Imines cyclohexanone

Enamines derived from ketones are allylated[79]. The intramolecular asymmetric allylation (chirality transfer) of cyclohexanone via its 5-proline ally ester enamine 120 proceeds to give o-allylcyclohexanone (121) with 98% ee[80,8l]. Low ee was observed in intermolecular allylation. Similarly, the asymmetric allylation of imines and hydrazones of aldehydes and ketones has been carried out[82]. 

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. 

Experimental evidence, obtained in protonation (3,6), acylation (1,4), and alkylation (1,4,7-9) reactions, always indicates a concurrence between electrophilic attack on the nitrogen atom and the -carbon atom in the enamine. Concerning the nucleophilic reactivity of the j3-carbon atom in enamines, Opitz and Griesinger (10) observed, in a study of salt formation, the following series of reactivities of the amine and carbonyl components pyrrolidine and hexamethylene imine s> piperidine > morpholine > cthyl-butylamine cyclopentanone s> cycloheptanone cyclooctanone > cyclohexanone monosubstituted acetaldehyde > disubstituted acetaldehyde. 

The formation of bicyclic imines (263,264) from piperidine enamines and y-bromopropyl amines may appear at first sight to be a simple extension of the reactions of enamines with alkyl halides. However, evidence has been found that the products are formed by an initial enamine exchange, followed by an intramolecular enamine alkylation. Thus y-bromodiethylamino-propane does not react with piperidinocyclohexene under conditions suitable for the corresponding primary amine. Furthermore, the enamine of cyclopentanone, but not that of cyclohexanone, requires a secondary rather than primary y-bromopropylamine, presumably because of the less favorable imine to enamine conversion in this instance. 

Imines with an electron-withdrawing group at the nitrogen atom are excellent acceptors for the acetate (1) or the carbonate (13) [36]. Thus, N-tosylimines (84) gave very good yields of pyrrolidines (85) under typical conditions. The strained cyclic imine (86) and a,/ -unsaturated imine (87) both participated smoothly in the cydoadditions. The hindered nitrimine (88) also reacts well with (1) (but not with 13) to produce the pyrrolidine (89) with a 17 1 diastereoselectivity. However, the unhindered nitrimines from cyclohexanone and 2-nonanone failed to react presumably due to enolization (Scheme 2.24). 

Reacdoti of cyclohexanone imines v/ith nitroalkenes provides a new synthedc method of tetrahydroindole derivadves fEq. 10.9. ... 

The Michael additions of chiral cycloalkanone imines or enamines, derived from (FV l-l-phcnyl-ethanamine or (5)-2-(methoxymethyl)pyrrolidine, are highly diastereofacially selective reactions providing excellent routes to 2-substituted cycloalkanones. This is illustrated by the addition of the enamine of (S)-2-(methoxymethyl)pyrrolidine and cyclohexanone to 2-(aryl-methylene)-l,3-propanedioates to give, after hydrolysis, the (2 5,a.S )-oxodicstcrs in 35-76% yield with d.r. (2 S,aS)/(2 S,a/ ) 94 6- > 97 3 and 80-95% ee214. 

Cyclohexanones have been converted to 8-chloroquinolines through a series of reactions involving imination, a-alkylation with Af,N-disilyl protected oa-bromoamines, transimination, a-chlorination of the resulting bicyclic imines, dehydrochlorination and dehydrogenation <96T(52)3705>. A short, high yielding one-pot synthesis of acenaptho(l,2-b)benzoquinolines... 

Cyclohexanone reacts similarly to give the corresponding imine and Ph2P(0)PPh2 [124]. 

Spectroscopic investigations of the lithium derivatives of cyclohexanone (V-phenylimine indicate that it exists as a dimer in toluene and that as a better donor solvent, THF, is added, equilibrium with a monomeric structure is established. The monomer is favored at high THF concentrations.110 A crystal structure determination was done on the lithiated A-phenylimine of methyl r-butyl ketone, and it was found to be a dimeric structure with the lithium cation positioned above the nitrogen and closer to the phenyl ring than to the (3-carbon of the imine anion.111 The structure, which indicates substantial ionic character, is shown in Figure 1.6. 

A thorough study of the factors affecting the rates of formation of lithiated imines from cyclohexanone imines has been carried out.117 Lithiation occurs preferentially anti to the /V-subsiiiueni and with a preference for abstraction of an axial hydrogen. 

Reaction of cyclohexanone imines with nitroalkenes provides a new synthetic method of tetrahydroindole derivatives (Eq. 10.9).11... 

The first example of this type of transformation was reported in 1974 [76]. Three catalysts were investigated, namely [Co2(CO)8], [Co(CO)g/PBu ], and [Rh6(CO)i6]. The [Co OJg/PBu ] catalyst showed activity for reductive animation using ammonia and aromatic amines. The [Rh6(CO)16] catalyst could be used for reductive animation using the more basic aliphatic amines that were found to poison the cobalt catalyst. This early report pointed out that the successful reductive animation of iso-butanal (Me2CCHO) with piperidine involves selective enamine hydrogenation, that reductive animation of cyclohexanone with isopropylamine probably involves imine hydrogenation, and that reductive amination of benzaldehyde with piperidine would presumably involve the reduction of a carbinolamine. 

The diastereoselective addition to imines proceeds well with aromatic enolsi-lanes (249). Propiophenone- and tetralone-derived enolsilanes provide good levels of diastereoselectivity (>95 5) and excellent enantioselectivity (>98% ee) with selective formation of the anti diastereomer. Nonaromatic enolsilanes are somewhat less selective although cyclohexanone enolsilane still provides useful levels of diastereoselectivity and enantioselectivity (92 8 anti/syn and 88% ee at -78°C). A one-pot procedure using glyoxylate, sulfonamide, and enolsilane as coupling partners was developed subsequently, leading to the product in comparable yields and selectivities (250, 251). 

Aliphatic c a -dibromo ketones, such as 2,4-dibromopentan-3-one (262), react with primary amines RNH2 (R = Me, Et, Pr, /-Pr or t-Bu) to give mixtures of imines 263 and lesser amounts of diimines 264. l,3-Dibromo-l-phenylpropan-2-one yields only the amide 265, the product of a Favorskii rearrangement. The nature of the products from aliphatic amines and cyclic a,a -dibromo ketones depends on ring size the cyclohexanone derivative 266 gave Favorskii amides 267 (R = Pr, /-Pr or t-Bu), while trans-2,5-dibromocyclopentanone afforded the enamines 268 (R = /-Pr or t-Bu) (equation 95)296. 

Like imines, some oximes are known to undergo metabolic hydrolysis by a nonenzymatic mechanism. Cyclohexanone oxime (11.69), an intermediate in the synthesis of polycaprolactam or Nylon-6, is a good example with which to begin our discussion. Following administration to male rats by various routes, cyclohexanone oxime undergoes rapid metabolism, and only trace amounts of the parent compound can be recovered in the urine [104], Although cyclohexanone (11.70) represented a small fraction of the urinary metabolites, most of the dose was recovered as glucuronides of cyclohexa-nol (11.71) and of cis- and /ran.v-cyclohexanc-1,2-diol. 

N-Chlorocyclohexylideneimine is of theoretical interest, being isoelectronic with the oxime tosylate. On treatment with 1 mole of base the imine undergoes a Neber-type rearrangement to the a-amino ketone and has been shown to be an intermediate in the rearrangement of N,N-dichloroc> clohexylamine to 2-2imino-cyclohexanone. ... 

In some very early work the conformation of a-methyl groups in cyclohexanone oximes (76) was assigned from solvent shifts. Results are summarized in Table 17. In solutes bearing a lone pair of electrons on nitrogen, the benzene-solute collision complex is likely to occur at a site as far as possible from the nitrogen. Shifts have been summarized for aziridines, oximes and imines, and for the latter a complex of type 77 was proposed. 

When cyclohexanone oxime 6e was used as amination reagent, primary amines were obtained from phenylmagnesium bromide. Reaction of 6e with alkyl Grignard reagents gave aziridines, whereas reaction with phenyllithium gave aziridine and the addition product of phenyllithium to the imine (Scheme 57) 24. 

Methylcyclohexene, from 2-methyl-cyclohexanone tosylhydrazone and methyllithium, 51,69 Methylenecyclopropanes, 50,30 Methyl iodide, with triphenyl phosphite and cyclohexanol, 51,45 with triphenyl phosphite and neopentyl alcohol, 51,44 METHYL ftrans-2-IODO-l-TETRA-LIN)CARBAMATE, 51,112 Methyl (frans-2-iodo-l-tetralin)carba-mate, with potassium hydroxide to give 1,2,3,4-tetrahydronaph-thalene(l,2)imine, 51,53 Methyllithium, with camphor tosylhydrazone to give 2-bomene, 51, 66... 

A way forward might be to form the imine 7.3 [and hence its enamine tautomer 7.4] by reacting the phenylamine 7.2 with cyclohexanone (Scheme 7.18). Then to generate the benzyne anion 7.5 by treating the tautomers with sodamide and sodium fcr/-buloxide in THF. Cydization to the required indole 7.1 occurs through nucleophilic addition to the benzyne, followed by protonation during work-up. 

Numerous chiral amines are reported to be useful in the asymmetric alkylation reaction of carbonyl compounds via their imine derivatives (see Section 1.1.1.4.1.)2,4. The asymmetric alkylation of chiral imines was first reported using simple, commercially available amines such as a-methylbenzeneethanamine (amphetamine)1, benzeneethanamine1 5 and exo-l, 7,7-trimethyl-bicyclo[2.2.1]heptan-2-amine (isobomylamine). In the case of cyclohexanone alkylation using these chiral auxiliaries, enantiomeric excesses of up to 72% were obtained1. 

Cyclohexanone imines derived from a-(methoxyniethyl)benzeneethanamine7 8, erythro-fl-methoxy-a-phenylbenzeneethanamine 6, and the tert-butyl esters of valine and rm-leucine3,17, as well as valine and h /-/-leucine derived enamines of /i-oxo esters3, are prepared by refluxing the amine and the carbonyl compound in benzene solution under azeotropic water removal, in 80-100% yield (see Table 1). 

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