Catalytic enantioselective hydrogenation of N-alkoxycarbonyl hydrazones: A practical synthesis of chiral hydrazines

Article abstract of DOI:10.1021/ol902602c

(Figure presented) An enantioselective hydrogenation of hydrazones catalyzed by Rh complexes (Rh-Josiphos or Rh-Taniaphos) has been developed. The protocol can be applied to hydrazones with three different protective groups (Boc, Cbz, and methoxycarbonyl)

Full text of DOI:10.1021/ol902602c

ORGANIC
LETTERS
2010
Vol. 12, No. 2
276-279
Catalytic Enantioselective Hydrogenation
of N-Alkoxycarbonyl Hydrazones: A
Practical Synthesis of Chiral Hydrazines
Naoki Yoshikawa,* Lushi Tan,* J. Christopher McWilliams, Deepa Ramasamy, and
Ruth Sheppard
Department of Process Research, Merck Research Laboratories, Merck & Co., Inc.,
Rahway, New Jersey 07065
naoki_yoshikawa@merck.com; lushi_tan@merck.com
Received November 10, 2009
ABSTRACT
An enantioselective hydrogenation of hydrazones catalyzed by Rh complexes (Rh-Josiphos or Rh-Taniaphos) has been developed. The protocol
can be applied to hydrazones with three different protective groups (Boc, Cbz, and methoxycarbonyl), allowing for selective deprotection and
further elaboration of the hydrazine products in the presence of other functional groups.
The development of enantioselective hydrogenation of a
CdN bond has received considerable attention as it provides
a convenient access to a wide variety of compounds bearing
C-N bonds with chiral stereogenic centers,1 including
precursors to numerous natural products and other biologi-
cally important compounds. One of the key factors in the
development of enantioselective hydrogenation of imines is
the choice of substituent on the nitrogen atom, which has
proven to have critical influence on the reactivity and
selectivity. N-Benzyl and N-aryl imines are commonly used
as substrates for the enantioselective hydrogenations and offer
opportunities for selective deprotection under different condi-
tions. Cyclic imines have also been extensively studied as
substrates. On the other hand, examples of the use of
heteroatom-substituted imines2 as substrate are rather limited
except for sulfonyl and phosphinyl groups that are introduced
as the protective groups.3 In 1991, Burk et al. reported an
asymmetric hydrogenation of N-acyl hydrazones catalyzed
by Rh-Duphos complexes.4 The resulting hydrazines can
be transformed into chiral amines by reductive cleavage of
the N-N bond. The hydrazine itself also constitutes an
important class of building blocks to form various hetero-
cyclic compounds.
In connection with our program to synthesize a pharma-
ceutical intermediate, we needed to prepare a large quantity
of unprotected chiral hydrazine with an ester moiety on the
phenyl ring (1, Figure 1).
(2) Burk et al. reported the use of oximes as precursor to enamides,
which could then be hydrogenated to give chiral amines. See: Burk, M. J.;
Casy, G.; Johnson, N. B. J. Org. Chem. 1998, 63, 6084. For asymmetric
reductive acylation of ketoximes, see: Han, K.; Park, J.; Kim, M.-J. J. Org.
Chem. 2008, 73, 4302.
(3) (a) Spindler, F.; Blaser, H.-U. AdV. Synth. Catal. 2001, 343, 68. (b)
Nolin, K. A.; Ahn, R. W.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 12462.
(c) Wang, Y.-Q.; Zhou, Y.-G. Synlett 2006, 1189. (d) Yang, Q.; Shang, G.;
Gao, W.; Deng, J.; Zhang, X. Angew. Chem., Int. Ed. 2006, 45, 3832. (e)
Wu, J.; Wang, F.; Ma, Y.; Cui, X.; Cun, L.; Zhu, J.; Deng, J.; Yu, B. Chem.
Commun. 2006, 1766. (f) Wang, Y.-Q.; Lu, S.-M.; Zhou, Y.-G. J. Org.
Chem. 2007, 72, 3729. (g) Wang, Y.-Q.; Yu, C.-B.; Wang, D.-W.; Wang,
X.-B.; Zhou, Y.-G. Org. Lett. 2008, 10, 2071.
(1) For recent reviews, see: (a) Tang, W.; Zhang, X. Chem. ReV. 2003,
103, 3029. (b) Spindler, F.; Blaser, H.-U. Handbook of Homogeneous
Hydrogenation; de Vries, J. G., Elsevier, C. J., Eds.; Wiley-VCH: Weinheim,
Germany, 2007; Vol. 3, Chapter 34, pp 1193.
(4) (a) Burk, M. J. J. Am. Chem. Soc. 1991, 113, 8518. (b) Burk, M. J.;
Martinez, J. P.; Feaster, J. E.; Cosford, N. Tetrahedron 1994, 50, 4399.
10.1021/ol902602c  2010 American Chemical Society
Published on Web 12/17/2009

Table 1. Selected Results from Initial Screening of Chiral
Ligands for Rhodium-Catalyzed Hydrogenation of 4a under
Dilute Condition
Figure 1. Unprotected hydrazine with an ester group as a synthetic
target.
convna ee
First of all, we repeated the Burk hydrogenation protocol
to prepare 1 in an enantioselective manner. As reported in
the literature, the hydrogenation of N-benzoyl-protected
hydrazone 2 in the presence of Rh-Et-Duphos catalyst
produced the corresponding hydrazine (3) with 91% ee
(Scheme 1). In order to covert 1 to our pharmaceutical
entry
ligand
(%)
(%)
1
2
3
4
5
6
7
8
9
(S)-P-Phos (Ar ) 3,5-Me2C6H3)
(R)-(S)-Josiphos (Ar ) Ph, R ) t-Bu) (6)
(S)-Synphos
28
22
44
79
62
18
39
18
5
91
91
84
82
81
77
76
75
74
64
45
31
26
24
23
22
18
17
(+)-tetraMe-BITIOP
(S)-Ph-Solphos
(S)-P-Phos (Ar ) Ph)
(S)-MeO-BIPHEP
(R)-(S)-Mandyphos
(R)-(S)-Josiphos (Ar ) 4-F-C6H4, R ) t-Bu)
Scheme 1. Hydrogenation of a N-Benzoyl-Protected Hydrazone
Catalyzed by a Rh-Duphos Complex and Deprotection of the
Benzoyl Group in the Presence of an Ester
10 (-)-Norphos
11 (S)-BINAP
12 (R)-(S)-Josiphos (Ar ) Ph, R ) c-hex)
13 (S)-(R)-Josiphos (Ar ) o-tol, R ) t-Bu)
14 (R,R)-i-Pr-Duphos
15 (R,R)-Et-Duphos
16 (R,R)-Diop
17 (R,R)-Chiraphos
18 (S)-Tol-BINAP
81
21
3
5
98
22
29
7
20
a Conversions were determined on the basis of area % by HPLC (230
nm). The hydrogenation reactions generally showed clean conversions.
intermediate, we needed to deprotect the benzoyl group
without affecting the ester moiety. When the deprotection
was conducted under acidic conditions (aq HCl), however,
the ester group was hydrolyzed in addition to the deprotection
of benzoyl group to give the corresponding hydrazino acid,
which was difficult to isolate from the aqueous reaction
mixtures. It is also reported by Burk that this type of
hydrazines can readily racemize under these deprotection
conditions.4
It was highly desirable for us to prepare the unprotected
hydrazine with the ester group retained. This would be made
possible by the use of a more labile protective group such
as a Boc group. When the Burk hydrogenation protocol was
applied to a Boc-protected hydrazone 4a, however, the
corresponding product (5a) was obtained in a lower yield
with only about 20% ee.
This result led us to develop a new catalyst system that
would open direct access to an enantioselective synthesis of
Boc-protected hydrazines. First, a wide variety of chiral
ligands were screened using 4a as the substrate in the
presence of 20 mol % Rh(COD)2BF4 in IPA as solvent under
dilute conditions (Table 1, Figure 2). As a result, some
bidentate phosphine ligands were identified to provide the
product with good to excellent enantioselectivities.
Some of those ligands that gave the best selectivities in
the initial screening were examined further under different
conditions. As a result, a Josiphos ligand (6, Ar ) Ph, R )
t-Bu)5 was found to be most suitable to our purpose in terms
of selectivity, reactivity, and immediate availability in a large
quantity at that time.
Thus, the reaction conditions were optimized using Rh-6
as the catalyst. Table 2 summarizes solvent effects. Although
good to excellent selectivities were obtained in all solvent
systems except for CH2Cl2, the conversions were low in some
solvents such as IPA, presumably due to low solubility of
the hydrazone.
Further optimization revealed that the hydrogenation was
most efficient when conducted in MeOH as solvent at a
higher temperature (50 °C) under 300 psi H2. When
hydrazone 4a was subjected to hydrogenation under these
conditions in the presence of 0.75 mol % catalyst, the desired
product (5a) was obtained in near quantitative yield with
86% ee (Table 3, entry 1).
The present protocol was applied to a variety of hydra-
zones to investigate the scope and limitations of the method
(Table 3). The hydrazones (4) were readily prepared from
the corresponding ketones and isolated by crystallization as
single geometric isomers.6 Boc-hydrazones prepared from
different acetophenones (4a-d) generally gave good to
(5) Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F.; Landert, H.; Tijani,
A. J. Am. Chem. Soc. 1994, 116, 4062.
Org. Lett., Vol. 12, No. 2, 2010
277

Table 3. Substrate Scope and Limitations
entry hydrazone product cat. (mol %) convna (%) ee (%)
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
5f
0.75
1.5
1.5
1.5
1.5
1.5
99b
100
99
100
100
97
86
91
86
84
64
44
a Conversions were determined on the basis of area % by HPLC (220
nm). The hydrogenations generally showed clean conversions. b The
chemical yield was determined to be near quantitative by HPLC assay.
zone 4f, prepared from methyl pyruvate, also gave an
excellent conversion with moderate enantioselectivity (44%
ee) under the same conditions without further optimization
(entry 6).
In order to expand the scope of the method, hydrazones
with different protective group (methoxycarbonyl and Cbz)
were also examined (Table 4). Gratifyingly, both hydra-
Table 4. Hydrogenation of Hydrazones with Different Protective
Groups
Figure 2. Some chiral ligands used for screening.
excellent results (84-91% ee) (entries 1-4). Hydrazone 4e,
derived from benzylacetone, was also applicable albeit with
a lower selectivity (64% ee) (entry 5). Interestingly, hydra-
Table 2. Solvent Screening Using Rh-Josiphos Catalyst
entry
4/5
ligand
cat. (mol %)
convna (%)
ee (%)
1
4a/5a
4g/5g
4g/5g
4h/5h
4h/5h
6
6
7
6
8
0.75
1.5
5.0
1.5
5.0
99b
99
97
100
99
86
73
88
78
91
2
3c
4
5d
a Conversions were determined on the basis of area % by HPLC (220
nm). The hydrogenations generally showed clean conversions. b The
chemical yield was determined to be near quantitative by HPLC assay.
c Solvent: 1,2-dichloroethane. d Solvent: 1,2-dichlorobenzene.
entry
solvent
MeOH
EtOH
IPA
THF
CH2Cl2
20% H2O/IPA
convna (mol %)
ee (%)
1
2
3
4
5
6
87
63
30
77
36
83
92
91
86
89
45
84
zones produced the corresponding hydrazine with good
enantioselectivities (73-78% ee) when Rh-6 was used as
the catalyst (entries 2 and 4). We then conducted further
catalyst screening to find out the best system for these
protective groups. As a result, the selectivities were
a Conversions (mol %) were determined on the basis of HPLC assay.
278
Org. Lett., Vol. 12, No. 2, 2010

significantly improved when Taniaphos (7)7 (entry 3,
Figure 3) was used as ligand for hydrazone 4g and
Josiphos 8 (entry 5, Figure 3) for 4h.
Scheme 3
.
Selective Deprotection of the N-Protective Group in
the Presence of Ester
be very practical. The product hydrazines can be used as
key building blocks for the syntheses of various heterocycles.
The protective group can be chosen from three different
options (Boc, methoxycarbonyl, and Cbz), which allow for
more flexible elaboration of products.
Figure 3. Chiral ligands that afforded best selectivities for
hydrogenation of hydrazones 4g and 4h.
With an efficient hydrogenation method in hand, we turned
our attention to the selective deprotection of the hydrazine
product for further elaboration. Unlike the benzoyl-protected
hydrazine (3), the Boc hydrazine (5a) was easily deprotected
by treatment with benzenesulfonic acid in EtOH at 60 °C
(Scheme 3) without affecting the ester group. The desired
unprotected hydrazine was crystallized out and isolated as
the benzenesulfonic acid salt (9) in pure form (>99% ee)
simply by charging heptane.8
Acknowledgment. We thank the following individuals
from Merck Research Laboratories: Dr. R. Scott Hoerrner
and Mr. Mark Weisel (some hydrogenation reactions); Ms.
Mirlinda Biba, Ms. Zainab Pirzada and Ms. Yekaterina
Vaynshteyn (chiral assays); Dr. Thomas J. Novak (HRMS
characterizaton of compounds 5d and 5e); Dr. Jerry A. Murry
and Dr. David M. Tschaen for fruitful discussions.
In conclusion, we have developed an enantioselective
hydrogenation of N-alkoxycarbonyl hydrazones catalyzed by
chiral Rh-complexes. This protocol has been demonstrated
at metric ton scale under essentially same conditions with a
catalyst loading of as low as 0.2 mol % and has proven to
Supporting Information Available: Experimental pro-
cedures for hydrazone preparation, hydrogenation reactions
and deprotection along with characterization data for hydra-
zones (4), hydrogenation products (5), and deprotected
hydrazine (9). This material is available free of charge via
the Internet at http://pubs.acs.org.
(6) See Supporting Information for detail.
(7) Tappe, K.; Knochel, P. Tetrahedron: Asymmetry 2004, 15, 91.
(8) The residual Rh in the isolated product was less than 50 ppm.
OL902602C
Org. Lett., Vol. 12, No. 2, 2010
279