Cyclohexylamine imines

A major breakthrough in the regioselectivity of enamine reactions followed from the observation by Pfau and Ughetto-Monfrin391 that the cyclohexylamine imine of acetone 191 underwent a,a-bis-alkylation to give 196, in addition to products 195 and 197 derived from self-condensation (Scheme 199). There was no evidence for the formation of the a,a -bis-alkylated product 194. Clearly, as we pointed out in 1982, this can be attributed... 

A number of recently described routes take rather different approaches to the synthesis of quinolines and isoquinolines, for example ozonolyses of indenes, as shown below provides homophthalaldehydes which are at exactly the right oxidation level for aromatic pyridine ring closure with ammonia. Another method for the generation of equivalent species depends on the side-chain lithiation of ortho-methylaraldehyde cyclohexylamine imines, then acylation with a Weinreb amide. 

Reductive amination of cyclohexanone using primary and secondary aHphatic amines provides A/-alkylated cyclohexylamines. Dehydration to imine for the primary amines, to endocycHc enamine for the secondary amines is usually performed in situ prior to hydrogenation in batch processing. Alternatively, reduction of the /V-a1ky1ani1ines may be performed, as for /V,/V-dimethy1 cyclohexyl amine from /V, /V- di m e th y1 a n i1 i n e [121 -69-7] (12,13). One-step routes from phenol and the alkylamine (14) have also been practiced. 

The catalysts bearing a cyclohexylamine moiety combined with a bulky sal-icylidene compound linked via one thiourea function to a terf-leucine ben-zylamide (Scheme 38, Ri = Bn, R2 = H) was the most efficient. The test was performed in solution at - 78 °C, with HCN as the cyanide source. Excellent results were obtained 78% isolated yield with 91% ee for the optimised substrate and 70-86% ee for other imine derivatives (65-92% isolated yield) [148,152-157]. 

The formation of dicyclohexylamine as the main product using MVS-derived Pt powders presumably involves dehydrogenation of cyclohexylamine to the corresponding imine with further addition of cyclohexylamine and elimination of NH3 (Scheme 6) [18]. 

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 A-acetyl derivatives of the 2-alkylthio-l,3-thiadiazol-4-imines (124, R = SR, R = Ac) undergo nucleophilic displacement reaction with amines (benzylamine, cyclohexylamine, morpholine, or aniline) giving the 2-amino derivatives (124, R = NRj, R = Ac). The salt (126, R = R = Ph, R = R = H, X = Cl) reacts with aniline at room temperature giving 4-anilino-2-phenyl-l,3-thiazole (128), presumably by a mechanism involving cleavage of the heterocyclic ring. ... 

In the absence of the iV-oxide, the reaction of 3-aminopyridazino[3,4-i/ pyrimidinediones 33 with imines takes a different course (Equation 17), and cyclization of the intermediate occurs to form a pyrrole ring <2005JHC375>. The reaction with cyclohexylamine in this instance results in the formation of highly fused dimeric products <2003T7669, 2006T652>. 

TV-Alkylidenalkylamines were found in the reaction products of the transformation of 1-butylamine [147,148], cyclohexylamine and isopropylamine [149] on alumina, and were probably formed by the dehydrogenation of the primary amine to an imine, followed by its condensation with a second molecule of the amine [148], rather than by the dehydrogenation of the dialkylamine [147], The TV-alkylidenalkylamines R=N—R decompose to an olefin and an imine a cyclic process has been postulated [148] which explains the increases in reactivity of amines with secondary alkyls. Also butyronitrile has been detected in appreciable amounts in the reaction products of 1-butylamine on alumina at 500° C [147],... 

These findings confirmed that glyoxal dicyclohexylimine is one of the products from the reaction of glucose with cyclohexylamine in ethanol. Although the formation of similar imines by the reaction of glucose with other alkylamines was not directly established, detection of glyoxal by silica gel TLC, shown in Fig. 9, in all of these cases seems to justify the assumption that the two-carbon diimines are always among the products of this kind of reaction, under the conditions employed. 

The pathway of the Kabachnik-Fields reaction depends on the nature of the substrates. The amine and hydrophosphoryl compound form a complex in which either one of the partners may react with the carbonyl compound. Often, the basicity of the amine determines the reaction pathway. Weakly basic amines such as anilines, which can act as proton donors, favour the formation cf an imine, whereas alkylamines such as cyclohexylamines do not form imines ... 

Notwithstanding, conformational factors apparently play a part in the enamine-imine equilibrium of the SchifF base prepared from cyclohexanone and cyclohexylamine, as shown by their infrared spectra 28 the base appears to be a mixture of both tautomeric forms, N-cyclo-hexylidenecyclohexylamine and N-1 -cyclohexenyIcyclohexylamine. Replacement of the cyclohexyl group by a phenyl group appears to stabilize the imino form.24... 

Only one aldehyde derivative has been prepared. Treatment of l-(2-hydroxyethyl)-l//-pyrazolo[3,4-b]pyrazine-5-carboxylaldoxine (272a) with sodium nitrite and HC1 gave the aldehyde (273) (92%) which is readily converted into the imine (272b) on treatment with cyclohexylamine (Equation (33)) <90JAP02172988>. 

Reductive Coupling. Formation of dicyclohexylamine (25) in hydrogenation of aniline probably involves addition of cyclohexylamine to an imine and subsequent hydrogenolysis of a carbon—nitrogen bond (11). 

A. 6-Bromo-3,4-dimethoxybenzaldehyde cyclohexylimine (1). A 2-L, threenecked flask is equipped with a Dean-Stark trap, reflux condenser, magnetic stirrer, and nitrogen inlet. The vessel is purged with nitrogen and charged with 40.0 g (0.16 mol) of 6-bron>o-3,4-dimethoxybenzal dehyde (6-bromo-veratral dehyde) (Note 1), 22.4 mL (0.20 mol) of cyclohexylamine (Note 2), and 800 id. of toluene. The mixture is refluxed for 16 hr (Note 3). The solution is cooled to room temperature and the solvent is removed on a rotary evaporator. The residual crystalline mass is recrystallized from a 3 1 hexane-methylene chloride mixture (1.5 L) to provide 48.4-51.4 g of the imine 1 as white crystals 1n two crops (mp 172-172.5°C)Z (Note 4). 

The overall sequence involves formation of the imine from the aldehyde that is to be alkylated— usually with a bulky primary amine such as t-butyl- or cyclohexylamine to discourage even further nucleophilic attack at the imine carbon. The imine is not usually isolated, but is deprotonated directly with LDA or a Grignard reagent (tl ese do not add to imines, but they will deprotonate them to give magnesium aza-enolates). 

Aza-enolate alkylation is so successful that it has been extended from aldehydes, where it is essential, to ketones where it can be a useful option. Cyclohexanones are among the most electrophilic simple ketones and can suffer from undesirable side-reactions. The imine from cyclohexanone and cyclohexylamine can be deprotonated with LDA to give a lithium aza-enolate. In this example, iodomethylstannane was the alkylating agent, giving the tin-containing ketone after hydrolysis. 

Draw a mechanism for the formation of the imine from cyclohexylamine and the following aldehyde. 

Cyclohexylamine gives a reasonably stable imine even with acetaldehyde and this can be isolated and lithiated with LDA to give the aza-enolate. The mechanism is similar to the formation of lithium enolates and the lithium atom binds the nitrogen atom of the aza-enolate, just as it binds the oxygen atom of an enolate. 

The steric influence on the enamine-imine tautomerism has also been observed in the cyclic ketone derivatives. Cyclohexanone imines of w-propylamine, cyclohexylamine and 2-bornylamine show no signals ascribed to the enamine tautomer in their NMR spectra, but the /-butylamine38 does display signals of the enamine. In DMSO-d6 it comprises 38% of enamine 56 at equilibrium. The proportion of the 3,3,5,5-tetra-methylcyclohexanone and cyclopentanone enamines 57 and 58 is even higher, rising to 52% and 58%, respectively, in DMSO-d663. 

Treatment of [RuC1(NH3)5]2+ with Ag(02CCF3), followed by zinc amalgam reduction and addition of amine yields [Ru(L)(NH3)5]2+ (L = cyclohexylamine, benzylamine, methylamine).192 Oxidation of these complexes with Br2 produces the corresponding ruthenium(TII) species [Ru(L)(NH3)5]3+.192 Subsequent oxidation of the amine ligand can readily occur to give imine and nitrile products, explaining the relatively few complexes of this type that have been isolated (see Section 45.4.2). 

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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