Amines, NaBH

Scheme 3.1. Combinatorial synthesis of benzimidazoles using 30(10 -1- 10-l 10) building blocks to prepare 1000(10 x 10 x 10) products in a combinatorial fashion. Reagents (i)amine/NaBH(AcO)3 in DMF/AcOH (ii) o-fluoronitrobenzene, DMSO, rt, overnight (iii) SnCl2-2H20 in NMP, rt, overnight (iv) acid chloride/DlEA in DCM, rt, overnight (v) AcOH, 80°C, overnight.

Microgram amounts of neutral sugars could be detected by reductive amination [NaBH CN-(NH )3 to produce 1-amino-l-deoxy-aldltols, followed by derlvatlzation with the fluorescent labelling reagent NBD-F ( 7-f luoro-i -nitrobenz-2-oxa-l, 3-dlazole ), and reversed phase h.p.l.c. analysis. These derivatives were also suitable for t.l.c. analysis on boric acid Impregnated silica... 

Allylic amines can be cleaved. Hydrogenolysis of allylic amines of different stereochemistry with NaBH CN was applied to the preparation of both dia-stereoisomers 655 and 657 of cyclopentenylglycine from the cyclic amines 654 and 656 of different stereochemistry[405]. 

Sodium Borohydride. Sodium borohydride [16940-66-2] is a thermally stable, white crystalline soHd that decomposes in vacuo above 400°C. The heat of formation is —192 kJ/mol (—45.9 kcal/mol). NaBH is hygroscopic and absorbs water rapidly from moist air to form a dihydrate that decomposes slowly to sodium metaborate and hydrogen. It is soluble in many solvents including water, alcohols, Hquid ammonia and amines, glycol ethers, and dimethyl sulfoxide. 

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). 

Yet a third method for the synthesis of a-amino acids is by reductive amination of an a-keto acid with ammonia and a reducing agent. Alanine, for instance, is prepared by treatment of pyruvic acid with ammonia in the presence of NaBH As described in Section 24.6, the reaction proceeds through formation of an intermediate imine that is then reduced. 

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]. 

Unless contraindicated for economic reasons, it is recommended to use 10 Eq. each of amine and NaBH3CN for the on-resin reductive amination step. In some cases, as little as 1-2 Eq. of amine will give efficient incorporation. NaBH(OAc)3 can be used instead of NaBH3CN. As a rule, reactions should be performed at 25°C. 

This isomerization was confirmed by means of a detailed kinetic NMR study (90T633), but is not detrimental to the synthesis of substituted 1,2,4-triazoles, because in all cases removal of the protecting group leads to a tautomeric mixture of 3- and 5-substituted products. The methods available for removal of the animal function actually depend upon the nature of the added C-5 substituent, with acid hydrolysis occurring only in some cases. More commonly, treatment with NaBH in refluxing ethanol is the method of choice (90T633). Lithiation and derivatization of the SEM protected compound (entry 6) can be achieved without the isomerization shown by the animal derivative, and deprotection can be achieved with either aqueous acid or anhydrous fluoride ion [92H(34)303], However, overall reaction yields are not as high as those for the aminal system. 

Protection of primary amines. Primary amines form the cyclic adducts 2 ("Stabasc adducts ) on reaction with I and a base (triethylamine for amines with pK 10 II, -butyllithium for less basic amines). The adducts are stable to n- and. KT-BuLi (-25°), LDA, H 0, CH3OH, KF, and NaHCOj but unstable to HOAc, HC1, KOH, and NaBH. ... 

NaBHa, diglyme, amine base NaBH , CoCI2-6H20... 

Fig. 10. Multiple derivatization of purines including palladium-catalyzed reaction at the poorly reactive C2 position, (a) NaBH(OAc)3, 1% HOAc, THF (b) 59 (0.5 equiv.), 2,6-dichloropurine (1 equiv.), DIEA (1.5 equiv.), BuOH 80° (c) R2OH, PPh3, DiAD (1.5 2 1.3) in excess, THF, RT (d) boronic acids (5 equiv.), 7% Pd2(dba)3, 14% carbene ligand, Cs2C03 (6 equiv.), 1,4-dioxane, 90°, 12 h (e) anilines (5 equiv.), 7% Pd2(dba)3, 14% carbene ligand, KO Bu (6 equiv.), 1,4-dioxane, 90°, 12 h (f) phenols (5 equiv.), 7% Pd2(dba)3, 28% phosphine ligand, K3P04 (7 equiv.), toluene, 90°, 12 h (g) primary or secondary amines (5 equiv.), 90°, 12 h.

Another early solid-phase synthesis focused on preparing l,4-benzodiazepine-2, 5-diones, a structure common to many different classes of drugs.20 The route started with preparation of a custom resin-linker (9.61) (Scheme 9.10). The resulting resin was divided into 10 equal portions. Each portion was mixed with a different a-amino acid in the presence of NaBH(OAc)3 to form amine 9.62 (Scheme 9.11). Each of the 10 different batches of amine 9.62 was in turn evenly divided into 12 portions for a new total of 120 individual batches of resin. Each batch was loaded into a tube with a fritted bottom. The... 

The reagent combination TiCl(0 Pr)3-NaBH(OAc)3 performs reductive amination of aldehydes by electron-deficient and heteroaromatic primary amines, to give secondary amine.317... 

To a stirred solution of 1.1 g (4.7 mmol) of jV-benzyloxycarbonyl-5-hexen-2-amine in 80mL of THF, 2.6g (8.2 mmol) of Hg(OAc)2 are added in one portion. The mixture is purged with N2 and stirred for 18 h in the dark. A solution of 0.2 g (5.3 mmol) of NaBH, in 0.5 mL of 2.5 M NaOH is added dropwise to the mixture. The mixture is stirred overnight, treated with 3 mL of sat. Na,C03 and stirred for an additional 4 h. After removal of THF, the residue is diluted with Et20 and extracted with sat. Na,COv The aqueous layers are combined and extracted with Et,0. The organic layers are combined, dried, filtered and concentrated to give an oil yield 1.05 g (95%). 

Complex hydride reductions of Nj, N O, [CN] and nitriles in reactions containing complex mixtures of metal-ion species produce N—H bonded products " by reactions that may relate to those of the biological nitrogenases". Complete reaction stoichiometries are not well established. These reactions are not competitive with other methods for NH or amine synthesis. Nitrogen reacts in H O with a mixture of NaBH, S-donor ligands (e.g., NH CjM SH) and Mo and Fe salts to form NHj and NjH in low yield . In similar systems, nitriles and isonitriles are reduced to NHj and amines in low yield . 

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