Four-Carbon Annulation

Four-carbon annulation onto the caprolactam ring is accomplished by intramolecular nucleophilic addition of an a-sulfinyl carbanion to the carbonyl group in order to obtain sulfinoenamine 110 (03OBC3495). Moreover, thiocaprolactam (111a) and its Michael adduct 111b, via... 

A new four-carbon annulation procedure is shown in Scheme 14, whereby the dienolate anion of an unsaturated carboxylic acid (99) is added to a ketone to give an acid which upon rearrangement at... 

However, palladium and nickel catalyzed versions promise, at the moment, an even wider range of possibilities. The need to maintain the catalytic cycle by continuous regeneration of the zerovalent metal catalyst limits, nevertheless, the functionalizability of the metallated center in the cyclized intermediate. For the same reason, the readily accessible starting materials may contain various functional groups which are compatible with the reaction conditions and which may be of value for the syntheses of complex heterocycles such as alkaloids. Carbon monoxide insertion reactions of the cyclized a-metal intermediates were shown to afford monocyclic methyl carboxylates and/or annulated cyclopentanones (cyclopentenones) with concomitant stereocontrolled formation of up to four carbon-carbm bonds. 

In order to study possible side reactions which may reduce the yield in the Woodward method of annulation of azetidin-2-ones (Scheme 31) similar reactions of ylides (214), which do not contain groups capable of conversion to carbonyl by DMSO-acetic anhydride treatment, have been investigated. 30 A range of products, e.g. (215) and (216), were obtained. A mild, four-carbon homologation of the 4-formyl-substituted azetidinone (217) involving reaction with the phosphonium ylide (218) has been used to synthesize (219), a useful intermediate in the synthesis of carbacephem antibiotics. 3 ... 

The classical methods of constructing six-membered rings are the Diels-Alder reaction or the Robinson annulation, which consist of the union of two fragments, one with two carbon atoms and the other with four carbons. A conceptually different method from the above involves the condensation of two three-carbon units, one with two nucleophilic sites and the other containing two electrophilic sites. Furthermore, the regiochemistry of the reaction is controlled by the differential reactivities of these sites. 

Two iminophosphorane groups separated by four carbon atoms are annulated by stirring the compound with an aroyl chloride and TEA. A review of recent work on seven-membered heterocycies has been published [3987]. 

A facile preparation of benz-annulated thiophenes, selenophenes, and furans were achieved at room temperature involving a Lewis acid/Bronsted acid-mediated annulation using 2,5-dimethoxytetrahydrofuran as a four-carbon synthon (14OL2720). 

Bicyclic cyclopenta[fc]dihydrofuran derivatives were produced from y-substituted allenoates, as four-carbon synthons, through phosphine-catalyzed sequential [2 + 3] and [3 + 2] annulation reactions in good-to-excellent yields under mild conditions (14CEJ3520). 

A few additional Pd-catalyzed schemes have been employed for Ilac type cyclization chemistry. Palladium-phenanthroline complexes were used by the Ragaini group to prepare indoles via the intermolecular cyclization of nitroarenes and alkynes in the presence of carbon monoxide <06JOC3748>. Jia and Zhu employed Pd-catalysis for the annulation of o-haloanilines with aldehydes <06JOC7826>. A one-pot Ugi/Heck reaction was employed in the preparation of polysubstituted indoles from a four-component reaction system of acrylic aldehydes, bromoanilines, acids, and isocyanides <06TL4683>. 

Whereas lactone annulation invokes a relief of strain of the four membered ring by migration of the ring bond to an electron deficient oxygen, a similar migration to an election deficient carbon creates a cyclopentanone synthesis (Eq. 73). The release of approximately 84 kJ/mole (20 kcal/mole) provides a strong driving force. Thus, the 1,1-cyclobutanone annulation of ketones translates into a 1,1-cyclopentanone annulation. 

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