Asymmetric synthesis of primary amines via the spiroborate-catalyzed borane reduction of oxime ethers

Article abstract of DOI:10.1021/ol0704791

The enantioselective borane reduction of O-benzyloxime ethers to primary amines was studied under catalytic conditions using the spiroborate esters 5-10 derived from nonracemic 1,2-amino alcohols and ethylene glycol. Effective catalytic conditions were achieved using only 10% of catalyst 5 derived from diphenylvalinol in dioxane at 0°C resulting in complete conversion to the corresponding primary amine in up to 99% ee.

Full text of DOI:10.1021/ol0704791

ORGANIC
LETTERS
2007
Vol. 9, No. 9
1793-1795
Asymmetric Synthesis of Primary
Amines via the Spiroborate-Catalyzed
Borane Reduction of Oxime Ethers
Xiaogen Huang, Margarita Ortiz-Marciales,* Kun Huang, Viatcheslav Stepanenko,
Francisco G. Merced, Angel M. Ayala, Wildeliz Correa, and Melvin De Jesu´s
Department of Chemistry, UniVersity of Puerto RicosHumacao, CUH Station,
Humacao, Puerto Rico 00791
mr_ortiz@webmail.uprh.edu
Received February 24, 2007
ABSTRACT
The enantioselective borane reduction of O-benzyloxime ethers to primary amines was studied under catalytic conditions using the spiroborate
esters 5 10 derived from nonracemic 1,2-amino alcohols and ethylene glycol. Effective catalytic conditions were achieved using only 10% of
−
catalyst 5 derived from diphenylvalinol in dioxane at 0
ee.
°C resulting in complete conversion to the corresponding primary amine in up to 99%
The asymmetric reduction of oxime ethers with nonracemic
chiral reducing agents represents an important synthetic route
to enantiopure primary amines.1-5 Over the past two decades,
oxazaborolidines have been developed as chirality transfer
reagents for the reduction of the carbonyl and imine
functionality.2 The borane-mediated catalytic reduction of
ketones using 1,3,2-oxazaborolidines has been extensively
investigated.2b These efforts have led to the synthesis of
highly enantiopure alcohols using less than 10 mol % of
catalyst. Applying this process to the reduction of CdN
provides direct access to nonracemic primary amines which
are widely used as key intermediaries in the synthesis of
pharmaceuticals, chiral auxiliaries, and catalysts.1-4 For the
borane-mediated reduction of oxime ethers, a stoichiometric
amount of the oxazaborolidine is usually required to obtain
high enantioselectivities.3,4 Fontaine et al.3k even employed
2.5 equiv of the diphenylvalinol-derived B-H oxazaboro-
lidine to achieve complete reduction with high selectivity.
(3) (a) Itsuno, S.; Nakano, M.; Miyazaki, K.; Masuda, H.; Ito, K. J. Chem.
Soc., Perkin Trans. 1 1985, 2039-2044. (b) Itsuno, S.; Sakurai, Y.; Ito,
K.; Hirao, A.; Nakahama, S. Bull. Chem. Soc. Jpn. 1987, 60, 395-396. (c)
Itsuno, S.; Sakurai, Y.; Shimizu, K.; Ito, K. J. Chem. Soc., Perkin Trans.
1 1990, 1859-1863. (d) Bolm, C.; Felder, M. Synlett 1994, 655-666. (e)
Cho, B. T.; Ryu, M. H. Bull. Korean Chem. Soc. 1994, 15, 191-192. (f)
Lantos, I.; Flisak, J.; Liu, L.; Matsunoka, R.; Mendelson, W.; Stevenson,
D.; Tubman, K.; Tucker, L.; Zhang, W.-Y.; Adams, J.; Sorenson, M.;
Garigipati, R.; Erhardt, K.; Ross, S. J. Org. Chem. 1997, 62, 5385-5391.
(g) Demir, A. S. Pure Appl. Chem. 1997, 69, 105-108. (h) Inoue, T.; Sato,
D.; Komura, K.; Itsuno, S.; Tetrahedron Lett. 1999, 40, 5379-5382. (i)
Itsuno, S.; Matsumoto, T.; Sato, D.; Inoue, T. J. Org. Chem. 2000, 65,
5879-5881. (j) Sailes, H. E.; Watts, J. P.; Whiting, A. J. Chem. Soc., Perkin
Trans. 1 2000, 3362-3374. (k) Fontaine, E.; Namane, C.; Meneyrol, J.;
Geslin, M.; Serva, L.; Roussey, E.; Tissandie´, S.; Maftouh, M.; Roger, P.
Tetrahedron: Asymmetry 2001, 12, 2185-2189. (l) Krzeminski, M. P.;
Zaidlewicz, M. Tetrahedron: Asymmetry 2003, 14, 1463-1466. (m) Sakito,
Y.; Yoneyoshi, Y.; Suzukamo, G. Tetrahedron Lett. 1988, 29, 223-224.
(4) (a) Tillyer, R. D.; Boudreau, C.; Tschaen, D.; Dolling, U.-H.; Reider,
P. J. Tetrahedron Lett. 1995, 36, 4337-4340. (b) Shimizu, M.; Kamei,
M.; Fujisawa, T. Tetrahedron Lett. 1995, 36, 8607-8610. (c) Shimizu, M.;
Tsukamoto, K.; Matsutani, T.; Fujisawa, T. Tetrahedron 1998, 54, 10265-
10274. (d) Masui, M.; Shioiri, T. Tetrahedron Lett. 1998, 39, 5195-5198.
(5) Chu, Y.-B.; Shan, Z.-X.; Liu, D.-J.; Sun, N.-N. J. Org. Chem. 2006,
71, 3998-4001.
(1) (a) Johansson, A. Contemp. Org. Synth. 1995, 2 66, 393-406 and
refs cited therein. (b) Deloux, L.; Srebnik, M. Chem. ReV. 1993, 93, 763-
784.
(2) (a) Glushkov, V. A.; Tolstikov, A. G. Russ. Chem. ReV. (Engl. Transl.)
2004, 73, 581-608 and refs cited therein. (b) Cho, B. T. Tetrahedron 2006,
62, 7621-7643 and refs cited therein. (c) Brown, J. M.; Guy, C.; Lloyd-
Jones, G. C.; Layzell, T. P. Tetrahedron: Asymmetry 1993, 4, 2151-2154.
(d) Lang, A.; Noth, H.; Schmidt, M. Chem. Ber. 1997, 130, 241-246. (e)
Mathre, D. J.; Thompson, A. S.; Douglas, A. W.; Carroll, J. D.; Corley, E.
G.; Grabowski, E. J. J. J. Org. Chem. 1993, 58, 2880-2888.
10.1021/ol0704791 CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/31/2007

Itsuno and co-workers3b reported the first catalytic borane-
based reduction of acetophenone O-benzyl oxime. With 10
mol % of the (S)-diphenylvalinol oxazaborolidine, generated
in situ, 52% ee was observed in the product (S)-1-phenyl-
ethanamine. This selectivity is much lower than the 93% ee
obtained for this substrate employing 1 equiv of the catalyst.
In addition to their high cost and air and moisture
sensitivity, B-H oxazaborolidines often contain impurities
which diminish their effectiveness.2c-e This has led to the
development of alternative catalytic systems for the reduction
of oximes, but with only modest success.5 In the present
study, a truly catalytic and highly enantioselective process
for the borane-mediated asymmetric reduction of oxime
ethers is reported for the first time.
isolated as its carbamate 4 in 75% yield and 93% ee. Seeking
milder conditions, we discovered that the reduction could
be conducted at 25 °C in THF solvent, and these conditions
were used with varying amounts and sources of borane and
5 to determine optimal conditions for the reduction. These
results are presented in Table 1.
Table 1. Spiroborate Ester 5 Catalyzed Reduction of 1a with
Different Borane Sources in THF at 25 °C
cat. 5
(mol %)
borane
reagents
time
(h)
2a, 3
(%)a
entry
eeb
1
2
3
4
5
6
7
8
9
50
50
50
25
25
20
10
10
10
1BH3‚DMS
2BH3‚DMS
4BH3‚DMS
2BH3‚DMSc
6BH3‚DMS
2.4BH3‚THFd
2.4BH3‚THFd
4BH3‚THFd
4BH3‚DEA
48
36
12
48
12
36
36
36
36
0, 60
94
96
93
93
89
89
86
87
-
15, 85
0, 100
17, 58
0, 85
Recently, we prepared stable enantiopure spiroborate esters
5-10 derived from 1,2-amino alcohols, as new catalysts for
the asymmetric reduction of ketones (Figure 1).6These
9, 91
16, 44
0, 100 (75)e
0, 0
b
a The product ratio was determined by GC analysis. The ee was
c
determined by GC analysis using a Crompack Chirasil-Dex-CB column.
The oxime 1a in THF was added in 10 h, then stirred for 38 h at 25 °C.
d
The borane reagent was stabilized with <0.005 M N-isopropyl N-methyl
e
tert-butylamine. The yield in parentheses was obtained after purification
of ethoxy carbamide.
The complete conversion of 1a to 3 under these conditions
was achieved by increasing the amount of BH3·DMS to 4
equiv (Table 1, entries 1-3) and using 50% of spiroborate
5. The reduction of 1a occurred faster and with complete
conversion to primary amine 3. Decreasing 5 to 25% and
using 6 equiv of BH3·DMS, the conversion was partial (85%,
entry 5). Hence, we decided to use BH3·THF stabilized by
N-isopropyl N-methyl tert-butylamine, which has been
demonstrated to be more stable and selective in carbonyl
reductions.8 Indeed, with 20% catalyst and using 2.4 equiv
of BH3·THF, we observed a nearly quantitative conversion
to 3 (91%, entry 6). Remarkably, with only 10% of catalyst
and 4 equiv of BH3·THF, the reduction of oxime 1a afforded
the primary amine 3 quantitatively with only a slight decrease
in ee (87%, entry 10). It must be mentioned that BH3·DEA
was unreactive in this oxime reduction.9
Figure 1. Spiroborate esters derived from nonracemic 1,2-amino
alcohols.
spiroborates proved to be highly reactive and enantioselective
catalysts for this process. Coupled with their operational
convenience, we felt that they may provide effective catalysts
for reduction of oxime ethers, thereby providing a new,
highly useful entry to nonracemic amines (Scheme 1).7
Scheme 1
A variety of solvents, temperatures, and borane sources
were screened for the reduction of 1a under the previous
optimized conditions.10 In general, ethereal solvents lead to
(6) (a) Stepanenko, V.; Ortiz-Marciales, M.; Correa, W.; De-Jesu´s, M.;
Espinosa, S.; Ortiz, L. Tetrahedron: Asymmetry 2006, 17, 112-115. (b)
Ortiz-Marciales, M.; Stepanenko, V.; Correa, W.; De Jesu´s, M.; Espinosa,
S. U.S. Patent Application 11/512,599, Aug. 30, 2006.
(7) Ortiz-Marciales, M.; Huang, X.; Stepanenko, V.; De Jesu´s, M.;
Merced, F. G. Provisional U.S. Patent Application 60/841,147, Aug. 30,
2006.
(8) See: Synthetic methods: Reduction. Aldrich Chemfiles 2005, 5, 4;
Josyula, K.V. B.; Potyen, M.; Gao, P.; Hewitt, C. Patent application pending
publication.
(9) Chung, J. Y. L.; Cvetovich, R.; Amato, J.; McWilliams, J. C.; Reamer,
R.; DiMichele, L. J. Org. Chem. 2005, 70, 3592-3601.
(10) The details of the results obtained using different solvents, sources
of borane, temperature, mode of addition, catalysts, and oxime substituents
are included in the Supporting Information.
Initially, we examined the reduction of (E)-benzyl oxime
ether 1a (R ) Bn) in toluene employing 50 mol % of
spiroborate ester 5 and 2 equiv of BH3·DMS at 50 °C for 12
h followed by 3 h at 110 °C. The amine product 2a was
1794
Org. Lett., Vol. 9, No. 9, 2007

ee). The BH3·THF, stabilized with NaBH4, affords 3 and after
being treated with ClC(O)OEt produced 4 in 95% ee at 25
°C in dioxane. Importantly, this reagent gives 96.5% ee at 0
°C, the same result as that for the amine-stabilized BH3·THF.
The BH3·DMS reagent proved to be a less effective borane
source for this reduction. Moreover, the selectivity does not
change with the addition time of the oxime ether.
Table 2. Asymmetric Reduction of Representative Oxime
Benzyl Ethers with 0.1 Equiv of Catalyst 5
The optimized reaction conditions were extended to the
other spiroborate esters indicated in Figure 1. At 0 °C, the
reactivity of catalysts 6-9 was rather low. Therefore, the
reaction temperature was changed to 25 °C, except for
catalyst 10, whose reactivity was examined at 0 °C. Spiro-
borate ester 5 derived from diphenylvalinol shows superior
enantioselectivity compared to these other systems.10
We further extended these studies to include the methyl
and various substituted O-benzyl derivatives of acetophenone
oxime (4-MeO-C6H4CH2; 4-CF3C6H4CH2; 2-NO2C6H4CH2).10
Although these all give excellent selectivities, the 4-CF3-
substituted benzyl oxime gives 4 in 99% ee.
Because similar high selectivities were observed with all
of the O-benzylated acetophenone oximes, the simple (E)-
benzyl oxime derivatives 11 of representative aryl alkyl
ketones were prepared by standard methods and submitted
to the optimized reductive conditions (0.1 equiv of 5,
dioxane, 25 and 0 °C). The product amines were isolated as
their N-acetyl derivatives 12. In general, the process gives
excellent enantioselectivity (83-99%) at 0 °C. These results
are summarized in Table 2.
In summary, a highly efficient new borane-based catalytic
process for the asymmetric synthesis of amines from oxime
ethers has been discovered. The new process employs the
easily prepared and stable spiroborate ester 5 as the chiral
transfer agent. Employing simple procedures, this methodol-
ogy provides a convenient entry to highly versatile and
important nonracemic amines. Mechanistic studies and
further applications of this new process are underway.
Acknowledgment. Financial support by the NIH through
their MBRS (GM 08216) and IMBRE (NC P20 PR-016470)
Grants is greatly appreciated. The NIH-IMBRE undergradu-
ate support is also gratefully acknowledged.
a
The reactions were carried out using 1 equiv of oxime ether, 0.1 equiv
of catalyst 5, and 4 equiv of borane stabilized with NaBH4 in dioxane for
36 h or until the conversion was 100%. Purified by column chromatog-
raphy. The ee was determined using a Crompack Chirasil-Dex-CB GC
column.
b
c
Supporting Information Available: Experimental pro-
cedures, full characterization for all new compounds, and
1H spectra and GC analysis for racemic and nonracemic
acetamides. This material is available free of charge via the
Internet at http://pubs.acs.org.
higher ee’s of the isolated product 4 with dioxane giving
the best results (90% ee). The reaction temperature was also
varied to further optimize the reaction conditions. At 0 °C,
the reaction requires longer reaction times for the complete
conversion to 3, but the enantioselectivity is higher (96.5%
OL0704791
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