Originally posted by Nicodem
Quote: | Originally posted by Ritter
While thinking about GHB syntheses today, the following scheme came to mind:
1. React succinic anhydride with an alkanol (methyl, ethyl) to get to alkyl hydrogen succinate.
2. Reduce the ester group with NaBH4 in THF/MeOH.
3. Isolate & purify your GHB, probably as a salt. I believe I've read that the Ca salt is non-hygroscopic. |
Quote: | I don't know any method for selectively reducing the ester group over the carboxylic one (or vice versa) that uses NaBH4, though probably it exists,
but NaBH4 in THF and/or methanol does not reduce either esters nor carboxylic acids. |
See http://www.springerlink.com/content/0678qn6571725r53/ for one reference to the NaBH4 reduction of esters to primary alcohols. And http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/2004/6/i22/a... as well as the links here http://gaussling.wordpress.com/2007/04/07/nabh4-reduction-of....
In March's Advanced Organic Chemistry (5th edition) on page 1546 in Table 19.5 there are 2 footnotes for the conversion of an alkyl ester
to a primary alcohol with NaBH4: B (Ref. 496) employs NaBH4 with LiCl; C (Ref. 506) employs NaBH4 with AlCl3. I haven't had time to find URLs for
these but here they are:
Ref. 496:
Brown, H.C. Tetrahedron, 1979, 35, 567
Walker, E.R.H. Chem. Soc. Rev. 1976, 5, 23
Brown, H.C. Boranes in Organic Chemistry 1972, p. 209
Additional cited references from Ref. 495:
Rerick, M.N. in Augustine, R.I. Reduction 1968
Ref. 506:
Brown, H.C. et al J Am Chem Soc 1970, 92, 7161
So there is precedent. And the hydride reduction of an ester will be a lot more facile than reduction of a COOH group. It would be interesting to
experiment in order to optimize the ester reduction. The only conditions given in March (albeit dated) are that it takes either borane or LAH to
reduce COOH groups.
Reduction of aldehydes, ketones and imines is more or less all for what such a system (NaBH4/MeOH) is useful for.
Quote: | As an added thought, if you started this using maleic anhydride instead you'd wind up with the more potent trans-4-hydroxycrotonic acid. The
intermediate would be the alkyl hydrogen maleate. |
Maleic anhydride gives monomethyl maleate with methanol (that is cis conformation) and the selective reduction of the ester group (or
carboxylic group) would give you the cis-4-hydroxy-but-2-enoic acid. |