Ketones borohydride reduction

Ketone reduction to alcohols, BOROHYDRIDE REDUCTION KETONIZATION... 

Sodium borohydride and lithium aluminum hydride react with carbonyl compounds in much the same way that Grignard reagents do except that they function as hydride donors rather than as carbanion sources Figure 15 2 outlines the general mechanism for the sodium borohydride reduction of an aldehyde or ketone (R2C=0) Two points are especially important about this process... 

A McMurry coupling of (176, X = O Y = /5H) provides ( )-9,ll-dehydroesterone methyl ether [1670-49-1] (177) in 56% yield. 9,11-Dehydroestrone methyl ether (177) can be converted to estrone methyl ether by stereoselective reduction of the C —double bond with triethyi silane in triduoroacetic acid. In turn, estrone methyl ether can be converted to estradiol methyl ether by sodium borohydride reduction of the C17 ketone (199,200). 

The borohydride reduction rate data are paralleled by the rate data for many other carbonyl addition reactions. In fact, for a series of ketones, most of which are cyclic, a linear free-energy correlation of the form... 

Although the nature of the general polar effect suggested by Kamernitzsky and Akhrem " to account for axial attack in unhindered ketones is not clear, several groups have reported electrostatic interactions affect the course of borohydride reductions. Thus the keto acid (5a) is not reduced by boro-hydride but its ester (5b) is reduced rapidly further, the reduction of the ester (6b) takes place much more rapidly than that of the acid (6a). Spectroscopic data eliminate the possibility that in (5a) there is an interaction between the acid and ketone groups (e.g. formation of a lactol). The results have been attributed to a direct repulsion by the carboxylate ion as the borohydride ion approaches. " By contrast, House and co-workers observed no electrostatic effect on the stereochemistry of reduction of the keto acid (7). However, in this compound the acid group may occupy conformations in which it does not shield the ketone. Henbest reported that substituting chlorine... 

A novel reaction of perchloryl fluoride with aromatic substrates was discovered by Neeman and Osawa, the oxofluorination reaction. These authors found that reaction of indene with perchloryl fluoride in dioxane-water yields five products, the major product being, 2-fluoroindanone. When applied to 6-dehydroestradiol diacetate (24) there is obtained as the major product the 7a-fluoro-6-ketone (25). Borohydride reduction of the... 

FIGURE 15.2 Mechanism of sodium borohydride reduction of an aldehyde or ketone. 

The final stages of the successful drive towards amphotericin B (1) are presented in Scheme 19. Thus, compound 9 is obtained stereoselectively by sodium borohydride reduction of heptaenone 6a as previously described. The formation of the desired glycosida-tion product 81 could be achieved in dilute hexane solution in the presence of a catalytic amount PPTS. The by-product ortho ester 85 was also obtained in approximately an equimolar amount. Deacetylation of 81 at C-2, followed sequentially by oxidation and reduction leads, stereoselectively, to the desired hydroxy compound 83 via ketone 82. The configuration of each of the two hydroxylbearing stereocenters generated by reduction of carbonyls as shown in Scheme 19 (6—>9 and 82->83) were confirmed by conversion of 83 to amphotericin B derivative 5 and comparison with an... 

Optically active /3-ketoiminato cobalt(III) compounds based on chiral substituted ethylenedi-amine find use as efficient catalysts for the enatioselective hetero Diels Alder reaction of both aryl and alkyl aldehydes with l-methoxy-(3-(t-butyldimethylsilyl)oxy)-1,3-butadiene.1381 Cobalt(II) compounds of the same class of ligands promote enantioselective borohydride reduction of ketones, imines, and a,/3-unsaturated carboxylates.1382... 

One of the most attractive features of borohydride reductions is that under micro-wave-enhanced conditions they can be performed in the solid state, and rapidly. We were attracted by the work of Loupy [57], and in particular Varma [58, 59] who has shown that irradiation of a number of aldehydes and ketones in a microwave oven in the presence of alumina doped NaBH4 for short periods of time led to rapid reduction (0.5-2 min) in good yields (62-93%). In our study [60] seven aldehydes and four ketones were reduced (Tab. 13.3). Again reduction was complete within 1 min, the products were of high purity (>95%), of high isotopic incorporation (95%, same as the NaBD4) and the reactions completely selective. 

Borohydride reduction of NiCl2 in dimethylformamide or dimethyl-acetamide leads to very active catalysts, thought to be homogeneous, for hydrogenation of monoolefins, unsaturated fats, cyclic dienes to monoenes, and saturated aldehydes and ketones (165, 538, 539). Cobaltous chloride systems have also been used (540). 

Ketone 166, the key intermediate of deplancheine was obtained in 63% overall yield by the reaction of harmalane (150) with l-bromo-2,3-epoxypropane, followed by sodium borohydride reduction and Moffat oxidation (116). Methods for the elaboration of the exocyclic, -configurated double bond are reviewed (117). 

The stereoselective total synthesis of both ( )-corynantheidine (61) (170,171) (alio stereoisomer) and ( )-dihydrocorynantheine (172) (normal stereoisomer) has been elaborated by Szdntay and co-workers. The key intermediate leading to both alkaloids was the alio cyanoacetic ester derivative 315, which was obtained from the previously prepared ketone 312 (173) by the Knoevenagel condensation accompanied by complete epimerization at C-20 and by subsequent stereoselective sodium borohydride reduction. ( )-Corynantheidine was prepared by modification of the cyanoacetate side chain esterification furnished diester 316, which underwent selective lithium aluminum hydride reduction. The resulting sodium enolate of the a-formyl ester was finally methylated to racemic corynantheidine (171). 

Although similar efforts have been devoted to related polymer systems (Overberger and Cho, 1968 Overberger and Dixon, 1977 Okamoto, 1978), large enantioselectivity has not been observed. Goldberg et al. (1978) conducted borohydride reduction of phenyl ketones in micelles of the chiral surfactant [44]. The result was disappointing, since the maximal enantioselectivity was only 1.66% for phenyl propyl ketone. A much better optical yield was reported when this reaction was carried out under phase-transfer conditions (Masse and Parayre, 1976). The cholic acid micelle and bovine serum albumin exhibited the relatively high enantioselectivity in the reduction of trifluoroacetophenone (Baba ef al., 1978). 

Bromination to 4 and substitution of the bromine by an amine gives 5. Sodium borohydride reduction of the ketone to an alcohol 6 is followed by a resolution with (-)-di-/ -toluoyltartaric acid and reduction of the ester group with lithium aluminum hydride to give diol 7. Catalytic debenzylation gives albuterol, sometimes called salbutamol. 

Some intramolecular aminations of olefins have been reported for solenopsin A (Id) and its isomer (Ic) (389-392). The dimer (200) of methyl vinyl ketone was converted to the ketone (202) by a standard procedure. Borohydride reduction of 202, followed by acid-catalyzed cyclization, yielded an exo/endo (60/40)... 

Acyl substituents at the 3- and/or 4-positions result in decreased hydrolytic stability compared with the alkyl and aryl derivatives described above. Despite this constraint most of the usual reactions of the carbonyl group are possible. Aldehydes <9ILA1211> and ketones are oxidized to the carboxylic acid, borohydride reduction affords the expected alcohols, and epoxides are formed on reaction with diazomethane. Oximes and arylhydrazones are formed with hydroxylamine and arylhydrazines, and the products may subsequently undergo monocyclic rearrangement involving the oxadiazole to give the corresponding isomeric furazans and 1,2,3-triazoles (Section 4.05.5.1.4). 

Since cyclobutanones are often produced by dichloroketene addition to an alkene (see Section 1.3.5.1.), a,a-dichlorocyclobutanones are very common intermediates. These can be reduced to the monochlorocyclobutanones (see Section 5.2.1.1.). It was reported249 that the C —Cl dipole has a pronounced effect on the sodium borohydride reduction of these compounds. For example, in the reduction of e ra-7-chloro-7-methylbicyclo[3.2.0]hept-2-en-6-one, the normal preference for an exo-face attack was reversed and the exo-alcohol was the major product exo-7-chlorobicyclo[3.2.0]hept-2-en-exo-6-ol exo-2d and exo-7-chlorobicy-clo[3.2.0]hept-2-en-en /o-6-ol endo-2A were obtained in a 78 22 ratio. On the other hand, when the corresponding endo-chloro ketones were reduced, the C —Cl dipole resulted in exclusive formation of the endo-alcohols endo-2b, c. 

The rates of sodium borohydride reduction of the ketones (46) in propan-2-ol have been measured (78JCS(P2)1232). The strategy was to vary X keeping Y = H, and then to vary Y with X = H. This permitted direct comparisons to be made of transmission of substituent effects through the aromatic rings to the same reaction centre. It was concluded that the... 

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