Enamines, sodium cyanoborohydride

Vinylamines (enamines) are reduced by alane, mono- and dichloroalane to saturated amines, and hydrogenolyzed to amines and alkenes [710]. Reduction is favored by dichloroalane while hydrogenolysis is favored by alane. Alane, chloroalane and dichloroalane gave the following results with -N-pyrrolidinylcyclohexene V-pyrrolidinylcyclohexane in 13, 15 and 22% yield, and pyrrolidine and cyclohexene in 80, 75 and 75% yields, respectively [710]. Saturated amines were also obtained by treatment of enamines with sodium borohydride [711], with sodium cyanoborohydride [103, 712] (Procedure 22, p. 210) and by heating for 1-2 hours at 50-70° with 87% or 9S% formic acid (yields 37-89%) [320]. 

With the procedure for constructing the quaternary carbon stereocenter in hand, the conversion of the ris-form to the trans form was explored in accordance with the synthetic plan shown in Scheme 9. The ketone moiety of the 1,4-conjugated adduct 61 was protected by an acetal group, followed by decarboxylation of compound 65 using sodium ethylthiolate to yield lactam trans-62 and cis-62 as an 8 1 diastereomixture [31]. The reason why the lactam trans-62 was obtained as a major product is that the subsequent protonation after decarboxylation proceeded kinetically. This assertion is supported by experimental results in which the trans- and cis-lactam diastereomixture (8 1) in ethanol was refluxed in the presence of potassium hydroxide to afford a 1 5 mixture [15,32,33]. The mixture of the lactam trans-62 and cis-62 was reduced with DIBALH, followed by treatment with sodium hydroxide to give bicyclic enamine 63. The kinetic iminium salt prepared from bicyclic enamine 63 with hydrochloric acid was reduced with sodium cyanoborohydride, leading to the frans-decahydroisoquinoline structure [22], The acetal moiety of the resultant 67 was removed to provide the objective ketones 68a and 2c. This method enabled the construction of the tra s-decahydroisoquinoline structure without an intermediate resembling the neurotoxic MPTP, and in fewer steps. 

Now the acetal can be hydrolysed to give the free amino-ketone and hence the enamine 55 that is reduced by the alternative reagent (chapter 4) sodium cyanoborohydride again stereoselectively so that all three H atoms in 48 are on the same face of the bicyclic structure. 

Reductive amination. Conversion of ketones or aldehydes to amines is usually accomplished by reduction of the carbonyl compound with sodium cyanoborohydride in the presence of an amine (Borch reduction, 4, 448-449). However, yields are generally poor in reactions of hindered or acid-sensitive ketones, aromatic amines, or trifluoromethyl ketones. Yields can be improved markedly by treatment of the ketone and amine first with TiCl4 or Ti(0-i -Pr)42 in CH2C12 or benzene to form the imine or enamine and then with NaCNBH3 in CH3OH to effect reduction. Note that primary amines can be obtained by use of hexamethyldisilazane as a substitute for ammonia (last example). 

Sodium cyanoborohydride reduces enamines to amines. Diborane reduces nitriles to amines but the nitro group remains unaffected. 

P-Amfno acids. Chiral enamines (1) are hydrogenated by 10% palladium hydroxide catalyst on charcoal to )3-amino acids (2) in optical purity of 7-28%. Optical yields are lower if the enamines are reduced with sodium cyanoborohydride. The two methods lead to opposite configurations of 2. 

The observation that enamines may be reduced by NBH in acetic acid/ THF ° and sodium cyanoborohydride coupled with the tendency for indoles to protonate at the 3-position enabled Gribble and co-workers to reduce indoles to indolines (201,205) in high yield. //-Alkyl indoles (204) were also reduced, as was 3-methylindole. The use of formic acid favored the formation of l-methyl-3-[2-(2-dimethylaminophenyl)ethyl]indoline (207) via an intermeuiate 3,2 dimer (206). ... 

Lhommet and co-workers synthesized (- )-436 by the route shown in Scheme 66 [422). Wittig-Homer reaction between the 2,5-rrans -disubstituted pyrrolidine aldehyde 509, made from (S)-pyroglutamic acid [423), and the protected keto-phosphonate 510 introduced all the skeletal carbon atoms of the target. Simultaneous hydrogenation and //-deprotection of enone 511 gave the aminoketone 512, which spontaneously formed the bicyclic enamine 513 in 98% yield when exposed to trifluoroacetic acid—apparently the first time that such an intermediate has actually been isolated en route to indolizidines. Reduction with sodium cyanoborohydride in acidic medium acid produced a diastereomeric mixture (92 8) of (- )-436 and (+ )-437. The former was isolated in 84% yield after chromatography on silica gel. The overall yield of this 15-step sequence was 8% based on (S)-pyroglutamic acid. 

Secondary amines react with aldehydes to form enamines, which may be reduced to amines by hydrogenation, or (via their iminium ion tautomer) with sodium borohydride or sodium cyanoborohydride. 

Evidence for the intermediacy of the enamine (138) and the immonium ion (140) derives from the condensation reaction in which potassium cyanide replaced sodium cyanoborohydride the immonium ion (140) was thus trapped by reaction with nucleophilic cyanide ion, with formation of 21-cyanotetrahydroalstonine (141a) and 21-cyanoakuammigine (141b). Both cyano-compounds suffered slow reduction to the parent alkaloid by sodium borohydride, and were re-converted (by silver acetate) into the precursor immonium ions (140), which could be rapidly reduced (NaBH4) to the alkaloids. Scheme 17 illustrates some, but not by any means all, of the numerous interconversions involved in these biomimetic experiments. 

As with reductive aminations and imine reductions that employ sodium cyanoborohydride, a significant number of enamine reductions now are reported to afford products stereoselectively. Two representative examples include a reduction and subsequent transformation of a bicyclic enamine (eq 47) and the reduction of a highly functionalized enamine (eq 48) In both instances the... 

We made the point above that the difference in reactivity between an iminium ion and an oxonium ion is that an iminium ion can lose H and form an imine or an enamine, while an oxonium ion reacts as an electrophile. Iminium ions can, however, react as electrophiles provided suitable nucleophiles are present. In fact, they are very good electrophiles, and are significantly more reactive than carbonyl compotmds. For example, iminium ions are reduced rapidly by the mild reducing agent sodium cyanoborohydride, Na(CN)BH3, while carbonyl compounds are not. An alternative to Na(CN)BH3 is NaBH(OAc>3 (sodium triacetoxyborohydride)—somewhat safer because strong acid can release deadly HCN from Na(CN)BH3. 

At this juncture, the stereochemistry of the amine-substituted carbon required inversion to the correct configuration of the natural product. Toward this end, lactone 354 was treated with tetramethylguanidine and 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) under an air atmosphere in THE. These conditions led to oxidation to yield enamine 355, which was subsequendy reduced with sodium cyanoborohydride to complete the epimerization process. These conditions were also sufficiently hydridic to reduce the ketone carbonyl. Heating in ethyl acetate then led to cycHza-tion to yield lactam 356. Oxidation using IBX next provided ketone 357, which was employed as a coupling partner for 2-iodoanihne in the key indolization step (Scheme 51). 

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