Aldehydes, reduction with NaBH

Methylthiomethyl p-tolyl sulfone 257 was shown to react with various esters in the presence of excess NaH, affording compounds 263 which, upon reduction with NaBH and further treatment with alkali, can be converted to the corresponding aldehydes ". Oxidation of 263 with hydrogen peroxide gives S-methyl a-ketocarbothioates 264. ... 

Microwave-induced imine formation, subsequent reduction with NaBH(OAc)3 and cyclisation of the resulting amino acid with isothiocyanates was used in an efficient one-pot multi-step synthesis of thiohydantoins (Scheme 4.26). The reductive animation was conducted as a two-step procedure to avoid direct reduction of the aldehyde at high temperatures48. 

Reduction. The differentiation of two aldehyde groups is important while (-F)-digitoxigenin is being synthesized. During reduction with NaBH(OAc), in benzene, the neopentyl aldehyde can be retained. 

Another interesting application involved the formation of allylic amines 33a-e in enantiomerically pure form as published by the Jprgensen group (Scheme 5.18) [25]. This Mannich reaction was conducted between the benzothiazolesulfonyl-derived aldehydes 31a-e and the Boc-protected aldimine 23a. After the initial Mannich reaction, a subsequent reduction with NaBH was carried out to give rise to the allylic amines 33a-e in moderate yields, but high E/Z-ratios and enantioselectivity. 

Sodium borohydride has been extensively used as a reducing agent. The solid state reduction with NaBH requires longer time and use of solvents slow down the reaction. A microwave irradiation reaction has been developed for the reduction of aldehydes and ketones using alumina supported NaBH (Scheme 23). 

Enamide hydroformylation was evaluated as a new route to an l-DOPA precursor (Scheme 4.73). The required prochiral substrate was derived by a three-step sequence starting from vanillin. The asymmetric catalysis was conducted in a 0.15 g scale at 10 bar. Noteworthy, the chiral aldehyde obtained did not racemize during reduction with NaBH at low temperatures. Moreover, the authors claimed that also oxidation of the chiral a-formyl amides is possible without epimerization, since such compounds are stable even at temperatures of 100 °C [45]. However,... 

Dimethylocta-l,6-diene was used as a substrate for the highly -selective hydroformylation with a homogeneous Rh(Xantphos) catalyst (Scheme 6.21) [95]. The odor of the aldehyde yielded was described as fresh, orange peel, and herbaceous with coriander leaf accents. Subsequent reduction with NaBH yielded the unsaturated alcohol, which was characterized from the olfactory point of view as rustic with a note of floral, bergamot, and cinnamon. 

The aforementioned transformation also can be performed with simple and inexpensive iV-chloro succinimide (95a). In this case either Cj-symmetric pyrrolidine 98 or prolinamide 99 in 10 mol% could be successfully used with the reaction conditions being milder than in the previous case (methylene chloride at room temperature, Scheme 4.21). The obtained chiral a-chloro aldehydes 96 are configurationally stable to pH neutral silica purification, although they can be easily transformed into a wide variety of different compounds, such as epoxides (reduction with NaBH and... 

Sodium cyanoborohydride is remarkably chemoselective. Reduction of aldehydes and ketones are, unlike those with NaBH pH-dependent, and practical reduction rates are achieved at pH 3 to 4. At pH 5—7, imines (>C=N—) are reduced more rapidly than carbonyls. This reactivity permits reductive amination of aldehydes and ketones under very mild conditions (42). 

Treatment of a monosaccharide with NaBH., reduces it to a polyalcobol called an alditol. The reduction occurs by interception of the open-chain form present in the aldehyde/ketone-hemiaceta) equilibrium. Although only a small amount of the open-chain form is present at any given time, that small amount is reduced then more is produced by opening of the pyranose form and that additional amount is reduced and so on, until the entire sample has undergone reaction. 

Homoallylic alcohols. A Barbier-type allylation of aldehydes in aqueous DMF is mediated by activated Sb (prepared by reduction of SbClj with NaBH or Zn powder ). 

Reduction of iminium salts. 1,3-Diamines can be elaborated via reduction of the monoiminium species which arise from condensation of enamines with aldiminium salts. The subsequent reduction is carried out with NaBH, in methanol. Oximes of a-aminocycloalkanones undergo fragmentation and reduction, furnishing co-amino nitriles. A route to substituted ureas involves reductive alkylation, condensation with aldehydes in the presence of MejSiCl followed by treatment with NaBH. The borohydride reduction of P-amino-a,P-unsaturated esters in the presence of isobutanoic acid may also proceed via iminium species. 

Boc-amino acid 472 was attached to 471 using CS2CO3 and KI in DMF to afford 473 (Scheme 9.57). After removal of the Boc group using the TFA/DCM method, treatment with aldehyde 474 and NaBH(OAc)3 in the presence of acetic acid in DCM facilitated the reductive alkylation of the free amine. Resin 475 was then treated with oxoacetic acid derivative 476 and DIC in DCM, forming the key intermediate 477, which was then treated with ammonium acetate 478 and acetic acid in toluene for cyclocleavage to generate the E-and Z-isomers of 479. 

Also, A-hydroxy- 3-amino alcohols 44 (R = H, Scheme 4.6) were achieved in high yields and enantioselectivities using axially chiral secondary amine catalyst 46a (10 mol%) to perform the hydroxyamination of linear aldehydes 42 with nitrosobenzene (43a, Ar=Ph), with excellent results (77-90%, 97-99% ee) [45]. Due to the instability of the resulting hydroxyamination product, in situ reduction to the corresponding alcohol was carried out using NaBH. ... 

The N-substituted aminoacids required could be prepared by microwave-assisted reductive amination of aminoacid methyl esters with aldehydes, and although in the Westman report soluble NaBH(OAc)3 was used to perform this step, other reports have shown how this transformation can be performed in using polymer-supported borohydrides (such as polymer-supported cyanoborohydride) under microwave irradiation [90]. An additional point of diversity could be inserted by use of a palladium-catalyzed reaction if suitably substituted aldehydes had been used. Again, these transformations might eventually be accomplished using supported palladium catalysts under microwave irradiation, as reported by several groups [91-93]. 

The drug candidate 1 was prepared from chiral cyclopentanol 10 as shown in Scheme 7.3. Reaction of 10 with racemic imidate 17, prepared from the corresponding racemic benzylic alcohol, in the presence of catalytic TfOH furnished a 1 1 mixture of diastereomers 18 and 19 which were only separated from one another by careful and tedious chromatography. Reduction of ester 18 with LiBH4 and subsequent Swern oxidation gave aldehyde 20 in 68% yield. Reductive animation of 20 with (R)-ethyl nipecotate L-tartrate salt 21 and NaBH(OAc)3 and subsequent saponification of the ester moiety yielded drug candidate 1. 

While ether is the common solvent for LiAlH, in which it is soluble, hydroxylic solvents like water, methanol and ethanol are preferred for NaBH, It is more soluble in methanol than in ethanol, but since it reacts with the former at an appreciable rate than the latter, hence ethanol is the preferred solvent. Isopropanol, in which NaBH4 is stable, is used for kinetic studies of the reduction of aldehydes and ketones. 

Alcohols are among the most versatile of all organic compounds. They occ. widely in nature, are important industrially, and have an unusually he chemistry. The most important methods of alcohol synthesis start with carbonyl compounds. Aldehydes, ketones, esters, and carboxylic acids are reduced by reaction with either NaBH,i or LiAIH4. Aldehydes, esters, and carboxylic acids yield primary alcohols (RCHgOH) on reduction ketones yield secondaiy alcohols (R CHOH). 

Treatment of a ketone or aldehyde with LiAlH or NaBH4 reduces the carbonyl group and yields an alcohol (Section 17.5). Although the exact details of carbonyl-group reduction are complex, LLAIH4 and NaBH act as if they were donors of hydride ion, H , and the key step is a nucleophilic addition reaction (Figure 19.7). Addition of water or aqueous acid after the hydride addition step protonates the tetrahedral alkoxide intermediate and gives the alcohol product. 

Reformatsky-type reactions and reductions. Enolates generated from a-bromoketones by reaction with BiClj-Al in an aqueous medium condense with various aldehydes to give J-hydroxy ketones." A modification of reaction conditions (BiClj-NaBH ) and in the absence of aldehydes leads to hydrodehalogenation of the haloketones. ... 

Oxidations and reductions. Phase-transfer catalyst enables the oxidation of benzylamines to benzamides with KMnO in an organic solvent, whereas reduction of aldehydes can be carried out in toluene using NaBH and polyethylene glycol. ... 

R,AR2 O./0 O bap w O rAr2 [273] Reducing agents used LiBH, BH,-py (BAP) NaCNBH, NaBH(OAc), Reductive alkylation works well with aminoesters and a range of anilines. BAP has been found to be the best reducing agent for less stable iminium ion intermediates formed with sec- amines and aldehydes/ketones. Partial racemization of amino acids is sometimes observed. Bfv-alkylation is sometimes observed with aliphatic aldehydes [26] [59] [65] [67] [107] [120] [161] [163] [186] [195] [196] [197] [198] [199] [219] [225] [260] [267-273]... 

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