Alkyl isocyanates 4+2 cycloaddition reactions

Nitrogen-based heterocycles can also be prepared through Ni/NHC-catalyzed cyclo addition reactions. For example, Ni/SIPr catalyzed the cycloaddition of diynes with isocyanates under the mildest conditions to date [26]. In particular, excellent yields of pyridones are obtained from diynes and isocyanates at room temperature using only 3 mol % catalyst. As shown in Eq. 8, a variety of diynes were subjected to these optimized conditions. Both aryl and alkyl isocyanates were readily converted to the respective 2-pyridone. Sterically hindered substrates appeared to have very little effect on the reaction, as excellent yields of product were obtained with bulky isocyanates and bulky diynes. 

Cyclic carbodiimides also undergo a facile [2+2] cycloaddition reaction with alkyl- and aryl isocyanates to give the cycloadducts 44. With aryl isocyanates the reaction is exothermic and is completed within several minutes. 

If cyanamide is used in place of isocyanate or thiocyanate, the cycloaddition reaction with an a-aminocarbonyl compound gives a 2-aminoimidazole (80AHC(27)24l). Alkylation of the sulfur atom of ethyl 2-thiooxamate gives products (85) which contain nucleophilic... 

Because of their predictable behavior and reactivity, thioacyl isocyanates comprise the bulk of this work, and extensive studies of their [4 + 2] reactions with olefins,83 enamines,84 enol ethers,843 thioacyl isocyanates,85 imines,85 1 86 carbodiimides,84387 isocyanates,843 azirines,88 /3-enaminoke-tones,89 dianils,86d azines,90 hydrazones,91 imidazoline-4,5-diones,92 aryl cyanates,93 disubstituted cyanamides,93 aldehydes,94 ketones,94 ketenes,94 alkyl or aryl iminodithiocarbonates,95 and the carbon-carbon double bond of ketenimines96 have been detailed. In an extensive comparative study of the [4 + 2] cycloaddition reactions of thioacyl isocyanates, the heterocu-mulenes bearing strong electron-withdrawing substituents were found to be more stable and less prone to participate in cycloaddition reactions.84 Representative examples are summarized in Scheme 9-IV. 

Chiral vinyl ethers attached to a Wang resin through the p-oxyphenylsulfonyl linker, have been reported to give the [2+2] cycloaddition reaction with chloro-sulfonyl isocyanates (CSI) [226]. The intramolecular alkylation of the (3-lactam nitrogen atom gave mixtures of the corresponding diastereomeric clavams or oxacephams, (Scheme 102). 

In summary, alkyl azides react with aryl isocyanates, acyl isocyanates, carboalkoxy isocyanates and sulfonyl isocyanates to afford the corresponding 1,4-disubstituted A -tetrazohne-5-ones. In contrast, the cycloaddition reaction of aryl azides to isocyanates is hmited to sulfonyl isocyanates, leading to l-aryl-4-sulfonyl-A -tetrazohne-5-ones. 

The reactivity of isocyanates in [2+2] cycloaddition reactions is as follows alkyl < aryl < nitroaryl << arenesulfonyl < halosulfonyl. Also, the reactivity of the substrate is determined by the substituents. For example, vinyl ethers and enamines are more reactive than olefins. Often the formation of the [2+2] cycloadducts involves polar linear intermediates, which can be intercepted by the isocyanate or the substrate to form six-membered ring [2+2+2] cycloadducts (see Section 3.3.1.4). Also, diynes react with isocyanates to give six-membered ring [2+2+2] cycloadducts. In the latter reactions catalysts play an important role. From Q, ty-diynes macrocyclic adducts are obtained. 

Heterocyclic carbenes also participate in the [1+2+2] cycloaddition reaction with isocyanates to give Spiro compounds. For example, reaction of four equivalents of alkyl-or aryl-isocyanates with 7V,7V-disubstituted diimidazolinylidene-2, 29, afford 1,3,6,9-tetraazaspiro[4,4]nonanes 30. ... 

Imines also undergo [2-I-2-I-2] cycloaddition reactions with isocyanates. Usually, one equivalent of the imine reacts with two equivalents of the isocyanate. For example, heating of an excess of azomethines or benzophenone anils with isocyanates affords six-membered ring [2+2- -2] cycloadducts (see Section 3.3.1.4). This reaction proceeds in a stepwise manner, as indicated by the formation of different cycloadducts when different isocyanates are used. Also, reaction of A-alkyl- and A-aryl formamidines with alkyl- or aryl isocyanates on heating or in the presence of zinc chloride as the catalyst gives 2 1 (iminedsocyanate) adducts. Some examples of these reactions are listed in Table 3.10. 

A [3-1-2] cycloaddition occurs in the reaction of l-oxa-3-azoniabutatriene salts and a nitrone. iV-Arylnitrilium salts undergo a [3-1-2] cycloaddition reaction with alkyl isocyanates to give salts of 4(3//)-quinazoUdinones 423". ... 

The cycloaddition reaction of azides across C=N bonds is also observed. For example, reaction of alkyl azides with aryl isocyanates affords 1,4-disubstituted tetrazolidinones 89... 

Isocyanates have been incorporated successfully in the cycloaddition reaction with diynes [21]. The reaction utilizes the combination of Ni(0) precursor and imidazoly-dene ligand (SIPr). This catalyst affected the cycloaddition of a variety of 1,6-and 1,7-diynes with alkyl and aryl isocyanates (Scheme 2.24). Malonate diyne and diynes bearing a nitrogen backbone reacted with phenyl isocyanate to afford pyridines (82 and 83) in high yields. Importantly, challenging terminal diynes... 

Cycloadditions of isocyanates and their derivatives with vinyiaziridines were first reported by Alper and coworkers. From their previous studies of cydoadditions to vinylepoxides or alkylaziridines, they investigated cydoadditions to vinyiaziridines and found that such reactions with isocyanates, carbodiimides, or isothiocyanates in the presence of catalytic amounts of Pd(OAc)2 (2 mol%) and PPh3 (10 mol%) at room temperature afforded five-membered ring products 249 in 34—97% yields (Scheme 2.61) [91]. When an aziridine 247 possessing an alkyl substituent at the... 

Two pathways were considered a dipolar cycloaddition across S(l) and N(4) (path (a)) and a dipolar cycloaddition across S(l) and the exocyclic nitrogen N(exo) (path (b)) (Figure 5). The reactions are, however, facilitated by more electrophilic isocyanates (RSO2NCO > RCONCO > ArNCO > Alkyl NCO) disfavoring path (a), and the observed reactivity order of the starting heterocycles ((85a) > (85b) (85c)) is in better agreement with path (b). The expected intermediate (86) was successfully trapped when the bulky t-butyl group was introduced in position... 

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. 

Alkyl azides readily undergo 1,3-dipolar cycloaddition to arylsulfonyl isothiocyanates (375) to yield thiatriazolines (376). Thermolysis of (376) in the presence of isocyanates or carbodiimides produces 1,2,4-thiadiazole derivatives (378) and (379), respectively. The intermediate formation of a thiaziridinimine (377) has been postulated as indicated in Scheme 137 (75JOC1728, 75S52). The use of isothiocyanates as dipolarophiles produces dithiazolidines (380) instead of the thiadiazole derivatives. In these reactions the intermediate thiazirine (377) functions as a 1,3-dipole with the positive charge primarily localized on sulfur. It was recently proposed that the reaction of oxaziridines (381) with isothiocyanates produces a similar thiazirine intermediate (382) which reacts in a different regiospecific manner with isothiocyanates to produce 1,2,4-thiadiazole derivatives (383) and (384 Scheme 138) (74JOC957). 

Acyl isocyanates are more reactive than alkyl or aryl isocyanates. However, the presence of an additional rr-bond conjugated to the C>i-N bond of the isocyanate opens the possibility for [4 + 2] cycloadditions to compete with normal [2 + 2] additions. Reactions with alkyl and aryl substituted alkenes are rather slow. Propene, tranj-2-butene, styrene and conjugated dienes give only 3-lactams, albeit in moderate yields (Scheme 25). The strained double bond of norbomene, a reactive dienophile, adds across the conjugated 4iT-system of trichloroacetyl isocyanate (equation 51). 

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