14593-16-9

The present invention provides processes for the synthesis of organic azides, intermediates for the production thereof, and compositions related thereto.

We herein report a direct intermolecular anti-Markovnikov hydroazidation method for unactivated olefins, which is promoted by a catalytic amount of bench-stable benziodoxole at ambient temperature. This method facilitates previously difficult, direct addition of hydrazoic acid across a wide variety of unactivated olefins in both complex molecules and unfunctionalized commodity chemicals. It conveniently fills a synthetic chemistry gap of existing olefin hydroazidation procedures, and thereby provides a valuable tool for azido-group labeling in organic synthesis and chemical biology studies.

Herein, a sequential and selective chemoenzymatic approach is described involving the metal-catalysed Wacker-Tsuji oxidation of allylbenzenes followed by the amine transaminase-catalysed biotransamination of the resulting 1-arylpropan-2-ones. Thus, a series of nine optically active 1-arylpropan-2-amines were obtained with good to very high conversions (74–92%) and excellent selectivities (>99% enantiomeric excess) in aqueous medium. The Wacker-Tsuji reaction has been exhaustively optimised searching for compatible conditions with the biotransamination experiments, using palladium(II) complexes as catalysts and iron(III) salts as terminal oxidants in aqueous media. The compatibility of palladium/iron systems for the chemical oxidation with commercially available and made in house amine transaminases was analysed, finding ideal conditions for the development of a general and stereoselective cascade sequence. Depending on the selectivity displayed by selected amine transaminase, it was possible to produce both 1-arylpropan-2-amines enantiomers under mild reaction conditions, compounds that present therapeutic properties or can be employed as synthetic intermediates of chiral drugs from the amphetamine family. (Figure presented.).

A highly enantioselective rhodium-catalyzed hydrogenation of both (Z)- and (E)-β-arylenamides was developed by using monodentate chiral spiro phosphite and phosphine ligands, respectively. The hydrogenation reaction provides an efficient access to optically active β-arylisopropylamines, important building blocks for the synthesis of biologically active compounds.

A process for making compound of formula Ifrom a phenylpropanolamine salt of formula IIwherein:R1 is hydrogen or a lower alkyl group;each R2 is independently a hydrogen, halogen, lower alkyl group, lower alkoxy groups, lower alkyl group substituted with 1 to 5 halogens, lower alkoxy groups substituted with 1 to 5 halogens, or both R2 together when on adjacent carbons constitute a -O(CH2)xO- where x is 1 to 4, thereby forming a ring structure fused with the phenyl group;R3 is a C1-C8-alkyl group, a C1-C12-aralkyl group, C1-C12-alkaryl group, or a phenyl group, each optionally substituted by 1 to 5 substituents selected from halogen, hydroxy, or C1-C6-alkyl; andHX is an equivalent of an organic or inorganic acid,the process comprising:(a) acylating the phenylpropanolamine salt of formula II with an acylating agent in a solvent at elevated temperature to make a reaction mixture containing an O-acylated phenylpropanolamine salt of formula III which can be isolated by the addition of a crystallization solvent, or optionally this mixture can be used in the next step; and(b) hydrogenating the O-acylated phenylpropanolamine salt to make the compound of formula I in the presence of a catalyst.

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A support functionalized by an indole or pyrrole aldehyde is useful for the solid phase synthesis of amide type compounds.

Magnesium and methanol reduction of N,9-dibenzyl-8-azabicyclonon-1(6)-en-7-one (6) gave all four racemates of N,9-dibenzyl-8-azabicyclononan-7-one (1)-(4), with a 13:6 ratio of cis-fused to trans-fused products.Selective reduction of N,9-dibenzyl-8-azabicyclonon-1(6),3-dien-7-one (5) gave almost exclusively the two cis-fused racemates of N,9-dibenzyl-8-azabicyclonon-3-en-7-one (9) and (10).Magnesium and methanol did not reduce (E)-N-benzyl-9-benzylidene-cis-bicyclononan-7-one (7) and (E)-N-benzyl-N-(1-methyl-2-phenylvinyl)-acetamide (16a), but did reduce (E)-N-benzyl-N-styrylacetamide (16b) and (E)- and (Z)-N-styrylpyrrolidin-2-one (13) and (14); incomplete reduction of (Z)-N-benzyl-N-(1-methyl-2-phenylvinyl)-acetamide (15a) and (Z)-N-benzyl-N-styrylacetamide (15b) was observed.Reduction does not occur when the styryl phenyl group is twisted out of conjugation.Sodium and liquid ammonia reduction of (E)-N-benzyl-9-benzylidene-cis-8-azabicyclononan-7-one (7) gave (1RS,6SR,9RS)-9-benzyl-8-azabicyclononan-7-one and N-benzyl-2-(2-phenylethyl)cyclohexane-1-carboxamide (20).A similar cleavage of the β-styryl-nitrogen bond was observed in the reduction of (Z)-N-benzyl-N-(1-methyl-2-phenylvinyl)acetamide (15a), but not with (E)-N-styrylpyrrolidin-2-one (13).Several tertiary N-styrylenamides were not reduced by sodium cyanoborohydride in acetic acid but N-benzyl-9-benzylidene-cis-8-azabicyclonon-3-en-7-one (8) and N-benzyl-9-benzylidene-cis-8-azabicyclononan-7-one (7) gave (1RS,6SR,9RS)-N,9-dibenzyl-8-azabicyclonon-3-en-7-one (9) and (1RS,6SR,9RS)-N,9-dibenzyl-8-azabicyclononan-7-one (2) respectively.

The decarboxylation of L-tryptophan catalyzed by the aromatic L-amino acid decarboxylase from Micrococcus percitreus was competitively inhibited by α-methyl-L-phenylalanine.During prolonged incubation with the α-methyl amino acid, the enzyme lost its activity and its absorption spectrum changed drastically.The activity was restored by the addition of a cofactor, pyridoxal phosphate (PLP).The reaction products from α-methyl-L-phenylalanine were isolated and identified as methylbenzylketone and α-methyl-β-phenylethyl amine.PLP added to the reaction mixture was found to change to pyridoxamine phosphate (PMP) after the reaction.These results indicate that the enzyme catalyzes decarboxylation-dependent transamination besides the normal decarboxylation of α-methyl-L-amino acids.

On the example of some alkenes containing the allyl group: 5,5-diallyl-4,6-dioxo-hexahydropyrimidine, 5,5-diallyl-2-oxo-hexahydropyrimidine, diallylacetamide, allylcyclohexane and allylbenzene, the course of sulfonation reaction, competitive to the Ritter reaction, was examined.Its mechanism was suggested and compared to the classical Ritter reaction.

The addition of different carboxamides and related compounds such as urethane or urea to olefins using mercury(II) nitrate followed by sodium borohydride reduction to give the corresponding N-substituted amides, urethanes, or ureas, respectively, is described.The monoalkylated ureas, through the same amidomercuriation-demercuriation procedure, yield symmetrical and unsymmetrical N,N'-disubstituted ureas.This amidomercuriation-demercuriation process provides a new, convenient, and general method for the Markovnikov amidation of carbon-carbon double bonds.

The reaction of olefins with anhydrous mercury(II) nitrate in the presence of primary amides leads, after in situ alkaline sodium borohydride reduction, to the corresponding N-substituted amides; this procedure provides a new, convenient method for the Markovnikov amidation of carbon-carbon double bonds.

Amphetamine, some N-alkyl homologs, and ring-methoxylated analogs were each treated with a slight excess of trimethylsilylketene in dimethoxyethane or carbon tetrachloride. N-(trimethylsilyl)acetate derivatives formed almost quantitatively within a few minutes at room temperature; this was ascertained by nuclear magnetic resonance and infrared studies on the compounds. The N-(trimethylsilyl)acetate derivatives decomposed to varying extents on GC; some were relatively stable with barely detectable decomposition, while others decomposed extensively to the corresponding N-acetates. The N-(trimethylsilyl)acetates were converted quantitatively to the corresponding N-acetates by the action of aqueous hydrochloric acid.