3-substituted cyclohexylamines

If there is no phenyl substituent in the 3-position the amination ability decreases. The acyloxaziridine (104) yields only 11% of a semicarbazide derivative with piperidine. In the presence of strong bases an intramolecular amination competes. Compound (104) reacts with methoxide within a couple of seconds to give phenylhydrazine carboxylic ester (106), and with cyclohexylamine to give the substituted semicarbazide (107). A diaziridinone (105) is assumed to be the common intermediate, formed by an intramolecular reaction from deprotonated (104) (67CB2600). 

Very recently equilibrium ion-pair acidities of substituted diphenylmethanes have been measured in cyclohexylamine . The meta series gives a normal Hammett plot (p = 9.69)... 

Although complete replacement of chlorine atoms can be accomplished with most kinds of amines, this becomes difficult in the reactions with sterically hindered amines. Thus in the reactions of N3P3C16 with cyclohexylamine (71) and adamantyl amine (72), the yields of fully substituted products are low. In the reactions of N3P3C16 with further sterically encumbered amines such as... 

The sulfide groups in mesoionic 1,3,4-thiadiazolium salts are activated toward nucleophilic substitution. The mercapto substituent of the thiadiazolium salt 117 can be displaced by cyclohexylamine to afford the 2//-thiadiazol-imine 118 (Equation 37) <2004BML4607>. 

The 2-phenylcyclobutylamines Structures 14 and 15 have also been prepared (161). In contrast to the cyclopropylamine, however, 15 showed no clinical activity following oral administration of a dose up to 25 mg of the racemic hydrochloride (199). The trimethoxy congener 14 has not been tested. The appropriately ring-substituted tran.s-2-phenylcyclopentyl or cyclohexylamines have not been reported. Based on the apparent lack of activity for 15, as well as the lack of activity for alpha-ethyl phenethylamine derivatives, however, these might be predicted to be inactive. 

Fig. 6.12. El mass spectram of 2-ethyl-cyclohexylamine. Double a-cleavage allows to identify the -substitution on one side of the ring. Spectrum used by permission of NIST. NIST 2002.

Scheme 46 Multiple-reaction cascade to 3-substituted cyclohexylamines scope and proposed reaction pathway...

Discovered in 1937 and patented in 1940, cyclamate is a derivative of cyclohexylamine, specifically, cyclohexane sulfonic acid. The sodium salt form is normally used, but the calcium salt may be substituted in low-sodium diets. See structural formulas below. 

For synthesis of N-substituted aziridinyl ketones, primary amines such as methylamine [11, 12, 13], cyclohexylamine [8, 11, 14, 15, 16, 17] and benzyla-mines [17, 18, 19, 20] are introduced in the reaction instead of ammonia. These reactions can be carried out in different solvents, such as alcohols, benzene, toluene, dimethylformamide, etc. On the basis of this chemistry, aziridinyl ketones containing either one or more three-membered cycles can be synthesized (e.g., compounds 7 and 10 Scheme 1.3). 

For example, Southwick and Christman [34] described obtaining trans-azir-idine 18 from chalcone 22 (Scheme 1.7). Reactions of 22 with cyclohexylamines and benzylamines forming the corresponding N-substituted derivatives are mentioned in the same publication. Zvonok et al. [35] studied the interaction of cyclohexylamine 9 with 6-phenyl-2,3-epoxyhex-5-en-4-ones 23, leading to compounds 24 (Scheme 1.7). 

Starting from 2-amino-3-cyano-4,5-dihydrothiophenes 60 the derived 2-benzamido derivatives 61 were treated with cyclohexylamine, morpholine, piperidine, or pyrrolidine to yield the respective 5,6-dihydro-2-phenyl 4-substituted aminothieno[2,3-d]pyrimidines 62a-d (83CPB401). In the presence of tin(IV) chloride, benzamides 61 reacted with acetic (or propionic) anhydride to give the corresponding 3-acetyl(or propionyl)thieno[2,3-[Pg.206]

The opportunity to introduce substituents at C-2 of the pyrrolopyrimidine is afforded by the use of 2-(substituted)amino-3-cyanopyrroles. Treatment of acylaminopyrroles (127), most commonly with R3 = Me, with phosphorus pentoxide, an arylamine hydrochloride, and jV,Ar-dimethyl-cyclohexylamine at elevated temperatures, gives the derivatives (128 X = NH) (Equation (42)) <83LA2066,84CS73, 85CS222,85S101,88CS303,90H(3l)367,93AP(326)303>. In some cases the 4-imino derivative has been converted to the 4-oxo derivative (128 X = O) by hydrolysis. 

Stereoselective reduction of cyclohexylimines. Imines of alkyl-substituted cyclohexyl ketones are reduced by this borohydride stereoselectively (>90%) to axial secondary amines. Axial primary cyclohexylamines are prepared conveniently by reduction of the imine derived from/ ,/) -dimethoxybenzhydrylamine and sub.scquent cleavage with formic acid (equation 1). 

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