Fukuyama indole synthesis

Based on the early studies of radical generation from organotin hydrides and their addition to multiple bonds [1-3], particnlarly in cyclization [4-7], several groups applied this chemistry to the synthesis of indoles and indolines. For example, in 1975 Beckwith and colleagues found that -(A -allyl-Af-methylamino)iodobenzene was converted to 1,3-dimethylindoline (78% yield) upon treatment with tri-n-butylstannane (prepared by the reduction of tri-n-butyltin chloride with LiAlH ) in the presence of AIBN (azobisisobutyronitrile) and benzene at 130°C in a sealed tube [4], 

A powerful extension of this method is the Stille-iodination of the initially formed 2-stannyUndoles with iodine orlV-iodosuccinimide (NIS) and further Pd-catalyzed 

Fuknyama and colleagnes employed this indole ring synthesis in total syntheses of ( )-vincadifformine [11], (-)-tabersonine [11], (-)-vindoline [13], (-)-aspidophytine [15, 16], and tryprostatins A and B [17]. For reviews of isocyanide-based indole synthesis and organic synthesis using isocyanides in general, see Campo and colleagnes and Tobisu and colleagues [19,20], 

The tin-mediated Fukuyama indolization from isocyanides has been used by Rainier [29, 30], Nakajima [31], Bendteau [32], and Jeon [33] to aaft various indoles. Notably, Rainier and coworkers effected a tin-mediated isocyanide-alkyne cyclization, but they attempted unsuccessfully to ambush the intermediate indolenine [29, 30], although this was successful under a sulfur-mediated radical cyclization (Chapter 52). 

Indole Ring Synthesis From Natural Products to Drug Discovery, First Edition. Gordon W. Gribble. 2016 John Wiley Sons, Ltd. Published 2016 by John Wiley Sons, Ltd. 

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The Fukuyama indole synthesis involving radical cyclization of 2-alkenylisocyanides was extended by the author to allow preparation of2,3-disubstituted derivatives <00S429>. In this process, radical cyclization of 2-isocyanocinnamate (119) yields the 2-stannylindole 120, which upon treatment with iodine is converted into the 2-iodoindole 121. These N-unprotected 2-iodoindoles can then undergo a variety of palladium-catalyzed coupling reactions such as reaction with terminal acetylenes, terminal olefins, carbonylation and Suzuki coupling with phenyl borate to furnish the corresponding 2,3-disubstituted indoles. 

The Fukuyama indole synthesis involves the intramolecular radical cyclization of 2-alkenylisocyanides, the availability of which often limits the utility of this process. In order to access a wider variety of such substrates, the author prepared the versatile Horner-Wadsworth-Emmons reagent 131 using the Pudovik reaction <01SL1403>. Reaction of 131 with a variety of aldehydes thus provides a convenient and general route to diverse alkenyl precursors 132. Additionally, instead of the standard radical conditions using tri-n-butyltin hydride, Fukuyama now finds that excess thiols arc quite effective for inducing cycliz.ation, whereupon desulfurization of the indoles 133 can be effected with Raney-Ni if desired. 

The second generation of the Fukuyama indole synthesis (Scheme 2) generally involves the intramolecular radical cyciization of 2-alkenylthioanilides, which can be readily accessed in a modular fashion from at least three different methods. In the first method, tetrahydropyran-protected o-(3-hydroxyallyl)thioanilides are prepared from quinolines by... 

FIGURE 1. Indole-containing alkaloids that are accessible by the Fukuyama indole synthesis. 

Because both the first and the second generations of Fukuyama indole synthesis involve the intramolecular radical cyclization, only the mechanism for the first generation is pro-... 

Other references related to the Fukuyama indole synthesis are cited in the literature. 

This reaction is related to the Fukuyama Indole Synthesis, both give 2,3-disubstituted indole derivatives. In addition, this reaction is very closely related to Me Murry Coupling in mechanism. 

The Fukuyama indole synthesis is a novel tin-mediated chemical transformation of o-isocyanostyrene derivatives 1. Conversion of the a-stannoimidoyl radical 2 results in the formation of 3-substituted indoles 3a or 2,3-disubstituted indoles 3b,c. Alternatively, 2,3-disubstituted indoles were formed from 2-alkenylthioanilides 4 via imidoyl radical species 5 and followed by radical cyclization to form indole 6. 

A proposal for the mechanism of the Fukuyama indole synthesis is proposed as shown below. Treatment of the isonitriles 1 with tributyltin hydride and a catalytic amount of AIBN, affords a-stannoimidoyl radical 2, followed by cyclization, to give radical 16. It was found that the substrates bearing radical-stabilizing groups at the P-position gave indoles 3 in excellent yield after tautomerization, and acidic workup. Similarly, when thioamide derivatives such as 2-alkenylthioanilide 18 are subjected to radical-initiating conditions, radical 5 or imidoyl radical species are formed, which then undergo radical cyclization to furnish 2,3-disubstiuted indoles 6. 

The Fukuyama indole synthesis was used during the total synthesis of aspidophytine 28. Tin-mediated indole formation was followed by the treatment of the 2-stannyl indole intermediate with iodine and gave the 2-iodoindole derivatives 27 in 85% yield. ... 

Recently, other groups have used this facile and mild tin-mediated Fukuyama indole synthesis. For example, a new route to the general core of the paullones 40, potential cyclin-dependent kinase (CDK) inhibitors that are particularly efficient against three disease-relevant kinases was reported. ... 

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