Sodium borohydride, reaction with imines

Phosphorylated allenes 195 (R1 = H or Me) are a source of secondary ( )-allylamines. The allenes are treated with an amine R2NH2 (R2 = t-Bu or 4-MeCgH4 and the products, which exist as equilibrium mixtures of enamines 196 and imines 197, are olefinated by successive reaction with methyllithium and an aldehyde R3CHO (R = i-Bu, 4-MeCgH4, PhCH2CH2 etc). Reduction with sodium borohydride finally yields the... 

Also other reaction types have been dealt with in CHEC(1984) and CHEC-II(19%) like reduction to alcohols (e.g., sodium borohydride), Wolff Kishner reduction, nucleophilic addition via reaction with Grignard reagents or organo-lithium compounds, and formation of imine type functional groups (e.g., hydrazones). New examples are the reaction of... 

Even if the imine may not be isolated, the transient species may sometimes be trapped by reaction with a suitable nucleophile. This is the basis of the reductive amination reaction in which an amine is formed from the reaction of ammonia with a carbonyl compound in the presence of a reducing agent such as sodium borohydride or formate. Use of a primary or secondary amine results in the specific formation of secondary or tertiary amines respectively (Fig. 5-45). This synthetic method allows the preparation of high yields of amines, in contrast to the unselective and uncontrollable reaction of alkylating agents with amines. A specific example involving the preparation of a-phenylethylamine from acetophenone is presented in Fig. 5-46. 

The standard synthesis for cyclam was developed by Barefield and Wagner in 1976.29 They used similar starting materials to the van Alphen procedure but the cyclisation yield is improved through the use of a nickel (II) template. Glyoxal completes the macrocycle by a Schiff base condensation reaction. The resulting imine functionalities are reduced with sodium borohydride to leave the complexed macrocycle. The metal ion is then removed by reaction with cyanide and the free ligand extracted with chloroform (Scheme 3.19). Yields are typically in the region of 60%. 

Preparative Methods both enantiomers of the a-methyl sultam may be prepared on a multigram scale in optically pure form by asymmetric hydrogenation of imine (2a) followed by simple crystallization (eq 1). The (7 )-enantiomer of the a-f-butyl sultam may also be prepared in enantiomerically pure form by asymmetric reduction of imine (2b) followed by fractional crystallization. However, multigram quantities of either enantiomer of the a-t-butyl sultam may be prepared by derivati-zation of the racemic auxiliary (obtained in 98% yield from reaction of (2b) with Sodium Borohydride in MeOH) with 10-Camphorsulfonyl Chloride, separation of the resulting diastere-omers by fractional crystallization, and acidolysis. Prochi-ral imines (2a) and (2b) are readily prepared from inexpensive Saccharine by treatment with Methyllithium (73%) and t-Butyllithium (66%), respectively. 

The cyclohexylidene protecting group has been employed in several syntheses. A preparation of 2,3-0-cyclohexylidene-4-deoxy-L-threose (445) fi om L-( + )-diethyltartrate (lb) in seven steps illustrates one synthetic application (Scheme 99). Conversion of the monobenzyl protected alcohol 443 to its tosylate followed by reduction with sodium borohydride provides the deoxy intermediate 444, which is reductively deprotected and Swem oxidized to 445 in good overall yield. Treatment with benzylamine provides an imine that undergoes a stereoselective carbon-carbon bond forming reaction with a-lithio-A, A -dimethylacetamide in the presence of the Lewis acid zinc bromide to furnish, after Cbz-amine protection, the j9-aminoamide 446. This is converted in four steps to A -acetyl-L-daunosamine (447), a sugar moiety particularly important as the carbohydrate constituent of the anthracycline antibiotics [149]. 

Primary amines are transformed into amides by substitution reactions of acid chlorides, and to imines by condensation with an aldehyde in the presence of an acid catalyst. Both amides and imines may be reduced to amines amides need LiAlH4, while imines may be reduced by sodium borohydride, sodium cyanoborohydride, or hydrogenation over a palladium catalyst. 

Chitosan is a multi-nucleophilic polymer due to the presence of the NH2 and OH functional groups. The initial sites where substitution occurs are the more nucleophilic amino groups. However, the experimental conditions and protection of the NH2 groups reduces the intermolecular hydrogen bonding and creates space for water molecules to fill in and solvate the hydrophilic groups of the polymer backbone (Sashiwa and Shigemasa 1999). A -alkylated derivatives can be obtained by the treatment of chitosan with aldehydes or ketones via formation of Schiff base intermediates, aldimines (from reactions with aldehydes), or ketimines (from reactions with ketones) followed by reduction of the imine with sodium borohydride. 

Isomannide (80) was the core for a hexahydrofurofuran library." Primary amines were loaded onto solid-support by reductive amination and acylated with bromoacetic acid to give bromides 79 (Scheme 7.16). Alkylation of bromides 79 on solid-support with isomannide (80) gave the solid-supported alcohols 81. A Mitsunobu reaction with phthalimide (82) proceeded to furnish amines 83 in excellent yield and purity after removal of the protecting group." " Support-bound primary amines 83 were converted to secondary amines by stepwise imine formation with aldehydes 84 and reduction with sodium borohydride." The hindered secondary amines 85 were acylated with acid chlorides, sulfonyl chlorides, isocyanates, and isothiocyanates to yield 87 after cleavage from solid-support. 

Reduction Add 4 mL of methanol to the stillpot, stir to dissolve the crude imine, and set up the apparatus for heating under reflux. Prepare a solution of 0.15 g of sodium borohydride in 3 mL of methanol. Because sodium borohydride reacts slowly with methanol to evolve hydrogen gas, this solution should be prepared in an unstoppered vessel immediately betore use. Using a Pasteur pipet or a syringe, transfer the methanolic solution of sodium borohydride dropwise through the top of the reflux condenser to the stirred solution of the imine the addition should be completed within 1 min. Try to add the solution d/recf/y into the flask without touching the walls of the condenser. After all of the borohydride solution is added, heat the reaction mixture under reflux for 15 min. 

Flafner et al first reported an oxidase-catalyzed deracemization method using amino acids as the substrate and pkDAAOx or LAAOx from Crotalus adamanteus together with sodium borohydride as the chemical reductant in 1971 [42]. A procedure for the successful deracemization of amino acids was previously reported by Soda et al. [43]. They focused on proline and pipecolic acid as substrates for the production of L-enantiomer by deracemization because these substrates formed stable imines rather than unfavorable keto acids in water by DAAOx. However, the enzyme was denatured by the chemical reaction with sodium borohydride. Turner et al developed an effective production method for (R)- or (S)-amino acids and (S)-amines by a deracemization method using milder chemical reducing reagents such as sodium cyanoborohydride and artificial transfer hydrogenase [44,45]. 

The highly strained and reactive 2iT-azirines have been extensively studied for various synthetic purposes, such as ring expansion reactions, cycloaddition reactions, preparation of functionalized amines and substituted aziridines. The older literature on azirines in synthesis has extensively been reviewed [69]. Concerning azirines with defined chirality only scarce information is available. Practically all reactions of azirines take place at the activated imine bond. Reduction with sodium borohydride leads to cz5-substituted aziridines as is shown in Scheme 48 [26,28]. 

Thus, treatment of the benzamide (35-1) from 2-phenethylamine with phosphorus oxychloride probably results in an initial formation of a transient enol chloride this then cycUzes to (35-2) under reaction conditions. The imine is then reduced with sodium borohydride. Resolution by means of the tartrate salt affords (35-3) in optically pure form. Acylation of that intermediate with ethyl chloroformate leads to carbamate (35-4). Reaction of this last with the anion from chiral quiniclidol (35-5) interestingly results in the equivalent of an ester interchange. There is thus obtained the anticholinergic agent solifenacin (35-6) [40]. 

Borohydrides normally do not attack carbon-carbon multiple bonds, and thus, a, 3-unsaturated imines (1-aza-1,3-butadienes) are reduced only at their C=N bond, under both thermal and microwave conditions. However, the corresponding (1-aza-1,3-butadiene)tricarbonyliron(O) complexes show a totally different reactivity under the same conditions, and a simultaneous reduction of both C=N and C=C takes place if microwave irradiation is applied25. When the reaction was performed with sodium borodeuterid, 1,2,3-trideutero, secondary amines were obtained. In contrast to their behaviour under microwave conditions, these complexes were totally inert to reduction by NaBH4 under thermal conditions (Scheme 4.7)25. 

Perhaps the most useful part of the reported synthesis is the facile preparation of (—)-pyrimidoblamic acid (12 Scheme 3). A key to this synthesis is the preparation of the fully substituted pyrimidine 8. This was done by a one-pot inverse electron demand Diels-Alder reaction between the symmetrical triazine 7 and prop-1-ene-1,1-diamine hydrochloride, followed by loss of ammonia, tautomerization, and loss of ethyl cyanoformate through a retro-Diels-Alder reaction. Selective low-temperature reduction of the more electrophilic C2 ester using sodium borohydride afforded 9, the aldehyde derivative of which was condensed with 7V -Boc-protected (3-aminoalaninamide to give the imine 10. Addition of the optically active A-acyloxazolidinone as its stannous Z-enolate provided almost exclusively the desired anti-addition product 11, which was converted into (—)-pyrimidoblamic acid (12). Importantly, this synthesis confirmed Umezawa s assignment of absolute configuration at the benzylic center. 

The reduction is usually effected catalytically in ethanol solution using hydrogen under pressure in the presence of Raney nickel. As in the reduction of nitriles (Section 5.16.1, p. 771), which also involves the intermediate imine, ammonia or the amines should be present in considerable excess to minimise the occurrence of undesirable side reactions leading to the formation of secondary and tertiary amines. These arise from the further reaction of the carbonyl compound with the initially formed amine product. Selected experimental conditions for these reductive alkylation procedures have been well reviewed.210 Sodium borohydride has also been used as an in situ reducing agent and is particularly effective with mixtures of primary amines and aliphatic aldehydes and ketones.211... 

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