Asymmetric reduction of ketoxime derivatives and N-alkylketimines with borane-oxazaborolidine adducts

Article abstract of DOI:10.1016/S0957-4166(03)00314-8

Oxime ethers of acetophenone, isopropyl methyl ketone, and tert-butyl methyl ketone were reduced to the corresponding hydroxylamine ethers of 45-94% ee with borane-oxazaborolidine 1 derived from (-)-norephedrine. A one-pot reduction of acetophenone oxime with 1 to 1-phenylethylhydroxylamine of 87% ee is described. The reduction of 6-methyl-2,3,4,5-tetrahydropyridine and N-methylimines of the above mentioned ketones with borane-B-methyloxazaborolidine adduct 2, derived from (-)-diphenylprolinol, gave the corresponding amines of 40-74% ee.

Full text of DOI:10.1016/S0957-4166(03)00314-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1463–1466
Asymmetric reduction of ketoxime derivatives and
N-alkylketimines with borane–oxazaborolidine adducts
Marek P. Krzemi n´ ski and Marek Zaidlewicz*
Department of Chemistry, Nicolaus Copernicus University, 87-100 Toru n´ , Poland
Received 13 February 2003; accepted 7 April 2003
Abstract—Oxime ethers of acetophenone, isopropyl methyl ketone, and tert-butyl methyl ketone were reduced to the correspond-
ing hydroxylamine ethers of 45–94% ee with borane–oxazaborolidine 1 derived from (−)-norephedrine. A one-pot reduction of
acetophenone oxime with 1 to 1-phenylethylhydroxylamine of 87% ee is described. The reduction of 6-methyl-2,3,4,5-tetra-
hydropyridine and N-methylimines of the above mentioned ketones with borane-B-methyloxazaborolidine adduct 2, derived from
(
−)-diphenylprolinol, gave the corresponding amines of 40–74% ee. © 2003 Elsevier Science Ltd. All rights reserved.
In contrast to excellent reagents and catalysts devel-
oped for the asymmetric reduction of prochiral ketones,
limited success has been achieved in the reduction of
methyl ketone oxime O-methyl ether 6a were reduced
with 1. The reaction run in tetrahydrofuran at 0°C
afforded mixtures of the corresponding hydroxylamine
O-methyl ethers and amines of 45–82% ee in 31–92%
yield (Table 1). The products were readily separated by
flash chromatography. Enantiomeric excesses of the
hydroxylamine ethers and amine products are the same,
since the amines are formed by the reduction of
hydroxylamine ethers not affecting the stereogenic cen-
tre. The reduction of 4a proceeded in a high yield to
give a mixture of 1-phenylethylhydroxylamine O-
methyl ether 7a and 1-phenylethylamine 10 of 55% ee in
a 54:46 ratio. Oxime ethers 5a and 6a were reduced
with 1 to the corresponding hydroxylamine O-methyl
ethers 8a and 9a with higher chemoselectivity, 87 and
1
prochiral ketoximes and ketimines. Boranes and boro-
hydrides are among the reagents of choice for these
2
reductions. Although many years ago it was reported
that the reduction of oximes can be controlled to
3
produce hydroxylamines, only recently, in connection
with the synthesis of 5-lipoxygenase inhibitor, has the
asymmetric reduction of 7-benzyloxycumaranone oxime
O-benzyl ether with borane–oxazaborolidine adduct 1
4a
derived from (−)-norephedrine, been achieved. The
reaction depends on the ether group as indicated by
unreactive hindered ethers, and mixtures of products
4b
obtained from O-methoxymethyl and allyl ethers.
However, its scope has not been delineated. Also, little
is known on the asymmetric reduction of N-alkylket-
imines with boranes. The small amount of reported
7
7%, respectively. Enantioselectivity increased to 82%
ee for 8a, but decreased to 45% ee for the more
5
hindered 9a.
data show low to moderate enantioselectivity. Conse-
quently, in continuation of our earlier studies on the
reduction of oximes, we decided to examine the asym-
6
The reduction of O-benzyl ether 4b with 1 showed
higher chemo- (77%) and enantioselectivity (94% ee) as
compared with 4a, whereas a slight decrease in selectiv-
metric reduction of representative ketoxime derivatives
and N-alkylketimines with borane-oxazaborolidine
adducts 1–3. The adducts 1 and 3 are prepared in
2
a,4b,7
tetrahydrofuran and used in situ,
whereas 2 is a
stable crystalline compound, and can be used in other
8
solvents (Fig. 1).
Acetophenone oxime O-methyl ether 4a, isopropyl
methyl ketone oxime O-methyl ether 5a, and tert-butyl
*
Corresponding author. Tel.: (+4856) 6114522; fax: (+4856) 6542477;
e-mail: zaidlevi@chem.uni.torun.pl
Figure 1.
0
957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00314-8

1
464
M. P. Krzemi n´ ski, M. Zaidlewicz / Tetrahedron: Asymmetry 14 (2003) 1463–1466
a
Table 1. Asymmetric reduction of 4–6, and the reduction of 4c–f with BH /THF and BMS
3
Oxime derivative
Reducing agentb
Temp. (°C)
Product
R1
7–12
Comp. (%)
c
Eed (%) (conf.)e
Yield (%)
f
4
–6
R
4
4
5
5
6
6
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
a
b
a
b
a
b
a
a
a
a
a
c
c
d
d
e
e
f
Ph
Ph
i-Pr
i-Pr
t-Bu
t-Bu
Me
Bn
Me
Bn
Me
Bn
1
1
1
1
1
1
A
B
C
D
0
0
0
0
0
0
20
20
20
20
20
0
0
0
0
0
0
0
0
0
0
0
0
0
7a/10
7b/10
8a/11
8b/11
9a/12
No r.
10
10
10
10
10
7g/10
7g/10
7g/10
7g/10
7g/10
7g/10
7g/10
10
7g/10
7g/10
7g/10
7g/10
7g/10
54:46
77:23
87:13
75:25
77:23
55 (S)
94 (S)
82
74
45
92
88
61
58
31
g
0
12
37
62
92
60
57
60
55
52
50
50
40
60
56
52
45
39
40
g
9 (S)
62 (S)
0
60 (S)
0
0
0
0
0
0
21 (R)
85 (S)
84 (S)
87 (S)
0
g
g
g
E
Ph
Ph
Ph
Ph
BBN
BH /THF
BMS
BH /THF
BMS
BH /THF
BMS
3:97
14:86
40:60
3
BChx2
3
d
h
B Ipc
67:33
83:17
81:19
2
3
d
i
B(2- Icr)
BH /THF
2
3
j
d
d
e
e
d
e
1
1
1
2
3
3
71:29
88:12
71:29
67:33
73:27
71 (S)
72 (S)
a
b
c
For representative procedures, see Refs. 9 and 10.
One molar equivalent was used, if not otherwise stated.
Determined by GC analysis on a Supelco SPB-5, 30 m×0.32 mm, column.
TFA derivatives of 10–12 and 7g were analyzed by GC on Chiraldex G-PN, 20 m×0.25 mm, or Supelco Beta-DEX 325, 30 m×0.25 mm, chiral
d
columns.
e
Configurations were established by comparing the signs of rotation with the literature data,11,12 and GC comparison with an authentic sample
of (S)-1-phenylethylamine TFA derivative.
Isolated yields.
f
g
A–D=NaBH /MCl /(−)-norephedrine (4:1:1), MCl : A=NiCl ; B=CoCl ; C=TiCl ; D=bis(cyclopentadienyl)titanium dichloride. E=NaBH /
4
2
2
2
2
4
4
TiCl /(−)-1,1-diphenylprolinol (4:1:1).
Derived from (+)-a-pinene, >99% ee.
Derived from (+)-2-carene, >99% ee.
4
h
i
j
Two molar equivalents.
ity was observed for 5b as compared with 5a. O-Benzyl
ether 6b was unreactive under the same conditions. The
decreasing yields of products obtained from 4a>4b>5a>
and low enantiomeric excess (Table 1). In contrast, the
reduction of 4a with sodium borohydride-titanium(IV)
chloride in the presence of (−)-norephedrine or (−)-1,1-
diphenylprolinol produced 10 of 60–62% ee in ꢀ60%
yield. Interestingly, 10 was obtained from 4a in much
higher yield when bis(cyclopentadienyl)titanium dichlo-
ride was substituted for titanium(IV) chloride, however,
the product was racemic. In spite of changes in the
molar ratio of components of the reducing mixtures, 7a
was not detected among the products of these reactions.
5
b>6a>6b reflect the increasing steric hindrance exerted
1
both by the ketone R group and the ether R sub-
stituent (Table 1).
1
3
Itsuno, introduced the sodium borohydride–zirconi-
um(IV) chloride mixture, modified with chiral amino
alcohols derived from
L-valine, for the asymmetric
reduction of ketoxime O-ethers. We used mixtures of
nickel(II), cobalt(II), and titanium(IV) chlorides (1
molar equiv.) with sodium borohydride (4 equiv.) in the
presence of (−)-norephedrine or (−)-1,1-diphenylproli-
nol (1 equiv.). The reduction of 4a with the first two
mixtures produced 1-phenylethylamine 10 in low yield
Next, the reduction of acetophenone oxime 13 with
d
diisopinocampheylborane ( Ipc BH) was attempted.
2
The reagent transformed the oxime into the corre-
sponding borinate 4e (Table 1), and no further reaction
was observed at room temperature. However, the addi-

M. P. Krzemi n´ ski, M. Zaidlewicz / Tetrahedron: Asymmetry 14 (2003) 1463–1466
1465
a
Table 2. Asymmetric reduction of 14–16 and 6-methyl-2,3,4,5-tetrahydropyridine (17) with 1 and 2
Imineb
R1
Reducing agent
Solvent
Temp. (°C)
Product
1
4–17
R
R2
18–21
Ee (%) (conf.)
c
e
Yieldd (%)
14
14
14
15
15
16
16
17
17
Ph
Me
Me
1
2
2
1
2
1
2
1
2
THF
0
0
20
0
0
0
0
0
0
18
18
18
19
19
20
20
21
21
38 (S)
74 (S)
41 (S)
13
60
40
5
21
50
58
60
78
71
79
55
85
70
92
Toluene
Toluene
THF
Toluene
THF
Toluene
THF
Toluene
i-Pr
t-Bu
Me
Me
Me
Me
Me
–(CH ) –
2
4
a
b
c
Representative procedure, see Ref. 14.
N-Methylketimines were prepared from the corresponding ketones and methylamine according to Ref. 15.
Determined by GC analysis of TFA derivatives on a Chiraldex G-PN, 20 m×0.25 mm, chiral column.
Isolated yields.
d
e
16
Configuration was determined by comparing the sign of rotation with the literature data.
tion of borane–tetrahydrofuran to 4e at 0°C produced a
mixture of racemic 1-phenylethylhydroxylamine 7g and
In conclusion, the asymmetric reduction of 4d and 4e
with 1 and 3 to give 7g demonstrates for the first time
a direct one-pot transformation of an oxime into the
corresponding hydroxylamine in high enantiomeric
excess with a borane reagent. O-Benzyl ethers 4b–6b
are reduced with 1 to the corresponding hydroxylamine
O-benzyl ethers of high to moderate ee. Adduct 2 is
more enantioselective than 1 in the reduction of
ketimines 14, 15, and 17.
1
0 (83:17) in 64% yield. Borinates derived from 13 and
9
-borabicyclo[3.3.1]nonane (9-BBN) or dicyclohexylbo-
rane (Chx BH) were also reduced with borane–tetra-
2
hydrofuran, producing 7g/10 in the ratio 3:97 and
4
0:60, respectively. The reduction of 4f with BMS pro-
duced 7g/10 (81:19) of 21% ee. The results demonstrate
the possibility of directing the reduction of oximes with
borane, either to hydroxylamine or amine, depending
on steric requirements of the dialkylboryl group. How-
ever, asymmetric induction exerted by chiral dialkylbo-
Acknowledgements
d
d
ryl groups (2- Icr B and Ipc B) in these reactions was
2
2
low, or none. Fortunately, when a chiral reducing agent
(2 molar equiv.) was used, 4d was transformed into 10
of 85% ee. One molar equiv. of 1 reduced 4d and 4e
mainly to 7g of 84% and 87% ee, respectively (Table 1).
The reaction of 4d and 4e with 3 in the same molar
ratio showed lower enantioselectivity, and the reduction
of 4e with 2 produced a mixture of racemic 7g/10.
1
Financial support from the State Committee for Scien-
tific Research, Warsaw, grant K005/T09/1999, is
acknowledged.
References
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5
0% ee, respectively. Enantioselectivity of 2 in these
reactions is among the highest achieved in the reduction
of N-alkylimimines of non-aromatic ketones with
5
b
boranes. However, 2 reacted with the most hindered
6 with low selectivity. The reduction of 14, 15 and 17
with borane in the presence of catalytic amounts (up to
0% molar) of 1 and 2 was less selective as compared to
the stoichiometric reactions.
1
1
4. (a) Lantos, I.; Flisak, J.; Liu, L.; Matsuoka, R.; Mendel-
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W.-Y.; Adams, J.; Sorenson, M.; Garigipati, R.; Erhardt,
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was carefully added to a suspension of Ipc BH (2.91 g,
2
10.4 mmol) in THF (5 mL) at room temperature under a
nitrogen atmosphere. The mixture was stirred until
hydrogen evolution ceased (1–1.5 h) and a clear solution
was obtained. The solution was cooled in an ice-bath,
and a solution of 1, prepared from (−)-norephedrine (1.81
g, 12 mmol) and a borane–THF solution (2 M, 12 mL, 24
mmol), was added dropwise. The stirring was continued
for 20 h. The reaction mixture was cooled in an ice-bath
and 3 M HCl (20 mL) was added. After stirring the
mixture at room temperature for 5 h, layers were sepa-
rated. The aqueous layer was extracted, with diethyl ether
(2×10 mL), alkalized with solid sodium carbonate, and
extracted with chloroform (4×20 mL). The chloroform
extracts were combined and dried with magnesium sul-
phate. Removal of the solvent provided a crude product.
GC analysis on a Supelco SPB-5, 30 m×0.32 mm, column
revealed 7g/10, 88:12. Crystallization from petroleum
ether (40–60°C) afforded 7g (0.71 g, 52%), mp 90–91°C,
5
. (a) Cho, B. T.; Chun, Y. S. J. Chem. Soc., Perkin Trans.
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1990, 3200–3201; (b) Nakagawa, M.; Kawate, T.;
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. Representative procedure. (S)-(−)-1-Phenylethylhydroxyl-
9
2
0
12
20
amine O-benzyl ether 7b: A borane–THF solution (2 M,
[h]
CHCl
Supelco Beta-DEX 325, 30 m×0.25 mm, column showed
D
=−30.1 (c 4.25, CHCl
3 D
), lit.: [h] =−34.6 (c 4.93,
2
.5 mL, 5 mmol) was added to a stirred solution of
3
) for the (S)-isomer. GC analysis of 7g on a
(
−)-norephedrine (0.76 g, 5 mmol) in THF (5 mL) at 0°C
1
under a nitrogen atmosphere. The mixture was stirred at
this temperature until hydrogen evolution ceased (0.5–1
h). A borane–THF solution (2 M, 2.5 mL, 5 mmol) was
added and stirring was continued for 3 h. A solution of
87% ee. 7g: H NMR (200 MHz, CDCl
J=6.0 Hz, 3H, CH ), 4.11 (q, J=6.0 Hz, 1H, CH), 5.19
(s, 2H, OH, NH), 7.26–7.35 (m, 5H, Ph). C NMR
(CDCl ): l 19.25 (CH ), 61.76 (CH–N), 127.11 (2×CH),
): l 1.38 (d,
3
3
13
3
3
4
b (1.01 g, 4.5 mmol) in THF (2 mL) was added dropwise
127.49 (CH), 128.44 (2×CH), 142.34 (C).
and the stirring was continued for 24 h. The mixture was
cooled in an ice-bath and 3 M HCl (10 mL) was added.
After stirring the mixture at room temperature for 5 h,
THF was evaporated under reduced pressure. The mix-
ture was alkalized with 6 M sodium hydroxide and
extracted with diethyl ether (3×15 mL). The extract was
washed with brine, and dried with anhydrous magnesium
sulphate. Removal of the solvent provided a crude
product. GC analysis on a Supelco SPB-5, 30 m×0.32
mm, column, revealed 7b/10, 77:23. Flash column chro-
matography on silica gel (petroleum ether/ethyl acetate,
11. Yamazaki, N.; Atobe, M.; Kibayashi, C. Tetrahedron
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3464–3474.
13. Itsuno, S.; Sakurai, Y.; Shimizu, K.; Ito, K. J. Chem.
Soc., Perkin Trans. 1 1990, 1859–1863.
14. (S)-(−)-N-Methyl-1-phenylethylamine 18: A solution of 2
(0.55 g, 2 mmol) in toluene (5 mL), was slowly added to
a stirred solution of 14 (0.27 g, 2 mmol) in toluene (3 mL)
at 0°C under a nitrogen atmosphere. After 3 h, a 3 M
sodium hydroxide (5 mL) was added dropwise, and stir-
ring was continued for 1 h. Layers were separated and
the aqueous layer was extracted with diethyl ether (3×5
mL). The extracts were combined and dried with magne-
sium sulphate. Evaporation of the solvents and flash
column chromatography on silica gel (petroleum ether/
ethyl acetate, 8:2), afforded 18 (0.16 g, 60%), identified by
20
8
:2), afforded 7b (0.69 g, 68%), [h] =−29.16 (c 1.16,
D
CHCl ), and 10 (0.11 g, 20%), identified by GC compari-
3
2
0
son with an authentic sample, [h] =−33.1 (c 1.05,
D
11
20
D
CHCl ), lit.: [h] =+34.5 (c 1.0, CHCl ), 98% ee for the
3
3
(
R)-isomer. Derivatization of 10 (20 mg) with trifl-
uoroacetic anhydride and GC analysis on a Supelco
1
Beta-DEX 325, 30 m×0.25 mm, column showed 94% ee.
comparison (GC, H NMR) with an authentic sample,
1
20
16 20
3 D
7
b: H NMR (200 MHz, CDCl ): l 1.37 (d, J=6.6 Hz,
[h]
CHCl
3
D
=−55.2 (c 1.22, CHCl
), lit.: [h] =+74.9 (c 1.02,
3
3
H, CH ), 4.18 (m, 1H, CH), 4.60 (d, J=11.7 Hz, 1H,
), 99% ee for the (R)-isomer. Derivatization of 18
3
OCH ), 4.66 (d, J=11.5 Hz, 1H, OCH ), 5.64 (s, 1H,
(20 mg) with trifluoroacetic anhydride, and GC analysis
on a Chiraldex G-PN, 20 m×0.25 mm, column showed
74% ee.
2
2
13
NH), 7.26–7.40 (m, 10H, 2×Ph). C NMR (CDCl ): l
3
1
9.86 (CH ), 60.57 (CH), 76.73 (CH ), 127.17 (2×CH),
3
2
1
27.29 (CH), 127.62 (CH), 128.23 (2×CH), 128.30 (2×
15. Cobas, A.; Guitian, E.; Castedo, L. J. Org. Chem. 1993,
58, 3113–3117.
CH), 128.37 (2×CH), 138.02 (C), 143.01 (C).
1
0. (S)-(−)-1-Phenylethylhydroxylamine 7g: A solution of ace-
16. Rezaei, H.; Marek, I.; Normant, J. F. Tetrahedron 2001,
57, 2477–2483.
tophenone oxime (13) (1.35 g, 10 mmol) in THF (5 mL)