Enamines reactions with isocyanates

Some imines behave like enamines in their reactions with isocyanates. For example, the reaction of the cyclopentanone anil 117 with phenyl isocyanate gives 1-anilinocyclopentene-2-carboxanilide 118. ... 

The reaction of isocyanates with enamines disubstituted at the -carbon gives -amino- -lactams (107,108). Thus the enamine (16) reacted exothermally with phenylisocyanate to give (33) dimethyl-l-phenyl-4-dimethylamino-2-acetidinone (157), which was converted by acid hydrolysis to 2-formyl-2-methyl propionanilide (158). 

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). 

Proof that the second mole of phenyl isocyanate did not react at the nitrogen of 160 was provided by the reaction of the enamine from 2-methylcyclo-hexanone, which gave only the monocarboxanilide on reaction with excess phenyl isocyanate. 

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). 

The addition of phenylisocyanate to aldehyde-derived enamines resulted in the formation of aminobutyrolactams (438,439). As aminal derivatives these produets can be hydrolyzed to the linear aldehyde amides and thus furnish a route to derivatives of the synthetically valuable malonaldehyde-acid system. With this class of reactions, a second acylation on nitrogen becomes possible and the six-membered cyclization products have been reported (440). Closely related to the reactions of enamines with isocyanates is the condensation of cyclohexanone with urea in base (441). 

Schiff s bases also underwent C or N acylation with isocyanates (698) and isothiocyanates (698,701). Further studies provided 2 1 and 2 2 reaction products of arylisothiocyanates and enamines (702) and polymers derived from enamines and bisisocyanates (703). 

Reactions of enamines with isocyanates (568) and isothiocyanates (569) in the presence of sulfur gave l,3-thiazolidine-2-ones and l,3-thiazolidine-2-thiones. 

Trimethylsilylketene and acyl isocyanates generate 4-trimethylsiloxy-l,3-oxazin-6-ones 12 in situ, which smoothly react with the enamines of cycloalkanones to give bicyclic 2-pyridones 13 <96TL(37)4977>. The heterocycles 12 also undergo the Diels-Alder reaction with dimethyl acetylenedicarboxylate or methyl propiolate to furnish substituted 2-pyridones <96TL(37)4973>. 

The urea, formed in the reaction of the enamine 344 with chlorosulphonyl isocyanate followed by water, cyclizes to the uracil 345, which lacks substituents on the nitrogen atoms (equation 140)170. 

V-tosylcarbamoylated enamine 14b results from an analogous reaction with tosyl isocyanate (dichloromethane, reflux) ... 

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. 

An interesting variant of the annulation of enamine substrates with acrylic acid derivatives was the thermal reaction of enamines with vinyl isocyanates (eq. 17).31 Treatment of 68 with DPPA produced the intermediate vinyl isocyanate, which underwent cycloaddition with the enamine followed by elimination of the pyrrolidine to give pyridone 70. Pyridone 70 was efficiently converted to the corresponding highly substituted pyridine. 

The more common triazine to pyridine ring transformation is illustrated by the formation of pyridines by reaction of 2,5,6-triethoxycarbonyl-1,2, -triazine with both alkynes and enamines.30,31 The addition of vinyl isocyanate to 1-diethylamino-propyne gives mainly the pyridone (1 ) as a result of initial (2+2) cycloaddition followed by rearrangement the thiopyridone (15) is however formed from the corresponding reaction with vinyl isothiocyanate as a consequence of a (A+2)cycloaddition reaction.32... 

Protection and Deprotection.—N-Protected a-amino-acids are readily esterified by methanol or ethanol in 60—80% yield after reaction with an enamine (e.g. from isobutyraldehyde and piperidine) and t-butyl isocyanate. Such amino-acids can also be esterified efficiently with alkyl halides under phase-transfer conditions with no racemization. Direct esterification of a-amino-acids with ethyl toluene-p-sulphonate in boiling ethanol gives a-amino-acid ethyl esters in 80—90% yield as the sulphonate salts. The protection of acid functions by formation of the 2-chloro-(or bromo-)ethyl esters has been discussed. These derivatives survive exposure to both moderately acidic and basic conditions and are removable by conversion into the iodoethyl analogues followed by zinc reduction. Alternatively, they may be converted into hydrophilic ammonium or phosphonium salts which exhibit enhanced acid stability but which are cleaved by very dilute base. Yet another method for the removal of such groups using supernucleophilic Co phthalocyanin anions has been reviewed. Further routes to 2,2,2-trichloroethyl esters have been described, one of which employs an activated ester intermediate and is suited to acid-labile substrates. 

Compounds of this class are aza-analogues of xanthone. Benzopyrano[2,3-b]pyridine (XXXVI) was synthesised by the cyclisation of 2-phenoxynicotinic acid (XXXV) by means of phosphorus oxychloride [25]. The carbonyl group of (XXXVI) can easily be reduced by sodium amalgam in ethanol. Compound (XXXVI) and its sulphur analogues were screened as possible drugs for treatment of schistosomiasis and for amoebic infection but the initial tests indicated that these compounds have no significant effects on schistosomiasis [25]. Recently, derivatives of (XXXVI) have been prepared from chromonyl-2-isocyanate by its reaction with enamines followed by acid cyclisation [26]. 

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. 

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