistry of metalation and is particularly useful for metalating sites that are typically unreactive. Halogenmetal exchange is one of the best methods for the regiocontrolled preparation of 3-(substituted)indoles from 3-haloindoles (Scheme 26). Reviews of the halogenmetal exchange reactions have been published by Parham [353] and more recently by Lete [354].

4.1

HalogenLithium Exchange at C2

Likely due to the propensity for most N-(substituted)indoles to undergo selective hydrogenlithium exchange at C2, there have only been a few reports involving halogenlithium exchange at C2. Often, these are found in the context of groups that could activate other positions to lithiation [355358]. One example of a simple 2-(substituted)indole substrate undergoing halogenmetal exchange was reported by Kaufmann [74]. They reported the conversion of 2-iodo-N-methylindole into an indol-2-ylborane via 2-lithioindole 11 generated by iodinelithium exchange. Herbert reported modest success in the generation of double anion 127 by treatment of 2-iodoindole (126) with n-butyllithium [359] (Scheme 27). Quenching with 127 with different electrophiles (two shown) then gave 2-(substituted)indoles

X N R X = Br or I

n-BuLi or t-BuLi N R

Li

electrophiles N R

Scheme 26 Halogenmetal exchange involving 3-haloindole substrates

176
n-BuLi (3 equiv) THF, 70 C N H 126 I N Li 127 Li

E.T. Pelkey

CO2 or PhNCO N H E

128a R = CO2H (61%) 128b R = CONHPh (55%)

Scheme 27 Generation and reactions of 1,2-dilithioindole 127

Table 26 Halogenmetal exchange reactions of 2,3-dihalo-N-methylindoles

R2 N Me 131 (R1 = R2) R1 1. t-BuLi (excess) 2. electrophiles X N X Me 129a X = Br 129b X = I 1. t-BuLi (1 equiv) 2. electrophiles N Me 130 R2 R1

Entry 1 2 3 4 5 6 7 8 9 10 11

SM 129a 129a 129a 129b 130c 129b 129b 129b 129b 129a 129b

Electrophile NH4Cl Me2NCHO MeI CO2 Me2NCHO NH4Cl Me2NCHO ClCO2Me CO2 [C7H7]+BF4 [C7H7]+BF4

R1 H CHO Me CO2H Me H CHO CO2Me CO2H Br I

R2 Br Br Br Br CHO H CHO CO2Me CO2H C7H7 C7H7

Product 130a 130b 130c 130d 130e 2 131a 131b 131c 130f 130g

Yield (%) 99 86 97 85 88 99 82 75 66 56 54

Ref. [246] [246] [246] [246] [246] [248] [248] [248] [248] [360] [360]

128. Much earlier, Shirley and Roussell had failed in attempt to generate 127 by treating indole (56) with excess n-butyllithium [7]. Gribble has explored halogenmetal exchange reactions of 2,3-dihaloindole substrates 129 (Table 26). Treatment of 2,3-dibromo-N-methylindole (129a) with one equivalent of tert-butyllithium followed by different electrophiles gave 3-bromo-2-(substituted)indoles 130 [246]. Subsequent treatment of 130d with additional tert-butyllithium then allowed for replacement of the C3 bromine atom (Table 26, entry 5). With 2,3-diiodo-N-methylindole (129b), only dilithiation reactions were studied [248]. Treatment of 129b with excess tert-butyllithium followed by different electrophiles gave 2,3-(disubstituted)indoles 131. Interestingly, Yamamura later reported conicting results regarding mono-halogenmetal exchange reactions with both 129a and 129b [360] (Table 26, entries 910). Treatment of either 129a or 129b with one equivalent of tert-butyllithium followed by quenching with tropylium ion led to products derived from the selective lithiationhalogen exchange at C3 and not C2. Both reports show compelling

Metalation of Indole
1. t-BuLi (excess) 2. NH4Cl NHSO2Ph 132 (81%) 1. t-BuLi (1 equiv) 2. NH4Cl

177
R2 N R1 SO2Ph 6 R1 = H; R2 = I 29a R1 = I; R2 = H

I I N SO2Ph 28

Scheme 28 Halogenmetal exchange reactions of 2,3-diiodo-N-(phenylsulfonyl)indole (28)

evidence for their results; Gribble prepared known materials whereas Yamamura obtained X-ray crystal structures. In addition, Yamamura followed a different route to prepare the regioisomers [360]. Compared to 129, halogenmetal exchange with 2,3-diiodo-N-(phenylsulfonyl) indole (28) was more complicated [361] (Scheme 28). Treatment of 28 with one equivalent of tert-butyllithium followed by ammonium chloride led to a (undetermined) mixture of 2-iodo-N-(phenylsulfonyl)indole (29a) and 3-iodo-N(phenylsulfonyl)indole (6). On the other hand, mixing 28 with excess tert-butyllithium led to alkyne 132 via a facile ring fragmentation.

4.2

HalogenLithium Exchange at C3

Halogenlithium exchange at the C3 position has been thoroughly explored and developed. Gribble reported the rst example in 1982 with 3-iodo-N-(phenylsulfonyl)indole (6) [14]. Treatment of 6 with two equivalents of tert-butyllithium at 100 C led to the formation of unstable 3-lithioindole intermediate 133. Quenching 133 at low temperatures (usually 100 C) gave 3-(substituted)indoles 134 (Table 27). During the synthesis of isoellipticine and 6-methoxyisoellipticine, Gribble generated 133 (and the 6-methoxy analog of 133) and quenched with 3,4pyridinedicarboxylic acid anhydride giving a ketoacid intermediate en route to a total synthesis of ellipticine [173]. There is one major drawback with using 133. At temperatures above 100 C, 3lithioindole 133 rearranges to 2-lithioindole 24 as evidenced by the formation of 2-methyl-N-(phenylsulfonyl)indole upon quenching with 2-iodomethane [14] (see also [363]). This rearrangement spurred the search for alternatives. A major advance came from Amat and Bosch in 1994 [364]. They showed that halogenlithium exchange reactions of 3-bromo-N-(tert-butyldimethylsilyl)indole (135) gave 3-lithioindole intermediate 136, which did not suffer ring fragmentation or rearrangement to the corresponding 2-lithioindole intermediate (even at room temperature). Since then, a number of reports have used this transformation for the preparation of 3-(substituted)indoles 137, and selected results are summarized below (Table 28). The silyl-protecting group can be conveniently removed

178 Table 27 Halogenmetal exchange reactions of 3-iodo-N-(phenylsulfonyl)indole (6)

I N SO2Ph 6 t-BuLi, THF, 100 C Li N SO2Ph 133 electrophiles

E.T. Pelkey

E N SO2Ph 134

Entry Electrophile E Product Yield (%) Ref. 1 MeI Me 134a 62 [14] CO2Et 134b 51 [14] 2 ClCO2Et 3 PhCHO CH(OH)Ph 134c 89 [14] CHO 134d 71 [14] 4 Me2NCHO 5 PhSSPh SPh 134e 84 [14] SiMe3 134f 76 [14] 6 SiMe3Cl Oxirane CH2CH2OH 134g 87 [31] 7a B(OMe)3 B(OH)2 134h 47 [362] 8a B(OiPr)3 B(OH)2 134h 85 [231] 9a ZnCl 134i b [102] 10 ZnCl2 SnMe3 134jc 85 [144] 11 Me3SnCl a Prepared by halogenmetal exchange of 3-bromo-N-(phenylsulfonyl)indole b Zincate 134i was generated and used directly in Pd-catalyzed cross-coupling reactions leading to 3-arylindoles c 134j N-(toluenesulfonyl)-3-(trimethylstannyl)indole which was prepared by halogenmetal exchange of 3-bromo-N-(toluenesulfonyl)indole

Table 28 Halogenmetal exchange reactions of 3-bromo-N-(tert-butyldimethylsilyl)indole (135)

Br N SiMe2tBu 135 t-BuLi, THF,78 C Li N SiMe2tBu 136 electrophiles E N SiMe2t Bu 137

Entry Electrophile E Product Yield (%) Ref. 1 MeI Me 137a 95 [364] 2 EtI Et 137b 96 [373] CO2Et 137c 84 [364] 3 ClCO2Et CO2H 137d 94 [364] 4 CO2 5 PhCHO CH(OH)Ph 137e 67 [364] SnMe3 137f 94 [364] 6 Me3SnCl ZnCl 137g a [150, 374] 7 ZnCl2 B(OH)2 137h b [371] 8 B(OMe)3 a Zincate 137g was generated and used directly in Pd-catalyzed cross-coupling reactions leading to 3-arylindoles b Boronic acid 137h was generated and used directly in Pd-catalyzed cross-coupling reaction leading to an imidazole-substituted indole

Metalation of Indole

179

by treatment with tetrabutylammonium uoride. Additional examples of this transformation [249, 365369] including benzene ring functionalized indoles [228, 347, 370, 371] have also appeared in the literature. In addition, N-(triisopropylsilyl)-3bromoindole 83c [372] and methoxy-substituted derivatives [370] have been investigated and worked well. Liu used a double halogenlithium exchange to prepare diindolo[3,2-b:4,5-b0 ] thiophenes (e.g., 139). For example, treatment of 3,30 -dibromo-2,20 -biindole 138 with n-butyllithium followed by quenching with bis(phenylsulfonyl) sulde gave 139 (Scheme 29) [60]. Halogenlithium exchange reactions have also been applied to the functionalization of 3-bromo-N-(benzyl)indole [375] and an N-reverse prenylated 3-bromoindole [376].

4.3

HalogenLithium Exchange in Benzenoid Ring

Compared to halogenlithium exchange at C3, relatively few studies have examined halogenlithium exchange in the benzenoid moiety of the indole ring. An early example was reported by Zilkha and co-workers with 5-bromoindoline 140 [377]. Treatment of 140 with lithium metal followed by trimethylsilyl chloride gave 5trimethylsilylindoline 141 (Scheme 30). The latter was converted into a number of indole derivatives including 5-trimethylsilyltryptamine (142). Much later, Dodd used a similar reaction to prepare an indoline-5-carboxamide derivative, which was then converted into 4,5-(disubstituted)indoles via DOM [349]. Rapoport developed a method of brominelithium exchange involving bromoindoles 7 lacking substitution on nitrogen [15]. The reaction was started by treating
Br N Me Br 138 Me N 1. n-BuLi, ether, 78 C to rt 2. (PhSO2)2S, 78 C to rt (51%) N Me 139

S N Me

Scheme 29 Double brominelithium exchange reaction

Br N CH2Ph 140

1. Li, ether 2. SiMe3Cl (80%)

Me3Si N CH2Ph 141

Me3Si N H 142

NH2

Scheme 30 Brominelithium exchange of 5-bromo-(N)-benzylindoline (140)

180
1. KH, ether, 0 C 2. t-BuLi, 78 C N H 4-bromo 5-bromo 6-bromo 7-bromo

E.T. Pelkey

Br

Li N K 143

Me2NCHO

OHC N H 4-formyl (57%) 5-formyl (53%) 6-formyl (60%) 7-formyl (61%)

7a 7b 7c 7d

144a 144b 144c 144d

Scheme 31 Brominelithium exchange of bromoindoles 7

Br Br N R N R Cl N Cl N Me 147

Br

Br

145 R = Me or SEM

146 R = Me or i Pr or SEM

Fig. 5 Regioselectivity of halogenmetal exchange reactions with dihalogenated substrates

the bromoindoles 7 with potassium hydride followed by tert-butyllithium to generate dianions 143. Quenching 143 with dimethylformamide then gave formylindoles 144 (Scheme 31). Weinreb amides were also used as electrophiles which gave ketoindoles. Martin used this method in the synthesis of additional 5-(substituted) indole derivatives [378]. Sauer used bromolithium exchange reactions to prepare benzene ring-substituted ergoline derivatives [379]. Andersen used a brominelithium exchange reaction to generate 5-lithio-N-(40 -uorophenyl)indole, which was transmetalated to both the corresponding indole-5-zincate and indole-5-stannane [380]. Tois prepared an indole-5-carboxylic acid by brominelithium exchange followed by quenching with carbon dioxide [350]. The regioselectivity of brominelithium exchange reactions in dibromoindole substrates has been studied by Li [381, 382]. With both 4,7-dibromoindoles (e.g., 145) [382] and 5,7-dibromoindoles (e.g., 146) [381], brominelithium exchange occurs preferentially at C7 (Fig. 5) upon treatment with tert-butyllithium. A similar result was reported recently by Lachance involving the selective chlorinelithium exchange observed with 6-azaindole 147 [383]. Buszek has used brominelithium exchange reactions to generate 4,5-, 5,6-, and 6,7-indolyne derivatives [384387]. Their total synthesis of cis-trikentrin A is illustrative of the power of their methodology (Scheme 32) [386]. Treatment of 6,7-dibromoindole 148 with two equivalents of n-butyllithium in the presence of cyclopentadiene gave cycloadduct 149. The latter was converted into cis-trikentrin A in three additional steps.

Metalation of Indole
n-BuLi (2 equiv)

181

toluene Br Br N TBS 148 N TBS 149 (77%) N TBS 150

3 steps N H cis-trikentrin A

Scheme 32 Generating a 6,7-indolyne derivative via brominelithium exchange

Table 29 Generation and reactions of indol-3-yl Grignard reagent

I N SO2Ph 6 EtMgBr, THF, 0C to rt MgBr N SO2Ph 151 electrophiles E N SO2Ph 134

Entry Electrophile E Product 1 PhCHO CH(OH)Ph 134c 2 EtCHO CH(OH)Et 134k CH2OH 134l 3 [CH2O]n CO2a CO2Me 134m 4a PhIb Ph 134n 5b a Intermediate treated with diazomethane to give methyl ester 134m b Reaction run with Pd(PPh3)4

Yield (%) 82 65 48 85 50

4.4

Indolyl Grignard Reagents

Another method used for halogenmetal exchange involves treating haloindoles with Grignard reagents (usually ethylmagnesium bromide or isopropylmagnesium chloride). Sakamoto investigated halogenmagnesium exchange reactions with 3-iodoindole 6 (Table 29) [388]. Treatment of 6 with ethylmagnesium bromide gave indoly-3-yl Grignard 151; quenching with electrophiles then gave 3-(substituted)indoles 134. Unlike the corresponding 3-lithioindole intermediate 133, 151 did not rearrange to form the indol-2-yl Grignard reagent even at room temperature. Sakamoto also investigated the formation of the indol-2-yl Grignard reagent derived from 2-iodo-N-(phenylsulfonyl)indole (29a) [388] and this also worked well. The reactions of indolyl Grignard reagents, generated in this fashion, have been explored further by others [389392]. A regioselective Grignard formation at C2 occurred upon treatment of 2,3-diiodo-N-(phenylsulfonyl)indole (28) with isopropylmagnesium chloride [393].

182
I N SO2Ph 6 ZnI N SO2Ph 151

E.T. Pelkey
Ph N SO2Ph 134n

active Zn, THF, rt

PhI, Pd(PPh3)4 (83%)

Scheme 33 Generation and reaction of indol-3-ylzinc iodide

Indolyl Grignard reagents have also been generated by direct deprotonation with a magnesium base (e.g., iPr2NMgBr) [281] and also by transmetalation of lithioindole intermediate 11 (Table 1, entry 2) [61].

4.5

HalogenMetal Exchange with Other Metals

In addition to the extensive use of lithium and magnesium, halogenmetal exchange of haloindole substrates has been investigated with zinc, copper, boron, and tin. Sakamoto reported the generation of indol-3-ylzinc iodide 152 by mixing 3iodo-N-(phenylsulfonyl)indole 6 with active zinc [363] (Scheme 33). Treatment of 152 with iodobenzene and a palladium catalyst provided another route to 3phenylindole 134n. Knochel reported the formation of indol-3-ylzincs by treating 6 with iPr2Zn and Li(Acac) [394]. Sakamoto generated indol-2-ylzincates by treating 2-iodo-N-(phenylsulfonyl)indole with Me3ZnLi/TMEDA [395]. Finally, a few examples of boroniodine exchange [396], tiniodine exchange [137, 397], and copperiodine (via cuprate) exchange [398, 399] have appeared in the literature. Cupration of 2,3-diiodo-N-(phenylsulfonyl) preferentially occurred at C2 [398, 399].

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