2+2 cycloadducts

Another form of selectivity can arise when substitirted dienes and dienophiles are employed in the Diels-Alder reaction. Two different cycloadducts denoted as endo and exo can then be formed (Figure 1.2). 

Theoretical work by the groups directed by Sustmann and, very recently, Mattay attributes the preference for the formation of endo cycloadduct in solution to the polarity of the solvent Their calculations indicate that in the gas phase the exo transition state has a lower energy than the endo counterpart and it is only upon introduction of the solvent that this situation reverses, due to the difference in polarity of both transition states (Figure 1.2). Mattay" stresses the importance of the dienophile transoid-dsoid conformational equilibrium in determining the endo-exo selectivity. The transoid conformation is favoured in solution and is shown to lead to endo product, whereas the cisoid conformation, that is favoured in the gas phase, produces the exo adduct This view is in conflict with ab initio calculations by Houk, indicating an enhanced secondary orbital interaction in the cisoid endo transition state . 

The 4-hydroxy-THISs react with electron-deficient alkynes to give cycloadducts (3) that spontaneously eliminate sulfur, producing 2-pyridones (3). Bulky 5-substituents lead to a decrease in the addition rate, and elimination of isocyanate with formation of thiophenes becomes favored (3, 12, 13). Benzyne yields an isolable adduct that exclusively extrudes isocyanate on thermolysis, but sulfur on irradiation (Scheme 7)... 

Electron-deficient alkenes add stereospecifically to 4-hydroxy-THISs with formation of endo-cycloadducts. Only with methylvinyl-ketone considerable amounts of the exo isomer are produced (Scheme 8) (16). The adducts (6) may extrude hydrogen sulfide on heating with methoxide producing 2-pyridones. The base is unnecessary with fumaronitrile adducts. The alternative elimination of isocyanate Or sulfur may be controlled using 7 as the dipolarenOphile. The cycloaddition produces two products, 8a (R = H, R = COOMe) and 8b (R = COOMe, R =H) (Scheme 9) (17). Pyrolysis of 8b leads to extrusion of furan and isocyanate to give a thiophene. The alternative S-elimi-nation can be effected by oxidation of the adduct and subsequent pyrolysis. 

Hydroxy-THISs react with electron-deficient alkynes to give nonisol-able adducts that extrude carbonyl sulfide, affording pyrroles (23). Compound 16 (X = 0) seems particularly reactive (Scheme 16) (25). The cycloaddition to benzyne yields isoindoles in low- yield. Further cyclo-addition between isoindole and benzyne leads to an iminoanthracene as the main product (Scheme 17). The cycloadducts derived from electron-deficient alkenes are stable (23, 25) unless highly strained. Thus the two adducts, 18a (R = H, R = COOMe) and 18b (R = COOMe, R = H), formed from 7, both extrude furan and COS under the reaction conditions producing the pyrroles (19. R = H or COOMe) (Scheme 18). Similarly, the cycloadduct formed between 16 (X = 0) and dimethylfumarate... 

Hydroxy-THISs add regioselectively to the C=N bonds of isocyanates or isothiocyanates. The initially formed cycloadducts eliminate carbonyl sulfide with formation of 4-hydroxy- or 4-mercaptoimidazolium hydroxide inner salts (21) (Scheme 21). 4-Hydroxyimidazolium hydroxide... 

Again, it is noteworthy that 4-substituted 5-hydrdxythiazoles (24) react like 5-hydroxy-THISs with alkynes to give pyrroles and sometimes with alkenes to give exo-cycloadducts (Scheme 22). In the latter case other processes compete with the cycloaddition, becoming dominant when 24 is treated with azo-compounds, enamines, or heterocumulenes (31). 

Gycloaddition Reactions. Isocyanates undergo cyclo additions across the carbon—nitrogen double bond with a variety of unsaturated substrates. Addition across the C=0 bond is less common. The propensity of isocyanates to undergo cycli2ation reactions has been widely explored for the synthesis of heterocycHc systems. Substrates with C=0, C=N, C=S, and C=C bonds have been found to yield either 2 + 2, 2 + 2 + 2, or 2 + 4 cycloadducts or a variety of secondary reaction products (2). 

The dimeri2ation and trimeri2ation of isocyanates are special cases of the cycloaddition reaction ia that they iavolve reageats of the same type. The uacataly2ed carbodiiaiidi2atioa of isocyanates likely iavolves a labile 2 + 2 cycloadduct (12) which Hberates carboa dioxide. 

Acyl isocyanates (13,X = O, S) have been shown to react as heterodienes ia most cycloadduct formations. Notable examples iaclude autodimerization and the addition to imines (46,47). Unlike aromatic isocyanates, it is not possible to predict the reaction pathway nor the stmcture of the products which may arise from a given approach or set of reaction conditions. 

Vinyl chloride forms a photo [2 + 2] cycloadduct with 1-isoquinolone [491-30-5] and its /V-methyl derivative (57). 

Mild acid converts it to the product and ethanol. With the higher temperatures required of the cyano compound [1003-52-7] (15), the intermediate cycloadduct is converted direcdy to the product by elimination of waste hydrogen cyanide. Often the reactions are mn with neat Hquid reagents having an excess of alkene as solvent. Polar solvents such as sulfolane and /V-m ethyl -pyrrol i don e are claimed to be superior for reactions of the ethoxy compound with butenediol (53). Organic acids, phenols, maleic acid derivatives, and inorganic bases are suggested as catalysts (51,52,54,59,61,62) (Fig. 6). 

Pyridazine fV-oxides react with benzyne to give a mbcture of 1-benzoxepin (129) and arylpyridazine (130), while fV-acetylpyridaziniumimide forms a cycloadduct (131) which is further transformed into (132) and (133) (Scheme 44). 

A large number of pyridazines are synthetically available from [44-2] cycloaddition reactions. In one general method, azo or diazo compounds are used as dienophiles, and a second approach is based on the reaction between 1,2,4,5-tetrazines and various unsaturated compounds. The most useful azo dienophile is a dialkyl azodicarboxylate which reacts with appropriate dienes to give reduced pyridazines and cinnolines (Scheme 89). With highly substituted dienes the normal cycloaddition reaction is prevented, and, if the ethylenic group in styrenes is substituted with aryl groups, indoles are formed preferentially. The cycloadduct with 2,3-pentadienal acetal is a tetrahydropyridazine derivative which has been used for the preparation of 2,5-diamino-2,5-dideoxyribose (80LA1307). 

This synthetic appproach has been used in a few cases for the preparation of pyridazines from diazo compounds and cyclopropenes. In general, cycloadducts (176) are formed first and these rearrange in the presence of acid or alkali to pyridazines (Scheme 98) (69TL2659, 76H(5)40l). Tetrachlorocyclopropene reacts similarly and it was found that the stability of the bicyclic intermediates is mainly dependent on substitution (78JCR(S)40, 78JCR(M)0582>. 

With unsymmetrically substituted cyclopropenes, isomeric cycloadducts (177) and (178) and pyridazines are formed (Scheme 99) (80LA590). 

Substituted pyrido[2,3-(i]pyrazinium salts form cycloadducts with quinones (75HCA2529), similar to those formed by quinoxalinium salts. 

Aminothiophenes and 3-aminobenzo[Z)]thiophene undergo thermal [2 + 2] cycloaddi-tion reactions with activated alkynes. The reactions are solvent dependent thus in non-polar solvents at -30 °C, 3-pyrrolidinothiophene adds to DMAD to give a [2 + 2] cycloadduct which is ultimately converted into a phthalic ester. In methanol, however, a tricyclic product is formed (Scheme 54) (81JOC424. ... 

Photolysis of a mixture of furan and benzene gives mainly the [4 + 4] cycloadduct (141) a substantial amount of the adduct (142) derived by addition of carbons 2 and 5 of furan and 1 and 3 of benzene is also obtained (81JOC2674. ... 

Reduction of indolenines with sodium and ethanol gives indolines. The pentachloropyr-role, obtained by chlorination of pyrrole with sulfuryl chloride at room temperature in anhydrous ether, was shown by spectroscopic methods to have an a-pyrrolenine (2H-pyrrole) structure (222). It is necessary, however, to postulate that it is in equilibrium with small but finite amounts of the isomeric /3-pyrrolenine form (3//-pyrrole 223), since pentachloropyrrole functions as a 2-aza- rather than as a 1-aza-butadiene in forming a cycloadduct (224) with styrene (80JOC435). Pentachloropyrrole acts as a dienophile in its reaction with cyclopentadiene via its ene moiety (81JOC3036). 

Enamines and enolate anions react with benzofuroxan to give quinoxaline di-A -oxides (Scheme 38) (69AHC(10)1). Sydnones (274) with phenyl isocyanate give 1,2,4-triazoles (275) (76AHC(19)l), and from (276) the intermediate adduct (277) can be isolated (73JA8452). This is one of the few instances in which such primary cycloadducts have been isolated in the oxazole series of mesoionic compounds. 

Dihydrofuran (376) and 2,5-dihydrofuran (377) react with nitrile oxides to give furo[2,3-6 ]isoxazoles (378) and furo[3,4-rf]isoxazoles (379), respectively, as cycloadducts. The double bonds of furan, pyrrole and thiophene also react when the nitrile oxide is generated in situ. Thus furan and benzonitrile oxide gave (380), and with 2-methyl-2-oxazoline the cycloadduct (381) was obtained (71AG(E)810). These and related cycloadditions are discussed in Chapter 4.36. 

Reaction of the A-nitrosoglycine (394) with acetic anhydride gave the anhydro-5-hydroxy-l,2,3-oxadiazolium hydroxide (395). Reaction with DMAD resulted in formation of the intermediate 1 1 cycloadduct (396) which was not isolated and which lost CO2 under the thermal reaction conditions to give dimethyl l-phenylpyrazole-3,4-dicarboxylate (397) (83MI40300). This reaction is capable of considerable variation in terms of the substituents... 

A similar product is obtained from the reaction of anhydro-4(5)-hydroxy-l,2,3-triazolium hydroxide (398). In this case reaction with DMAD occurred in 1 hour in boiling benzene. Extrusion of methyl isocyanate from the initial 1 1 cycloadduct (399) occurred during the reaction giving (400). 

Anhydro-3-hydroxy-2-phenylthiazolo[2,3-6]thiazolylium hydroxide (407) underwent ready thermal reaction with alkynic and alkenic dipolarophiles in refluxing toluene. With the former dipolarophile sulfur was lost from the intermediate 1 1 cycloadduct (408) to give the substituted 5H-thiazolo[3,2- i]pyridin-5-ones (409). With the latter, the intermediate (410) lost H2S, also forming (409). 

Dipoles can also be built into heterocyclic systems, and though of limited use, they may also be utilized for the synthesis of [5,6] ring-fused systems. Reaction of 2 3H)-benzothiazolethione with (chlorocarbonyl)phenylketene in warm anhydrous benzene gave the heteroaromatic betaine (416). On heating with DMAD in boiling toluene the tricyclic pyridinone (418) was obtained, presumably by elimination of COS from the intermediate cycloadduct (417) (80JOC2474). 

Although in its reactions with several mesoionic systems diphenylthiirene dioxide (439) does not lose SO2 from the cycloadducts, in its reactions with pyridinium, quinolinium and isoquinolinium phenacylides it behaves as an acetylene equivalent. Thus, reaction of (439)... 

In the indazole series an example of a type (c) reaction (Figure 25) has been described utilizing a 1,3-dipole instead of a diene (Scheme 32) (76H(4)1655). The cycloadduct (351) is transformed into the triazole (352) on reaction with hydrochloric acid. 

Diazoalkanes and ynamines react with the electrophilic C(4)—C(5) double bond of pyrazolenine (359) to afford the cycloadducts (360) and (361), respectively, whereas diphenylketene yields the bicyclic diazetidinone (362) by reaction with the c/s-azo system of (359) (79CC568). 

The oxygen of 1,2-benzisoxazole fV-oxides can be removed by treatment with triethyl phosphite (80CC42l), and the oxygen of 3,4,5-triphenylisoxazoline A-oxide with H2 catalysis and PCI5 (69JOC984). Isoxazoline A-oxide (272) reacts with styrene to give cycloadduct (273) (66ZOR2225). 

The evidence obtained clearly indicates that the above photorearrangements proceed by a mechanism involving a nitrile ylide intermediate since cycloadducts could be isolated when the irradiations were carried out in the presence of trapping agents. Intramolecular cycloaddition of the nitrile ylide followed by a 1,3-sigmatropic hydrogen shift of the initially formed five-membered ring readily accounts for the formation of the final product. 

The photochemical behavior of the isomeric 3-methyl-2-phenyl-2-allyl-l-azirine (66) system was also studied. Irradiation of (66) in cyclohexane gave a quantitative yield of azabicyclohexenes (67) and (68). Control experiments showed that (65) and (66) were not interconverted by a Cope reaction under the photolytic conditions. Photocycloaddition of (66) with an added dipolarophile afforded a different 1,3-dipolar cycloadduct from that obtained from (65). The thermodynamically less favored endo isomer (68b) was also formed as the exclusive product from the irradiation of azirine (66b). 

Diphenylisobenzofuran has been reported to react with azirine (75) in refluxing toluene to give cycloadduct (81), the primary product of a [4 + 2] cycloaddition (72JOC2508, 74JOC2031). ... 

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