Enantioselective borodeuteride reduction of aldimines catalyzed by cobalt complexes: Preparation of optically active deuterated primary amines

Article abstract of DOI:10.1021/ol0349920

[Equation presented] The enantioselective borodeuteride reduction catalyzed by optically active β-ketoiminato cobalt complexes was applied to N-(di(o-tolyl)phosphinyl)-aldimines to afford the corresponding optically active deuterated primary amines in hig

Full text of DOI:10.1021/ol0349920

ORGANIC
LETTERS
2003
Vol. 5, No. 20
3555-3558
Enantioselective Borodeuteride
Reduction of Aldimines Catalyzed by
Cobalt Complexes: Preparation of
Optically Active Deuterated Primary
Amines
Daichi Miyazaki, Kohei Nomura, Tatsuya Yamashita, Izumi Iwakura,
Taketo Ikeno, and Tohru Yamada*
Department of Chemistry, Faculty of Science and Technology, Keio UniVersity,
Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
yamada@chem.keio.ac.jp
Received June 4, 2003 (Revised Manuscript Received August 12, 2003)
ABSTRACT
The enantioselective borodeuteride reduction catalyzed by optically active â-ketoiminato cobalt complexes was applied to N-(di(o-tolyl)phosphinyl)-
aldimines to afford the corresponding optically active deuterated primary amines in high yields with high enantiomeric excesses after simple
deprotection. The present deuteride reduction of aldimines is in the opposite sense of the enantioselective for the previously reported borohydride
reduction of ketones or diphenylphosphinyl aldimines. The stereochemical course in these enantioselective reductions is discussed.
Deuteride is one of the most available labeling atoms for
the mechanistic investigations of both chemical and biologi-
cal reactions,1 and reliable isotope labeling techniques have
been desired for these purposes. Optically active primary
amines with deuteride of the chiral center are employed as
versatile precursors for various labeled compounds containing
a nitrogen atom adjacent to the deuterated chiral center.2 Two
strategies should be synthetically considered for the prepara-
tion of the deuterated primary amines; one is the derivation
from the corresponding primary alcohols by functional group
interconversion,3 and the other is the application of the
enantioselective deuteride reduction to the corresponding
aldimines or their equivalents (Scheme 1). In the former
Scheme 1. Two Strategies for Preparation of Optically Active
Deuterated Amine
(1) (a) Stille, J. K.; Lau, K. S. Y. J. Am. Chem. Soc. 1976, 98, 5832-
5840. (b) Parry, R. J.; Trinor, D. A. J. Am. Chem. Soc. 1978, 100, 5243-
5244. (c) Shibuya, M.; Chou, H.-M.; Fountoulakis, M.; Hassam, S.; Kim,
S.-U.; Kobayashi, K.; Otsuka, H.; Rogalska, E.; Casssady, J. M.; Floss, H.
G. J. Am. Chem. Soc. 1990, 112, 297-304. (d) Mu, Y.-Q.; Omer, C. A.;
Gibbs, R. A. J. Am. Chem. Soc. 1996, 118, 1818-1823.
(2) (a) Lown, J. W.; Akhtar, M. H. J. Chem. Soc., Chem. Commun. 1973,
511-513. (b) Battersby, A. R.; Staunton, J.; Summers, M. C. J. Chem.
Soc., Perkin Trans. 1 1976, 1052-1056. (c) Meyers, A. I.; Dickman, D.
A. J. Am. Chem. Soc. 1987, 109, 1263-1265.
method, the corresponding primary alcohol deuterated on a
chiral center must be prepared in advance and routine
synthetic steps are required for the transformation to the
10.1021/ol0349920 CCC: $25.00
© 2003 American Chemical Society
Published on Web 09/03/2003

deuterated amine. In the latter method, the optically active
primary amine with deuteride on the chiral center could be
directly obtained by the enantioselective deuteride reduction
of the CdN bond followed by conventional deprotection of
the amino group; however, there has been no report on the
catalytic enantioselective deuteride reduction of aldimine or
its equivalent.
Table 1. Enantioselective Deuteride Reduction of Various
Aldimines or Their Equivalents Derived from
p-Phenylbenzaldehydea
Sodium borodeuteride is commercially available and is an
easily handled reducing agent like the borohydride. The
highly enantioselective reductions of ketones4 and ketimines5
with sodium borohydride were realized in the presence of
the optically active â-ketoiminato cobalt complexes to afford
the corresponding secondary alcohols or amines in high
yields with high enantiomeric excesses. The enantioselective
reduction system with sodium borodeuteride was recently
applied to aldehydes to obtain the corresponding optically
active deuterated primary alcohols in high yields with good
optical yields.6 In this letter, we report that the cobalt-
catalyzed reduction system with sodium borodeuteride was
successfully applied to aldimines or their equivalents to
provide a convenient and preparative method for chiral
deuterated primary amines with high enantioselectivity.
The enantioselective deuteride reduction of various aldi-
mines or their equivalents derived from p-phenylbenzalde-
hyde was initially examined using sodium borodeuteride
modified by tetrahydrofurfuryl alcohol-d (THFA-d)7 in the
presence of 5 mol % cobalt catalyst 1 (Table 1). Under these
conditions, the N-p-methoxybenzylimine 2 and the N-p-
methoxyphenylimine 3 were not reduced at all even at room
temperature (entries 1 and 2). The oxime ether 4 and the
hydrazone 5 were also inert under the same conditions
(entries 3 and 4). The reduction of the N-mesylimine 6 and
the N-tosylimine 7 rapidly proceeded even at -60 °C and
afforded the corresponding sulfonamides in high yields, while
their enantiomeric excesses were determined to be less than
10% ee8 (entries 5 and 6). In the absence of the catalyst 1,
the reduction of the N-sulfonylimines 6 and 7 with only the
modified borodeuteride was completed in 0.25 h. Eventually,
entry
X
temp/°C
yield/%b
ee/%c
1
2
3
4
5d
6d
7e
8e
p-CH3OC6H4CH2-
p-CH3OC6H4-
CH3O-
2
3
4
5
6
7
8
rt
rt
rt
rt
-60
-60
-40
no reaction
no reaction
no reaction
no reaction
>99
>99
>99
>99
Me2N-
Ms
Ts
<10
<10
83
Ph2P(O)-
(o-Tol)2P(O)-
9a -40
93
a Reaction conditions: to a solution of the cobalt catalyst and the aldimine
or its analogue was added a solution of the modified borodeuteride; 0.25
mmol of the aldimine or its analogue, 0.0125 mmol (5 mol %) of cobalt
catalyst, 0.375 mmol of NaBD4, and 1.5 mmol of THFA-d in CHCl3.
b Isolated yield. c After deprotection, the enantiomeric excesses were
determined by the 1H NMR analysis of the corresponding (R)-2-methoxy-
2-(1-naphthyl)propionic amide. d Reaction was completed in 15 min.
e Reaction was completed in 4 h.
it was found that the N-(diphenylphosphinyl)imine9 8 was
appropriately reactive and smoothly reduced to the corre-
sponding phosphinamide in high yield (entry 7). The obtained
phosphinamide was treated with HCl/MeOH to afford the
desired chiral deuterated primary amine in quantitative yield
(Scheme 2).10 The enantiomeric excess was determined to
Scheme 2. Deprotection of N-Diphenylphosphinamide
(3) (a) Streitwieser, A.; Wolfe. J. R. J. Org. Chem. 1963, 28, 3263-
3264. (b) Hammerschmidt, F.; Hanbauer, M. J. Org. Chem. 2000, 65, 6121-
6131.
(4) (a) Nagata, T.; Yorozu, K.; Yamada, T.; Mukaiyama, T. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2145-2147. (b) Sugi, K. D.; Nagata, T.;
Yamada, T.; Mukaiyama, T. Chem. Lett. 1996, 737-738. (c) Sugi, K. D.;
Nagata, T.; Yamada, T.; Mukaiyama, T. Chem. Lett. 1996, 1081-1082.
(d) Nagata, T.; Sugi, K. D.; Yamada, T.; Mukaiyama, T. Synlett 1996,
1076-1078.
(5) Sugi, K. D.; Nagata, T.; Yamada, T.; Mukaiyama, T. Chem. Lett.
1997, 493-494.
be 83% on the basis of 1H NMR analysis of the correspond-
ing (R)-2-methoxy-2-(1-naphthyl)propionic amide ((R)-
MRNP amide).11
(6) Miyazaki, D.; Nomura, K.; Ichihara, H.; Ohtsuka, Y.; Ikeno, T.;
Yamada, T. New J. Chem. 2003, 27, 1164-1166.
(7) For the borodeuteride reduction of the aldehyde, employing THFA
resulted in decreasing the isotopic purity of the corresponding alcohol
because the deuteride of sodium borodeuteride could be exchanged with a
proton from the alcohol: (a) Cornforth, R. H. Tetrahedron 1970, 26, 4635-
4640. (b) Davis, R. E.; Bromels, E.; Kibby, C. L. J. Am. Chem. Soc. 1962,
84, 885-892. Therefore, THFA-d was prepared and employed for the
borodeuteride modification instead of THFA, and the product was obtained
with a >95% deuteration degree.
Various types of optically active â-ketoiminato cobalt
complexes12 were then examined by adopting the imine 8
(9) (a) Hutchins, R. O.; Abdel-Magid, A.; Stercho, Y. P.; Wambsgans,
A. J. Org. Chem. 1987, 52, 704-706. (b) Soai, K.; Hatanaka, T.; Miyazawa,
T. J. Chem. Soc., Chem. Commun. 1992, 1097-1098.
(10) Greene, T. W.; Wuts, P. G. ProtectiVe Group in Organic Synthesis;
John Wiley & Sons: New York, 1999; p 598.
(11) (a) Ichikawa, A.; Hiradate, S.; Sugio, A.; Kuwahara, S.; Watanabe,
M.; Harada, N. Tetarahedron: Asymmetry 1999, 10, 4075-4078. (b)
Harada, N.; Watanabe, M.; Kuwahara, S.; Sugio, A.; Kasai, Y.; Ichikawa,
A. Tetarahedron: Asymmetry 2000, 11, 1249-1253.
(8) Enantiomeric excesses were determined by 1H NMR analysis of the
corresponding (R)-MRNP amide after deprotection of the sulfonamides. The
mesyl group was removed by reduction with LiAlH2(OCH2CH2OCH3)2 in
toluene, while the tosyl group was removed by treatment with SmI2 in THF
(Fujihara, H.; Nagai, K.; Tomioka, K. J. Am. Chem. Soc. 2000, 122, 12055-
12056). It was, however, found that the degree of deuteration of the products
decreased through both deprotection processes.
3556
Org. Lett., Vol. 5, No. 20, 2003

as the model substrate. These complexes exhibited excellent
catalytic activity for the reduction of the imine 8 to afford
the phosphinic amides in high yields, though none of them
improved the enantioselectivity. It was expected that the more
sterically demanding aryl of the phosphinyl group could
enhance the discrimination of the (Re)- and (Si)-faces of the
prochiral imine using the cobalt-deuteride intermediate.4d,13
Actually, the phosphinylimine 9a, possessing o-tolyl groups14
in place of the phenyl in the phosphinylimine 8, was
subjected to the reduction system to afford the corresponding
phosphinic amide 10a with 93% ee (Table 1, entry 8).
The catalytic and enantioselective borodeuteride reduction
was successfully applied for the preparation of various
optically active deuterated primary amines from the corre-
sponding N-(di(o-tolyl)phosphinyl)imines 9 (Table 2). Vari-
oxybenzaldehyde, and p-chlorobenzaldehyde were converted
into the corresponding deuterated phosphinic amides 10b-e
in quantitative yields. Each product was treated with HCl/
MeOH to afford the corresponding deuterated amine 11b-e
in high yields. Benzyl-R-d amine 11b and 2-naphthalene-
methyl-d amine 11c were obtained with 90 and 89% ees,
respectively (entries 2 and 3). Both electron-donating and
electron-withdrawing groups were found to be tolerated in
the present enantioselective reduction system, i.e., the
enantiomeric excesses of p-methoxybenzyl-R-d amine 11d
and p-chlorobenzyl-R-d amine 11e were 88 and 94%,
respectively (entries 4 and 5).
The absolute configuration of the optically active deuter-
ated primary amine was confirmed; (R)-benzyl-R-d amine
was obtained by the borodeuteride reduction catalyzed by
the (R,R)-cobalt complex 1 on the basis of a comparison of
1
the H NMR spectrum of the corresponding (R)-MRNP
amide with that of the authentic sample prepared as reported
in the literature.3b This observation of enantioselection in the
present deuteride reduction of the aldimines is in the opposite
sense of the enantioselection for the previously reported
borohydride reduction of the ketones4 or diphenylphosphinyl
ketimines.5
Table 2. Enantioselective Deuteride Reduction of Various
N-(Di(o-tolyl)phosphinyl)iminesa
The stereochemical course of the cobalt complex-catalyzed
reduction could be explained as follows.4d,15 When the
modified borohydride was added to the cobalt(II) complex
solution, the reaction mixture instantly turned from yellowish
orange, the color of the original catalyst solution, to reddish
violet. The FAB mass analysis of this solution indicated the
mass number corresponding to cobalt-hydride.6,13 These
observations suggested that the cobalt(II) complex was
converted to the corresponding cobalt-hydride intermediate
by the modified borohydride. The cobalt-hydride of (S,S)-
configuration formed in this manner reduced the aryl ketones
via Re-face attack to afford the corresponding (S)-alcohols.
During the reaction, the aryl groups of the optically active
diamine and the side chain effectively blocked the undesired
approach (TS2 in Figure 1),16 and the aromatic ring of the
substrate was placed parallel to the delocalized π-system
plane of the cobalt complex by π-interaction17 as depicted
in TS1. Since in the enantioselective reduction of imines,
the diphenylphophinyl group is comparatively sterically
demanding, its competitive repulsion18 should be considered
(TS1 vs TS2). A preliminary investigation of the structure
of the diphenylphosphinyl aldimine by DFT method19
suggested that its steric repulsion could be enhanced in the
reaction of aldimines. Comparing the calculated structures,
a Reaction conditions: to a solution of the cobalt catalyst and the N-di(o-
tolyl)phosphinyl aldimine was added a solution of the modified borodeu-
teride; 0.25 mmol of N-di(o-tolyl)phosphinyl aldimine, 0.0125 mmol (5
mol %) of cobalt catalyst, 0.375 mmol of NaBD4, 1.5 mmol of THFA-d in
CHCl3. b Isolated yield. c After deprotection, the enantiomeric excesses were
determined by the 1H NMR analysis of the corresponding (R)-2-methoxy-
2-(1-naphthyl)propionic amide.
(14) (a) Tolman, C. A. Chem. ReV. 1977, 77, 317-348. (b) White, D.;
Coville, N. J. AdV. Organomet. Chem. 1994, 36, 95-158.
(15) Yamada, T.; Nagata, T.; Sugi, K. D.; Yorozu, K.; Ikeno, T.; Ohtsuka,
Y.; Miyazaki, D.; Mukaiyama, T. Chem. Eur. J. 2003, 9, in print.
(16) (a) Ohba, S.; Nagata, T.; Yamada, T. Acta Crystallogr. E 2001,
m124-m126. (b) Kezuka, S.; Mita, T.; Ohtsuki, N.; Ikeno, T.; Yamada, T.
Bull. Chem. Soc. Jpn. 2001, 74, 1333-1342. (c) Kezuka, S.; Kogami, Y.;
Ikeno, T.; Yamada, T. Bull. Chem. Soc. Jpn. 2003, 76, 49-58.
(17) Observation that the aryl ketones were reduced faster than the alkyl
ketones could be explained similarly by π-π interaction between the
substrate and cobalt complex. Ohtsuka, Y.; Koyasu, K.; Miyazaki, D.; Ikeno,
T.; Yamada, T. Org. Lett. 2001, 3, 3421-3424.
ous aromatic imines 9b-e derived from the corresponding
aldehyde such as benzaldehyde, 2-naphthaldehyde, p-meth-
(12) Catalysts employed all appeared in the following report: Ohtsuka,
Y.; Koyasu, K.; Ikeno, T.; Yamada, T. Org. Lett. 2001, 3, 2543-2546.
(13) Cobalt-hydride was assumed to be the reactive intermediate in the
borohydride reduction catalyzed by the optically active â-ketoiminato cobalt
complexes and was recently detected by FAB mass analysis: Ohtsuka, Y.;
Ikeno, T.; Yamada, T. Tetrahedron: Asymmetry 2003, 14, 967-970.
(18) Diphenylphosphinyl imine of tetralone could not be reduced in the
enantioselective borohydride reduction catalyzed by the cobalt complex 1.
See ref 5.
Org. Lett., Vol. 5, No. 20, 2003
3557

Figure 2. Side views of the diphenylphosphinyl aldimine and
ketimine.
enantiomeric excesses were achieved. Further applications
to other aldimines such as aliphatic aldimines are currently
underway.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 1. Possible transition states of enantioselective reduction
catalyzed by the cobalt complex.
OL0349920
it is assumed that the space occupied by two aromatic rings
on the phosphinyl group in aldimine could be larger than
that of ketimine (Figure 2). Therefore, the steric repulsion
of diphenylphosphinyl group would dominate the stereo-
chemical course of reduction and Si-face attack (TS2) on
aldimines would be preferred, affording the (S)-deuterated
primary amines enantioselectively. This hypothesis is fully
in accord with the observation that a di(o-tolyl)phosphinyl
group improved the enantioselectivity in aldimine reduction.
It is noted that the enantioselective borodeuteride reduction
catalyzed by the optically active â-ketoiminato cobalt
complexes was used for the preparation of optically active
deuterated primary amines and that high yields with high
(19) Theoretical analysis of the structures of diphenylphosphinyl aldimine
and ketimine was performed using the B3LYP method with 6-31G* as basis
sets. (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652. (b) Lee, C.
T.; Yang, W. T.; Parr, R. G. Phys. ReV. B 1988, 37, 785-789. (c) Frisch,
M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
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3558
Org. Lett., Vol. 5, No. 20, 2003