Phenyl isocyanate 4+2 cycloaddition reactions

Cycloaddition reactions have been carried out with corresponding bases of Vilsmeier salts of pyrroles. Thus reaction of 153 with dimethyl acetylenedicar-boxylate gave pyrrolizines 154 and 3a-azaazulenes 155 in a nonsynchronous reaction. The structure of 3H-pyrrolizine 154a was proved by X-ray analysis.96 In a closely related reaction, pyrrolizinones 156 and 157 were obtained from the corresponding Vilsmeier salts with phenyl isocyanate.97 Reaction of 2-p-nitrobenzoylindolin-3-one (158) with methyl acetoacetate gave the benzopyrrolizinone (159).5 7... 

Aziridinones are also known to undergo cycloaddition reactions. Thus, treatment of (321) with phenyl isocyanate gave adducts (335) and (336) (76CL47). 

Intermolecular reactions with typical cycloaddition components are also possible. Phenyl isocyanate in ether converts triisopropyldiaziridinimine (182) to the 1,2,4-triazolidine under mild conditions. Labeling with a deuterated isopropyl group revealed that cycloaddition is not preceded by N—N cleavage, which should have resulted in deuterium randomization (77AG(E)109). 

Enamines of cyclic ketones do not form cycloaddition products, but give the mono- or dicarboxanilides (110,111). Thus the enamine (113) on reaction with 1 equivalent of phenyl isocyanate gave 160. Treatment of 113 with 2 equivalents, or 160 with 1 equivalent, of phenyl isocyanate gave the 2,6-disubstituted product (161). Mild acid hydrolysis of 160 and 161 produced the corresponding cyclohexanone(2-mono- and 2,5-di)carbox-anilides (110). 

Vinyl ethers undergo many cycloaddition reactions similar to those which take place with enamines. In general, however, these cycloaddition reactions with vinyl ethers take place less readily than those with enamines. These reactions include cycloaddition of vinyl ethers with ketene (200-205), phenyl isocyanate (206), sulfene (207,208), methyl acrylate (209), diethyl acetylenedicarboxylate (210), and diphenylnitrilimine (183). 

Analogously to ynamines and o, /3-acetylenic ketones, 4-aminobut-3-yn-2-ones react with 1,3-dipoles (68HCA443 73HCA2427 92KGS867). The reaction of 4-dimethylaminobut-3-yn-2-one with diphenylketene follows a route of [2-1-21-cycloaddition (30°C, THF, 1 h) to give 2-acetyl-3-dimethylamino-4,4-diphenyl-cyclobut-2-en-l-one (377) in 15% yield. With ethyl azidoformate (30°C, THF, 3 h), the tiiazole 378 is formed in 82% yield, whereas with phenyl isocyanate, the quinoline 379 is the product (by a [2- -4] scheme) in 70% yield (68HCA443). 

The class of 1,3-dipolar cycloadditions embraces a variety of reactions that can accomplish the synthesis of a diverse array of polyfunctional and stereochemically complex five-membered rings.3 The first report of a 1,3-dipolar cycloaddition of a nitrone (a 1,3-dipole) to phenyl isocyanate (a dipolarophile) came from Beckmann s laboratory in 1890,4 and a full 70 years elapsed before several investigators simultaneously reported examples of nitrone-olefin [3+2] cycloadditions.5 The pioneering and brilliant investigations of Huisgen and his coworkers6 have deepened our under-... 

Several syntheses of annulated uracils of biological value were recently reported. The key reaction was a microwave-assisted one-pot [4 -i- 2] cycloaddition of oxazino[4,5-d]-, pyrano-[2,3-d]-, pyrido[2,3-dj- and pyrimido[4,5-djpyrimidines, in the sohd state [134] and under solvent-free conditions [135]. The synthetic approach was based on the reaction of NJ -di-methyl-5-formylbarbituric acid 208 with maleimide in the sohd state for 5 min under microwave irradiation at 120 °C to give the pyrano[2,3-d]pyrimi-dine derivative 209 in 90% yield (Scheme 76). The reaction of 208 with phenyl isocyanate under microwave irradiation in the absence of solvent... 

Thermally induced intra-intermolecular criss-cross cycloaddition of nonsymmetrical azines 363 in the presence of phenyl isocyanate provides the corresponding products of the mixed criss-cross cycloaddition 364 (Scheme 55) <2002TL6431>. Two different reaction mechanisms, intra-intermolecular and inter-intramolecular, of the mixed criss-cross cycloaddition with opposite sequence of reaction steps are possible. Quantum chemistry calculations suggest the intra-intermolecular mechanism as the most probable mechanism of this reaction <2004CCC231>. 

The Mukaiyama-Hoshino reaction between a nitroalkane and phenyl isocyanate generates a nitrile oxide, and this method has been used in the synthesis of 1,2,4-oxadiazoles as discussed in CHEC-II(1996) <1996CHEC-II(4)179>. In a more recent advance, nitroethane undergoes ultrasound-mediated cycloaddition with trichloroacetonitrile to give the extremely useful (see Equation 11) 5-trichloromethyl-l,2,4-oxadiazole 228 (Equation 45) <1995TL4471>. 

Closure of the oxadiazole ring is still achieved through cycloaddition between pyridine iV-oxides and isocyanates, affording adducts such as 142 (Scheme 38) <1995T6451>. Nonaromatic imine fV-oxides exhibited similar reactivities, since azasugar-derived fV-oxides as a mixture of 143 and 144 underwent cycloaddition reactions in the presence of phenyl isocyanate or trichloroacetonitrile. Compounds 145 and 146 (Scheme 39) were obtained from the aldoxime W-oxide 143 two other regioisomeric heterocycles arose from the ketoxime derivative 144 <1996T4467>. 

However, when pyridyliminophosphorane (306a) is treated with phenyl isocyanate or isothiocyanate (Scheme 110), mixed carbodiimides are obtained, which are capable of an intermolecular Diels-Alder reaction resulting in triazine 308. The cycloaddition occurs specifically with one C = N double bond of the carbodiimide serving as the dienophile (77ZC371). 

Besides removal of alkyl-based groups located at the N-2 of a pyridazin-3(27/)-one also real reactions in the side chain appeared. Pyridazinium ylides, obtained via deprotonation of iV-alkylpyridazinium salts, have been reacted with phenyl isocyanates and benzenediazonium salts <2002MI287, 1997T4411>. As discussed in Section 8.01.5.7.2 1,3-dipolar cycloaddition with ethyl acrylate and ethyl propiolate were also studied. 

Silyl-substituted diazoketones 29 cycloadd with aryl isocyanates to form 1,2,3-triazoles 194 (252) (Scheme 8.44). This reaction, which resembles the formation of 5-hydroxy-l,2,3-triazoles 190 in Scheme 8.43, has no analogy with other diazocarbonyl compounds. The beneficial effect of the silyl group in 29 can be seen from the fact that related diazomethyl-ketones do not react with phenyl isocyanate at 70 °C (252). Although the exact mechanistic details are unknown, one can speculate that the 2-siloxy-1-diazo-1-alkene isomer 30 [rather than 29 (see Section 8.1)] is involved in the cycloaddition step. With acyl isocyanates, diazoketones 29 cycloadd to give 5-acylamino-l,2,3-thiadiazoles 195 by addition across the C=S bond (252), in analogy with the behavior of diazomethyl-ketones and diazoacetates (5). 

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). ... 

Diazadienes have been shown by various groups to be suitable precursors of imidazoline derivatives by means of [4 + 1 ] cycloaddition reactions. In 1976 Matsuda and co-workers were able to cycloadd heterodienes 303, available from AMrimethylsilyl benzophenone imine and phenyl isocyanate, with cyclohexyl isocyanide to obtain 305 in 91% yield, after methanolysis of the initial adduct 304 [76JCS(P1)1523] (Scheme 67). 

Quinoxaline 1-oxide (209) reacts with phenyl isocyanate to give 2-anilinoquinoxaline (210) together with 1,3-diphenyl-l-(2-quinoxalinyl)-urea (211) and cyclized oxidation product of the urea 212.215 2-Quinoxalinone 4-oxide (205) and its 1-methyl derivative undergo addition reactions, e.g., with phenyl isocyanate and benzyne to give compounds 214 and 216, respectively.216 These reactions are formulated as proceeding via the intermediate cycloadducts 213 and 215. Compound 216 has also been obtained by photolysis of 3-(o-hydroxy-phenyl)quinoxaline 1-oxide.51 1,3-Dipolar cycloaddition of quinoxaline... 

When acrylonitrile or ethyl acrylate was used as the dipolarophile, the azomethine adducts (134) and (135) were formed no thiocarbonyl ylide addition products were isolable in refluxing toluene or xylene, although the isoindoles (136a) and (136b) derived from them were isolated. In contrast to the reactions with fumaronitrile or AT-phenylmaleimide, the azomethine adducts (134) and (135) were still present at higher reaction temperatures — almost 50% in toluene and 4-5% in xylene. Under the same reaction conditions other electron-deficient dipolarophiles like dimethyl fumarate, norbornene, dimethyl maleate, phenyl isocyanate, phenyl isothiocyanate, benzoyl isothiocyanate, p-tosyl isocyanate and diphenylcyclopropenone failed to undergo cycloaddition to thienopyrrole (13), presumably due to steric interactions (77HC(30)317). 

One of the earliest reported photochemical reactions of t-1 is the formation of the -lactam 84 in 45% yield upon irradiation in neat phenyl isocyanate (137). Because isomerization of t-1 is more rapid than cycloaddition, - -t is the presumed intermediate in this reaction. Methyl isocyanate fails to react with It. ... 

Kozikowski s group has been particularly active in the application of the INOC reaction toward the construction of a variety of natural products. One of the many examples from his laboratory involves the synthesis of tetracyclic compounds possessing suitably functionalized C rings for elaboration to a diverse number of ergot alkaloids via the INOC reaction. A total synthesis of chanoclavine I (65) was accomplished by this chemistry (Scheme 15). The key step in the synthesis involved the conversion of the nitro group of indole (62) into the corresponding nitrile oxide using the phenyl isocyanate procedure developed by Mukaiyama.57 The major product corresponded to isoxazoline (64). The isoxazoline nucleus was converted into chanoclavine I (65) in a series of subsequent steps. The application of nitrile oxide cycloaddition chemistry to the construction of other natural products can be expected to be an active area in future years. 

A 1,4-dipolar cycloaddition between tetrahydropyrido[l,2-a]pyrimidi-none 114 (R = Me) and 4-methyl-l, 2,4-triazoline-3,5-dione 666gave stable adduct 667 in acetonitrile or in acetic acid at room temperature for 1 hour (Scheme 44) (85CB4567). When ethyl cyanoformate was used as dienophile in boiling toluene for 20 hours, ethyl 3-methyl-4-oxo-6,7,8,9-tetrahydro-4//-pyrido[ 1,2-a]pyrimidine-2-carboxylate 669 was obtained (86CB1445). Pyrido[l,2-a]pyrimidine-2-carboxylate 669 was formed from the initial adduct 668 by elimination of phenyl isocyanate. Reaction of tetrahydropyr-ido[l,2-a]pyrimidinone 114 (R = Me) with l-(diethylamino)-l-propyne in... 

Nitroalkenes have also been used as cycloadduct precursors in the INOC reaction (Scheme 86). The nitroalkene (647 R1 = Me, R2 = COEt) was prepared by the addition of an unsaturated alkoxide (645) to the /3-nitroenone (646). Formation of the required nitrile oxide was accomplished by dehydration of the primary nitromethyl group with phenyl isocyanate and triethylamine. The resulting nitrile oxide underwent cycloaddition and gave the adduct (648 R1 = Me, R2 = COEt). 

Oxazole N-oxides having a 4-methyl substituent are attacked by acetic anhydride to yield 4-acetoxyoxazoles (equation 21). The combined action of benzoyl chloride and potassium cyanide leads to compounds of the Reissert type, e.g. (177). The reaction of 4-methyloxazole Yoxides with phenyl isocyanate gives 5-hydroxy-4-methylene-l-phenyl-4,5-dihy-droimidazoles by cycloaddition, extrusion of carbon dioxide and recyclization (Scheme 12) with 4-phenyloxazole JV-oxides the reaction takes a different course, yielding imi-dazooxazolidinones (Scheme 13). 

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