Conjugate reductions sodium borohydride

On the other hand, 4-alkoxycarbonyl- and 4-aminocarbonyl-substituted isoxazoles 6 undergo unusual conjugate reduction with sodium borohydride and sodium... 

A difference in the reactivities and selectivities between tetra-n-butylammonium borohydride and sodium borohydride in the reduction of conjugated ketones is well illustrated with A1-9 2-octalone (Scheme 11.3) [17], Reduction with the sodium salt in tetrahydrofuran is relatively slow and produces the allylic alcohol (1) and the saturated alcohol (2) in a 1.2 1 ratio whereas, in contrast, tetra-n-butylammonium borohydride produces the non-conjugated alcohol (3) (50%) and the saturated alcohol (2) (47%), with minor amounts of the ketone (4), and the allylic alcohol (1) [16]. It has been proposed that (3) results from an initial unprecedented formation of a dienolate anion and its subsequent reduction. 

Cyclopropanecarboxylic esters have been prepared, in 75—86 % yield, by intramolecular alkylation of 4-chloroalkyl esters, using phase-transfer catalysis. Monoalkylation of nitro-alkenes by acrylic esters occurs in a controlled manner if a two-phase system is used, to give products of Michael addition in 45—65 % yield for five examples. An interesting variant on this reaction involves the generation of the a-nitro-carbanion by conjugate reduction of a nitroalkene with sodium borohydride followed by its conjugate addition to methyl acrylate yields of 62—95% are reported for five cases (Scheme 39). ... 

Conjugate addition of methyl magnesium iodide in the presence of cuprous chloride to the enone (91) leads to the la-methyl product mesterolone (92) Although this is the thermodynamically unfavored axially disposed product, no possibility for isomerization exists in this case, since the ketone is once removed from this center. In an interesting synthesis of an oxa steroid, the enone (91) is first oxidized with lead tetraacetate the carbon at the 2 position is lost, affording the acid aldehyde. Reduction of this intermediate, also shown in the lactol form, with sodium borohydride affords the steroid lactone oxandrolone... 

The sterically unbiased dienes, 5,5-diarylcyclopentadienes 90, wherein one of the aryl groups is substituted with NO, Cl and NCCHj), were designed and synthesized by Halterman et al. [163] Diels-Alder cycloaddition with dimethyl acetylenedicarbo-xylate at reflux (81 °C) was studied syn addition (with respect to the substituted benzene) was favored in the case of the nitro group (90a, X = NO ) (syrr.anti = 68 32), whereas anti addition (with respect to the substituted benzene) is favored in the case of dimethylamino group (90b, X = N(CH3)2) (syn anti = 38 62). The facial preference is consistent with those observed in the hydride reduction of the relevant 2,2-diaryl-cyclopentanones 8 with sodium borohydride, and in dihydroxylation of 3,3-diarylcy-clopentenes 43 with osmium trioxide. In the present system, the interaction of the diene n orbital with the o bonds at the (3 positions (at the 5 position) is symmetry-forbidden. Thus, the major product results from approach of the dienophile from the face opposite the better n electron donor at the (3 positions, in a similar manner to spiro conjugation. Unsymmetrization of the diene % orbitals is inherent in 90, and this is consistent with the observed facial selectivities (91 for 90a 92 for 90b). 

Chemo- and stereoselective reduction of (56) to (55) is achieved In highest yield by sodium borohydride in ethanol. The isolated ketone is reduced more rapidly than the enone and (55) is the equatorial alcohol. Protection moves the double bond out of conjugation and even the distant OH group in (54) successfully controls the stereochemistry of the Simmons-Smith reaction. No cyclopropanation occurred unless the OH group was there. Synthesis ... 

The conjugate may be stabilized by addition of a reductant such as sodium borohy-dride or sodium cyanoborohydride. Usually sodium cyanoborohydride is recommended for specific reduction of Schiff bases, but since the conjugate has already formed at this point, the use of sodium borohydride will both reduce the associated Schiff bases and eliminate any remaining aldehyde groups. Add sodium borohydride to a final concentration of lOmg/ml. Continue to react for 1 hour at 4°C. 

Hapten molecules containing aldehyde residues may be crosslinked to carrier molecules by use of reductive animation (Chapter 3, Section 4). At alkaline pH values, the aldehyde groups form intermediate Schiff bases with available amine groups on the carrier. Reduction of the resultant Schiff bases with sodium cyanoborohydride or sodium borohydride creates a stable conjugate held together by secondary amine bonds. 

Note Some protocols do not call for a reduction step. The addition of borohydride at this level may result in disulfide bond cleavage and loss of protein activity in some cases. As an alternative to reduction, add 50pi of 0.2M lysine in 0.5M sodium carbonate, pH 9.5 to each ml of the conjugation reaction to block excess reactive sites. Block for 2 hours at room temperature. Other amine-containing small molecules may be substituted for lysine—such as glycine, Tris buffer, or ethanolamine. 

Unlike with sodium borohydride (see Section 11.01.5.2), pyrrolizin-3-one 2 reacts with lithium aluminohydride mainly as an amide. No conjugate addition occurs, and only the reductive lactam cleavage takes place to give stereoselectively the (Z)-allylie alcohol 77. Similarly, benzo-annulated pyrrolizin-3-one 17 gives the corresponding benzylic alcohol 78. The same reactivity was observed with organometallics such as methyllithium which gives exclusively the tertiary (Z)-allylic alcohol 79 (Scheme 7). 

Kinetic studies established that tetra-n-butylammonium borohydride in dichloromethane was a very effective reducing agent and that, by using stoichiometric amounts of the ammonium salt under homogeneous conditions, the relative case of reduction of various classes of carbonyl compounds was the same as that recorded for the sodium salt in a hydroxylic solvent, i.e. acid chlorides aldehydes > ketones esters. However, the reactivities, ranging from rapid reduction of acid chlorides at -780 C to incomplete reduction of esters at four days at 250 C, indicated the greater selectivity of the ammonium salts, compared with sodium borohydride [9], particularly as, under these conditions, conjugated C=C double bonds are not reduced. 

Reductions with sodium amalgam are fairly mild. Only easily reducible groups and conjugated double bonds are affected. With the availability of sodium borohydride the use of sodium amalgam is dwindling even in the field of saccharides, where sodium amalgam has been widely used for reduction of aldonic acids to aldoses. 

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