Cyclization, reductive 3+2 Cycloaddition

An unusual reductive cycloaddition leading to a bridged bicyclic 1,3-dioxane was reported by Taylor and coworkers <20030L4441, 20050BC756>. They found that 2-acyl-2 -benzyloxy-substituted (Z)-stilbenes cyclize upon treatment with tin dichloride at room temperature to give the bicyclic product 220 in 94% yield (Equation 85). 

A new synthesis of 2,4,4,6-tetramethyl-4//-l,3-oxazine (155) simply involves a reductive cycloaddition of 4-methylpent-3-en-2-one and acetonitrile in the presence of trimethylsilyl chloride and sodium iodide (Scheme 42) <89TL4741>. Other cycloaddition reactions have been used previously to synthesize 4//-l,3-oxazines and this methodology has been extended to include cycloadditions between alkynes and l-oxa-3-azabuta-1,3-dienes. For example, phenylethyne and the A-benz-oylimine (156) afford 4,4-bis(trifluoromethyl)-2,6-diphenyl-4//-l,3-oxazine (157). The reaction proceeds through a Michael-type addition between the alkyne and the heterodiene giving an adduct which when heated to 80-90°C cyclizes to the oxazine (Scheme 43) <83CC945,89ZN(B)1298>. 

Whereas the preceding processes involving ring openings of cyclopropanes provide useful [3+2] entries to cyclopentanes, the use of simpler substrates in [3+2] cycloadditions is made possible by the development of reductive cycloaddition pathways. Such reactions were initially developed in the context of stoichiometric processes, where metallacycles were prepared by oxidative cyclizations of enones and alkynes, followed by either protonation or alkylation of the nickel 0-enolate functionality. Catalytic protocols involving various intramolecular combinations of 7t-systems include formal [3+2] reductive cycloadditions of bis-enones to form bicyclooctanols (Scheme 3-33), of enones with unsaturated acyl oxazolidinones to form triquinane derivatives, and of enals with alkynes to form bicyclooctenols. ... 

Dipolarophiles D3. 1,3-Dipolar cycloadditions of suitably functionalized cyclic nitrones with terminal alkenes, which have potential leaving groups X at the end of the alkane chain -(CHo),- (D3), were successfully used for the synthesis of pyrrolozidine, indolizidine and quinolizidine alkaloids, such as (+ )-and (—)-lentiginosine, a potent amyloglucosidase inhibitor (Scheme 2.243) (742). Reductive cleavage of the N-0 bond in the cycloadduct is important for the subsequent cyclization to pyrrolozidines, indolizidines, and quinolizidines. 

The present volume contains 13 chapters written by experts from 11 countries, and treats topics that were not covered, or that are complementary to topics covered in Volume 1. They include chapters on mass spectra and NMR, two chapters on photochemistry complementing an earlier chapter on synthetic application of the photochemistry of dienes and polyenes. Two chapters deal with intermolecular cyclization and with cycloadditions, and complement a chapter in Volume 1 on intramolecular cyclization, while the chapter on reactions of dienes in water and hydrogen-bonding environments deals partially with cycloaddition in unusual media and complements the earlier chapter on reactions under pressure. The chapters on nucleophiliic and electrophilic additions complements the earlier chapter on radical addition. The chapter on reduction complements the earlier ones on oxidation. Chapters on organometallic complexes, synthetic applications and rearrangement of dienes and polyenes are additional topics discussed. 

Particularly interesting is the reaction of enynes with catalytic amounts of carbene complexes (Figure 3.50). If the chain-length between olefin and alkyne enables the formation of a five-membered or larger ring, then RCM can lead to the formation of vinyl-substituted cycloalkenes [866] or heterocycles. Examples of such reactions are given in Tables 3.18-3.20. It should, though, be taken into account that this reaction can also proceed by non-carbene-mediated pathways. Also Fischer-type carbene complexes and other complexes [867] can catalyze enyne cyclizations [267]. Trost [868] proposed that palladium-catalyzed enyne cyclizations proceed via metallacyclopentenes, which upon reductive elimination yield an intermediate cyclobutene. Also a Lewis acid-catalyzed, intramolecular [2 + 2] cycloaddition of, e.g., acceptor-substituted alkynes to an alkene to yield a cyclobutene can be considered as a possible mechanism of enyne cyclization. 

Recently it has been shown that radical anionic cyclization of olefinic enones effectively compete with intramolecular [2 -I- 2]-cycloaddition to form spirocy-clic compounds [205, 206], 3-Alkenyloxy- and 3-alkenyl-2-cyclohexenones 235 are irradiated in the presence of triethylamine. As depicted in Scheme 46 two reaction pathways may operate. Both involve electron transfer steps, either to the starting material (resulting in a direct cyclization) or to the preformed cyclobutane derivative 239, which undergoes reductive cleavage. The second... 

Scheme 1.64). The Ag(I)-mediated cyclization afforded dipole 306 for 1,3-dipolar cycloaddition with methyl vinyl ketone to yield adducts 307 and the C(2) epimer as a 1 1 mixture (48%). Hydrogenolytic N—O cleavage and simultaneous intramolecular reductive amination of the pendant ketone of the former dipolarophile afforded a mixture of alcohol 308 and the C(6) epimer. Oxidation to a single ketone was followed by carbonyl removal by conversion to the dithiolane and desulfurization with Raney nickel to afford the target compound 305 (299). By this methodology, a seven-membered nitrone (309) was prepared for a dipolar cycloaddition reaction with Al-methyl maleimide or styrene (301). 

With an ot, y-ketodiol, cyclization to produce a 3-furanone derivative is feasible, as is shown for the synthesis of ascofuranone (71) and geiparvarin (72) (Scheme 6.57) (286). The precursor for 71 was prepared by the cycloaddition of diene 66 to nitroalcohol 67. In this case, regioselective attack occurred only on the terminal double bond. Reductive cleavage-hydrolysis of the isoxazoline adduct 68 with Mo(CO)6 followed by acid-induced cyclization led to the furanone intermediate (286). A similar strategy was used for the synthesis of geiparvarin (72) (Scheme 6.58) (286). 

The sesquiterpene skeleton has also been assembled by the intramolecular nitrile oxide cycloaddition sequence. Oxime 238 (obtained from epoxy silyl ether 237), on treatment with sodium hypochlorite gave isoxazoline 239, which was sequentially hydrolyzed and then subjected to the reductive hydrolysis conditions-cyclization sequence to give the furan derivative 240 (330) (Scheme 6.93). In three additional steps, compound 240 was converted to 241. This structure contains the C11-C21 segment of the furanoterpene ent-242, that could be obtained after several more steps (330). 

Other cycloadditions were reported. The intramolecular cycloaddition of alkenylnitrones was 2q>phed to the synthesis of piperidines <99TL1397, 99JCS(P1)185>. Cycloaddition of an alkenyl azide afforded piperidines after reduction of the bicyclo triazole <99T1043, 99EJOC1407>. Similar to the cyclization of the diazo imide 2 in section 6.1.2.1, isomiinchnone intermediates can rearrange to functionalized piperidines <99JOCS56>. 

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