Heterocycles intramolecular anionic cyclization

The development of intramolecular anionic cyclization for the preparation of heterocyclic systems provides routes to several oxygen and nitrogen heterocycles. Tetrahydro-furans, pyrrolidines144, indohnes145 or indoles146 have been synthesized via intramolecular... 

The synthesis of oxygen- and nitrogen-containing heterocyclic compounds by anionic cyclization of unsaturated organolithium compounds has been reviewed recently. " Broka and Shen reported the first intramolecular reaction of an unstabilized a-amino-organolithium compound using reductive lithiation of an A,5-acetal derived from a homoaUylic secondary amine (Scheme 21). Just one example was reported treatment with lithium naphthalenide gave the pyrrolidine product, predominantly as the cis isomer. 

A variety of five-membered nitrogen heterocycles can be prepared efficiently by inter- or intramolecular addition/cyclizations of sulfonamide anions with alkynyliodonium salts. The intermolecular variant employs the combination of the amides 172 or anilides 174 with propynyl(phenyl)iodonium triflate (Scheme 65) [131,132]. The yield of dihydropyrroles 173 in this cyclization is extremely sensitive to the nature of the protective group P the tosyl group in 172 proved... 

Thus the synthesis of heterocyclic compounds with one or more heteroatoms along with perfluoroalkyl groups is possible if the fluorinated molecule has a multiple bond and if an anionic center may be generated at the heteroatom or carbon atom of the functional group in intramolecular nucleophilic cyclization reactions. These new approaches point to the specific effect of fluorine atoms and to the important role of the electronic effects in... 

Although the synthesis of dihydrobenzofuran derivatives seems to be not possible by this anionic cyclization methodology, there are some particular examples in which these heterocycles are prepared by an intramolecular carbolithiation reaction. In this respect Baldwin and coworkers described in 1980 the preparation of 350 by rearrangement of 349 when it was treated with BuLi in THF/TMEDA (Scheme 91)151. The most likely explanation starts with an orf/zo-lithiation giving a dilithium intermediate, which undergoes an intramolecular 5-exo carbolithiation reaction affording a 3-lithiomethyldihydrobenzofuran... 

The intramolecular trapping of benzyne intermediates with tethered nucleophiles is a powerful strategy for the synthesis of benzo-fused heterocycles. In this field, 7-functionalized benzoxazoles 59 and benzothiazoles 60 have been prepared by anionic cyclization of the corresponding lithiated benzyne (thio)amides and (thio)carbamates, which were generated from 3-haloaniline derivatives (Scheme 12.34) [55]. Related to this, substituted indolines 61 have also been accessed by benzyne-mediated cyclization-functionalization from Boc-protected (2-bromo-4-methoxy)phenetylamines using Mg(TMP)2 2LiCl as a base. This methodology has also been applied to the preparation of functionalized carbazoles (Scheme 12.34) [56]. 

The photolysis of donor-acceptor systems shows a reaction pattern of unique synthetic value. Direct irradiation of the donor-acceptor pairs, such as arene-amine, leads by intramolecular electron transfer, to amine radical cations and arene radical anions. The generated radical cation and radical anion intermediates undergo cyclization reactions providing efficient synthetic routes to N-heterocycles with a variety of ring sizes. 

Numerous carbo- and heterocyclic compounds of various sizes have been prepared by HR-type monocyclization. Cyclopropanes are formed only when neopentylpalladium intermediates are formed in the absence of anions. Intramolecular carbopalladation of the alkenyl triflate 201 generates the neopentylpalladium 202, and its 3-exo cyclization and jd-H elimination afford the cyclopropane 203 [95]. Intermolecular carbopalladation of the alkyne 204 generates 205. Its 5-exo cyclization provides the neopentylpalladium 206, which undergoes 3-exo cyclization to construct the three-membered ring 207. Finally y3-H elimination gives rise to the cyclopropane 208 [96]. 

A range of imines derived from trifluoromethyl aryl ketones have been converted into heterocyclic products via intramolecular cyclization with loss of the CF3 group. For example, o-aminoimine (15), when treated with strong base, cyclizes to benzimidazole (16), with loss of trifluoromethyl anion. The corresponding o-phenols yield benzoxazoles, and examples using an external amine lead to aziridines. 

Rodinovskaya LA, Shestopalov AM, Gromova AV, Shestopalov AA (2008) One-Pot synthesis of diverse 4-Di(tri)fluoromethyl-3-cyanopyridine-2(lH)-thiones and their utilities in the cascade synthesis of annulated heterocycles. J Comb Chem 10(2) 313-322 Suzuki H, Sakai N, Jwahara R, Fujiwa T, Satoh M, Kakehi A, Konakahara T (2007) Novel synthesis of 7-fluoro-8-(trifluoromethyl)-lH-l,6-naphthyridin-4-one derivatives intermo-lecular cyclization of an N-silyl-l-azaallyl anion with perfluoroalkene and subsequent intramolecular skeletal transformation of the resulting pentasubstituted pyridines. J Org Chem 72(15) 5878-5881... 

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