Radical cyclization Fukuyama indole synthesis

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. 

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-... 

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. 

Tin-mediated-radical cyclization of isonitriles provides a useful strategy for the preparation of indoles (Fukuyama reaction).90 This radical cyclization is used for synthesis of 6-hydroxy-indole-3-acetic acid, which is the aromatic subunit of Nephilatoxin. The requisite isonitriles are prepared from nitroarenes via amines (Eq. 10.66).91... 

A few type lb intramolecular strategies for construction of the indole core have appeared. In their synthesis of (+)-vinblastine, the Fukuyama group employed radical cyclization of thioanilide 93 to generate the indole skeleton of 94 in 77% yield <07OL4737>. 

The Fukuyama group has developed a versatile indole synthesis that relies on cyclization of iminoyl radicals generated by addition of tri- -butylstannyl radicals to isonitriles. For example isonitrile 43 [4 steps from 7V-(o-iodophenyl)formamide] was converted to 44 in 71% overall yield as shown in Eq. (15) [31]. This reaction takes place via an iminoyl radical cyclization followed by tautomerization of the resulting imine. Indole 44 was a key intermediate in a synthesis of vincadifform-... 

Fukuyama and colleagues employed hypophospho-rous acid to induce indoUzation of u-alkenylthioanilides (Scheme 2, equation 1), including a synthesis of ( )-catharanthine and a 2-adamantylindole [7, 8]. Rainier and Kennedy succeeded in capturing the intermediate indole-nine from the radical cyclization of the isocyanide 1 to... 

Instead of the standard radical conditions using tri- -butyltin hydride, Fukuyama examined the radical cyclization by screening using various thiols and eventually found that the excess ethanethiol is quite effective for promoting the cyclization (24 to 25), illustrating another tin-free indole synthesis. 

Aromatic isonitriles, particularly orf/jo-alkenyl-substituted aryl isonitriles, were also successfully employed by Fukuyama in the synthesis of indole derivatives [19]. Cyclization of compounds 26 was accomplished with tin radicals, and 6-membered ring closure did not significantly compete except in one case (R = -Bu) where, on the other hand, this problem was interestingly alleviated by using the Z-alkene instead of the Z-analog (Scheme 11). 

Fukuyama devised a novel tin-mediated indole ring synthesis leading directly to 2-stannylindoles that can capture aryl and alkyl halides in a Pd-catalyzed crosscoupling termination reaction [110-112]. The presumed pathway is illustrated and involves initial tributylstannyl radical addition to the isonitrile 65, cyclization, and final formation of stannylindole 66. 

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