Cycloadducts isocyanates

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 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... 

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. 

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. 

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). 

AT-Unsubstituted azetidin-2-ones are versatile intermediates in the preparation of a variety of novel /3-lactam containing systems. They are usually made either by reductive dechlorosulfonylation of alkene/chlorosulfonyl isocyanate cycloadducts cf. Section 5.09.3.3.2), which... 

Four-membered heterocycles are easily formed via [2-I-2] cycloaddition reac tions [65] These cycloaddmon reactions normally represent multistep processes with dipolar or biradical intermediates The fact that heterocumulenes, like isocyanates, react with electron-deficient C=X systems is well-known [116] Via this route, (1 lactones are formed on addition of ketene derivatives to hexafluoroacetone [117, 118] The presence of a trifluoromethyl group adjacent to the C=N bond in quinoxalines, 1,4-benzoxazin-2-ones, l,2,4-triazm-5-ones, and l,2,4-tnazin-3,5-diones accelerates [2-I-2] photocycloaddition processes with ketenes and allenes [106] to yield the corresponding azetidine derivatives Starting from olefins, fluonnaied oxetanes are formed thermally and photochemically [119, 120] The reaction of 5//-l,2-azaphospholes with fluonnated ketones leads to [2-i-2j cycloadducts [121] (equation 27)... 

Alkoxy)alkynylcarbene complexes have been shown to react with nitrones to give dihydroisoxazole derivatives [47]. Masked 1,3-dipoles such as 1,3-thia-zolium-4-olates also react with alkynylcarbene complexes to yield thiophene derivatives. The initial cycloadducts formed in this reaction are not isolated and they evolve by elimination of isocyanate to give the final products [48]. The analogous reaction with munchnones or sydnones as synthetic equivalents of... 

Phenyl isocyanate reacts, at room temperature, with substituted 3,4-dihydroquinazoline 108 to give the 1,3,5-triazinoquinazoline 109 by the expected [2+2+2] cycloaddition. However, at higher temperatures, the unexpected cycloadducts 110, and 111 are formed from these substrates <00EJOC2105>. 

Among heteroaromatic compounds able to react with nitrile oxides as dipo-larophiles, furan, probably, is the best known. Recently, a novel nitrile oxide was generated from a sulfoximine and converted in situ to a cycloadduct with furan (Scheme 1.25) (287). The starting racemic N-methyl-S-nitromethyl-S-phenylsul-foximine 124 was prepared in 87% yield via nitration of N,S-dimethyl-S-phenyl-sulfoximine. Reaction of 124 with p-chlorophenyl isocyanate and a catalytic quantity of triethylamine, in the presence of furan, afforded dihydrofuroisoxazole 125, the product of nitrile oxide cycloaddition, in 42% yield (65 35 diastereomer ratio). The reaction of 125 with phenyllithium and methyllithium afforded compounds 126, which are products formed by replacement of the sulfoximine group by Ph and Me, respectively. 

Cyclic a-methoxynitrones (225f) and (223 g) react respectively with isocyanates and isothiocyanates at ambient temperature, giving 1,3-dipolar cycloaddition products (763) and (764) (Scheme 2.314). Under similar conditions, the reaction of aldonitrone (223a) proceeds much more slowly to give cycloadducts... 

The reaction of diazoazoles and isocyanates leading to azolo-tetra-zinones of type 258 (Scheme 75) can be regarded as a [7 -l- 2]cycloaddition of the diazoazoles to the electron-deficient hetero double-bond of the isocyanates (pathway a) or, alternatively, as a two-step reaction involving [3 -I- 2]cycloaddition of the diazoazoles to the isocyanates, leading to the spirostructure 259 and subsequent [l,5]acyl shift (pathway b). An additional two-step mechanism (pathway c) could involve nucleophilic attack by the azole ring nitrogen on the carbonyl isocyanate to give a zwitterionic intermediate that collapses to the [7 + 2]cycloadduct 258. 

A successful method for preparing 1,3-thiazetidines is the cycloaddition of carbodiimides with isocyanates. The cycloadduct 151 was derived by the interaction of carbodiimide 152 and tosyl isothiocyanate . Reaction of 152 with methyl or phenyl isothiocyanate preferentially leads to iminotriazine-thiones. Cycloaddition between aryl isothiocyanates and dicyclohexylcar-bodiimide produced 153. ... 

Under thermal conditions, o ,/3-diarylvinylcarbodiimides 349 reacted as 2-azadienes (47t-component) with /)-tosyl isocyanate at the C=0 bond (27t-component) to form the intermediate cycloadducts 350 which, through Fl-migration, gave 2-amino-l,3-oxazin-6-imines 351 in moderate yields (Scheme 65) < 1998J(P 1)3065 >. 

Another related synthesis made use of the intramolecular cycloaddition of co-nitroalkene 243, also derived from geraniol epoxide 237. Generation of the expected nitrile oxide dipole using p-chlorophenyl isocyanate and triethylamine quantitatively gave the annulated isoxazoline 244 as a 2 1 mixture of diastereo-isomers (Scheme 6.94). Reductive hydrolysis of the cycloadduct to the aldol product followed by dehydration provided enone 245, which was used to prepare the sesquiterpene nanaimoal 246 (242). 

An intramolecular cycloaddition of the tetradecatrienyl nitroethyl ether 263 was used in the synthesis of the 14-membered bicyclic precursor 265 of crassin acetate 266, a cembrane lactone possessing antibiotic and antineoplastic activity (332). Nitro compound 263 was obtained from farnesyl acetate (262) in several steps and was then treated with phenyl isocyanate and triethylamine to give the tricyclic isoxazoline 264 (Scheme 6.98). Conversion to ketone 265 was accomplished by hydrogenation of the cycloadduct with Raney Ni and boric acid followed by acetylation (332). In this case, the isoxazoline derived from a 3-butenyl nitroethyl ether moiety served to produce a 3-methylenetetrahydropyran moiety (332). 

Shibasaki and co-workers used an intramolecular nitrile oxide cycloaddition to prepare the skeleton of phorbol (272) (Scheme 6.99), a tumor promoter that activates protein kinase C (PKC) (333). Nitroalkene 268 was elaborated in several steps from (+)-3-carene (267) and was subjected to cycloaddition by means of -chlorophenyl isocyanate-triethylamine to give cycloadduct 269 in 88% yield. Reductive hydrolysis employing Raney Ni and boric acid afforded hydroxyketone 270, that was subsequently used for the construction of the optically active derivative 271, which contains the phorbol skeleton (333). 

The imidates (62) also serve as nitrile yhde synthons via cycloaddition and subsequent spontaneous elimination of ethanol (34,35). Cycloadditions were carried out to aldehydes, leading to 2-oxazolines (e.g., 64) and to isocyanates and isothiocyanates. In the preparation of the 2-oxazolines, a solvent-less mixture of the imidate and the required aldehyde were heated at 70 °C and the cycloadducts 64 (R=Ph, 2-furyl, Mc2CH, 2-HO C6H4, 2-pyridyl, cinnamyl) were isolated in yields of 64—91%. 

Padwa et al. (38) also explored the rhodium-catalyzed reaction of diazo imides to form isomtinchnones (Scheme 10.10). Thus, 70 smoothly forms isomtinchnones 71 that can be intercepted in high yield with DM AD to give furans 73, following loss of methyl isocyanate from the cycloadducts 72. 

The 1,3-dipolar cycloaddition of a-keto carbenoids to the polar double bond of heterocumulenes provides a direct access to five-membered heterocycles. The reaction of a-diazo ketones 132 with phenyl isocyanate in the presence of a Rh2(OAc)4 catalyst affords the 1,3-cycloadduct, 3-phenyl-2(3//)-oxazolones 133 (Fig. 5.32). ... 

The 1,3,5-thiadiazepine (559) has been prepared by the thermal rearrangement of the [4 + 2] cycloadduct (558) of the azirine (557) and thiobenzoyl isocyanate (74JOC3763). The benzoyl isocyanate adduct does not rearrange to give an oxadiazepine. 

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