With Borohydride

Kuthan and E, Janeckova, Collect. Czech. Chem. Commun. 29, 1654 (1964). 

The reduction of 3-cyanopyridine (20) in ethanol leads mainly to the tetrahydropyridine 22. Reduction in pyridine or diglyme however, produces 1,4-dihydropyridine (21) as the major product. Minor amounts of the 3-pyridylmethylamine 23 are also obtained with ethanol, and the aprotic solvents prevent further ring reduction. 

The reduction of nicotinamide (31) with NBH in diglyme at 140° C gave a low yield of tetrahydropyridine (22) and the piperidine 32. Addition of ethanol as a proton source raised the yield of 22 to 42%. The dehydration of primary amides with borohydride is known to occur in moderate yield. The reduction of 2-alkylamino- and 2-arylamino-3,5-dinitropyridines (33) in water leads to the tetrahydropyridines 34 in high yields. - The 

Kikugawa, S. Ikegami, and S.-I. Yamada, Chem. Pharm. Bull. 17, 98 (1969). 

An interesting occurrence is the complete reduction of the pyridine ring in 5,6-dihydro-11 //-benzo[5,6]cyclohepta[ 1,2-6]pyridin-11 -one (37) to the piperidine 38 in 2-propanol with NBH.  

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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. 

Amino groups a to nitrogen are hydrolyzed to the corresponding oxo compounds (as in the purines and pteridines) in bo h acid and alkaline conditions. Schiff bases are reduced to benzylamino derivatives with borohydride. 

The double bond migration which normally occurs on forming ethylene ketals from A -3-ketones has frequently been utilized to form derivatives of the A -system. The related transformation of A -3-ketones into A -3-alcohols is usually accomplished by treatment of the enol acetate (171) (X = OAc) with borohydride. This sequence apparently depends on reduction of the intermediate (172) taking place faster than conjugation ... 

With Af-acyl or Af-sulfonyl hydrazines as nucleophiles, Zincke salts serve as sources of iminopyridinium ylides and ylide precursors.Reaction of the nicotinamide-derived Zincke salt 8 with ethyl hydrazino urethane 42 provided salt 43, while the tosyl hydrazine gave ylide 44 (Scheme 8.4.14). ° Benzoyl hydrazines have also been used in reactions with Zincke salts under similar conditions.Af-amino-1,2,3,6-tetrahydropyridine derivatives such as 47 (Scheme 8.4.15), which showed antiinflammatory activity, are also accessible via this route, with borohydride reduction of the initially formed ylide 46. ... 

Fenticonazole (106), on the other hand, is used topically to combat a wide variety of dermatophytes and yeasts, particularly Candida albicans. It can be synthesized from 2,4-dichlo-rophenacyl chloride (104) by reduction with borohydride and subsequent displacement with imidazole to give 105. This last undergoes ether formation with p-thiolphenylbenzyl chloride mediated by NaH to produce fcnticonazole (106) [37]. 

Bifonazole (109) is claimed to be remarkably non-toxic and is marketed as a topical antifungal agent overseas. It can be conveniently synthesized in the by now familiar way by reduction of p-phenylbenzophenone (108) with borohydride, conversion to the chloride with thionyl chloride, and then imidazole displacement to bifonazole (109) [39]. 

The Schiff reaction between chitosan and aldehydes or ketones yields the corresponding aldimines and ketimines, which are converted to N-alkyl derivatives upon hydrogenation with borohydride. Chitosan acetate salt can be converted into chitin upon heating [130]. The following are important examples of modified chitosans that currently have niche markets or prominent places in advanced research. 

Mono-substituted derivatives of [C5HjMn(NO)(CO)2] (32) and di-substituted (20, 146) derivatives of [CH3C5H4Mn(NO)(CO)2] have been prepared by direct reactions of the isocyanide and [C5H5Mn(NO)(CO)2] or [CH3CjH4Mn(NO)(CO)2]. Brunner and Schindler (32) observe variations of vqq and i no for the series [C5H5Mn(NO)(CO)L]+ (L = phosphines, and cyclohexyl isocyanide) in the order CNC H, > P(OPh)3->--->(PPh3)3 > PBuj. Reactions of the mono- and disubstituted complexes with pentafluorophenyllithium (20,146), and of the disubstituted species with borohydride (148) were noted above. 

By analogy with the reduction of nickel salts with borohydride ion, a mechanism involving hydride, or H, ions as the purported reducing species was advanced by Hersch [41] and elaborated on by Lukes [42], and is shown here in part for acidic solutions ... 

The hydrogenations become analogous to those involving HMn(CO)5 (see Section II,D), and to some catalyzed by HCo(CN)53 (see below). Use of bis(dimethylglyoximato)cobalt(II)-base complexes or cobaloximes(II) as catalysts (7, p. 193) has been more thoroughly studied (189, 190). Alkyl intermediates have been isolated with some activated olefinic substrates using the pyridine system, and electronic and steric effects on the catalytic hydrogenation rates have been reported (189). Mechanistic studies have appeared on the use of (pyridine)cobaloxime(II) with H2, and of (pyridine)chlorocobaloxime(III) and vitamin B12 with borohydride, for reduction of a,/3-unsaturated esters (190). Protonation of a carbanion... 

In the presence of strong alkali, the rhodium analog of 62, or RhCl(C8H,2)PPh3, hydrogenates aliphatic ketones at 1 atm and 20°C, and after treatment with borohydride the systems similarly reduce aromatic ketones to the alcohols (526). Deuterium exchange data for acetone reduction were interpreted in terms of hydrogen transfer within a mononuclear hydroxy complex containing substrate bound in the enol form (63). 

Most of the attempted asymmetric reductions have used sodium borohydride in conjunction with quaternary ammonium catalysts. Recently, the solution structures of ion pairs formed by quaternary ammonium ions derived from quinine with borohydride ion have been characterized by nuclear magnetic resonance methods in CDC13.1741... 

Deoxy-l-fluoro-L-glycerol (18) has been prepared by, among other methods, the treatment of 3,4-0-benzylidene-2,5-0-methylene-l,6-di-O-p-tolylsulfonyl-D-mannitol107 (17) with tetrabutylammonium fluoride in acetonitrile, followed by removal of the benzylidene group, periodate oxidation, reduction with borohydride, and hydrolysis. 1,6-Dideoxy-l,6-difluorogalactitol108 was obtained by treatment of 2,3 4,5-di-0-isopropylidene-l,6-di-0-(methylsulfonyl)galactitol with tetra-... 

D-Glucose 6-phosphate is converted enzymically into L-wyo-inositol 1-phosphate (20) in a process which requires NAD+. The base-catalysed cyclization of d-xylo-hexos-5-ulose 6-phosphate (21), followed by reduction with borohydride, leads to (20) and epi-inositol 3-phosphate (22) (Scheme 3).59 This has been put forward as a chemical model for the enzymic synthesis. The phosphorylation of inositols with polyphosphoric acid has been described80 and the p-KVs of inositol hexaphosphate have been determined by 31P n.m.r.61... 

For some purposes an alternative method, reducing the S-S link, was used (Moore et al.,1954). The protein was dissolved in 8 M urea, reduced with borohydride and the free thiol groups then treated with iodoacetate. Carboxymethyl cysteine could then be estimated chromatographically. 

A further synthetic approach to carbon-metal double bonds is based on the acid-catalyzed abstraction of alkoxy groups from a-alkoxyalkyl complexes [436 -439] (Figure 3.11). These carbene complex precursors can be prepared from alk-oxycarbene complexes (Fischer-type carbene complexes) either by reduction with borohydrides or alanates [23,55,63,104,439-445] or by addition of organolithium compounds (nucleophilic addition to the carbene carbon atom) [391,446-452]. 

Chaplin used methanolysis for the analysis of carbohydrates in glycoproteins. His method was a variation of the foregoing procedures, with an improvement of using tert-hvAyX alcohol to remove hydrogen chloride by coevaporation, instead of prolonged trituration with silver carbonate. His method is useful for samples containing uronic acids and lipids. Mononen studied methanolysis, followed by deamination and reduction with borohydride, for determination of the monosaccharide constituents of glycoconjugates. This method was applied to a lipid-free, protein fraction of rat brain. 

In the reductions with borohydrides and boranes the isolation of products differs from that used in the reductions with lithium aluminum hydride, the... 

Periodic acid oxidation has proved to be a very useful tool in enzymology since a wide variety of biochemicals contain hydroxyl groups on adjacent carbon atoms. For example, periodate-oxidized ATP (also called adenosine 5 -triphosphate 2, 3 -dialdehyde) has often been used as an alternative substrate or an irreversible inhibitor for a wide variety of ATP-utilizing enzymes. This compound, and many others, are now commercially available, even though they are readily synthesized e.g., periodic acid oxidized ADP, AMP, adenosine, P, P -di(adenosine-5 )pentaphosphate, P, P -di(adenosine-5 )tetraphos-phate, GTP, GDP, GMP, guanosine, CTP, CDP, CMP, etc. In the case of the nucleosides, commercial sources also can supply the dialcohol form of the nucleoside i.e., the nucleoside has first been oxidized with periodic acid and then reduced to the dialcohol with borohydride. 

Reduction of the azepinone ring in 63 can be accomplished selectively. Thus, hydrogenation results in selective 1,4-reduction of the enone moiety and furnishes the corresponding saturated ketone 65. Selective enone 1,2-reduction can be performed with n-BuLi-BHs to produce allylic alcohol 64. Reduction with borohydride is non-selective and gives saturated hydroxyl compound 66 (Scheme 13, Section 2.1.1.5 (2000T9351)). 

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