Sodium borohydride in reduction

Lynestrenol is the des-3-oxo derivative of norethindrone (28). It has been prepared through a similar synthetic pathway as aHylestrenol (37) (52), ie, addition of potassium acetyUde, rather than aHyl magnesium bromide, affords lynestrenol (73). Lynestrenol is also available from norethindrone (28). Reduction of the 3-keto group is accompHshed by treating norethindrone (28) with sodium borohydride in the presence of trifluoro- or trichloroacetic acid... 

Unusual reducing properties can be obtained with borohydride derivatives formed in situ. A variety of reductions have been reported, including hydrogenolysis of carbonyls and alkylation of amines with sodium borohydride in carboxyHc acids such as acetic and trifluoroacetic (38), in which the acyloxyborohydride is the reducing agent. 

The least troublesome routes to 3,4-dihydro- and 1,2,3,4-tetrahydro-quinazoline are probably the reduction of quinazoline by sodium borohydride, in water for the former or in methanol for the latter. Both must be isolated as salts. The dihydroquinazoline may be formed also by reduction with LAH in ether (65JHC157). In contrast, 5,6,7,8-tetrahy-droquinazoline is best made by primary synthesis from 2-formylcyclohexanone and for-mamide (57CB942) or from cyclohexanone and trisformamidomethane (60CB1402). 

Thus the critical synthetic 1,6-dihydropyridine precursor for the unique isoquinuclidine system of the iboga alkaloids, was generated by reduction of a pyridinium salt with sodium borohydride in base (137-140). Lithium aluminum hydride reduction of phenylisoquinolinium and indole-3-ethylisoquinolinium salts gave enamines, which could be cyclized to the skeletons found in norcoralydine (141) and the yohimbane-type alkaloids (142,143). 

R" = CH20H). The use of sodium borohydride in place of lithium aluminum hydride did not lead to ring closure but to 3-[j8-(A-l,2,3,4-tetrahydroisoquinolyl)ethyl]indole derivatives (53). Reductive cyclization by means of lithium aluminum hydride of the j8-(3-indolyl)ethyl-l-isoquinoline (52) to the pentacyclic tetrahydro-j8-carboline 49 (R = R = R" = H) has been reported. Strong acid alone sufficed to convert 52 into 54, the 0x0 derivative of 49. ... 

Step D Chemical Reduction Preparation of 3-Morpholino-4-(3-tert-Butylamino-2-Hydroxy-propoxyl-l,2,5-Thiadiazole — The 3-morpholino-4-(3-tert-butylamino-2-oxopropoxy)-1,2,5-thiadiazole (0.01 mol) is dissolved in isopropanol (10 ml). To the solution is added sodium borohydride in portions until the initial evolution of heat and gas subsides. The excess sodium borohydride is destroyed by addition of concentrated hydrochloric acid until the mixture remains acidic. The precipitate of sodium chloride is removed, ether is added, and the solution is concentrated to crystallization. The solid material is removed by filtration and dried thus providing 3-morpholino-4-(3-tert-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole, MP 161° to 163°C (as hydrochloride). 

Intermediate 10 must now be molded into a form suitable for coupling with the anion derived from dithiane 9. To this end, a che-moselective reduction of the benzyl ester grouping in 10 with excess sodium borohydride in methanol takes place smoothly and provides primary alcohol 14. Treatment of 14 with methanesulfonyl chloride and triethylamine affords a primary mesylate which is subsequently converted into iodide 15 with sodium iodide in acetone. Exposure of 15 to tert-butyldimethylsilyl chloride and triethylamine accomplishes protection of the /Mactam nitrogen and leads to the formation of 8. Starting from L-aspartic acid (12), the overall yield of 8 is approximately 50%, and it is noteworthy that this reaction sequence can be performed on a molar scale. 

Bromo-6,7,8,9-tetrahydro-l//-3-benzazepin-2-amine(6) with thiocyanate ion undergoes substitution of bromide to give the thiocyanatotetrahydro-l//-3-benzazepine 7.105 Attempts to replace bromide by azide ion failed, as did diazotization of the amine group with sodium nitrite in 6 M sulfuric acid. Oddly, treatment of the aminobromo compound with sodium borohydride in methanol results not in reduction, but in methoxy-debromination to give the 2-methoxy derivative which, on the basis of HNMR spectral data, is best represented as the 2-imino tautomer 8. 

On heating with sodium borohydride in glacial acetic acid. 5//-dibenz[/t,/ azepine (5) undergoes sequential acylation and reduction to yield 5-ethyl-5/7-dibcnz[A,/ ]azepine (8, R = Et).192 Similarly, reduction in trifluoroacetic acid produces the trifluoroethyl derivative 8 (R = CF3CH2 61% mp 69-70 C).193... 

Acetyl-5//-dibenz[/>,/]azepine-10-car bon itrile (17, R = CN) when treated with sodium borohydride undergoes reduction (73 % yield) at the CIO - Cl 1 double bond without reduction of the acetyl or cyano groups.212 However, hydroboration of 5-acetyl-5//-dibenz[/y/]azepine (17, R = H) with diborane in tetrahydrofuran under standard conditions is accompanied by reduction of the acyl function to yield 5-ethyi-10,l l-dihydrodibenz[6,/]azepin-10-ol (18).72... 

Some other typical examples of regiosclcctivc reductions of imides with sodium borohydride in ethanol are42 ... 

Dittmer and Christy64 studied the reactions of thiete sulphone. Included in these was an attempt to synthesize thiete itself, a highly strained olefin of theoretical interest, by the LAH reduction of thiete sulphone. The reduction was expected to be feasible since Bordwell and McKellin63 had found that thietane sulphone was readily reduced, but the only product that Dittmer and Christy isolated was 1-propanethiol (equation 23). Reduction of the thiete sulphone with sodium borohydride in basic aqueous methanol gave a 61% yield of the saturated ring, thietane sulphone. 

Examples of a desulphonylation procedure on complex molecules are provided by Fuchs and coworkers199 who reported on a triply convergent synthesis of L-( —)-prostaglandin E2. The molecules can be classified as homoallylic sulphones and reductive desulphonylation was best achieved with a mixture of sodium methoxide and sodium borohydride in methanol, with yields being better than 90%, despite the complexity of the molecules involved (equation 87). 

It was shown that dibenzothiophene oxide 17 is inert to 1-benzyl-l,4-dihydro nicotinamide (BNAH) but that, in the presence of catalytic amounts of metalloporphyrin, 17 is reduced quantitatively by BNAH. From experimental results with different catalysts [meso-tetraphenylporphinato iron(III) chloride (TPPFeCl) being the best] and a series of substituted sulfoxides, Oae and coworkers80 suggest an initial SET from BNAH to Fe1 followed by a second SET from the catalyst to the sulfoxide. The results are also consistent with an initial coordination of the substrate to Fem, thus weakening the sulfur-oxygen bond in a way reminiscent of the reduction of sulfoxides with sodium borohydride in the presence of catalytic amounts of cobalt chloride81. 

Sodium borohydride reductions of gold(I) complexes give Au clusters at RT if sodium borohydride in ethanol is dropped slowly into a suspension of the Au(I) complex in the same solvent. The immediate coloring of the reaction mixture (mostly red), even after only a few drops of the borohydride have been added, indicates fast formation of Au clusters. In view of the complicated composition of these compounds the fast formation is surprising. The use of H2 and CO with HjO as reducing agents in the synthesis of gold clusters has been described (see Table 1, Method A, 8.2.2.2). 

Dibenzobicyclo[2.2.2]octadienones (34) bearing an aromatic substituent were designed to probe the unsynunetrization of the carbonyl it orbital arising from the aromatic % orbitals [103,104], Reduction of the carbonyl moiety of 2- (R H) and 3-substituted (R3 H) dibenzobicyclo[2.2.2]octadienones (34) was studied by using sodium borohydride in methanol at - 3 °C. The 2- (34a) and 3-nitrodibenzo-bicyclo[2.2.2]octadienones (34d)... 

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 ... 

Amides can also be deacylated by partial reduction. If the reduction proceeds only to the carbinolamine stage, hydrolysis can liberate the deprotected amine. Trichloroac-etamides are readily cleaved by sodium borohydride in alcohols by this mechanism.237 Benzamides, and probably other simple amides, can be removed by careful partial reduction with diisobutylaluminum hydride (see Section 5.3.1.1).238... 

Shenlin Huang has implemented method C with 2,4-bis-OBoc-3-bromobenzyaldehyde 27 (Fig. 4.22) and 2-(trimethylsilyl)ethoxy]methyl-lithium 38 at —78 °C in THF.24 Surprisingly, lithium-halogen exchange does not happen and the intermediate benzyl alcohol undergoes reduction with sodium borohydride in the same pot to afford the desired bromophenol 39 in 68% yield. This material... 

Epiberberine and berberine were stereoselectively converted to fumaritrine (421) and its analog via 8,14-cycloberbines 216). The cycloberbine 432, derived from epiberberine (431) in the established way, was treated with p-toluenesulfonic acid in methanol and then with methyl iodide to give stereoselectively the cis-fused indenobenzazepine 433 in excellent yield (Scheme 86). Deoxygenation of the hydroxyl group in 433 was accomplished by treatment with methanesulfonyl chloride and subsequent reduction with sodium borohydride in dimethoxyethane to give (+ )-fumaritrine (421) (216). 

Gheorghe et al. make use of sodium cyanoborohydride as a hydride source in the synthesis of 5-arylpiperidines <06OL1653>. Kellehar and Kelly report the formation of a spiro -lactam using sodium borohydride in the key reductive animation step <06TL3005>. 

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