Larock heteroannulation

The scope and mechanism of palladium-catalyzed annulation of internal alkynes to give 2,3-disubstituted indoles, the effect of substituents on the aniline nitrogen or on the alkynes, as well as the effect of the salts such as LiCl or n-BuaNCl were studied by Larock and coworkers (1998 JOC7652). The mechanism they propose for indole synthesis proceeds as follows (a) reduction of the Pd(OAc)2 to Pd(0) (b) coordination of the chloride to form a chloride-Ugated zerovalent palladium species (c) oxidative addition of the aryl iodide to Pd(0) (d) coordination of the alkyne to the 

The first and third steps are well known and integral to a wide variety of Pd(0)-catalyzed processes. Less hindered alkynes are known to insert more readily than more hindered alkynes (1993T5471). Sy -addition of the arylpalladium compound to the alkyne has been estabHshed for the analogous palladium-catalyzed hydroarylation process (1986G725, 2004JOM4642) and implemented in many other alkyne insertion processes (1989JA3454, 

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A complete reversal of regioselectivity was observed by M. Isobe and co-workers during the Larock heteroannulation of o-iodoaniline with a-C-glucosylpropargyl glycine in an attempt to prepare C-glycosyltryptophan. " ... 

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). 

The mechanism was estabhshed by several experimental control processes and involved Larock heteroannulation, subsequent elimination of a molecule of 4-methylbenzenesulfinic acid, electrocyclization of the resulting dienimine, and, finally, oxidative aromatization (Scheme 18). 

Scheme 19 Larock heteroannulation using a chiral auxiliary.

The procedure is based on a Larock heteroannulation using a silylated chiral alkyne with an N-protected oxazohdine substituent as the key reaction step that affords compounds 32 pC = O, NTs), which are precursors of substituted glycines (2012JOC7081 Scheme 21). 

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). 

Later the same group described the total synthesis of psychotrimine and more complex peptides containing the same bond between two Trp units, such as kapakahines B and F, using a Larock heteroannulation as the key step (Figure 7 2009JA6360, 2010JA7119, 2011AG(E)2716). 

Scheme 28 Larock heteroannulation for the synthesis of gonadotropin antagonists 42 and 43.

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. 

The Larock heteroannulation was used to prepare multikilogram quantities of avitriptan (72). The palladium-catalyzed heteroannulation of... 

On the other hand, efficient asymmetric synthesis of optically active substituted tryptophans 91 was realized via Larock heteroannulation of o-iodoaniline 92 and alkyne 93 derived from the Schdllkopf chiral auxiliary to afford the corresponding key intermediate 94 as the major isomeric product. ... 

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. 

Pd-catalyzed annulation of meso-hQxyny Zn(II) porphyrin 103 with 4-amino-3-iodopyridine efficiently provides we5o-3-(5-azaindolyl)-substitut-ed Zn(II) porphyrin 104 as the major product, which assembles to form a slipped cofacial dimer by the complementary coordination of the pyridine moiety to the Zn(Il) center." Isomer 105 was predicted to be the major isomer based on the general trend for Larock heteroannulation. In contrast, the reaction gave only a trace amount of 104. 

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. 

SCHEME 2 Larock heteroannulation through additive-free heterogeneous supported palladium catalysis. 

N. Batail, V. Dufaud, L. Djakovitch, Larock heteroannulation of 2-bromoanilines withintemal alkynes cia Ugand and salt free Pd/C catalyzed reaction. Tetrahedron Lett. 52 (2011) 1916-1918. 

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... 

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