Phenyl isocyanate, cycloaddition with

The [4+2] cycloaddition of acylisocyanates to isocyanates to give 2,4-dioxo-2,4-2/-l,3 5-oxadiazines is well established <1981BSF28, 1970ZNB1180>. Thus, the water-sensitive 1,3,5-oxadiazine 61, formed from acylisocyanate 284 and phenyl isocyanate, reacts with 0,0-diethyl dithiophosphate to afford the oxadiazine 92 (Scheme 59) <1996SC783>. However, these oxadiazines are difficult to isolate as they undergo rapid decomposition. 

Kurahashi and Matsubara have used an isocyanate as both a nitrogen source and CO equivalent in a [24-2+1] cycloaddition to give 3-pyrrolin-2-ones (Scheme 110 2010CC8055). Mixing methyl acrylate (415), 2-octyne (416), and phenyl isocyanate (417) with a Ni catalyst and carbene hgand gives a 5 1 mixture of the 3-pyrrolin-2-ones 418 and 419, respectively. 

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). 

Other isocyanates undergo [2 + 2] cycloaddition, but only with very electron rich alkenes. Thus phenyl isocyanate gives /3-lactams with ketene acetals and tetramethoxyethylene. With enamines, unstable /3-lactams are formed if the enamine has a /3-H atom, ring opened amides are produced 2 1 adducts are also found. Photochemical addition of cis- and traH5-stilbene to phenyl isocyanate has also been reported (72CC362). 

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). 

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>. 

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>. 

Chalcogenation of a divalent germanium compound with styrene sulfide has been examined as an alternative route to the first free germanethione Tbt(Tip)Ge = S 165142 (Scheme 32) and later on allowed the synthesis of new base-stabilized germanethiones 187 and 188156 [Eq. (37)]. Phenyl isocyanate also may serve as a sulfur source leading to 165, which was evidenced by electronic spectroscopy and underwent a subsequent [2 + 2] cycloaddition with phenyl isocyanate157 (Scheme 36). 

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). 

Isoxazoline derivatives of Cgo such as 250 (Scheme 4.40) are accessible by 1,3-dipolar cycloadditions of nitrile oxides to [6,6] double bonds of the fullerene [2, 278, 291-305]. The nitrile oxides 249 with R = methyl, ethyl, ethoxycarbonyl and anthryl are generated in situ from the corresponding nitroalkane, phenyl isocyanate and triethylamine. The isoxazoline derivative of Cgo 250 (with R = anthryl) crystallizes in black prisms out of a solvent mixture of CS2 and acetone (3 2) [292]. X-ray crystal structure analysis shows that addition of the nitrile oxide occurs on a [6,6] double bond of the fullerene framework. 

Anhydro-5-hydroxy-l,2,3,4-oxatriazolium hydroxides (4) and anhydro-5-thiolo-l,2,3,4-oxatri-azolium hydroxides (5) do not act as 1,3-dipoles <79JCS(P1)732>. However, anhydro-5-phenylamino-1,2,3,4-oxatriazolium hydroxides (16) react with aryl isocyanates with exchange of the exocyclic aryl group <79JCS(P1)736>. This process can be explained in terms of a 1,3-dipolar cycloaddition to give (18) which then eliminates phenyl isocyanate producing (19) (Scheme 3). 

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. 

Intramolecular [3- -2]-cycloadditions of thiocarbonyl ylides with nonactivated acetylenes have also been described. Most representative examples involved the use of mesoionic substrates. The initially formed polycyclic adducts of type 110 undergo spontaneous elimination of phenyl isocyanate (24,62,151). A typical example leading to compound 111 is shown in Scheme 5.40. 

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). 

Few examples of total syntheses have been reported that involve an intramolecular nitrile oxide cycloaddition and ensuing reduction to an aminoalcohol. The very first example was reported by Confalone et al. (334) and involved a synthesis of the naturally occurring vitamin biotin (287). The nitro precursor 284 was easily prepared from cycloheptene. When treated with phenyl isocyanate-triethylamine, cycloaddition led to the all-cis-fused tricyclic isoxazoline 285 with high stereoselectivity (Scheme 6.102). Reduction with LiAlFLj afforded aminoalcohol 286 as a... 

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). ... 

Only a few examples of this type have been reported. Cycloaddition of (Pr 2N)2P(Cl)=C=N2 to CS2 gives the thiadiazole system 134 while with phenyl isocyanate the triazole ylide 135 is formed <87JA4711>. Cycloaddition of azides to Ph3P=C=C=NPh... 

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). 

The 1,3-dipolar nitrone character of dibenz[c,e]azepine N-oxide (161) is apparent in its cycloadditions with phenyl isocyanate, JV-phenylmaleimide (74ZN(B)425> and JV-sulfinylaryl-sulfonamides (ArS02NS0) (81TL2141). 

Nitrile oxide J -I- 2 cycloaddition.1 A key step in a recent stereospecific synthesis of biotin (6) from cycloheptene (1) is an intramolecular [3 + 2]cyclo-addition of a nitrile oxide (a), obtained by dehydration of a primary nitro compound (3), preferably with phenyl isocyanate. This cycloaddilion is more efficient than the well-known olefinic nitrone cycloaddition. The carbon atoms in 6 derived from cycloheptene are marked with asterisks. 

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