Sodium borohydride reductive amination

Keywords aldehyde, ketone, primary amine, sodium borohydride, reductive amination, K-10 clay, microwave irradiation, secondary amine... 

Scheme 2 shows Rapoport s synthesis [15]. The cinnamic acid derivative 3 prepared from m-methoxy benzaldehyde [20] was ethylated by diethyl sulfate to give ethyl cinnamate derivative 4, followed by Michael addition with ethyl cyanoacetate to afford compound 5. Compound 5 was converted to lactam 6 by the reduction of the cyano group and subsequent cyclization. Selective reduction of the lactam moiety of 6 was achieved by treatment with trimethy-loxonium fluorob orate followed by sodium borohydride reduction. Amine 8 was obtained by the reductive methylation of amine 7. Amine 8 was converted to compound 9 by methylene lactam rearrangement [21], followed by selenium dioxide oxidation to provide compound 10. Allylic rearrangement of compound 10 and subsequent hydrolysis gave compound 12. The construction of the decahydroisoquinoline structure began with compound 12,... 

Condensation between aldehyde 40 and amine 29 followed by sodium borohydride reduction of the resultant imine and cyclisation yielded isoquinoline 41 in good yield. Cyclisation occurred exclusively at the more electron-rich aromatic group. 

Bromination to 4 and substitution of the bromine by an amine gives 5. Sodium borohydride reduction of the ketone to an alcohol 6 is followed by a resolution with (-)-di-/ -toluoyltartaric acid and reduction of the ester group with lithium aluminum hydride to give diol 7. Catalytic debenzylation gives albuterol, sometimes called salbutamol. 

In this approach the R-amine moiety in in was considered likely, in view of the work of Yamada and Koga5 and later Kametani et al.,6 to provide some inductive control in the sodium borohydride reduction of IV. Moreover, the R-amine moiety is a necessary component of dilevalol. Desired inductive control was quickly demonstrated by Gold et al. (internal communication, October 25,1979). However, a broad study of process conditions, particularly of solvent and temperature effects, only gave, at best, a ratio of RR to SR of... 

The above result provided a basis for the idea that if both alkyl substituents on the amine moiety were R-configuration inductive control in the sodium borohydride reduction of the keto group might be greatly increased. Since a-methylbenzylamines are known to hydrogenolyze relatively easily (cf. benzylamine itself), a-methylbenzyl substitution was considered a good choice. The ready availability of both RS- and R-a-methylbenzylamine prompted investigation of this proposal. 

Sodium borohydride reduction of dienamines in the presence of a weak acid (acetic acid or methanol) results in kinetically favoured C-/ protonation followed by rapid hydride addition at C-a17. The method therefore provides a convenient method for converting an a,/ -unsaturated ketone into a y,<5-unsaturated amine as in the synthesis of con-nessine17 (Scheme 11). 

Cyclopropenylium ions 1 were converted into the corresponding cyclopropenes 2 by the addition of hydride ion derived from various hydride sources, such as lithium aluminum hydride,sodium borohydride, borane-amine complex, triethylsilane, and tributyl-tin hydride. Particularly in the case of borohydride reduction of the diphenylcyclo-propenylium ion, the order of reagent addition was quite important. The slow addition of an acetonitrile solution of the cyclopropenylium salt into a solution of the borohydride gave the cyclopropene derivative,whereas the inverse order of addition resulted in quantitative formation of 1,2,4,5-tetraphenylbenzene (see Section 2.1.2.3.), No such precaution of the inverse addition was required in the case of borane-amine reduction of the l-chloro-2,3-diphenyl-cyclopropenylium ion. ... 

Tin(ll) chloride reduction of the azidotriflates 81 followed by intramolecular cycliza-tion with sodium acetate in methanol and subsequent protection of the resulting secondary amine with benzyl chloroformate afforded the a- and -furanoside carbamates 83 and 82. Hydrolysis of 82 and 83 by TEA in aqueous dioxane followed by sodium borohydride reduction of the resulting lactol furnished the protected 1-deoxynojirimcin 84 (49%). Subsequent hydrogenation of 84 afforded 2. 

A synthesis of the intermediate 71, as aprecursor to (-)-swainsonine (1), has been reported (Scheme 8). Prolonged hydrogenation of the azide 69, obtained from D-mannose in eight steps, in methanol and then in acetic acid afforded the pyrrolidine 70 in 90% yield. Protection of the secondary amine in 70 with benzyl chloroformate followed by sodium periodate oxidation and subsequent sodium borohydride reduction gave 71. 

The main alkaloid was macromerine, C12H19O3N [mp 66° [a]u — 147° (CHCI3) [a]j) —42.6° (EtOH)] whose structure (CIX) was confirmed by two syntheses (1) chloracetoveratrone was reacted with excess trimethyl-amine and the product reduced with sodium borohydride (2) a Hoesch condensation of veratrole with dimethylaminoacetonitrile followed by sodium borohydride reduction. 

An example of the use of the tandem Staudinger/aza-Wittig reaction to form a seven-membered ring comes from the total synthesis of the alkaloid (-)-stemospironine (76).34 In this example, azidoaldehyde 74 was treated with triphenylphosphine to form a seven-membered cyclic imine which was then followed by an in situ sodium borohydride reduction to afford 75. Treatment of the resulting amine with iodine initiated the formation of the pyrrolidino butyrolactone system of the final target. 

On treatment of acomonine with potassium permanganate in aqueous acetone, an anhydro-oxy-derivative resulted. This internal carbinol amine ether was converted into the original base by sodium borohydride reduction. Permanganate oxidation of desoxyacomonine gave an oxo-derivative containing a y-lactam. On the basis of this chemical and additional spectral data, the secondary hydroxy-group was located at C-3. 

Various secondary pyridylamines have been prepared by the sodium borohydride reduction of the corresponding arylidene-amines. For example, pyridine-3-aldehyde condenses with p-nitroaniline to give IX-237, which, on reduction, gives the secondary amine IX-238. ... 

A quite different method converted the amino moiety of isoleucine to an hydroxyl group (see 6.204). Conversion to the azide, reduction to the amine and condensation of the ester with lithio methyl (2-trimethylsilyloxycarboxy) acetate gave 6.205. Sodium borohydride reduction gave 6.206, along with 9% of 5.207. Hydrolysis and re-protection of 6.206 gave N-Boc isostatine, 6.208. In this work, it was noted that amino acid 6.208 is a component of didemnin cyclodipeptide. 

Imines can be reduced to amines by catalytic hydrogenation, or by reduction with lithium aluminium hydride, sodium borohydride or amine-borane complexes . For many purposes, it is not necessary to prepare the imine as the desired amine can, at least in principle, be obtained by catalytic reduction of a mixture of the corresponding carbonyl compound and precursoral amine (reaction 95) The... 

Reaction of an aliphatic or aromatic aldehyde (RCHO) with sodium hydrogen selenide and an amine hydrochloride, followed by a sodium borohydride reduction, yields symmetrical diselenides (RCH2SeCH2R). ... 

The route commenced with the condensation of amine 229 and carboxylic acid 230 at 200 °C. Subsequent Bischler-Napieralski reaction and sodium borohydride reduction established the C/D ring system of morphine and delivered tetrahydroisoquinoline 231 in good yield. Next, Birch reduction and Af-formylation afforded enol ether 232, which was converted into the corresponding ketal before reaction with bromine allowed the isolation of the cyclization precursor. The halide in 233 serves to protect the para position in the aromatic ring in the subsequent acid-mediated electrophilic cyclization reaction—a common strategy that has also been applied by other research groups in their endeavors toward morphine and related alkaloids. 

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. 

AletalHydrides. Metal hydrides can sometimes be used to prepare amines by reduction of various functional groups, but they are seldom the preferred method. Most metal hydrides do not reduce nitro compounds at all (64), although aUphatic nitro compounds can be reduced to amines with lithium aluminum hydride. When aromatic amines are reduced with this reagent, a2o compounds are produced. Nitriles, on the other hand, can be reduced to amines with lithium aluminum hydride or sodium borohydride under certain conditions. Other functional groups which can be reduced to amines using metal hydrides include amides, oximes, isocyanates, isothiocyanates, and a2ides (64). 

Morpholiaoglucopyranosides have beea syathesized from sucrose by selective lead tetraacetate oxidatioa of the fmctofuranosyl ring to a dialdehyde (6). This product was subjected to reductive amination with sodium borohydride and a primary amine such as benzylamine to produce the /V-henzy1morpho1ino derivative (7) (99). 

Pyridoxal Derivatives. Various aldehydes of pyridoxal (Table 3) react with hemoglobin at sites that can be somewhat controlled by the state of oxygenation (36,59). It is thereby possible to achieve derivatives having a wide range of functional properties. The reaction, shown for PLP in Figure 3, involves first the formation of a Schiff s base between the amino groups of hemoglobin and the aldehyde(s) of the pyridoxal compound, followed by reduction of the Schiff s base with sodium borohydride, to yield a covalendy-linked pyridoxyl derivative in the form of a secondary amine. 

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