Rhodium-catalyzed enantioselective hydrogenation of oxime acetates

Article abstract of DOI:10.1021/ol303282u

Rh-catalyzed enantioselective hydrogenation of oxime acetates was first reported, which afforded a new approach for chiral amine synthesis.

Full text of DOI:10.1021/ol303282u

ORGANIC
LETTERS
2013
Vol. 15, No. 3
484–487
Rhodium-Catalyzed Enantioselective
Hydrogenation of Oxime Acetates
Kexuan Huang,† Shengkun Li,‡ Mingxin Chang,† and Xumu Zhang*,†
Department of Chemistry and Chemical Biology and Department of Pharmaceutical
Chemistry, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854,
United States, and Institute of Pesticide Science and College of Science,
Northwest Agriculture & Forestry University, Yangling, Shaanxi 712100, China
xumu@rci.rutgers.edu
Received November 29, 2012
ABSTRACT
Rh-catalyzed enantioselective hydrogenation of oxime acetates was first reported, which afforded a new approach for chiral amine synthesis.
Chiral amines and their derivatives are important
synthetic targets and powerful pharmacophores for defin-
ing new pharmaceutical drugs.1 In the past decade, many
researchers have focused their efforts on the enantioselec-
tive synthesis of amines, and tremendous progress has been
made toward truly practical methods.2 New concepts and
optimized methods are still needed to achieve both com-
plete enantiocontrol and efficiency under different circum-
stances. The asymmetric reduction of oximes and their
derivatives has been considered to be a facile and direct
approach to chiral amine because of the ease of prepara-
tion and stability of oxime substrates.3 However, this area
has been less explored over the last 10 years, and limited
results have been achieved. Successful examples include
borane-mediated reduction of oxime ethers.4 Itsuno and
co-workers reported the first catalytic borane reduction
of O-benzyl oxime in 1987.5 Recent research results from
Fontaine, Zaidlewicz, and Ortiz-Marciales’s groups showed
that chiral diphenylvalinolborane, oxazaborolidine, and
spiroborate esters could serve as remarkable catalysts to
afford chiral amines with high enantioselectivities.6
(Scheme 1, eq 1).
Asymmetric hydrosilylation of ketoximes is another
reliable approach for this transformation. Brunner and
co-workers developed the rhodium-catalyzed asymmetric
hydrosilylation of ketoximes using DIOP as ligand (up
to 36% ee)7 (Scheme 1, eq 2). Recently, Hidai reported
asymmetric reduction of cyclic oximes by using Ph2SiH2
and a Ru-oxazolinylferrocenylphosphine catalyst.8 Lipase/
palladium-catalyzed asymmetric transformations of
ketoximes to chiral amines were also reported by Park
and Kim.9
Ever since the success of the L-DOPA process, enantio-
selective hydrogenation has proven to be an efficient way
(6) Selected examples: (a) Fontaine, E.; Namane, C.; Meneyrol, J.;
Geslin, M.; Serva, L.; Roussey, E.; Tissandie, S.; Maftouh, M.; Roger, P.
Tetrahedron: Asymmetry 2001, 12, 2185–2189. (b) Krzeminski, M. P.;
Zaidlewicz, M. Tetrahedron: Asymmetry 2003, 14, 1463–1466. (c) Chu,
Y.; Shan, Z.; Liu, D.; Sun, N. J. Org. Chem. 2006, 71, 3998–4001. (d)
Huang, X.; Ortiz-Marciales, M.; Huang, K.; Stepanenko, V.; Merced,
F. G.; Ayala, A. M.; Correa, W.; De Melvin, J. Org. Lett. 2007, 9, 1793–
1795.
† Rutgers, The State University of New Jersey.
‡ Northwest Agriculture & Forestry University.
(1) Nugent, T. C. Chiral Amine Synthesis. Methods, Developments
and Applications; Wiley-VCH: New York, 2010.
(2) Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; Keßeler, M.;
€
Sturmer, R.; Zelinski, T. Angew. Chem., Int. Ed. 2004, 43, 788–824.
(3) Nugent, T. C.; El-Shazly, M. Adv. Synth. Catal. 2010, 352, 753–
819.
(4) (a) Deloux, L.; Srebnik, M. Chem. Rev. 1993, 93, 763–84. (b)
Glushkov, V. A.; Tolstikov, A. G. Russ. Chem. Rev. 2004, 73, 581–608.
(c) Payette, J. N.; Yamamoto, H. Boronic Acids (2nd Ed.) 2011, 2, 551–
590.
(7) (a) Brunner, H.; Becker, R. Angew. Chem., Int. Ed. 1984, 23, 222–
223. (b) Brunner, H.; Becker, R.; Gauder, S. Organometallics 1986, 5,
739–746.
(8) Takei, I.; Nishibayashi, Y.; Ishii, Y.; Mizobe, Y.; Uemura, S.;
Hidai, M. Chem. Commun. 2001, 2360–2361.
(9) (a) Han, K.; Park, J.; Kim, M.-J. J. Org. Chem. 2008, 73, 4302–
4304. (b) Choi, Y. K.; Kim, M. J.; Ahn, Y.; Kim, M.-J. Org. Lett. 2001, 3,
4099–4101.
(5) Itsuno, S.; Sakurai, Y.; Ito, K.; Hirao, A.; Nakahama, S. Bull.
Chem. Soc. Jpn. 1987, 60, 395–398.
r
10.1021/ol303282u
Published on Web 01/22/2013
2013 American Chemical Society

for the synthesis of chiral amines and their derivatives.10
Many practical catalytic systems have been developed
for the enantioselective hydrogenation of enamines and
imines.11 However, until now, direct hydrogenation of
simple ketoneoximes and their derivatives still remains a
long-standing problem.12 A typical example was reported
by Chan in 1995 for the catalytic asymmetric hydrogena-
tion of 1-acetonaphthone oxime with Rh chiral phosphine
catalysts (Scheme 1, eq 3). It should be noted that the
reaction can only proceed under high temperature (100 °C)
and with long reaction time (5 days).12c
Table 1. Selected Results from Initial Screening of Chiral
Ligands for Rhodium-Catalyzed Hydrogenation of 1aa
entry
ligand
(S)-MonoPhos
convb (%)
eec (%)
1e
<10
10
<5
15
17
10
12
14
55
52
55
18
88
82
85
74
>95
<5
<5
13
90
82
78
40
35
20
<5
63
14
nd
3
2
(S)-BINAP
3
(R)-MeO-BIPHEP
(S)- Segphos
4
Scheme 1. Previous Strategy for Asymmetric Reduction of
Oximes and Oxime Derivatives
5
(S)-C3-TunePhos
(S,S)-CHIRAPHOS
(S,S)-BDPP
5
6
35
7
7
8
(S)-PhanePhos
(S,S)-Me-DuPhos
(S,S)-Et- DuPhos
(S,S)-Me-BPE
(S,S)-Ph-BPE
19
12
27
37
64
23
15
12
9
9
10
11d
12
13d
14d
15d
16d
17d
18
19
20
21
22
23
24
25
26
27
TangPhos
(1S,10S,1R,1R0)-DuanPhos
(S)-ZhangPhos
(S)-BINAPINE
(R)-TCFP
2
(R)-(S)-Mandyphos
(R)-(R)-Walphos
(R)-(R)-Ph-Taniaphos T1
(R)-(R)-Cy-Taniaphos T2
Josiphos L1
2
9
14
1
65
61
17
47
3
Josiphos L2
Josiphos L3
Josiphos L4
Josiphos L5
Inspired by the success of N-acetylenamides and enol
acetates as substrates for asymmetric hydrogenation,10a we
envisioned that ketoneoxime acetates might be significant
substrates for hydrogenation.13 Recently, oximeestershave
already gained much attention especially for their applica-
tions in the coupling reactions.14 Herein, we report the first
enantioselective hydrogenation of ketoneoxime acetates.
We began our study by investigating the hydrogena-
tion of 1a as the model substrate. After initial screening of
Josiphos L6
nd
a Unless otherwise mentioned, reaction conditions: Rh(cod)2BF4/
ligand/substrate = 1:1.1:10, at 40 °C, under 50 atm of hydrogen for 24 h.
b Conversions were determined by 1H NMR of the crude product.
c Determined by GC on a chiral phase. d [Rh(cod)L]BF4 complex was
used directly. e Rh(cod)2BF4/ligand = 1:2.1.
different combinations of metal complexes and ligands,
we were surprised to find that using Rh(I)/phosphine
complexes as catalyst afforded the corresponding chiral
acetamide as the major product, rather than O-acetyl-
N-(1-phenylethyl)hydroxylamine15 (Table 1). The Mono-
Phos ligand family was first tested, and (S)-MonoPhos was
found to afford the highest ee (63%) (Figure 1). However,
low catalytic activity was observed under our screening
conditions (conversions <10%). Atropisomeric bisphos-
phine ligands such as BINAP, SEGPHOS, MeO-
BIPHEP, and TunePhos were tested with up to 14% ee
albeit with low conversions. Low catalytic activity was
also observed with ligands such as BDPP, CHIRAPHOS,
and PhanePhos. Chiral bisphosphane ligands such as
Me-DuPhos and Et-BPE improved the reaction conversions
(10) (a) de Vries, J. G.; Elsevier, C. J. Handbook of Homogeneous
Hydrogenation; Wiley-VCH: New York, 2006. (b) Knowles, W. S. Asym-
metric Hydrogenations (Nobel Lecture). Angew. Chem., Int. Ed., 2002.
(11) Xie, J.-H.; Zhu, S.-F.; Zhou, Q.-L. Chem. Rev. 2011, 111, 1713–
1760.
(12) (a) Krasik, P.; Alper, H. Tetrahedron: Asymmetry 1992, 3, 1283–
1288. (b) Xie, Y.; Mi, A.; Jiang, Y.; Liu, H. Synth. Commun. 2001, 31,
2767–2771. (c) Chan, A. S. C.; Chen, C.-C.; Lin, C.-W.; Lin, Y.-C.;
Cheng, M.-C.; Peng, S.ꢀM. J. Chem. Soc., Chem. Commun. 1995, 1767–
1768.
(13) Too, P. C.; Wang, Y.; Chiba, S. Org. Lett. 2010, 12, 5688–5691.
(14) Recent examples: (a) Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc.
2010, 132, 3676–3677. (b) Liu, S.; Yu, Y.; Liebeskind, L. S. Org. Lett.
2007, 9, 1947–1950. (c) Faulkner, A.; Bower, J. F. Angew. Chem., Int. Ed.
2012, 51, 1675–1679. (d) Ren, Z.-H.; Zhang, Z.ꢀY.; Yang, B.-Q.; Wang,
Y.-Y.; Guan, Z.-H. Org. Lett. 2011, 13, 5394–5397. (e) Maimone, T. J.;
Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 9990–9991. (f) Liu, S.;
Liebeskind, L. S. J. Am. Chem. Soc. 2008, 130, 6918–6919. (g) Too, P. C.;
Wang, Y. -F.; Chiba, S. Org. Lett. 2010, 12, 5688–5691. (h) Gerfaud, T.;
Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2009, 48, 572–577. (i)
Prithwiraj, D.; Nonappa, N.; Pandurangan, K.; Maitra, U.; Wailes, S.
Org. Lett. 2007, 9, 2767–2770.
(15) (a) Smithen, D. A.; Mathews, C. J.; Tomkinson, N. C. O. Org.
Biomol. Chem. 2012, 10, 3756–3762. (b) Fujita, M.; Hiyama, T. J. Org.
Chem. 1988, 53, 5415–5421.
Org. Lett., Vol. 15, No. 3, 2013
485

Table 2. Optimization of the Reaction Conditionsa
entry
Rh precursor
solvent
CH2Cl2
yield of 2ab (%) eec (%)
1
Rh(cod)2BF4
Rh(cod)2BF4
Rh(cod)2BF4
Rh(cod)2BF4
Rh(cod)2BF4
Rh(cod)2BF4
Rh(cod)2BF4
Rh(nbd)2BF4
78
61
57
47
63
<5
<5
59
48
65
69
25
65
45
55
62
2
THF
3
toluene
ethyl acetate
1,4-dioxane
MeOH
iPrOH
THF
4
5
6
n.d.
7
nd
65
68
75
81
8
d
9
[Rh(cod)Cl]2
THF
10
11
Rh(cod)2SbF6
THF
Rh(cod)2SbF6 1,4-dioxane
a Unless otherwise mentioned, reaction conditions: Rh precursor/
ligand/substrate =1:1.1:10, at 40 °C, under 50 atm of hydrogen for 24 h.
b Determined by 1H NMR of the crude product after acylation with
Ac2O. c Determined by GC on a chiral phase. d [Rh(cod)Cl]2/L1 = 1:2.2.
Table 3. Substrate Scope and Limitationsa
Figure 1. Selected phosphine ligands tested for the reaction.
(up to 55%) and enantioselectivities (37% ee). Based on
the ligand effect observed, we hypothesized that election-
rich phosphine ligands are more favored for this reaction.
We then performed screening of some electron rich P-chiral
ligands such as TangPhos, DuanPhos, ZhangPhos, and
BINAPINE. Up to 88% conversions were achieved by
TangPhos and DuanPhos; however, only about 20% ee
was provided. A three-hindered quadrant ligand TCFP
gave almost complete conversion with low enantioselectivity
(2% ee). We then focused on the ferrocene-based ligands.
Walphos and Mandyphos showed little activity for the
reaction. Cy-Taniaphos ligand afforded good conversion;
however, almost racemic products were observed. To our
delight, when Josiphos L1 was tested in the reaction, 65%
ee was achieved in THF with 82% conversion (Table 1,
entry 22).
8
R1
C6H4
R2
E/Z of 1
E (1a)
yieldb (%)
eec,d (%)
1
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
69
72
76
80
72
76
71
58
70
65
66
74
63
52
48
51
37
68
41
45
81 (S)
91 (S)
91
2
3
4-MeC6H4
4-EtC6H4
4-FC6H4
E (1b)
E (1c)
E (1d)
E (1e)
E (1f)
4
90 (S)
86 (S)
85 (S)
73 (S)
47 (S)
84
5
4-ClC6H4
4-BrC6H4
4-CF3C6H4
4-MeOC6H4
3-FC6H4
6
7
E (1g)
E (1h)
E (1i)
8
9
10
11
12
13
14
15
16
17
18
19
20
3-CF3C6H4
3-ClC6H4
3-BrC6H4
3-MeC6H4
3-MeOC6H4
2-MeOC6H4
2-MeOC6H4
2-ClC6H4
2-naphthyl
C6H5
E (1j)
82
E (1k)
E (1l)
89
83
E (1m)
E (1n)
E (1o)
E/Z =5:1
E/Z =3:1 (1p)
E (1q)
E (1r)
76
74
Solvent screening revealed that the reaction was most
efficient when conducted in THF or 1,4-dioxane (Table 2).
i
Moreover, protic solvents such as MeOH and PrOH
41
39
44
60
would completely lead to the corresponding oxime 3a as
final product. Further optimization showed that the en-
antioselectivity could be improved by using Rh(cod)2SbF6
as the Rh precursor in 1,4-dioxane (81% ee) (Table 2,
entry 11). The yield could be improved by acylation of the
product with Ac2O due to some primary amine remained
during the process (no ee value change observed after
acylation).
61
C6H5
nPr
E (1s)
53
a Conditions: Rh(cod)2SbF6/ligand/substrate = 1:1.1:10, in 1,4-
dioxane, at 40 °C, under 50 atm of hydrogen for 24 h. b Determined by
1H NMR of the crude product after acylation with Ac2O. c Determined
by GC on a chiral phase. d Absolute configuration determined by
comparison with literature (see the Supporting Information).
486
Org. Lett., Vol. 15, No. 3, 2013

To further explore the efficiency and tolerance of the
reaction, we subjected a series of substrates to asymmetric
hydrogenation under the optimized conditions. Substrates
bearing para-substituted methyl or ethyl groups gave
91% ee with moderate yields (Table 3, entries 2 and 3).
Substrates with para-substituted electron-withdrawing
groups on the aromatic ring were hydrogenated with good
to high enantioselectivities (ee’s up to 90%, entries 4ꢀ7).
A methoxy group on the para-position caused a dramatic
loss of enantioselectivity (entry 8). Substrates with meta-
substituted moiety on the aromatic ring also gave compar-
able results with up to 89% ee (entries 9ꢀ13). However,
ortho-substituted groups on the aromatic ring dramatically
lower the reactivity and enantioselectivities of the substrates
(entries 15ꢀ17). Moreover, E/Z conformers of ortho-
substituted substrates were often obtained as a mixture and
difficult to separate them from each other. Loss of enantio-
selectivities and activities were also observed when substrates
with bulkier R2 groups were tested (entries 19 and 20).
The reaction mechanism is still not clear. Similar en-
antioselectivities given by the E/Z substrate conformers
may suggest the NꢀO bond cleavage before the hydro-
genation process (Table 3, entries 15 and 16). Cleavage of
the NꢀO bond in oxime carboxylates has been established
for Pd- and Cu-catalyzed systems,14a,b but studies still
remain rare for Rh(I)-involved reactions. Moreover, acyl-
ation of chiral primary amine with oxime acetates was
observed and considered responsible for the final amide
formation.
In conclusion, we have successfully applied Rh-catalyzed
enantioselective hydrogenation of oxime acetates to
give chiral acetamides, which afforded a new approach
for the synthesis of chiral amines from oxime derivatives.
Commercially available phosphorus-based ligands were
screened, and the highestenantioselectivitieswereachieved
by the Josiphos ligand family. Further studies focusing on
mechanistic aspects and hydrogenation of other challeng-
ing substrates are ongoing.
Acknowledgment. Support from Solvias for ligand
screening and from the National Institutes of Health
(GM58832) is gratefully acknowledged.
Supporting Information Available. Experimental de-
tails and NMR and GC spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 3, 2013
487