literature revealed that N-H imines have received scant
attention as synthetic intermediates. With a few exceptions,
N-H imines have been reported as inherently unstable,
leading to difficulties in their preparation and isolation, and
often exist as mixtures of E/Z isomers.14 Thus, we were
delighted to find that solvolysis of N-TMS-ketimine 2c in
MeOH proceeded readily and led to cleavage of the
nitrogen-silicon bond and isolation of a stable N-H imine
7 (Scheme 3).
Table 2. Enantioselective Reductions of N-H Imine Mixturesa
entry
Ar
5-12 [a:b:c]b 14 yield (%)c % eed
1
2
3
4
5
6
7
8
Ph
3-BrC6H4
4-BrC6H4
2-MeSC6H4
3-MeSC6H4
2-PhC6H4
2-naphthyl
5 [18:8:74]
6 [41:15:44]
7 [65:19:16]
8 [68:32:0]
9 [57:23:20]
10 [76:24:0]
11 [45:15:46]
a
b
c
d
e
f
87
72
95
93
84
88
86
84
86e
86 (91)
91e
88 (99)
85
98 (99)
75e
Scheme 3. Synthesis of N-H Imines
g
h
9-phenanthryl 12 [65:19:16]
97 (99)
a Reagents and conditions: (a) 5 mol % (S)-Bu-OAB [(S)-4b], 150 mol
% catecholborane, toluene, -15 °C, then HCl in Et2O. b Isomer ratios
determined by 500 MHz 1H NMR spectroscopy in CDCl3 at 25 °C. c Isolated
yields of hydrochloride salts. d % ee determined by chiral HPLC analysis
of crude free amine, values in parentheses for isolated hydrochloride salts.
e (R)-configuration assigned on the basis of comparison with literature values
for optical rotations (see ref 3g).
This represents one of the few reported examples of stable,
readily isolable N-H ketimines.14 A comprehensive study
1
of imine 7 (Ar ) 4-BrPh) by H NMR spectroscopy in d8-
toluene determined that it existed as a mixture of Z/E isomers
7a/7b along with variable amounts of a methanol adduct 7c.
The existence of a dynamic equilibrium between the imine
isomers was demonstrated when irradiation of the aromatic
resonance of one isomer (in an NOE experiment) led to
transfer of magnetization to the corresponding resonance in
the other imine isomer. Further proton NOE experiments
were used to prove the geometry of the imines, as NOE
enhancements were observed from the N-H to the aromatic
protons in the minor E-isomer. The same NOE was absent
in the major Z-isomer.
structure A involving coordination of boron with the steri-
cally more accessible nitrogen lone pair anti to the CF3 group
of Z-imine, similar to that proposed by Corey and co-
workers.17 Alternatively, a chairlike transition state structure
B involving coordination of boron with the nitrogen lone
pair syn to the CF3 group of E-imine may also be plausible
on the basis of stereoelectronic arguments. Since high
enantioselectivity is observed, we presume that N-H imine
E/Z isomers and methanol adduct may all converge to
Enantioselective additions to imines are often complicated
by the existence of imine isomerization equilibrium that can
lead to plural transition states and correspondingly low ee’s.1c
Therefore, we were gratified to find that treatment of a crude
three-component mixture of 7a:7b:7c [65:19:16] with 5 mol
% (S)-Bu-OAB [(S)-4b] and 150 mol % catecholborane in
toluene at -15 °C gave amine (R)-14c in 91% ee and 95%
isolated yield (Table 2, entry 3). To the best of our
knowledge, the catalytic asymmetric reduction of N-H
imines is unprecedented in the literature. After optimization
of reaction parameters, we directly applied this procedure
to other aryl trifluoromethyl N-H ketimines.15 As illustrated
in Table 2, the enantioselectivities (75-98% ee) and yields
(72-95%) were consistently high with imines bearing
substituents in either the ortho, meta, or para positions.
Notably, similar levels of enantioselectivity were observed
with commercially available methyl-OAB catalyst 4a.16
However, use of phenyl-OAB 4c as catalyst led to poor
enantioselectivity.
(15) Representative Procedure. (S)-2,2,2-Trifluoro-1-(4-bromophenyl)-
ethylamine hydrochloride [(S)-14c]: A solution of (R)-B-butyl-diphenylpyr-
rolidino-oxazaborolidine (R)-4b (3.14 mL, 0.94 mmol, 2.5 mol %, 0.3 M
in toluene) was dissolved in toluene (10 mL) and cooled to -15 °C, and
catecholborane (6.01 mL, 56.5 mmol, 150 mol %) was added to the solution.
A solution of 1-(4-bromophenyl)-2,2,2-trifluoroethylimine 7 (10.0 g, 37.6
mmol) in toluene (40 mL) was added dropwise via syringe pump over a
period of 2.5 h. After the addition was complete, the reaction mixture was
stirred at -15 °C for 18 h. The reaction was quenched with aqueous 1 N
HCl (50 mL) and allowed to warm to room temperature, and the layers
were separated. The aqueous layer was basified with 10 N NaOH to pH
12. The aqueous layer was extracted with MTBE (1 × 50 mL). The layers
were separated, and the organic layer was washed with aqueous 2 N NaOH
(2 × 50 mL) and water (50 mL). The organic layer was treated with
Amberlite IRC-50S ion-exchange resin (5 g) for 40 min to remove (R)-
diphenylprolinol and filtered. The organic layer was dried and filtered. A
solution of hydrogen chloride (40 mL, 2 M in diethyl ether) was added to
the crude solution of amine. A white precipitate formed. After aging at
room temperature for 1 h, the slurry was filtered, and the solids were washed
with MTBE (10 mL) to afford (S)-2,2,2-trifluoro-1-(4-bromophenyl)-
ethylamine hydrochloride (S)-14c as a white powder (10.9 g, 95% yield,
91% ee HPLC): 1H NMR (CD3OD) δ 7.73 (d, 2H, J ) 8.5), 7.51 (d, 2H,
J ) 8.5), 5.42 (q, 1H, J ) 7.4); 13C NMR (CD3OD) δ 133.8, 131.6, 128.7,
126.3, 124.6 (q, J ) 280), 55.9 (q, J ) 33); 19F NMR (CD3OD) δ -72.1.
HRMS calcd for C8H8NF3Br [M + H] 253.9792, found 253.9790.
Enantioselective reduction with (S)-butyl-OAB (S)-4b as catalyst gave amine
The sense of stereochemical induction was found to be
the same as that observed with OAB-catalyzed reductions
of trihalomethyl ketones.17 Thus, the stereochemical outcome
of the reduction is consistent with a boatlike transition state
(R)-14c in 95% yield and 91% ee HPLC (method A, AD column: tR
)
6.9 min; tR ) 7.9 min; see Supporting Information) with identical spmeacjotrral
minor
characterictics; [R]23 ) -13.7 (c ) 0.75, MeOH). lit.3g [R]25 ) +11.2
D
D
(c ) 1.5, MeOH).
(16) For example enantioselective reduction of N-H imine 7 with 5 mol
% of commercially available (R)-methyl-OAB afforded amine (S)-14c in
90-91% ee on a 10 g scale. See Supporting Information.
(17) Corey, E. J.; Link, J. O.; Bakshi, R. K. Tetrahedron Lett. 1992, 33,
7107-7110.
(14) Chen, G.-M.; Brown, H. C. J. Am. Chem. Soc. 2000, 122, 4217-
4218 and references therein.
Org. Lett., Vol. 7, No. 2, 2005
357