Subject reductive amination

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). 

To investigate the feasibility of employing 3-oxidopyridinium betaines as stabilized 1,3-dipoles in an intramolecular dipolar cycloaddition to construct the hetisine alkaloid core (Scheme 1.8, 77 78), a series of model cycloaddition substrates were prepared. In the first (Scheme 1.9a), an ene-nitrile substrate (i.e., 83) was selected as an activated dipolarophile functionality. Nitrile 66 was subjected to reduction with DIBAL-H, affording aldehyde 79 in 79 % yield. This was followed by reductive amination of aldehyde x with furfurylamine (80) to afford the furan amine 81 in 80 % yield. The ene-nitrile was then readily accessed via palladium-catalyzed cyanation of the enol triflate with KCN, 18-crown-6, and Pd(PPh3)4 in refluxing benzene to provide ene-nitrile 82 in 75 % yield. Finally, bromine-mediated aza-Achmatowicz reaction [44] of 82 then delivered oxidopyridinium betaine 83 in 65 % yield. 

For the solution-phase preparation of functionalized tropanylidenes, the authors simply dispensed solutions of the bromo N-H precursor in 1,2-dichloroethane (DCE) into a set of microwave vials, added the aldehydes (3 equivalents) and a solution of sodium triacetoxy borohydride in dimethylformamide (2 equivalents), and subjected the mixtures to microwave irradiation for 6 min at 120 °C. Quenching the reductive amination with water and subsequent concentration allowed a microwave-assisted Suzuki reaction (Section 6.1.2) to be performed directly on the crude products [295]. 

The described fluorous-tag strategy has also been applied to the synthesis of biaryl-substituted hydantoins (Scheme 7.81) [94]. 4-Hydroxybenzaldehyde was converted into the corresponding perfluorinated species, which was then subjected to a reductive amination. The resulting amine was treated with an isocyanate to produce the fluorous-tagged urea, which spontaneously cyclized to form the corresponding hydantoin. Finally, the fluorous tag was detached by a Suzuki-type carbon-carbon bond formation to furnish the desired target structure in good yield. 

Synthesis of a C(8)-C(18) segment of the larger fragment of lb using the same basic strategy is depicted in Scheme 25. Here, hydroxy ketone 176 was subjected to syn-selective (dr of crude product=90 10) reductive amination [42] with sodium cyanoborohydride and benzylamine followed by tetrahydro-oxazine formation using aqueous formaldehyde. The resulting heterocycle 182 was then converted to unsaturated ester 184 by successive desilylation, oxidation, and entirely (Z)-selective Horner-Wadsworth-Emmons olefination. Re-... 

In a multistep transformation between Gly and piperonal, the tetracyclic system ISO was prepared [92H(33)537]. During the studies of Securinenga alkaloids, ethyl 2-thienylacetoacetate was subjected to reductive amination with L-Pro-OMe after cyclization, two tetracyclic diastereoisomers 151 and 152 were formed (83JOC3428). 

The Merck process group subsequently published a more detailed route amenable towards multikilogram scales (Blacklock et al., 1988). This synthesis begins with treatment of alanine with phosgene to produce A-carboxyanhydride (NCA) 16 (Scheme 10.3). Under basic aqueous conditions this anhydride is coupled with proline to produce, upon acidic work-up, the dipeptide alanyl-proline (14). Enalapril is then prepared in one synthetic step by a diastereoselective reductive amination between ethyl-2— oxo-4-phenylbutyrate (13) and 14. This reaction was the subject of extensive optimization, and it was found that the highest diastereoselectivity was obtained by hydrogenation over Raney nickel in the presence of acetic acid (25%), KF (4.0 equiv.), and 3 A molecular sieves (17 1 dr). Enalapril is then isolated in diastereomerically pure form as its maleate salt (Huffman and Reider, 1999 Huffman et al., 2000). 

The application of resin 13 to the sohd-phase synthesis of other useful target compounds was also explored and an example of this is the multistep synthesis of Meclizine (Fig. 10).26 The starting material, 3-methyl-4-hydro-xybenzaldehyde, is attached to the PFS hnker, and a polymer-bound amine intermediate is prepared by a reductive amination of resin 23 with amine 24. The resulting resin 25 is subjected to a palladium-mediated reductive cleavage to give Meclizine 26 in 80% yield, based on the original resin loading. 

Quinazolines are of great interest in the pharmaceutical industry as protein tyrosine kinase inhibitors. Dener et al 8 described a synthesis starting from 2-methoxybenzaldehyde, Wang, or Rink resins. With the aldehyde resin reductive aminations were undertaken to yield polymer-bound secondary amines (Fig. 7). The latter were subjected to 2,4-dichloro-6,7-dimethoxyquinazoline to give the 4-amino-substituted derivatives. These were then allowed to react with primary or secondary amines at 135-140° in the presence of DBU in DMA. As a result of a detailed scope and limitation study, Dener et al,28 note that some bifunctional amines, such as piperazine, give to some extent dimeric derivatives. 

Scheme 16 shows parallel syntheses of cyclic and acyclic amide compounds. Fluorous benzaldehydes were first subjected to reductive amination reactions. The resulting amines were then reacted with isocyanates to form substituted hydantoin rings 14 or with benzoyl chlorides to form amides 15. Purified F-sulfonates were used for palladium-catalyzed cross-coupling reactions to form corresponding biaryl 16 [31] and arylsulfide 17 [32] products, respectively. 

The synthesis of the derivatives (339)-(346) was carried out as shown in Scheme 28. Metalation of the acetal (336), followed by thiolation and alkylation, gave the ester derivative (337). Acetal deprotection to form (338) and subsequent treatment under Knoevenagel conditions with piper-idinium acetate in benzene afforded the desired ester (339). Reduction of compound (339) gave alcohol (340), which was converted to aldehyde (341) and protected as its acetal (342) under standard conditions. Deprotonation was effected by Bu"Li in THF at — 78 °C and subsequent conversion to the sulfonyl chloride was carried out by sequential treatment with sulfur dioxide and A-chloro-succinimide. Treatment of the sulfonyl chloride (343) with concentrated NH4OH in acetone provided the sulfonamide (344), which was deprotected (345) and subjected to reductive amination to provide compounds in the aminomethyl sulfonamide series (346). 

The biosynthetic pathway from SA into L-Phe [69, 70] is shown in Fig. 8.15. The synthesis of chorismate (CHA), the common intermediate in the biosynthesis of the aromatic amino acids, requires an extra equivalent of PEP, which limits the yield of L-Phe from glucose to 0.30 mol mol-1 if PEP is not conserved [91]. The further transformation of CHA into phenylpyruvic acid (PPY) suffers from inhibition by L-Phe and is also subject to transcriptional control [69, 92]. The final step is a reductive amination of PPY into L-Phe with consumption of l-G1u. 

In a modified version, the aniline 258, which is readily available from the corresponding o-nitrotoluene, was subjected to reductive amination with the ketone 259 providing 260, which gave the target indole 261 after a final acid-induced cyclization (Scheme 30) <1996TL6045>. Additional applications of this approach have emerged later <2003T7215>. 

Construction of the second part of the molecule starts with palladium-catalyzed coupling of the substituted pyridine (238) with phenylboronic acid to give 239. Hydrogenation reduces both the nitro group and the supporting pyridine ring to afford 240 as the cis isomer. The enantiomers of this are then separated by resolution. The desired isomer is then subjected to reductive amination with aldehyde 237 affording 241. " ... 

The enantioselective reductive amination of ketoacid substrates has been dem onstrated and provides amino acids that are beyond the scope of this review [6]. Enzymatic based reductive amination is now possible and allows nonamino acid chiral amine synthesis, however, this field of study is also beyond the scope of this material [7]. Finally, much of the material discussed here also appeared in a recent review of ours on the general subject of chiral amine synthesis. 

L-Arabino-hexos-5-nlose (41) has been nsed to synthesize 1-deoxygalactostatin (4) (Scheme 9). Componnd 41, obtained from methyl (3-D-glucopyranoside (40), was subjected to reductive amination with benzhydrylamine and sodium cyanoborohydride in a diastereospecitic manner to give a moderate yield (36%) of 42. The conversion of componnd 42 into 4 was achieved by hydrogenation. ... 

In this contribution, we first review the hydrogenation of carbohydrates to polyols. Section 8.4.3 will focus on the reductive amination of carbohydrates and, finally (Section 8.4.4), the facile dehydrogenation of carbohydrates under alkaline conditions will be reported. The hydrogenolysis of carbohydrates is beyond the scope of this chapter. Readers interested in this subject should consult Ref. 3 and references cited therein. 

Leuckart-like reactions have been noted for the co-phosphinoylalkanals 304 and related compounds In these reactions, and also for those with analogous ketones the carbonyl reactant is subjected to reductive amination with ammonia (as ammonium acetate) or amines and NaBH3CN in MeOH at pH 7-7.5 the process is very sensitive to steric hindrance and probably proceeds via an enaminophonate intermediate. The sequence is illustrated (Scheme 38) by a direct synthesis of racemic phosphinothricin, but the involvement of the optically active 1,2-azaphospholidine 118 led to an optically active product ". ... 

Reductive amination. L ire subject to reduction. This imines. 

Reductive amination. Imines formed in situ from amines and carbonyl compounds are subject to reduction. This method constitutes a convenient synthesis of secondary amines. 

Oximes which are treated with tosyl chloride can also be used as substrates in the Neber rearrangement to a-amino ketones. The mixture shown in eq 26 was further subjected to reductive amination to 3ueld 14% of the CNS-active cis-lV,A(-dimethylated a-amino alcohol. 

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