3‐Amino‐2‐carbamoylthiophene (2) was obtained in 75% yield by reaction of methyl 3‐aminothiophene‐2‐carboxylate with saturated aqueous ammonia containing ammonium chloride catalyst at room temperature over a period of 2,3 months, Treatment of 2 with cyclopentanone, cyclohexanone, and cycloheptanone in ethanol at pH 3.4 gave facile formation of 2‐carbamoyl‐3‐cycloalkylidenaminothiophenes in yields of 73%, 86%, and 60%, respectively. Infrared and 1H nmr spectra of these imines indicate that they occur in intramolecularly hydrogenbonded form, i.e. with chelate rings. Comparison is made with reported syntheses and reactions of 2 and its isosteric 2‐aminobenzamide.
Interaction of 1-methoxycyclohexene-2 and aqueous N-bromosuccinimide gave a mixture of stereoisomeric bromohydrins, which, on treatment with aqueous sodium hydroxide, furnished 1~-methoxy-2a,3a-epoxycyclohexane (I) and la-methoxy-2a,3a-epoxycyclohexane (11) in the ratio 3: 1. The mixture from the N-haloimide-olefin reaction was separated by preparative vapor phase chromatography into three isomeric bromohydrins, la-methoxy-2a-hydroxy-3B-bromocyclohexane (IV), la-methoxy-2a-bromo-3B-hydroxycyclohexane (V), and la-methoxy-2B-bromo-3a-hydroxycyclohexane (VI) in the relative proportions 1:10:4. The 3-bromo isomer IV was identified by comparison with an authentic specimen prepared by the action of hydrobromic acid on the oxide 11. Compounds V and VI were shown to have the indicated structures by deetherification to the corresponding bromodiols VII and VIII in high yield, followed by debromination of the latter to trafzs-and cis-1,3-cyclohexanediol respectively. T h e product distribution is considered in relation to the intervention of electronic and steric factors in a possible mechanism suggested for the reaction between aqueous N-bron~osuccinimide and 1-methoxycyclohewne-2.Several years ago (1) we reported that the action of hydrobroinic acid on the stereoisoineric 1-methoxy-2,3-epoxycyclohexanes I and I1 led t o the formation of la-methoxy-2P-hydroxy-3a-bromocyclohexane (111) and 1a-n~ethoxy-2a-hydroxy-3~-broinocyclohexane (IV) respectively. The structures of these substances were established by a variety of chemical means (1) because we wished t o determine their relationship t o the mixture of bromohydrins resulting froin the action of aqueous N-broinosuccinimide upon l-inethoxycyclohexene-2. The latter bromohydrin mixture furnishes the oxides I and I1 in the ratioof 3 : l on treatment with aqueous sodium hydroxide and since 1,2-halohydrin t o oxide conversions involve a trans ring closure (3,4), it is apparent that the trans oxide I could have arisen from either or both of la-methoxy-2P-hydroxy-3a-brornocyclohexane (111) and la-methoxy-2a-bromo-3p-hydroxycyclohexane (V). Likewise the cis-oxide I1 wouId be formed if the mixture contained either la-methoxy-2a-hydroxy-3P-bromocyclol~exane (IV) or 1a-t~~ethoxy-2~-bromo-3a-hydroxycyclohexane (VI) or both. The present coinrnunication describes the manner in which the conlposition of the bronlohydrin mixture from the olefin-N-haloirnide reaction was determined and provides an unequivocal proof of structure for 1a-methoxy-2a-bromo-3~-hydroxycyclohexane (V) and la-n1etlloxy-2P-brorno-3a-h~.droxycyclohexane (VI).Attempts t o separate the components of the bromohydrin mixture by fractional distillation i n vacz~o and by coluinn chronlatography on alumina were unsuccessful. We therefore explored chemical separations based upon the forillation of crystalline derivatives. In this connection, the possible utility of acetate, p-toluenesulfonate, 2,4-dinitrobenzenesulfenate, dichloroacetate, 3-nitrophthalate, phenylurethane, and naphthylurethane derivatives was examine...
Optimum conditions for the preparation of trans-2-aminocyclohexanol by ammonolysis of l,2-epoxycyclohexane or trans-2-bromocyclohexanol are realized by use of a 20-fold excess of aqueous aIcoholic ammonia a t 100'. Under these conditions formation of secondary amines .is minimized. Lower ammonia-reactant ratios, or the use of absolute methanolic atnmonla or aqueous ammonla, lead to lower yields of primary amine and higher yields of secondary amines. 1,2-Epoxycyclohesane has been isolated from the interaction of t m n s -2-bromocyclohexanol with aqueous ammonia. The oside reacts more rapidly with aqueous alcoholic ammonia than the bromohydrin and the rate of conversion of the latter to amine is thus controlled by the rate of conversion of bromohydrin to oxide. INTRODUCTIONWinstein and Henderson (31) have emphasized that reactions involving trans-1,2-halohydrins under basic conditions can proceed via the corresponding oxide as intermediate. If such is the case, approximately equal yields of primary amine should be obtainable from either reactant, and the preferred starting material for preparation of 1,2-aminocyclanols would be the halohydrin rather than the oxide, a synthetic step thereby being eliminated. For the synthesis of a 1,2-aminocyclanol, practical considerations demand that attention be given to the possible intervention of side reactions. Mousseron and Granger (16), for example, fouild in a number of instances that ammonolysis of alicyclic epoxides or 1,2-chlorohydrins led to formation of considerable quantities of secondary amines together with the desired primary amine. Bruilel (4) prepared trans-2-aminocyclohexanol by heating 1,2-epoxycyclohexane with a sixfold excess of aqueous ethanolic ammonia a t 110-115". When a twofold excess of ammonia was used, however, the main products were two diastereoisomeric bis-2-hydroxycyclohexylamii~es (I) of m.p. 114" and 153", subseque~ltly shown by i\~Iousseron and Granger (16) to be dl and meso forms respectively.Godchot and Mousseron (9), however, studying the same reaction, obtained cyclohexadiene a s by-product. Osterberg and Kendall (17) obtained a 61% yield of trans-2-aminocyclohexanol by heating trans-2-chlorocyclohexanol a t 100" with an unspecified excess of aqueous alcoholic ammonia, and reported that omission of the alcohol resulted in formation of secondary and tertiary amines as the main products. They failed, however, to characterize these substances. Wilson and Read (32) studied the same reaction a t room temperature, and did not note formation of by-products. Our purpose was t o determine whether the halohydrin is the preferred starting material and to establish experinlental conditions leading to maximum yield of primary amine, since we required lilfa?zz~script receioed J u I y 15, 1967.
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