Enamines, alkylation from amines

Because of self-condensation under the conditions of the alkylation reaction, enamines derived from acetaldehyde or monosubstituted acetaldehydes cannot usually be alkylated 28) except when there is a bulky secondary amine used to produce the enamine 32a). In these cases C alkylation takes place in good yield. 

Enamines prepared from the more basic amines are alkylated more easily and in higher yield, but yields are also affected by the ease of formation of an exocyclic double bond in the transition state (32). Thus the enamines derived... 

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. 

The formation of 3-acylpyridinium compounds (59/) from primary amines and l-methoxybutene-3-one can be regarded as the enamine alkylation of a vinylogous amide followed by cyclization and loss of methanol and water. 

Rearrangement of an enamine to a Sehiff s base through N- to C-alkyl migration was reported 729). These authors also found that enamines, rather than aminals, were formed from butyraldehyde and seeondary amines (730). Chloramines and aeetylenes reacted to give chloroenamine intermediates, which hydrolyzed on work-up of the reactions (731). 

C(R)=NR group with a nitrilium salt RCssNR .222 The acylation of the enamine can take place by the same mechanism as alkylation, but another mechanism is also possible, if the acyl halide has an a hydrogen and if a tertiary amine is present, as it often is (it is added to neutralize the HX given off). In this mechanism, the acyl halide is dehydrohalogenated by the tertiary amine, producing a ketene (7-14) which adds to the enamine to give a cyclobutanone (5-49). This compound can be cleaved in the solution to form the same acylated imine salt (27) that would form by the more direct mechanism, or it can be isolated (in the case of enamines derived from aldehydes), or it may cleave in other ways.223... 

Early investigations have demonstrated that aldehydes and ketones can be enantioselectiveiy a-alkyl-ated via Michael reactions of the corresponding enamines, prepared from proline-derived secondary amines.149-156 However, optical purities of the products were generally low and never exceeded 59% ee.iS1 This kind of asymmetric a-alkylation could later be improved, allowing for example the preparation of compound (141) with high ee (Scheme 51).156-160... 

The imines are prepared by the reaction of secondary amines with aldehydes or ketones, mainly ketones (16-13). The enamine salt method has also been used to give good yields of mono a alkylation of a,p-unsaturated ketones.Enamines prepared from aldehydes and butylisobutylamine can be alkylated by simple primary alkyl halides in good yields.A-Alkylation in this case is presumably prevented by steric hindrance. 

A variety of secondary amines have been used for enamine alkylation. Nonetheless, the three most commonly used, pyrrolidine, piperidine and morpholine, appear to still represent the best compromise between ease of access to the amine and formation of the enamine and the degree of conversion to mono-alkylated product. Pyrrolidine appears to be the best amine for the specific case where the electrophilic paitner for the enamine is a Michael acceptor, such as an a, 3-unsaturated ester, - and enamines derived from this base are generally more reactive than the piperidine and morpholine analogs. The use of optically active amines for asymmetric induction will be covered in Section 4.1.2.3. 

Whitesell and Felman therefore concluded that an amine with a C2 axis of symmetry was required in order to ensure that the same side of the cyclohexene ring was shielded from attack whichever conformation of the enamine underwent alkylation. The en-antioselectivity was thereby considerably increased, but in the opposite chiral sense, by using the cyclohexanone enamine derived from ( + )-/mnj-2,5-dimethylpyrrolidine. This was assumed to have the S, S-configuration based on the results of the alkylation (Scheme 70). Optical yields of 82-93% ee were obtained. Also noteworthy was the low level of dialkylation observed (4-7%) and the fact that formation of enamine 77 was at least ten times faster using type 3A molecular sieves compared to 4A molecular sieves. Similar methodology has been applied to the alkylation of 4-substituted cyclohexanone enamines to give mainly the less stable trans disubstituted cyclohexanone s . 

Chiral amines have been transformed into chiral imines RCH=NG, which are usually in equilibrium with the tautomeric enamines. These enamines undergo asymmetric alkylations, and the best results are often obtained with ethers 1.58 or with valine derivatives 1.59 (R = i-Pr, R = tert-Bu) [169, 173,253] in the presence of bases. Enamines, lithioenamines and zinc enamines derived from imines are very potent Michael donors that often participate in highly stereoselective reactions [161, 162, 169, 173, 254, 257, 260, 262, 267], Chiral imines can suffer very selective addition reactions of organomagnesium reagents [139, 253, 254] and allyl-metals [154, 258]. They also suffer stereoselective Ti-catalyzed silylcyanation [268], Strecker reaction [266], and [2+2] or [4+2] cydoadditions [131, 256, 263], When the reaction produces an imine product, the chiral auxiliary is recovered after acidic hydrolysis. However, when an amine is obtained as the product, as is often the case from phenethylamine derivatives, the chiral residue is cleaved by hy-drogenolysis. In such cases, the chiral amine is not, strictly speaking, a chiral auxiliary. But these processes will be discussed anyway because of their importance in asymmetric synthesis. 

Sec. enamines from enol ethers Method for the alkylation of amines... 

An interesting and useful property of enamines of 2-alkylcyclohexanone is the substantial preference for the less-substituted isomer to be formed. This tendency is especially pronounced for enamines derived from cyclic secondary amines such as pyrrolidine, a preference that can be traced to Ai allylic strain. In order to maximize conjugation between the nitrogen lone pair and the carbon-carbon double bond, the nitrogen substituent must be coplanar with the double bond. This creates a steric repulsion when the enamine bears a 6-substituent and leads to a preference for the unsubstituted enamine. Because of the same preference for coplanarity in the enamine system, a-alkyl substituents adopt an axial conformation to minimize steric interaction with the amino group. 

The ability to reduce compounds under acidic conditions is ideal for the reduction of enamines. Protonation of nitrogen gives an iminium salt in acidic media that is then reduced with cyanoborohydride to an amine.Imines can be reduced in acidic media in the presence of many other functional groups, as shown by Cook s reduction of imine 165 to give 166 in 79% yield in a synthesis of substituted tetrahydro-P-carbolines. 2 This reagent is excellent for the reduction of iminium salts at neutral pH as well,l 3 and it is also useful for the reductive alkylation of amines. Dimethylamino derivatives such as 168 can be prepared from the amine (167 in this case) by treatment with formaldehyde and cyanoborohydride, even in the presence... 

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