ORGANIC
LETTERS
2007
Vol. 9, No. 2
355-357
A Convenient, NMR-Based Method for
the Analysis of Diastereomeric Mixtures
of Pseudoephedrine Amides
William J. Chain and Andrew G. Myers*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
Received November 27, 2006
ABSTRACT
Amides of pseudoephedrine and ephedrine are shown to undergo highly stereospecific, invertive cyclization to form 4,5-dihydro-3,4-dimethyl-
5-phenyl-1,3-oxazolium triflate derivatives in the presence of triflic anhydride-pyridine. 1H NMR spectra of the unpurified reaction products are
remarkably clean, with sharp, well-defined peaks, and allow for rapid assessment of the diastereomeric purities of the starting amides.
Line-broadening greatly complicates the analysis of diaster-
eomeric mixtures of pseudoephedrine amide alkylation
products by NMR spectroscopy, necessitating the use of
some more time-consuming analytical technique such as gas
or liquid chromatography.1 Here, we report that pseudoephe-
drine amides react stereospecifically with triflic anhydride
and pyridine to form cis-4,5-dihydro-3,4-dimethyl-5-phenyl-
1,3-oxazolium triflate derivatives (Scheme 1), providing the
basis for a simple NMR-based technique for the analysis of
diastereomeric mixtures of pseudoephedrine amides.
Scheme 1 illustrates four parallel transformations of
(1S,2S)-pseudoephedrine and (1R,2S)-ephedrine amides of
the enantiomeric R-methylbenzenepropanoic acids (I-IV).
In each case the substrate (∼0.04 M) was treated with triflic
anhydride (2 equiv) and pyridine (3 equiv) in dichlo-
romethane at 0 °C;2 after 2 min the cold product suspension
was concentrated and the residue was held in vacuo at 23
°C (1 mmHg, 1 h); addition of CDCl3, hand-mixing, and
removal of the supernatant by pipet then provided a sample
for 1H NMR analysis. In Figure 1 are reproduced, in order,
1H NMR spectra of the products of the four transformations
I-IV (Scheme 1), obtained in the manner described. Analysis
of the data makes it evident that the transformations are
uniformly clean, that unlike the starting materials, the
products give rise to H NMR spectra with sharp, well-
resolved signals, and that the diastereomeric products are
readily differentiated spectroscopically.
Cyclization is stereospecific in each case, proceeding with
inversion of the benzylic stereocenter, as established by NOE
analysis (summarized in Scheme 1). Thus, pseudoephedrine
amides give rise to cis-4,5-disubstituted oxazolium hetero-
cycles (g96% stereospecificity) and ephedrine amides
produce the trans-4,5-disubstituted products (g99% ste-
reospecificity).3 From this data we conclude that cyclization
proceeds by triflation of the side chain hydroxyl group
followed by invertive triflate displacement by the amide
carbonyl oxygen (triflation of the carbonyl oxygen, for which
there is precedent,4 followed by cyclization would have led
to retention of stereochemistry at the benzylic position).5
1
(1) Coalescence of 1H NMR signals for the two rotameric forms of
(2R)-N-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-N,2-dimethylben-
zenepropionamide requires temperatures in excess of 120 °C at 400 MHz
(d6-DMSO); see: Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.;
Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496-6511.
(2) The transformation has also been successfully conducted with as little
as 1.2 equiv of triflic anhydride (3.0 equiv of pyridine).
(3) The ephedrine amide substrate of transformation III was prepared
by coupling (1R,2S)-ephedrine and (2R)-2-methyl-3-phenylpropionic acid
(97% ee) in the presence of PyBOP. The ephedrine amide substrate of
transformation IV was prepared by coupling (1R,2S)-ephedrine and (2S)-
2-methyl-3-phenylpropionic acid (94% ee) in the presence of PyBOP.
10.1021/ol0628762 CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/19/2006