Larock indole annulation

The regioselectivity of Larock indole annulation with 2-alkynylpyridines and o-iodoaniline to give 3-substituted-2-pyridin-2-ylindoles has also been rationalized by a combination of steric and electronic coordinative effects (2008TL363 Scheme 3). A coordination of the pyridine nitrogen during the catalytic cycle was postulated to justify the different regioisomeric ratios 94 6, 68 32, and 72 28 of the Larock reaction obtained with cyclopentyl 2-, 3- and 4-pyridyl acetylenes, respectively. 

To make tryptophan analogs, Gronowitz and coworkers conducted a pyrrole annulation from an aminoiodopyrimidine utilizing the Larock indole synthesis conditions (see Section 1.10.) [80]. They prepared heterocondensed pyrrole 115 by treating 4-amino-5-iodopyrimidine 114 with trimethylsilyl propargyl alcohol under the influence of a palladium catalyst The regiochemical outcome was governed by steric effects. 

Larock indole synthesis was also employed to prepare substituted tryptophans 88 via annulation of silylated alkyne 89 with o-iodoanilines 90. ... 

The palladium catalysed annulation of / -iodoamines and acetylene derivatives has been widely used in the construction of pyrroles and indole derivatives. The strategy, first reported by Larock, is efficient in converting both cyclic and open chain 2-iodo-allylamine derivatives to 3-alkylidene-... 

Related to the Heck reaction is the Larock annulation of internal alkynes, which is a general route to heterocyclic and carbocyclic systems. Especially attractive is the construction of the pharmaceutically important indole ring system via palladium-catalyzed coupling of 2-iodo-aniline and the corresponding V-methyl, acetyl, and tosyl derivatives with a wide variety of internal alkynes. The catalytic process appears to involve arylpalladium formation, regioselective addition to the carbon-carbon triple bond, and subsequent intramolecular palladium displacement.- ... 

Roesch, K. R., Larock, R. C. Synthesis of lsoindolo[2,1-a]indoles by the Palladium-Catalyzed Annulation of Internal Alkynes. Org. Lett. 

Their synthesis began with protected dipeptide 220, reaction of which with o-iodoaniline and (V-iodosuccinimide in the absence of an acid-scavenger afforded the indole-aniline coupled product 221 as a single diastereomer. Larock annulation of 221 with tripeptide 222 obtained in two steps from serine-derived 223 through... 

The Larock method for annulation between vicinal iodo-arylamines and 1,2-dienes in the preparation of indoles can be adapted for preparation of azaindoles using corresponding azine substrates. Thus, substituted-3//-pyrrolo[2,3-fc]pyridin-3-ones can be prepared from 2-amino-3-iodopyridine derivatives by a palladium carboannulation process with al-lenic compounds (Scheme 104). The bicychc products, the methylene derivatives 308, and the alkylidenes 309 can be oxidatively cleaved with ketone formation. The reaction may proceed by formation of a pyridinylpaUadium complex followed by the rr-allyl complexa-tion of aUenic derivatives 310. Since the polar substituents on terminal carbons of the 7r-allyl system influence the regiochemistry of the reactions, nucleophilic attack of the nitrogen atom on the most electron-deficient carbon atom of the rr-allyl system affords either of the... 

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. 

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... 

Jia and coworkers have described a concise total synthesis of dictyodendrins B and C, utilizing palladium-catalyzed Larock annulation for the construction of the highly substituted indole core of compounds 37 and 38 (Scheme 26 2014EJO5735). 

Annulation Reactions. Larock et al. have described the synthesis of different heterocyclic systems using a [3+2] annulation approach. For instance, pharmaceutically important pyrido[l,2-fl]indole derivatives such as 93 are easily accessible from 2-substituted pyridines and aryne precursors (Scheme 12.48) [83]. More recently, the 1/f-indazole skeleton has been accessed through a [3+2] annulation from arynes and hydrazones. The reaction with Al-arylhy-drazones leads to 1,3-disubstituted indazoles 94 through an annulation-oxidation process (Scheme 12.48). The use of iV-tosylhydrazones also affords 3-substituted-Ai(H)-indazoles, although probably via a [3+2] cycloaddition (see Scheme 12.18) with in situ generated diazo compounds [84]. 

Rogness DC, Markina NA, Waldo JP, Larock RC (2012) Synthesis of pyrido[l,2-a]indole malonates and amines through aryne annulation. J Org Chem 6 2743-2755... 

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