Hydrolysis allylic enamines

As the allylated enamine has higher reactivity (i.e., lower ionization potential) the selective mono-allylation of cyclohexanone required excess (2 equiv.) ketone reagent. Nevertheless 20 equivalents of cyclobutane were necessary for the selective reaction with cyclobutanone and only 2,5-bis-allylated cyclopentanone was obtained, as the second oxidation occurred immediately on the iminium intermediate prior to hydrolysis with this substrate. The allylation reaction was compatible with alkyl and heteroatom substituents at the p and y positions. When non-symmetrical heteroatom containing substrates were used, C(4) allylation occurred selectively in high yields (70-86%) and in high ee (80-99%) (Figure 39.2). 

The enamine 315 as a carbon nucleophile reacts with 7r-allylpalladium complexes to give allyl ketones after hydrolysis[265],... 

That the methyl group in the less substituted isomer of the enamine (20) is axial was borne out by the work of Johnson et al. (18) in the total synthesis of the glutarimide antibiotic //-dehydrocycloheximide (24). The acylation of the morpholine enamine of 2,4-dimethylcyclohexanone (25) with 3-glutarimidylacetylchloride (26), followed by the hydrolysis of the intermediate product (27) with an acid buffer, led to the desired product in 35 % yield. The formation of the product in a rather low yield could most probably be ascribed to the relatively low enamine-type aetivity exhibited by the tetrasubstituted isomer, which fails to undergo the acylation reaction, and also because in trisubstituted isomer one of the CHj groups is axial. Since the methyl groups in the product are trans to each other, the allylic methyl group in the less substituted isomer of the enamine should then be in the axial orientation. 

With enamines of cyclic ketones direct C alkylation occurs with allyl and propargyl as well as alkyl halides. The reaction is again sensitive to the polarity of the solvent (29). The pyrrolidine enamine of cyclohexanone on reaction with ethyl iodide in dioxane gave 25% of 2-ethylcyclohexanone on hydrolysis, while in chloroform the yield was increased to 32%. 

Although the asymmetric isomerization of allylamines has been successfully accomplished by the use of a cationic rhodium(l)/BINAP complex, the corresponding reaction starting from allylic alcohols has had a limited success. In principle, the enantioselective isomerization of allylic alcohols to optically active aldehydes is more advantageous because of its high atom economy, which can eliminate the hydrolysis step of the corresponding enamines obtained by the isomerization of allylamines (Scheme 26). 

Separation of catalysts from high-value products such as fine chemicals or pharmaceuticals is often accomplished by precipitating the catalyst from the product solution. Recycling of these catalysts is feasible, provided that they do not decompose. In industry, catalyst recovery by means of catalyst precipitation is applied only in relatively small batch processes. An example of such a process is the production of (—)-menthol (id) in which an Rh-BINAP isomerization catalyst converts the allylic amine substrate into (R)-citronellal (after hydrolysis of the enamine) in high yield (99%) and with high enantioselectivity (98.5% ee). After distillation of the solvent (THF) and product, the catalyst is recovered from the residue by precipitation with -heptane. 

Copper(I) salts of enamines have been allylated with the 2-allyloxybenzimidazoles to give y,5-unsaturated ketones upon hydrolysis (79CL957). Primary allylic ethers react preferentially at their a-carbon with retention of double bond configuration whereas secondary allylic ethers react mainly at the y-carbon to afford alkenes of predominantly (E)-stereochemistry. 

Allylic double bonds can be isomerized by some transition metal complexes. Isomerization of alkyl allyl ethers 480 to vinyl ethers 481 is catalysed by Pd on carbon [205] and the Wilkinson complex [206], and the vinyl ethers are hydrolysed to aldehydes. Isomerization of the allylic amines to enamines is catalysed by Rh complexes [207]. The asymmetric isomerization of A jV-diethylgeranylamine (483), catalysed by Rh-(5)-BINAP (XXXI) complex to produce the (f )-enaminc 484 with high optical purity, has been achieved with a 300 000 turnover of the Rh catalyst, and citronellal (485) with nearly 100% ee is obtained by the hydrolysis of the enamine 484 [208]. Now optically pure /-menthol (486) is commerically produced in five steps from myrcene (482) via citronellal (485) by Takasago International Corporation. This is the largest industrial process of asymmetric synthesis in the world [209]. The following stereochemical corelation between the stereochemistries of the chiral Rh catalysts, diethylgeranylamine (483), diethylnerylamine (487) and the (R)- and (5)-enamines 484... 

Z75. (a) Dieckmann of dimethyl adipate, alkylation by allyl bromide, hydrolysis and decarboxylation (c) Robinson with CH3CH = CHCOCH3 then reduction (d) form enamine or enolate, acylate with CICOOEt, methylate with CH3I, do aldol with benzaldehyde. 

Normally the less substituted double-bond isomer (la) is the more reactive since reaction at the more substituted position It engenders severe allylic interactions (A1,3-strain5) in the transition state. Further reaction therefore occurs preferentially to give the / ,/ -disubstituted enamine or iminium salt (3) and hence the a,a -disubstituted ketone (5) on hydrolysis. However, there are exceptions to this (see Sections III.B, V and VI.D). A recent development uses the observation6 that such steric interactions do not apply to secondary enamines (Section VIII) since a conformation (2) can be adopted... 

The acceleration of the 3-aza-Cope rearrangement of A-allylenamines through formation of a cationic quaternary nitrogen center (enammonium salt) has obvious advantages. However, direct allylation of enamines in order to form the enammonium ions is unsatisfactory, and difficult. Moreover, the rearrangement-hydrolysis product is often contaminated by the C-allylated product when an unsymmetrical allyl halide is employed... 

Capon and Wu have shown that the rate of hydrolysis of secondary enamines of cyclohexanone (13 and 14) is decreased only slightly by the 2) methyl group. They have therefore concluded that the methyl substituent has little effect on the ground state or the transition state conformations of secondary enamines . However, in this case there is no developing allylic strain whether the transition state is reactant-like or product-like (see also Section VIII) and pn-conjugation is uninhibited. The pn-conjuga-tion in secondary, -disubstituted acyclic enamines (15) compared to the corresponding tertiary enamines (16) is also demonstrated by the UV and NMR evidence provided by Capon and Wu . 

The lithium derivative from the unsymmetrical allylic carbazole 141 reacts with the unsym-metrical allyl chloride 142 to give 143. The starting material was made from carbazole 132 and 142 so this allyl electrophile has reacted twice at its less substituted end, but the nucleophilic homoenolate from 141 has reacted at its more substituted end, because that is y-addition relative to the nitrogen atom.38,39 Hydrolysis of the resulting enamine ii-143 gives the aldehyde 144. 

The lithium derivative of 153 can equilibrate to the chelated isomer Z-154 that reacts cleanly in the y-position with alkyl and allyl halides to give, after hydrolysis of the initially formed enamine 155, the ketones 156 with generally good enantiomeric excess. Structure Z-154a shows the chelation in the lithiated intermediate best. 

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. 

Allylic substitutions. The catalyt preparation of (V-protected allylic amio cyclic carbamates. Asymmetric a-allj ried out by treating the enamines d (Ph3P)4Pd and subsequent hydrolysis. 1 bonates to l-allyl-2(l//)-pyrimidinonei peptides through ester enolate Claisci set. l-Arylprop-2-enols are suitable fa allyl ether cleavage treatment with a < suffices. 

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