Synthesis of chiral aliphatic amines through asymmetric hydrogenation

Article abstract of DOI:10.1002/anie.201302943

The direct route: A Rhodium-catalyzed asymmetric hydrogenation method for the efficient synthesis of a broad range of chiral allylic amines and aliphatic amines from readily available materials was developed. A chiral Z-allylic amine was obtained for the first time through a Rhodium-DuanPhos-catalyzed asymmetric hydrogenation. TMS=Trimethylsilyl, cod=cyclooctadiene, TON=turnover number. Copyright

Full text of DOI:10.1002/anie.201302943

.
Angewandte
Communications
DOI: 10.1002/anie.201302943
Asymmetric Hydrogenation
Synthesis of Chiral Aliphatic Amines through Asymmetric
Hydrogenation**
Tang-Lin Liu, Chun-Jiang Wang,* and Xumu Zhang*
Chiral amines and their derivates are important building
blocks for the synthesis of many pharmaceutical and biolog-
ically active molecules.[1] Methods for preparing chiral
aromatic amines have been developed. The preparation of
a series of chiral amines that contain only aliphatic groups
proved to be difficult. Among the different types of chiral
amines, chiral aliphatic amines are of particular interest, and
they were found as key intermediates (1–8) in drugs and drug
candidates such as chloroquine, a corticotropin releasing
factor (CRF) drug candidate, suvorexant, dolutegravir, atre-
leuron, and other biologically active molecules (9–16;
Scheme 1).[2] In comparison with the known methods to
generate chiral aromatic amines, less attention was devoted to
the synthesis of chiral aliphatic amines. Functionalized
aliphatic amines are important chiral amines; aliphatic
amines are exemplified by allylic amine, which can be
converted to simple aliphatic amines.[3] The preparation of
simple chiral aliphatic amines such as 2-aminobutane (1)
remains a challenging task, and the best enzymatic processes,
such as those developed by BASF, for preparing chiral amines
could not be used to distinguish a methyl from an ethyl group
in the reductive amination of 2-butanone (a major limitation
of the enzymatic processes from BASF for the preparation of
chiral amines is that the aliphatic amines 1–3 are not
efficiently prepared). It is highly desired to develop simple
and efficient synthetic strategies for the preparation of simple
chiral aliphatic amine building blocks, such as those listed in
Scheme 1 (1–8).
Recently, Widenhoefer and co-workers[4] reported a new
approach to synthesize chiral allylic amines through a gold-
catalyzed intermolecular hydroamination of allenes with
moderate yields and enantioselectivities. Common
approaches to prepare chiral allylic amines involve the
addition of organometallic reagents to ketimines[5] and the
intermolecular allylic amination of allylic alcohol deriva-
tives.[6] Among the methods for the preparation of chiral
aliphatic allylic amines, the catalytic asymmetric synthesis of
Scheme 1. Aliphatic chiral amines and pharmaceutical products.
ACC2 =Acetyl-CoA carboxylase.
allylic amines through transition-metal-catalyzed asymmetric
hydrogenation holds a great potential and remains to be
developed. Herein, we report the highly enantioselective
hydrogenation of (E)-N-(buta-1,3-dien-2-yl)acetamides cata-
lyzed by a Rh–DuanPhos complex to give directly allylic
amines in high yields and enantioselectivities (Scheme 2).
Herein we often refer to the products, which are in fact
acetamides (acetylated amines), as amines, since the acetyl
groups can be easily removed to give the corresponding
amines. A number of key chiral aliphatic amine intermediates
such as 2–6 in Scheme 1 could be prepared by this simple and
efficient method.
[*] T.-L. Liu, Prof. Dr. C.-J. Wang, Prof. Dr. X. Zhang
College of Chemistry and Molecular Sciences, Wuhan University
Wuhan, Hubei, 430072 (P. R. China)
E-mail: cjwang@whu.edu.cn
xumu@whu.edu.cn
[**] This work was financially supported by a grant from Wuhan
University (203273463), the NSFC (21172176, 20972117), the
Program for New Century Excellent Talents in university (NCET-10-
0649), the Fundamental Research Funds for the Central Univer-
sities, an academic award for excellent Ph.D. candidates funded by
the Ministry of Education of China (5052011203011).
The Rh-catalyzed asymmetric hydrogenation of N-acyl
enamines is an elegant efficient method for the enantiose-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302943.
8416
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 8416 –8419

Angewandte
Chemie
Table 1: Optimization of the hydrogenation of dienamide 18a.[a]
Entry Cat. Solvent
t
[h]
S/C
Conv.
[%]
19/20[b] TON ee
[%]
1
2
3
4
5
6
7
8
21
21
21
21
21
21
21
22
23
24
25
21
21
26
26
26
MeOH 20
100 100
91:9
>98:2
85:15
93:7
95:5
98:2
98:2
93:7
98:2
94:6
95:5
>98:2
95:5
>98:2
>98:2
>98:2
91 98.9
98 99.6
85 92.3
93 96.5
95 96.7
98 98.2
98 96.4
93 94.7
98 98.7
94 90.4
94 98.0
325 98.7
400 98.6
500 99.6
1000 99.6
5000 99.5
MeOH
CH2Cl2
EtOAc
THF
PhCH3
DCE
MeOH
MeOH
MeOH
MeOH
MeOH
2
2
2
2
2
2
2
2
2
2
2
100 100
100 100
100 100
100 100
100 100
100 100
100 100
100 100
100 100
100 100
Scheme 2. The design and synthesis of allylic amines. Readily available
starting materials (17) are used, and the substrates (18) are generated
in high yields under mild conditions. Enamides (19) are obtained with
well-defined geometry. cod=cyclooctadiene.
9
lective synthesis of secondary chiral amines.[7] Since the work
reported by Kagan and Dang[8] on the Rh-catalyzed enantio-
selective hydrogenation of (E)-N-(1-phenylprop-1-enyl)acet-
amide by using the diphosphine ligand DIOP, a variety of
enamides have been prepared and selectively hydrogenated
to obtain secondary chiral amines. However, there are still
new enamide substrates that have not been prepared and
hydrogenated to produce chiral amines. For example, the
chemo- and enantioselective reduction of enamides linked
10
11
12
13
14
15
16
500
500
65
80
MeOH 20
MeOH 20
MeOH 20 1000 100
MeOH 20 5000 100
500 100
[a] Reaction conditions: 18 (0.1 mmol), catalyst (0.001 mmol–
0.02 mmol), MeOH (1 mL) under 1 bar H2. S/C=substrate/catalyst
ratio, DCE=1,2-dichloroethane. [b] Determined by NMR spectroscopy.
[c] Enantioselectivity was determined by HPLC using a chiral stationary
phase.
=
=
ꢀ
with C O, C C double and C C triple bonds is a new area.
Recently, we reported the selective hydrogenation of keto-
enamides and achieved excellent results.[9] Herein, we have
developed a new route for the chemo- and enantioselective
hydrogenation of dienamides 18 to yield chiral aliphatic
allylic amines in high yields and excellent enantioselectivities.
Dienamides can be easily prepared in one step from
readily accessible a,b-unsaturated ketones under mild con-
ditions.[10] With (E)-N-(4-phenylbuta-1,3-dien-2-yl)acetamide
(18a) as a model substrate, our initial experiment began with
[Rh(cod)(SC,RP)-DuanPhos]BF4 in methanol under H2
(1 bar) for 20 h and offered allylic amine 19a with 99% ee,
albeit with a small amount of byproduct 20a (Table 1,
entry 1). With a shorter reaction time (2 h), 18a could be
completely transformed to 19a with excellent enantioselec-
tivity and chemoselectivity (Table 1, entry 2). Solvent screen-
ing revealed that MeOH was the optimal solvent, which led to
the best reactivity and selectivity for 19a (Table 1, entries 2–
7). We also tested other chiral ligands, such as TangPhos,
ZhangPhos, f-binaphane, and Et-DuPhos; slightly lower
reactivities or enantioselectivities were obtained with these
chiral ligands. When the catalyst loading was reduced to
0.2 mol%, lower conversion was obtained (Table 1, entries 12
and 13), but changing the catalyst from [Rh(cod)(SC,RP)-
DuanPhos]BF4 to [Rh(cod)(SC,RP)-DuanPhos]BArF, the
asymmetric hydrogenation of 18a was completed with high
enantioselectivity (Table 1, entry 14). When using 0.02 mol%
of [Rh(cod)(SC,RP)-DuanPhos]BArF, the reaction still pro-
ceeded smoothly with high chemo- and enantioselectivity
(Table 1, entry 16). This method is potentially practical for
preparing chiral aliphatic amines on a large scale.
21: [Rh(cod)(SC,RP)-DuanPhos]BF4; 22: [Rh(cod)(TangPhos)]BF4;
23: [Rh(cod)(ZhangPhos)]BF4; 24: [Rh(cod)(f-Binaphane)]BF4; 25: [Rh-
(cod)(Et-DuPhos)]BF4; 26: [Rh(cod)(SC,RP)-DuanPhos]BArF.
BArF =tetrakis[3,5-bis(trifluoromethyl)phenyl]borate.
stituent on the phenyl ring of the substrate had a minor effect
on yields and enantioselectivities. All of the tested substrates
gave full conversion and excellent enantioselectivities (98–
99% ee). Dienamides derived from 1- and 2-naphthylalde-
hyde also worked well in this asymmetric hydrogenation,
providing the allylic amines 19l and 19m with 99% ee,
respectively (Table 2, entries 12 and 13). The scope of the Rh-
catalyzed asymmetric hydrogenation was not only restricted
to 4-aryl dienamides; many 4-alkyl dienamides also per-
formed extremely well, and thus this method provided an
alternative for preparing aliphatic chiral amines such as 2–5
(Scheme 1). The catalytic hydrogenation of (E)-N-(4-alkyl-
buta-1,3-dien-2-yl)acetamides, such as (E)-N-(pent-1,3-dien-
2-yl)acetamide (18o), (E)-N-(hexa-1,3-dien-2-yl)acetamide
(18p), and (E)-N-(4-cyclohexylbuta-1,3-dien-2-yl)acetamide
Under these optimized reaction conditions (Table 1,
entry 2), a variety of (E)-N-(4-arylbuta-1,3-dien-2-yl)acet-
amides were hydrogenated, and high chemo- and enantiose-
lectivities were observed (Table 2, entries 1–13). The sub-
Angew. Chem. Int. Ed. 2013, 52, 8416 –8419
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8417

.
Angewandte
Communications
Table 2: Asymmetric hydrogenation of dienamides by Rh–DuanPhos.[a]
Scheme 3. a) Synthesis of Z-allyllic amine 28. b) Synthesis of (S)-but-3-
yn-2-amine 31 and (S)-butan-2-amine 32. TMS=trimethylsilyl, TBAF=
tetrabutylammonium fluoride. c) Catalytic enantioselective synthesis of
2-methyl-1,2,3,4-tetrahydro-quinoline (33) starting from 19 f. Reaction
conditions: 1) [Rh(cod)(SC,RP)-DuanPhos]BF4, 1 bar H2, MeOH, RT,
2 h.
high yield and the alkyne group stayed untouched
(Scheme 3b). Therefore, a key chiral intermediate such as 6
and its enantiomer 31 can be efficiently prepared.
Removal of the TMS group from 30 generates the useful
chiral building block 31, which can be used for producing the
drugs 11[2d] and 14[2g] (Scheme 1) through a Sonogashira
coupling. Importantly, we have prepared simple aliphatic
amines such as the chiral 2-aminobutane 32 and its derivative
in high yields and enantioselectivities (Scheme 3b). These
simple chiral aliphatic amines are useful building blocks for
producing drugs and drug candidates such as 9[2b] and 13.[2f] To
our knowledge, this is the first report addressing the synthesis
of 32 through asymmetric hydrogenation reaction.
[a] Reaction conditions: 18 (0.1 mmol), 21 (0.001 mmol), MeOH (1 mL)
under 1 bar H2 for 2 h. Yields of isolated products are given. The
enantioselectivities were determined by HPLC using a chiral stationary
phase.
(18q) all led to chiral 4-alkyl allylic amines in full conversion
and with up to 99% ee (Table 2, entries 15–17). A slightly
lower ee value has been observed with substrate 18r (Table 2,
entry 18).
The hydrogenation was also performed on a large scale to
test its practicality (Scheme 4). When the reaction was
conducted at 5 mmol, allylic amines 19a, 19 f, and 19h could
be prepared in high yields with full conversion and high
enantioselectivities (98–99% ee).
To further demonstrate the potential of this simple and
highly efficient catalytic asymmetric hydrogenation method,
we prepared key intermediates for the synthesis of several
bioactive active compounds. The 2-methyl-1,2,3,4-tetrahydro-
quinolines are ubiquitous in many naturally occurring alka-
loids and related biologically active molecules, and this motif
exists in many pharmaceutical products. Product 19 f was used
for the preparation of 2-methyl-1,2,3,4-tetrahydroquinolines
by using the Buchwald–Hartwig amination reaction.[11] The
hydrogenation of dienamide 18 f gave direct access to 19 f
with > 99% ee and full conversion (Scheme 3c). This trans-
To expand the substrate scope of enamides, we have also
prepared an enamide bearing an alkyne moiety. The asym-
metric hydrogenation of N-(4-phenylbut-1-en-3-yn-2-yl)acet-
amide (27) by using the [Rh(cod)(SC,RP)-DuanPhos]BF4
complex as the catalytic system surprisingly did not lead to
the corresponding N-(4-phenylbut-3-yn-2-yl)acetamide, but
offered (Z)-N-(4-phenylbut-3-en-2-yl)acetamide (28) as the
hydrogenation product with full conversion and an excellent
ee value (99% ee; Scheme 3a). To our knowledge, this is the
first synthesis of Z-allylic amine derivates through an
asymmetric hydrogenation method (Scheme 3a). However,
the hydrogenation of 29 offered 30 with high ee values and
8418
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 8416 –8419

Angewandte
Chemie
Weitzberg, R. F. Clark, X. Xu, Q. Li, T. Zhang, T. M. Hansen, G.
Liu, Z. Xin, X. Wang, R. Wang, T. McNally, H. Camp, B. A.
Beutel, H. L. Sham, J. Med. Chem. 2006, 49, 3770 – 3773; e) T. L.
Moda, C. A. Montanari, A. D. Andricopulo, Bioorg. Med. Chem.
2007, 15, 7738 – 7745; f) H. M. Branley, R. M. du Boisb, A. U.
Wells, H. A. Jones, Nucl. Med. Biol. 2008, 35, 901 – 909; g) J. M.
Drazen, C. N. Yandava, L. Dubꢀ, N. Szczerback, R. Hippensteel,
A. Pillari, E. Israel, N. Schork, E. S. Silverman, D. A. Katz, J.
Drajesk, Nat. Genet. 1999, 22, 168 – 170; h) E. E. Hodgkin, A.
Miller, M. Whittaker, Bioorg. Med. Chem. Lett. 1992, 2, 597 –
602; i) C. R. Hopkins, ACS Chem. Neurosci. 2012, 3, 647 – 648.
[3] For reviews on the synthesis of simple aliphatic amines, see:
a) A. E. Jacobson, E. L. May, L. J. Sargent, Medicinal chemistry,
VCH, Weinheim, 1970; b) D. Lednicer, L. A. Mitscher, Organic
chemistry of drug synthesis, VCH, Weinheim, 1984; c) S. I. Inoue,
H. Takaya, K. Tani, S. Otsuka, T. Sato, R. Noyori, J. Am. Chem.
Soc. 1990, 112, 4897 – 4905; d) K. Burgess, L. T. Liu, B. Pal, J.
Org. Chem. 1993, 58, 4758 – 4763; e) J. Krysan, T. W. Rockway,
A. R. Haight, Tetrahedron: Asymmetry 1994, 5, 625 – 632.
[4] K. L. Butler, M. Tragni, R. A. Widenhoefer, Angew. Chem. 2012,
124, 5265 – 5268; Angew. Chem. Int. Ed. 2012, 51, 5175 – 5178.
[5] a) M. Shibasaki, M. Kanai, Chem. Rev. 2008, 108, 2853 – 2873;
b) M. T. Robak, M. A. Herbage, J. A. Ellman, Chem. Rev. 2010,
110, 3600 – 3740; c) J. Hannedouche, O. Riant, Org. Biomol.
Chem. 2007, 5, 873 – 888; d) E. N. Jacobsen, P. Vachal, Org. Lett.
2000, 2, 867 – 870; e) S. J. Connon, Angew. Chem. 2008, 120,
1194 – 1197; Angew. Chem. Int. Ed. 2008, 47, 1176 – 1178; f) D.
Enders, K. Gottfried, G. Raabe, Adv. Synth. Catal. 2010, 352,
3147 – 3152; g) Y. Suto, M. Kanai, M. Shibasaki, J. Am. Chem.
Soc. 2007, 129, 500 – 501; h) D. M. Spero, S. R. Kapadia, J. Org.
Chem. 1997, 62, 5537 – 5541; i) D. A. Cogan, J. A. Ellman, J. Am.
Chem. Soc. 1999, 121, 268 – 269; j) D. Enders, U. Reinhold,
Tetrahedron: Asymmetry 1997, 8, 1895 – 1946; k) C. Lauzon, A.
Charette, Org. Lett. 2006, 8, 2743 – 2745; l) R. Wada, T.
Shibuguchi, S. Makino, K. Oisaki, M. Kanai, M. Shibasaki, J.
Am. Chem. Soc. 2006, 128, 7687 – 7691.
Scheme 4. Gram-scale reaction for the preparation of the enantiomer-
ically enriched allylic amine 19.
formation is efficient in the preparation of the corresponding
chiral aliphatic amines.
In summary, we have developed a Rh-catalyzed asym-
metric hydrogenation to synthesize chiral aliphatic amines
such as allylic amines and their derivatives. Notably, full
conversion and excellent enantioselectivities were obtained in
the hydrogenations of (E)-N-(buta-1,3-dien-2-yl)acetamides.
A chiral Z-allylic amine was obtained for the first time
through an Rh–DuanPhos catalyzed asymmetric hydrogena-
tion. The general method for preparing chiral aliphatic
amines should have
a broad impact in synthesizing
a number of chiral pharmaceutical products.
Experimental Section
General hydrogenation procedure: In a nitrogen-filled glovebox, the
Rh complex (0.01 mmol) was dissolved in anhydrous MeOH (1.0 mL)
and the solution was equally divided into 10 vials charged with
dienamide substrates (0.1 mmol) in anhydrous MeOH solution
(1.0 mL). The resulting vials were transferred to an autoclave,
which was charged with 1 atm of H2, and the reaction mixtures
were stirred at room temperature for 2 h. The hydrogen gas was
released slowly and the solution was concentrated and passed through
a short column of silica gel to remove the metal complex. The chiral
amines were then analyzed by using HPLC and GC on a chiral
stationary phase to determine the enantiomeric excesses.
[6] Reviews on the intermolecular allylic amination of allylic
alcohol derivatives: a) B. M. Trost, M. L. Crawley, Chem. Rev.
2003, 103, 2921 – 2944; b) J. F. Hartwig, M. L. Stanley, Acc.
Chem. Res. 2010, 43, 1461 – 1475.
[7] Reviews on the enantioselective synthesis of secondary chiral
amines through Rh-catalyzed asymmetric hydrogenation: a) W.-
J. Tang, X. Zhang, Chem. Rev. 2003, 103, 3029 – 3070; b) J.-H.
Xie, S.-F. Zhu, Q.-L. Zhou, Chem. Rev. 2011, 111, 1713 – 1760.
[8] H. B. Kagan, T.-P. Dang, J. Am. Chem. Soc. 1972, 94, 6429 – 6433.
[9] a) H. Geng, W. Zhang, J. Chen, G. Hou, L. Zhou, Y. Zou, W. Wu,
X. Zhang, Angew. Chem. 2009, 121, 6168 – 6170; Angew. Chem.
Int. Ed. 2009, 48, 6052 – 6054; b) H. Geng, K. Huang, T. Sun, W.
Li, X. Zhang, L. Zhou, W. Wu, X. Zhang, J. Org. Chem. 2011, 76,
332 – 334.
[10] J. T. Reeves, Z. Tan, Z. S. Han, G. Li, Y. Zhang, Y. Xu, D. C.
Reeves, N. C. Gonnella, S. Ma, H. Lee, B. Z. Lu, C. H.
Senanayake, Angew. Chem. 2012, 124, 1429 – 1433; Angew.
Chem. Int. Ed. 2012, 51, 1400 – 1404.
[11] a) B.-L. Chen, B. Wang, G.-Q. Lin, J. Org. Chem. 2010, 75, 941 –
944; b) J. P. Wolfe, S. Wagaw, J.-F. Marcoux, S. L. Buchwald, Acc.
Chem. Res. 1998, 31, 805 – 818; c) J. F. Hartwig, Acc. Chem. Res.
1998, 31, 852 – 860; d) J. F. Hartwig, Angew. Chem. 1998, 110,
2154 – 2177; Angew. Chem. Int. Ed. 1998, 37, 2046 – 2067; e) S. L.
Buchwald, A. Muci, Top. Curr. Chem. 2002, 219, 131 – 209.
Received: April 9, 2013
Revised: May 23, 2013
Published online: July 1, 2013
Keywords: amines · asymmetric catalysis · hydrogenation ·
.
rhodium
[1] For a review, see: T. C. Nugent, Chiral Amine Synthesis, Wiley-
VCH, Weinheim, 2008.
[2] a) A. Savarino, M. B. Lucia, F. Giordano, R. Cauda, Lancet
Oncol. 2006, 7, 792 – 793; b) P. J. Gilligan, T. Clarke, L. He, S.
Lelas, Y.-W. Li, K. Heman, L. Fitzgerald, K. Miller, G. Zhang, A.
Marshall, C. Krause, J. F. McElroy, K. Ward, K. Zeller, H. Wong,
S. Bai, J. Saye, S. Grossman, R. Zaczek, S. P. Arneric, P. Hartig,
D. Robertson, G. Trainor, J. Med. Chem. 2009, 52, 3084 – 3092;
c) A. Sasse, K. Kiec-Kononowicz, H. Stark, M. Motyl, S.
Reidemeister, C. R. Ganellin, X. Ligneau, J.-C. Schwartz, W.
Schunack, J. Med. Chem. 1999, 42, 593 – 600; d) Y. G. Gu, M.
Angew. Chem. Int. Ed. 2013, 52, 8416 –8419
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8419