Indole Larock heteroannulation

This reaction was first reported by Larock et al. in 1991. It is a palladium-catalyzed chemoselective and ligandless heteroannulation between ort/io-iodoanilines and disub-stituted alkynes to form substituted indole derivatives. Therefore, this reaction is generally known as the Larock heteroannulation or Larock indole synthesis. ... 

The Larock indole synthesis, also known as the Larock heteroannulation, is a one-pot palladium-catalyzed heteroannulation of o-iodoaniline and internal alkynes for the synthesis of 2,3-disubstituted indoles. The original Larock reaction was performed with Pd(OAc)2 using carbonate or acetate bases with or without catalytic amounts of triphenyl phosphine and K-BU4NCI. However, it was subsequently observed that Li Cl is often more effective and reproducible (Scheme 1 1991JA6689). The reaction... 

A sequential Larock and cross-coupling strategy may solve the problem of regioselectivity that appears by using alkynes with two similar brrlky substituents (2009T3120). Larock heteroannulation of substituted 2-iodoanilines and alkynyldimethylsilyl tert-butyl ether afford 3-substituted indole-2-silanols after hydrolysis. The cross-coupling between sodium 2-indolylsilanolate salts with aryl bromides and chlorides successfully afforded multisubstituted indoles (Scheme 6). The development of an alkynyldimethylsilyl terf-butyl ether as a masked silanol equivalent enabled a smooth... 

A small library of 2,3,5-trisubstituted indoles was obtained by Schultz and coworkers starting from a solid-supported 3-bromo-2-iodoaniline on commercially available PS-TsCl resin (polystyrene sulfonyl chloride Argonaut Technologies). A successive Larock heteroannulation, followed by electrophilic substitution on indole position three and final Suzuki or Sonogashira cross-coupling reactions, gave excellent results for the preparation of an important number of indole derivatives 19 and 20 (Scheme 9 20010L3827). 

Jana and Sinha have described the total synthesis of ibogaine, epiibo-gaine, and their analogs utilizing the Larock heteroannulation reaction for the creation of the suitably substituted indole (Scheme 25 2012T7155). 

Larock indole synthesis, also known as Larock heteroannulation, is the one-pot palladium-catalyzed heteroannulation of ort/ro-iodoaniline and its derivatives 1 and internal alkynes 2 for the synthesis of 2,3-disubstituted... 

As mentioned early in the chapter, one of the general features of Larock indole synthesis is that the reaction gave exclusively 2-silyl indoles when a silyl-substituted alkyne was present, and the corresponding 2-silyl indoles can be further functionalized. In this respect, Denmark and Baird recently reported a sequential Larock heteroannulation and silicon-based... 

In addition, the above multicomponent process was used to prepare the indole A -carboxamide derivatives 23 via Larock heteroannulation reaction. 

Similarly, reaction of 5-amino-4-iodobenzothiophene 61 with internal acetylenes gave 7,8-disubstituted thieno[3,2e]indoles 62 under Larock heteroannulation conditions. The choice of the base such as Na2C03, NaOAc, or KOAc significantly affected the yield of the reaction of different alkynes. 

Two (5)-P-methyl-2-aryltryptamine-based gonadotropin-releasing hormone antagonists 95 and 96 were synthesized via a consecutive Larock indole synthesis and Suzuki cross-coupling reaction." The key transformation involved the Larock heteroannulation of o-iodoaniline 97 with chiral silyl alkyne 98 in the presence of Pd(OAc)2, PPha, 1 equiv of LiCl, and 2.5 equiv of K2CO3 in DMF at 100 °C to give 99 in 72% yield. 

Larock heteroannulation reaction was further extended and an intramolecular Larock indole synthesis of 2-chloroanilines bearing tethered acetylenes 106 was developed for the elaboration of a variety of polycyclic indole skeletons 107, for example, in 108-112. This intramolecular indolization method unveiled an unusual >sy -anidopalladation pathway of a tethered alkyne. The major side product is the dechlorinated starting material as a result of a reductive process. 

Well-defined palladium complexes are interesting from an academic point of view. In 2013, Shi, Cao and their co-workers prepared a well-defined fer-rocenyl functionalized NHC-palladium complex and applied it as an efficient catalyst for Larock heteroannulation. 2,3-Disubstituted indoles were isolated in good yields (69-90%) with high regioselectivity from the reactions between 2-iodoanilines or 2-bromoanilines and their derivatives with various internal alkynes (Scheme 2.98). The reactions occur in a broad scope and with a high tolerance of functional groups. NHC-palladium complexes could be excellent candidates to replace expensive palladium-phosphine complexes for Larock indole catalysis. 

Notably, the nickel-catalyzed decarbonylative cycloaddition affords a regioisomer opposite to that formed in the palladium-catalyzed Larock heteroannulation [21], For example, the nickel-catalyzed reaction of anthranilic acid derivatives 39 with l-trimethylsilyl-2-phenylacetylene (43) affords indole 44 with phenyl substituents at the 2-position [Scheme 12.18(a)], whereas the palladium-catalyzed reaction... 

The 5-, 6-, and 7-azaindoles were synthesized via the Pd-catalyzed heteroannulation of internal alkynes using orf/w-aminopyridine derivatives in an extention of Larock s indole synthesis [169], LiCl was found to be an essential component in order to obtain regioselectivity, reproducibility and improved yields. 

Substituting the benzene ring with a double bond, Pd-catalyzed intramolecular alkoxylation of alkyne 122 also proceeded via an alkenyl palladium complex to form furan 123 instead of a benzofurans [99, 100]. In addition, 3-hydroxyalkylbenzo[fc]furans was prepared by Bishop et al via a Pd-catalyzed heteroannulation of silyl-protected alkynols with 2-iodophenol in a fashion akin to the Larock indole synthesis, [101]. 

Undoubted, 2-haloaniline derivatives still maintain most vored precursor status for the preparation of the indole nucleus. Larock now reports the frill details of his examination of the asymmetric addition of IV-tosyl-2-iodoaniline (63) to allenes 64 (e.g. 1,2-undecadadiene) in the presence of palladium catafysts and chiral bisoxazoline ligand to afford chiral indolines 65 in up to 88% ee <99JOC7312>. Cook has utilized the palladhjm-catafyzed heteroannulation of iodoanilines with alkynes derivatized with the Schollkopf chiral auxiliary as a reliable route to optically active ring-A substituted tryptophans <99TL657>. 

The indole pharmacophore has attracted further attention in the work of Zhang et al. (see also below, Scheme 10), who used the route developed by Larock for the heteroannulation of internal alkynes with o-iodoanilines (Scheme 7). The cyclization proceeded well on the solid phase. In the case of unsymmetrical alkynes, the predominant species was the expected one with the more sterically demanding group in the 2-position. 

Nishikawa, T., Wada, K., Isobe, M. Synthesis of novel a-C-glycosylamino acids and reverse regioselectivity in Larock s heteroannulation for the synthesis of the indole nucleus. Biosci. Biotechnol. Biochem. 2002, 66, 2273-2278. 

The most popular Pd-catalyzed method for the production of furans and benzofurans involves reactions of alkynols. Acyclic alkynols are converted into furans, while benzene substituted alkynols are transformed into benzofurans. The use of this strategy is widespread for the synthesis of benzofurans however, it is occasionally used for the syntheses of furans. For example, intramolecular alkoxylation of alkyne 189 proceeds via an alkenylpalladium complex and subsequent carbonylation to form furan 190 [156, 157]. In addition, 3 -hydroxyalkyl-benzo[/)J furans were prepared by Bishop et al. via a Pd-catalyzed heteroannulation of silyl-protected alkynols with 2-iodophenol in a fashion akin to the Larock indole synthesis [158]. In a related series of experiments, Qing demonstrated that alkynes 191 could be efficiently converted into furans 192 [159]. 

Internal Alkynes. Several applications of the Larock synthesis of indoles have been published where heterocycles are used as substrate. f " In the Larock method for indol construction, Pd-catalyzed heteroannulation of internal alkynes using ort/to-iodoanilines are used. Similarly, Pd-catalyzed heteroannulation of internal alkynes using ortho-amino-iodopyridine substrates produces azaindoles (Scheme 103). The method provides a convenient access to a structurally diverse range of 5-, 6-, and 7-azaindoles, 304, 305, and... 

Larock modified the annulation process to access 3-substituted indoles by employing silyl-substituted alkynes. In this case, the bulky silyl group dominates the regioselectivity of the annulation and thus serves as a phantomdirecting group in the heteroannulation step. Silylated alkynes provide 2-silyl-3-substituted indoles with excellent regioselectivity. Subsequent desilylation affords 3-substituted indoles in good yield. 

Boger and coworkers reported the first total synthesis of chloropeptin II and later its transformation into chloropeptin I (2009JA16036). The key step to this total synthesis was macrocycHzation of peptide 31 by an intramolecular Larock indole heteroannulation. This intramolecular reaction between a substituted 2-bromoaniline with a removable terminal alkyne substituent afforded simultaneous regioselective indole ring formation and macrocycli-zation. The TES substituent of the alkyne dictates indole cyclization regio-selectivity (Scheme 20). 

In 1991, Larock and Yum reported the heteroannulation of internal al-l nes with 2-iodoanilines, which is now known as Larock indole synthesis.In the presence of a palladium catalyst, the desired indoles were isolated in moderate to good yields under mild reaction conditions (Scheme 2.90). However, a large excess of all nes was necessary in some cases (5 equiv.). 

Ring Closure Reactions Palladium(II) complexes (PdCl2L2, L=P, CN), covalently immobilized onto SBA-15 silica by a postsynthetic method, were used as catalysts in the Larock synthesis of indoles [86]. The reaction consisted of the heteroannulation of 2-iodoaniline and 2-bromoaniline with triethyl(phenylethynyl)silane showing high activities and selectivities to 3-phenyl-lH-indole 26 (Scheme 17). 

Since it was first reported in 1991, the Larock indole synthesis has become one of the most attractive and practical methods for the preparation of 2,3-disubstituted indoles (Scheme 24.46, disconnection D-1). In the seminal publication, Larock and Yum described the palladium-catalyzed heteroannulation of internal alkynes such as 71 with o-iodoanilines to generate substituted indoles such as 73 in excellent yield (Scheme 24.47) [149]. Unsymmetrical alkynes could be regioselectively incorporated, with the more sterically hindered group of the alkyne resulting at the 2-position of the indole. Trimethylsilyl-substituted alkynes were found to be particularly effective, affording the corresponding 2-silylated products such as 73 in exemplary yields. 

---