Larock Reaction

Thankfully, some of the conventional and modem indole synthesis methods do apply to make azaindoles. They include the Larock reaction, Mori-Ban indole synthesis, Bartoli indole synthesis, Batcho-Leimgmber indole synthesis, and Cadogan-Sundberg indole synthesis. 

The Larock reaction is applicable to make all azaindoles. In one case, 4-azaindoles were synthesized as novel inhibitors of C-Met kinase. Interestingly, 4,7-diazaindole was assembled via a Larock reaction. The resulting product as the C-Met kinase inhibitor is potentially a cancer therapy by disruption of signal pathways that mediate tumor formation and growth. 

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... 

Several reviews about the synthesis of heterocycles via palladium-catalyzed reactions containing revisions of Larock procedures have been made until the end of 2014 (2005CR2873, 2006CR2875, 2006CR4644). This chapter provides a review and update of the Larock reaction. It will be implemented not only for the preparation of indole and its derivatives but also for other heterocyclic systems, natural compounds, and derivatives. 

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. 

Scheme 5 Larock reaction with pseudothiourea-Pd(ll) complex 12.

The volume commences with an account of The Larock Reaction in the Synthesis of Heterocyclic Compounds by Mercedes Alvarez and colleagues at the University of Barcelona, Barcelona, Spain. This palladium-catalyzed heteroannulation of 2-iodoanihnes and substituted alkynes is now often the method of choice for the preparation of many heterocyclic derivatives since it can provide both excellent regioselectivity and high yields. This is followed by a chapter entided HeHcal Phosphorus Derivatives Synthesis and Applications by David Virieux and colleagues at the Ecole Nationale Superieure de Chimie de MontpeUier, Montpellier, France. This review surveys helical structures based on organophosphorus derivatives and describes the synthesis of heterocycHc derivatives and their applications, particularly the specificity introduced by the presence of phosphorus. 

The Larock indole synthesis is the internal alkyne version of the Yamanaka-Sakamoto-Sonogashira indole synthesis presented in Chapter 75. Also known as the Larock heter-oannulation, it affords 2,3-disubstituted indoles, in contrast to 2-snbstituted indoles from the Sonogashira reaction (Scheme 1, eqnations 1-3) [1-12], Like the Sonogashira, the Larock reaction has been of enormous utility in indole synthesis. With unsymmetrical alkynes, the regiochemistry is such that the more bulky group (e.g., t-butyl relative to... 

The Cacchi synthesis of indoles via the Pd-catalyzed cyclization of 2-aIkynylaniUnes and subsequent functionalization has extended enormously the original Yamanaka-Sakamoto-Sonogashira and Larock reactions. For a review of these methods see Beller [41]. 

Batail et al. (2009) constructed some indoles in good to high isolated yields via a new ligand- and salt-free heterogeneous palladium-catalyzed Larock reaction (Scheme 2.1). Recycling studies have shown that the palladium catalysts can be readily recovered and reused. Reactions and recovery of the palladium catalysts can be carried out in the presence of air, without any particular precaution. 

---