Larock annulation

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.- ... 

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... 

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). 

Larock R (2005) Palladium-Catalyzed Annulation of Alkynes. 14 147-182 Larrow JF, Jacobsen EN (2004) Asymmetric Processes Catalyzed by Chiral (Salen)Metal Complexes 6 123-152... 

The acyclic version of Larock s heteroannulation was successfully applied to the synthesis of highly substituted pyridines [166]. The annulation of rert-butylimine 210 with phenyl propargyl alcohol produced pyridine 211 regioselectively in excellent yield. The regiochemistry obtained was governed by steric effects. Furthermore, the choice of imines was crucial to the success of the heteroannulations. terr-Butylimine was the substrate of choice, since all other imines including methyl, isopropyl, allyl and benzyl imines failed completely to produce the desired heterocyclic products. 

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. 

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-... 

Larock has also extended the annulation chemistry to olefins. 1,3-Dienes, both acyclic and cyclic, were reacted with iodophenol110 and analogous compounds to give condensed benzofurans. The 7-acetoxy-8-iodocoumarin derivative shown in 3.87., for example, was converted to the corresponding tetracyclic furocoumarin derivative in good yield.111... 

M. Synthesis, 1973, 703 (e) see, for example, the list of more than a dozen of the modified Michael acceptors for Robinson-like annulations in Larock, R. C. Comprehensive Organic Transformations, VCH, New York, 1989, p. 669. 

Larock and co-workers [47] have studied the palladium-catalyzed arylation of 1,3-dienes followed by intramolecular attack by an oxygen nucleophile. o-Iodophenols and o-iodobenzyl alcohol were used as substrates. However these reactions, which are annulation reactions, lead to a 1,2-addition to the conjugated dienes and will not be further treated here. Amides, also, were used as nucleophiles in these reactions. 

Larock, R. C. Palladium-catalyzed annulation. PureAppl. Chem. 1999, 71,1435-1442. 

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

Although somewhat different, Larock s annulation reactions of allenes with aryl halides also belong to this category, as they involve an intermolecular car-bopalladation followed by an intramolecular allylation as the key step. The best results were obtained with the bisoxazoline ligand 77 where ees of up to 82% were observed. Scheme 39 [121]. 

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