Cyclizations nitrogen heterocycles

Negishi reaction 157 Nitriles, reduction/hydrolysis 25 Nitrogen heterocycles, on-resin cyclization, minopropenones 108 C-Nucleoside analogues 274... 

The majority of sequential radical reactions deal with cyclizations as the key steps. The constructions of carbocycles, oxygen, and nitrogen heterocycles using (TMSlsSiH as a mediator are many and represents the expansion and importance of these synthetic approaches. For example, Nicolaou and coworkers found that (TMSlsSiH serves as a superior reagent in the radical-based approach toward the synthesis of azadirachtin, an antifeedant agent currently used as an insecticide, and in other related systems. ° ° Here below we collected a number of reactions mostly from the recent work in the area of intramolecular reactions. 

An efficient methodology for the construction of pyrrolizidines and other polycyclic nitrogen heterocycles using a radical domino sequence has been revealed by Bowman and coworkers [46]. These authors employed sulfenamides as substrates, which easily form aminyl radicals by treatment with tributyltin hydride and AIBN. For instance, 3-101 smoothly underwent a twofold 5-exo-trig cyclization to give the tetracyclic pyrrolizidine product 3-105 in 90% yield (Scheme 3.26). As intermediates, the radicals 3-102 to 3-104 can be assumed. 

Norrish Type II photocyclizations have been employed in many instances in the synthesis of nitrogen heterocycles. Type II cyclizations are the result of an intramolecular hydrogen abstraction by an excited carbonyl group followed by cyclization of the resulting biradical. Hydrogen abstraction from the y-carbon atom is normally preferred. The introduction of a nitrogen atom... 

In contrast to the palladium-catalyzed reactions, little attention has been paid to other transition-metal catalysts. Recently some efficient reactions using copper(i or 11), gold(m), platinum(n), and tungsten(O) have been developed for the synthesis of nitrogen-heterocycles. The copper-catalyzed cyclizations of 2-alkynylaniline derivatives into... 

Aminocarbonylation of alkenylureas.1 In the presence of PdCI2 (with CuCl2 as reoxidant) alkenylureas undergo carbonylation and cyclization to five- and six-membered nitrogen heterocycles. 

Another oxidative cyclization to afford a nitrogen heterocycle is illustrated in Scheme 12 [33]. This reaction was accomplished using a platinum gauze electrode at a controlled potential of -t-1.8 V versus Ag/AgCl. The reaction proceeded through the initial oxidation of the amide. Evidence... 

The recent impact of solid-phase synthesis on medicinally relevant benzoaime-lated nitrogen heterocycles has been recently reviewed [16], therefore in this section only recent publications are included. Benzoannelated heterocycles can be prepared efficiently through cyclization on solid supports employing classical heterocycle forming reactions such as the Fischer [425], the Bischler-Napieralski [426], Tsuge [427], Nenitzescu [428], and Richter [140] reactions. In addition, the... 

Reductive cyclization of the 2-halogenophenyl group onto an adjacent phenyl substituent is a useful reaction for the preparation of condensed ring nitrogen heterocycles. Examples of the process include the formation of aromatic and conjugated 7t-systems [168, 169]. It has been applied to the synthesis of an aporphine... 

In oximes 305 with a nucleophile anti to the oxime oxygen atom, the cyclization is endo and a nitrogen heterocycle 306 is formed. These cyclizations are extremely useful in natural product syntheses. 

During studies on the use of amidines as azomethine ylide sources, Jones et al. (67-69) reported in a series of papers the application of their general strategy to an asymmetric process. Quatemization of the dihydroimidazole 214 with an a-halo ester followed by DBU-induced ylide formation and subsequent cyclization furnished a range of nitrogen heterocycles in a one pot generation and cyclization protocol (70) (Scheme 3.73). 

Yttrium-catalyzed diene cyclization/hydrosilylation was applied to the synthesis of aliphatic nitrogen heterocycles such as the indolizidine alkaloid ( )-epilupinine. l-Allyl-2-vinylpiperidine 30 was synthesized in four steps in 59% overall yield from commercially available ( )-2-piperidinemethanol (Scheme 10). Treatment of 30 with phenylsilane and a catalytic amount of Gp 2YGH3(THF) gave silylated quinolizidine derivative 31 in 84% yield, resulting from selective hydrometallation of the A-allyl G=G bond in preference to the exocyclic vinylic G=G bond. Oxidation of the crude reaction mixture with tert-huVf hydrogen peroxide and potassium hydride gave (i)-epilupinine in 51-62% yield from 30 (Scheme 10). 

Mori has independently developed a procedure for the cyclization/stannylsilylation of enynes similar to that developed by Lautens. As an example of Mori s procedure, reaction of dimethyl allylpropargylmalonate with trimethylsilyltributylstannane catalyzed by Pearlman s catalyst [Pd(OH)2/C] in THF at room temperature for 20 h formed cyclopentane 94 [X = C(C02Me)2] in 90% yield (Equation (61)). The transformation was compatible with a number of functional groups, tolerated limited substitution of the G=C bond, and was applicable to the synthesis of nitrogen heterocycles. In a notable example, reaction of the benzhydryl-protected allylpropargylamine 95 with MesSiSnBus catalyzed by Pd(OH)2/C formed the bis(functionalized) octahydroindole 96 in 66% yield as a single diastereomer (Equation (62)). 

Cyclization of haloamines (cyclic amines) dealkylation of quaternary salts of nitrogen heterocycles 0-45 Reaction between dihalides and cy-anamide (cyclic amines)... 

Cyclization of a variety of alkylideneketenes generated by the Meldrum s acid method has provided a number of useful syntheses of nitrogen heterocycles. Thus, for example, FVP of 382 leads to the azepinone 383177, and the indole compounds 384 may give... 

Wu and co-workers developed a synthesis of benzannulated nitrogen heterocycles 120 and 121 based on the addition of sodium methoxide to 2-alkynylbenzo-nitriles 118 in methanol, followed by the Pd(PPh3)4-catalyzed heteroannulation of ketimine intermediate 119 with aryl iodides [104]. The 5-exo versus 6-endo mode of cyclization leading to isoindoles 120 or isoquinolines 121, respectively, proved to be dependent on the nature of the substituent on the terminal alkyne carbon. 2-(2-Phenylethynyl) benzonitrile 118a underwent exclusive 5-exo cyclization whereas 2-(l-hexynyl)benzonitrile 118b led to mixtures of isomers with a marked preference for the 6-endo mode of cyclization. This endo/exo balance was attributed to steric interactions between the entering group and the substituent on the terminal alkyne carbon (Scheme 8.49). 

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... 

Imines have been employed as radical acceptors in the preparation of nitrogen heterocycles [95AJC291]. A highly selective 6-endo-trig radical cyclization onto a chiral aldehyde imine has been developed by Werstiuk et al. Reductive cyclization of 218 provides a 3.8 1 diastereomeric mixture of the tetrahydroisoquinoline 219. A minor amount of 220, a product arising from a 5-exo cyclization is also produced. 

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