Intermolecular cyclization cycloadditions

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. 

Elsewhere, Heaney et al. (313-315) found that alkenyloximes (e.g., 285), may react in a number of ways including formation of cyclic nitrones by the 1,3-APT reaction (Scheme 1.60). The benzodiazepinone nitrones (286) formed by the intramolecular 1,3-APT will undergo an intermolecular dipolar cycloaddition reaction with an external dipolarophile to afford five,seven,six-membered tricyclic adducts (287). Alternatively, the oximes may equilibrate to the corresponding N—H nitrones (288) and undergo intramolecular cycloaddition with the alkenyl function to afford five,six,six-membered tricyclic isoxazolidine adducts (289, R = H see also Section 1.11.2). In the presence of an electron-deficient alkene such as methyl vinyl ketone, the nitrogen of oxime 285 may be alkylated via the acyclic version of the 1,3-APT reaction and thus afford the N-alkylated nitrone 290 and the corresponding adduct 291. In more recent work, they prepared the related pyrimidodiazepine N-oxides by oxime-alkene cyclization for subsequent cycloaddition reactions (316). Related nitrones have been prepared by a number of workers by the more familiar route of condensation with alkylhydroxylamines (Scheme 1.67, Section 1.11.3). 

Another class of intermolecular cyclizations are the Cycloaddition Reactions of Alkenes and Alkynes... 

In constrast with intermolecular nitrone cycloadditions to alkynes and allenes, very little work has been done on the corresponding intramolecular cycloadditions. The bicyclic isoxazolidines (65a-b) were reported as products from reaction of an alkynone with methylhydroxylamine in ethanol.26b Presumably the initial strained bridgehead C—C double bond of the AMsoxazoline added ethanol under the reaction conditions. Cyclization of an allenyl ketone with methylhydroxylamine in ethanol solution also led to isoxazolidines (65a-b) as the major products and isoxazolidine (66) as a minor product.266 Thus, preferential cyclization to the internal C—-C double bond of the allene occurred followed by addition of ethanol to the exocyclic C—C double bond of the methyleneisoxazolidine intermediate. 

Very recently examples of tandem Michael-azomethine ylide cyclization reactions have been presented.626 Thus, divinyl sulfone reacted with imine (124) in the presence of lithium bromide and tri-ethylamine to give (126) in 40% yield (Scheme 38). Presumably formation of Michael adduct (125), tau-tomerization to an azomethine ylide and ensuing intramolecular [3 + 2] cycloaddition afforded (126). Indeed, (125) could be independently synthesized and converted to (126) under the reaction conditions. The preference for initial Michael addition, rather than cycloaddition, was variable. When (124) and divinyl sulfone were treated with silver acetate and triethylamine in DMSO, intermolecular azomethine cycloaddition occurred giving (127) in 27% yield. 

In summary, the metal-catalyzed decomposition of diazo compounds results in a broad array of opportunities for the development of new asymmetric catalytic transformations. In the last few years considerable advances have been made in enantioselective intermolecular C-H insertion, novel cycloadditions, and tandem cyclization/cycloadditions. These new transformations offer new strategies for the rapid enantioselective construction of complex structures. 

A tandem sequence of double [2,3]-sigmatropic rearrangement-six-electron electro-cyclization-4 + 2-cycloaddition has been shown to convert acyclic ene-bis(propargyl alcohols) such as (71), via the corresponding bis-sulfenic ethers such as (72), into anthracene (with an intermolecular final cycloaddition) or phenanthrene or related (with an intramolecular cycloaddition) skeletons. The sequence is illustrated in Scheme 12 for synthesis of a steroid skeleton, estra-l,3,5(10)-trien-17-one (73).81... 

The disadvantage of the intermolecular dipolar cycloaddition strategy is nonstereoselectivity. A recent stereoselective synthesis of lasubine 1 (2) utilizes the intramolecular tt cyclization of an /V-acyliminium ion as a key step (Scheme 4) (16). The reaction of carbinol 38, prepared from 3,4-dimethoxybenzaldehyde (33) and allylmagnesium bromide, with glutarimide under Mitsunobu conditions... 

Intermolecular cyclization reactions which involve 1,3-dipolar cycloaddition reactions 133... 

Numerous methods of preparing bicyclic systems from monocyclic precursors have been reported and four general strategies can be identified. These are (i) intermolecular cyclization reactions which do not involve 1,3-dipolar cycloaddition reactions (ii) intermolecular 1,3-dipolar cycloaddition reactions (iii) nonoxidative intramolecular cyclizations and (iv) oxidative intramolecular cyclization reactions. These four general methodologies are now considered. 

Hydrazonyl chlorides have been employed in the synthesis of 1,2,4-triazoles. Intermolecular cyclization of hydrazonyl chlorides 166 with nitriles catalyzed by ytterbium(I) triflate afforded a series of 1,3,5-trisubstituted-1,2,4-triazoles 167 in good yields <05SC1435>. Dipolar cycloadditions between hydrazonyl chlorides 168 and nitriles in aqueous sodium bicarbonate in the presence of a surfactant provided mild conditions for the syndesis of l-aryl-5-substituted-... 

Thermolysis of 1,2,4-triazines with a side-chain terminal nitrile group leads to the formation of condensed pyrazines <89JOCl245>. This reaction involves cycloaddition of the nitrile dienophile across C-3 and C-6 of the 1,2,4-triazine followed by aromatization of the intermediate cycloadduct by extrusion of the N—N bridge. As a typical example, the 5,6-diphenyl-1,2,4-triazine (167) is fused under nitrogen at 225-235°C to form the condensed pyrazine (168) in 71% yield (Equation (21)). Intermolecular cyclization of oxadiazinones with enamines also yields condensed pyrazines. The bicyclic intermediates lose carbon dioxide to generate 1,4-diazadienes, which aromatize to the... 

Intramolecular dipolar cycloaddition may also result in products that do not correspond to experience with related intermolecular cyclizations. An example is the intramolecular reaction of 6-diazohex-l-ene (6.32), which was investigated by Kirmse and Grassmann (1966). This reaction leads to 2,3-diaza-bicyclo[3.3.0]oct-2-ene (6.34), i. e., with a regioselectivity that corresponds to the formation of a 4-alkyl-l-pyrazoline. 

The intramolecular Bradsher cyclization refers to the acid-catalyzed aromatic cyclodehydration of ort/zo-acyl diaryImethanes to form anthracenes. On the other hand, the intermolecular Bradsher cycloaddition often involves the Diels-Alder reaction of a pyridium with a vinyl ether or vinyl sulfide. 

The benzene derivative 401 by the intermolecular insertion of acrylate[278], A formal [2 + 2+2] cycloaddition takes place by the reaction of 2-iodonitroben-zene with the 1,6-enyne 402. The neopentylpalladium intermediate 403 undergoes 6-endo-lrig cyclization on to the aromatic ring to give 404[279],... 

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