Catalytic Hydrogenation of 5,6‐Dihydro‐4H‐1,2‐oxazines Bearing a Functionalized Methylene Group at C‐3

Abstract

The catalytic hydrogenation of readily available methyl 2‐(5,6‐dihydro‐4H‐1,2‐oxazin‐3‐yl)acetates 6 has been studied. Dihydrooxazines 6 without an alkoxy substituent at C‐6 under mild hydrogenation conditions in methanol produce a dynamic mixture of enamines 7 and tetrahydro‐2‐furanamines 7′(α + β). These products can be transformed into 1,4‐amino alcohols 8 under more robust hydrogenation conditions or into isomeric dihydrofurans 9 and 10 if the reduction is carried out in glacial acetic acid. Reduction of dihydrooxazines 6h,i, which possess an alkoxy substituent at C‐6, under similar conditions affords pyrrolidine derivatives 12, 13 and 14. A general mechanistic scheme for the hydrogenation reaction that involves an initial N–O bond cleavage has been suggested. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Synthesis of Substituted 5-(3-Hydroxypropyl)pyrrolidin-2-ones and Pyrrolizidinones from Nitroethane via C3 Functionalized 5,6-Dihydro-4H-1,2-oxazines: A Novel Approach to Some Analogues of the Antidepressant Rolipram

“…c Yield of isolated product based on converted 1e (conversion of 1e: 56%). In the transformation 5f,g into 8f,g the reductive oxazine ring contraction to pyrrolidine, apparently, is a multistep process (Scheme 3), which involves the hydrogenolysis of an N-O bond, leading to intermediate A, subsequent recyclization of A to dihydropyrrolidine B and the reduction of B to pyrrolidine C. 2,14 Intramolecular cyclization of C furnishes a mixture of diastereomeric pyrrolizidinones 8¢ and 8¢¢ isolated in good yield by column chromatography. 15 The final stage, removal of the CO 2 Me group (step 3, Scheme 2), was realized by refluxing the products 7 or 8 in wet dimethyl sulfoxide in the presence of sodium bromide.…”

A General Metal‐Assisted Synthesis of α‐Halo Oxime Ethers from Nitronates and Nitro Compounds

“…Subsequent reductive transformation of the oxime group provides access to a variety of polyfunctionalized nitrogen‐containing products 5. In this context, six‐membered cyclic ethers of α‐halo oximes are of special interest because they have proved to be useful intermediates in the stereoselective synthesis of unnatural β‐ and γ‐amino acids,6a,6b functionalized pyrrolidines,3f,6a pyrroles,3f tetrahydrofurans,6c dihydrofurans,6d γ‐lactams,6e and oxaazaspirononanones 6f. Owing to their high synthetic potential, α‐halo oxime ethers 1 have found widespread applications in the target‐oriented synthesis of natural and bioactive molecules both in academia1,7,8 and the pharmaceutical industry 9…”

Stereoselective Synthesis of Unnatural β-Amino Acids from Nitroethane via 5,6-Dihydro-4H-1,2-oxazin-3-ylacetates

“…Recently, it was demonstrated on three examples 11 that the catalytic hydrogenation of diastereomerically pure dihydrooxazines 2 can lead to the corresponding methyl esters of b-amino acids of types 3 and 4 (Scheme 1). Unfortunately, the process of hydrogenation of the oxyimino group in 2 was not stereoselective, whereas for biochemistry applications only diastereomerically or enantiomerically pure samples of b-amino acids are usually needed.…”

“…There are two general methods for the transformation of the oxyimino group in 5,6-dihydro-4H-1,2-oxazines into an amino group: direct catalytic hydrogenation catalyzed by Raney nickel (see Scheme 1, route 1, method A) or two-step reduction of the oxyimino fragment (route 2) with sodium cyanoborohydride in acetic acid as the first step (method B) and catalytic hydrogenation of intermediate 5 as the second step (method C). [3][4][5]11 The key distinction between these two approaches is the different sequence of bond reduction of the oxyimino fragment of the starting oxazine 2 (Scheme 2). 11 In route 1, the N-O bond is hydrogenated first, so that intermediates A or their tautomers A¢ are generated (Scheme 2, route 1).…”

“…[3][4][5]11 The key distinction between these two approaches is the different sequence of bond reduction of the oxyimino fragment of the starting oxazine 2 (Scheme 2). 11 In route 1, the N-O bond is hydrogenated first, so that intermediates A or their tautomers A¢ are generated (Scheme 2, route 1). Subsequent reduction of the C=N bond in A or the C=C bond in intermediates A¢ provides derivatives of target amino acids 3.…”