isolated in pure form by simple filtration (g88% yield,
100ꢀ600-g scale, Table 1). Without careful control of the
reaction time and temperature, further reaction to produce
bis-methylimino benzil can occur. We have established
that the crystalline methylimino benzil we obtain has
(Z)-geometry by NOE and HMBC NMR correlations as
well as X-ray crystallography (see Supporting Information).
Scheme 2. Hydrogenation of Methylimino Benzil To Form
(()-Ephenamine
Table 1. Synthesis of Methylimino Benzil
a dr refers to the ratio of (()-4 to (()-1.
monoimines using lithium aluminum hydride (LAH),10
we investigated the use of this reagent for the reduction of
methyliminobenzil.11 Inaninitial experiment, reduction of
methylimino benzil with LAH in THF at ꢀ78 °C afforded
a 4:1 mixture of diastereomeric amino alcohols favoring
pseudoephenamine. Further investigations revealed that
the diastereoselectivity of the reduction varied as a func-
tion of the rate of addition of LAH to the reaction mixture,
and it was noted that addition of powdered LAH too
quickly led to delayed exotherms. Controlled addition of
LAH with a powder addition funnel prevented this and
allowed an internal temperature of ꢀ70 °C to be main-
tained. It is useful to note that exotherms more commonly
occur early in the course of the reaction; thus, the rate of
LAH addition may be increased as the reaction progresses.
Efficient mechanical stirring of the reaction is very impor-
tant, especially on a large scale, so as to prevent the
aggregation of powdered LAH on the surface of the
reaction mixture. In this manner, we routinely obtained
racemic pseudoephenamine of 4.7ꢀ5.4:1 dr on 75ꢀ570 g
scales in reproducibly high yield (>85%; see Table 2). As
noted by Alcaide et al. in their study of the reduction of
N-aryl and N-benzyl benzil monoimines, the observed
diastereoselectivity of the reduction is consistent with the
polar FelkinꢀAhn model.10
scale (g)
isolated yield (%)
100
300
600
88
92
91
Two prior studies of the reduction of methylimino benzil
explored the use of Raney nickel5 and sodium boro-
hydride6 as reductants, and in each case ephenamine was
reported to be the major or exclusive product. We are
unaware of any reports of the reduction of methylimino
benzil to form pseudoephenamine as the primary product.
Initially, we attempted to achieve both an enantio- as well
as diastereoselective reduction of monoimine 3 by explor-
ing various chiral reductants;7 however, in each instance
we obtained only racemic ephenamine. Parenthetically, we
found that mixtures of the four possible stereoisomeric
amino alcohols are conveniently assayed by admixing an
equimolar quantity of (S)-mandelic acid in CDCl3 fol-
1
lowed by H NMR analysis (500 MHz). Multiple reso-
nances are found to be well-resolved for each diastereomer
(see Supporting Information). Although reduction of 3 to
form racemic ephenamine was not our objective, in
Scheme 2 we depict a convenient method by which we
achieved this transformation with g19:1 dr.8,9
Direct resolution of pseudoephenamine from the mix-
ture of diastereomers obtained in the LAH reduction was
achieved with mandelic acid. We found that (R,R)-pseudo-
ephenamine preferentially formed a highly crystalline salt
with (R)-mandelic acid but not with (S)-mandelic acid.12,13
Beneficially, neither diastereomeric ephenamine mande-
late salt crystallized in our experiments. Two procedures
for the direct resolution of the LAH reduction products
were developed, one with and one without stirring. Both
methods yield highly diastereoenriched mandelate crystals
(g19:1 dr by 1H NMR, with no trace of either ephenamine
mandelate salt) with good recovery (defined as the percent
of the theoretical amount of the targeted enantiomer of
Based upon the promising report of the reduction in the
desired sense of achiral N-aryl and N-benzyl benzil
(7) See, for example: (a) Prasad, K. R. K.; Joshi, N. N. J. Org. Chem.
1996, 61, 3888–3889. (b) Murata, K.; Okano, K.; Miyagi, M.; Iwane, H.;
Noyori, R.; Ikariya, T. Org. Lett. 1999, 1, 1119–1121. (c) Touge, T.;
Hakamata, T.; Nara, H.; Kobayashi, T.; Sayo, N.; Saito, T.; Kayaki, Y.;
Ikariya, T. J. Am. Chem. Soc. 2011, 133, 14960–14963.
(8) Reductive amination of benzil in the presence of methylamine and
a platinum catalyst has been reported to form ephenamine: Skita, A.;
Keil, F. Manufacture of Aminoalcohols. U.K. Patent 313,217, July 24,
1930.
(9) While we recognize the importance of ephenamine in asymmetric
synthesis, we have made no attempt to resolve the racemic substance.
For a resolution of racemic ephenamine with penicillin, see ref 5.
(12) For a comprehensive guide to the optical resolution of racemic
compounds via formation of diastereomeric salts, see: CRC Handbook
of Optical Resolutions via Diastereomeric Salt Formation; Kozma, D., Ed.;
CRC Press: Boca Raton, FL, 2002.
(13) For selected resolutions of structurally similar amino alcohols,
see: (a) Erlenmeyer, E.; Arnold, A. Justus Liebigs Ann. Chem. 1904, 337,
307–328. (b) Manske, R. H. F.; Johnson, T. B. J. Am. Chem. Soc. 1929,
51, 1906–1909. (c) Weijlard, J.; Pfister, K., III; Swanezy, E. F.; Robinson,
C. A.; Tishler, M. J. Am. Chem. Soc. 1951, 73, 1216–1218. (d) Saigo, K.;
Sugiura, I.; Shida, I.; Tachibana, K.; Hasegawa, M. Bull. Chem. Soc. Jpn.
1986, 59, 2915–2916.
ꢀ
ꢀ
(10) Alcaide, B.; Lopez-Mardomingo, C.; Perez-Ossorio, R.; Plumet,
J. J. Chem. Soc., Perkin Trans. 2 1983, 1649–1653.
(11) For the use of LAH in the reduction of chiral benzil monoimines,
ꢀ
see: (a) Haro-Ramos, R.; Jimenez-Tebar, A.; Perez-Ossario, R.; Plumet,
ꢀ
J. Tetrahedron Lett. 1979, 20, 1355–1356. (b) Alcaide, B.; Fernandez de
ꢀ
ꢀ
la Pradilla, R.; Lopez-Mardomingo, C.; Perez-Ossorio, R.; Plumet, J.
J. Org. Chem. 1981, 46, 3234–3238. (c) Alcaide, B.; Dominguez, G.;
ꢀ
ꢀ
Lopez-Mardomingo, C.; Perez-Ossorio, R.; Plumet, J. J. Chem. Soc.,
Perkin Trans. 2 1986, 99–103.
B
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