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1,2‐Oxazines as Building Blocks for Stereoselective Synthesis: Preparation of Oxygen‐Substituted 1,2‐Oxazines, either by Alcohol Addition or by Epoxidation, and Subsequent Hydrogenation Leading to 1,2‐Amino Alcohols and Pyrrolidines
Author(s) -
Zimmer Reinhold,
Buchholz Monika,
Collas Markus,
Angermann Jörg,
Homann Kai,
Reissig HansUlrich
Publication year - 2010
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201000425
Subject(s) - oxazines , chemistry , enantiopure drug , organic chemistry , alcohol , hydrogen peroxide , chemoselectivity , stereoselectivity , ether , medicinal chemistry , catalysis , enantioselective synthesis
Stereodefined oxygen‐substituted 1,2‐oxazines were prepared by three different routes. The cycloaddition of enol ethers such as 1 with α‐nitrosoalkenes generated in situ gave the heterocycles 3 and 4 . Acid‐catalysed additions of alcohols to the 6 H ‐1,2‐oxazines 5 led to mixtures of the adducts 6 and the substitution products 7 with moderate chemoselectivity. Epoxidation of the 6 H ‐1,2‐oxazines 5 proceeded more efficiently and furnished the corresponding epoxides 25 and 32 in reasonable to excellent yields. It was demonstrated that the resulting oxygen‐substituted 1,2‐oxazines were suitable precursors for the preparation of cyclic or acyclic primary and secondary amines in racemic or enantiopure form. Hydrogenation of the 3‐phenyl‐substituted 1,2‐oxazines 3 and 25a and of (6 S )‐ and (6 R )‐ 32 preferentially furnished the 1,2‐amino alcohols 15 , rac ‐ 29 and (2 S )‐ and (2 R )‐ 29 . On the other hand, reduction of the 3‐ethoxycarbonyl‐substituted 1,2‐oxazines 4 , 6d and 20 led to the formation of the N ‐protected proline esters 21 – 24 in moderate yields. It was also found that the 5‐methyl‐6 H ‐1,2‐oxazine 10 was a good precursor for the propargylic ether 11 , which allowed a Pauson–Khand reaction leading to the tricyclic compounds 13 and 14 . Hydrogen peroxide converted 10 into a hydroperoxide intermediate, which was further transformed into the 1,2‐oxazin‐6‐one 28b . Overall, the results demonstrate the remarkable potential of suitably substituted 1,2‐oxazine derivatives for the stereoselective synthesis of amines.