Enantioselective synthesis of β-substituted chiral allylic amines: Via Rh-catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1039/c6cc06047a

An asymmetric mono-hydrogenation of 2-acetamido-1,3-dienes catalyzed by a Rh-DuanPhos complex has been developed. This approach provides easy access to chiral allylic amines with excellent enantioselectivities and high regioselectivities. The products are valuable chiral building blocks for pharmaceuticals.

Full text of DOI:10.1039/c6cc06047a

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Enantioselective synthesis of ß-substituted Chiral Allylic Amines
via Rh-Catalyzed Asymmetric Hydrogenation
Received 00th January 20xx,
Accepted 00th January 20xx
†
Qingli Wang, a Wenchao Gao,a† Hui Lv,*a and Xumu Zhang*a b
DOI: 10.1039/x0xx00000x
www.rsc.org/
Rh-DuanPhos
complex-catalyzed
asymmetric
mono- allylic substitution reaction ( Scheme1, 1),3 vinylation of
hydrogenation of 2-acetamido-1,3-dienes has been developed,
which provides a readily accessible approach to chiral allylic
amines
with
excellent
enantioselectivities
and
high
regioselectivities. The products are valuable chiral building blocks
in chiral pharmaceuticals.
Chiral allylic amines are versatile building blocks in organic
chemistry and be widely used in synthesis of pharmaceuticals
and biologically active compounds.1-2 Considerable efforts
have been devoted to exploring efficient methods for the
synthesis of chiral allylic amines and many approaches have
imines,4 direct allylic amination of simple alkenes,5 aza-Claisen
rearrangement of allylic trichloroacetimidates,6 and kinetic
resolution of primary allylic amines.7 However, access to
ß-
been developed. Among them, the methods for γ-substituted
chiral allylic amines are well documented, and the
substituted chiral allylic amines is rare, and the main approach
heavily relies on an asymmetric aza-Morita-Baylis-Hillman
reaction ( Scheme1, 2), despite the inherent drawbacks, such
as limited substrate scope and long reaction time.8 Developing
representative approaches include transition-metal catalyzed
efficient methods for enantioselecitive synthesis of
ß-
substituted allylic amines is highly desired but remains a
challenge.
Fig. 1 Structures of the phosphine ligands for hydrogenation of
1a.
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Table
1
Ligand Screening for Rh-Catalyzed Asymmetric success of these examples, we envisioned that
ß-substituted
Hydrogenation of 1aa
chiral allylic amines may also be obtained by regio- and
enantioselective hydrogenation of 3-branched 2-acetamido-
1,3-dienes. Herein, we report a new approach for asymmetric
synthesis of chiral allylic amines via Rh-catalyzed regio- and
enantioselectivitive hydrogenation.
entry
ligand
Conv. (%)b
2a:3ab
>98:2
>98:2
>98:2
37:63
40:60
>98:2
>98:2
90:10
>98:2
>98:2
ee(%)c
28
Our strategy for the synthesis of chiral allylic amines is
listed in Scheme 2. Initially, N-(3-phenylbuta-1,3-dien-2-
yl)acetamide 1a was prepared and chosen as a model
substrate to optimize the reaction conditions. First of all, the
effect of ligands on the reaction was investigated at room
temperature under 1 atm H2 in methanol in the presence of 1
mol% [Rh(cod)2]BF4. As shown in Table 1, axial chiral
biphosphrous ligands, such as (R)-MeO-Biphep, (S)-C3-
TunePhos and (S)-SegPhos, exhibited poor reactivities and
enantioselectivities but excellent regioselectivities (entries 1-
3). When planar chiral ligands, such as Josiphos and (S,S)-f-
Binaphane, were used, the reactivity improved dramatically,
1
2
(R)-MeO-Biphep
(S)-C3-TunePhos
(S)-SegPhos
35
38
46
>99
60
29
7
11
3
27
4
JosiPhos
50
5
(S,S)-f-Binaphane
(R.R)-Quinoxp
(S,S)-Me-DuPhos
(S)-Binapine
48
6
92
7
67
8
50
67
>99
43
9
TangPhos
95
10
(Sc,Rp)-DuanPhos
96
aUnless otherwise mentioned, all reactions were carried out
with a [Rh(cod)2]BF4/ligand/substrate ratio of 1:1.1:100, in 1
mL MeOH at room temperature under 1 atm H2 for 6 h.
but the regioselectivity and enatioselectivity
were
disappointing (entries 4-5). To our delight, excellent
bDetermined by H NMR spectroscopy. Determined by HPLC
1
c
regioselectivity and high enantioselectivity were obtained
when P-chiral ligand (R, R)-Quinoxp was employed, though the
yield is very low. Subsequently, a series of P-chiral diphophine
ligands developed in our group were screened, electron-
donating and rigid (Sc, Rp)-DuanPhos was proved to be the
best ligand to give the desired product with full conversion and
excellent regio- , enantioselectivity (entries 7-10). The solvent
effects on this reaction was also evaluated. As shown in Table
2, the solvent screening revealed that MeOH was the best
choice (Table 2, entries 1-9).
analysis using a chiral stationary phase.
Table
Hydrogenation of 1aa
2 Solvent Screening for Rh-Catalyzed Asymmetric
entry
solvent
MeOH
MeOH
i-PrOH
EtOH
Conv. (%)b
>99
>99
76
2a:3ab
>98:2
91:9
ee(%)c,
96
Under the optimized reaction conditions (1 mol%
[Rh(cod)(Rc, Sp)-DuanPhos]BF4 , in MeOH at rt under 1 atm
H2 ), the substrate scope was examined. As shown in Table 3,
all of the 2-acetamido-1,3-dienes examined here were good
1
2d
3
96
>98:2
>98:2
80:20
>98:2
95:5
93
4
78
90
substrates for this reaction and afforded the corresponding β-
5
CF3CH2OH
EA
>99
98
98
substituted allylic amines with high yields and good
enantioselectivities.14 When R1 was aromatic group, the
substituent on the phenyl ring, no matter electron-donating
group or electron-withdrawing group, had no effect on the
yields and enantioselectivities except for p-F or p-Br
substituted substrates with slightly lower enantioselectivity
6
96
7
THF
46
96
8
toluene
CH2Cl2
>99
>99
90:10
91:9
94
9
97
aUnless otherwise mentioned, all reactions were carried out
with a catalyst/substrate ratio of 1:100, in 1 mL of solvent at rt
under 1 atm H2 for 6 h. bDetermined by 1H NMR spectroscopy.
cDetermined by HPLC analysis using a chiral stationary phase.
d24h.
(
2a-2h). 2-naphthyl substituted dienamide can also be
hydrogenated under this reaction condition but the
enantioselectivity was decreased dramatically and need a
longer reaction time to get a good yield (2i). When phenyl
group was replaced by Bn group, the reaction went smoothly
and gave the desired product with good yield and excellent ee
In the past decades, asymmetric hydrogenation,9 due to
its atom economy, cost effectiveness and environmentally
friendly nature, has become one of the most powerful
strategies for the synthesis of chiral compounds. In this
context, our group has developed several efficient catalysts for
asymmetric hydrogenation and successfully synthesized a
series of chiral amines and alcohols.10 Recently, our group
(
2j). When R2 was aromatic group, the reaction also worked
very well (2k, 2l). (E)-N-(5-benzylidenecyclopent-1-en-1-
yl)acetamide was also well tolerated for this reaction albeit the
enantioselectivity decreased to some extent (2m).
To demonstrate the potential utility of this method, the
asymmetric hydrogenation of N-(3-(4-methoxyphenyl)buta-
1,3-dien-2-yl)acetamide (2d) was carried out on preparative
scale, and 0.65 gram desired product was obtained smoothly
without any loss in yield and enantioselectivity. Notably, when
the reaction was carried out under 50 atm hydrogen pressure
developed the protocols to synthesize
amino acids,11
ketones13 by regioselective asymmetric hydrogenation of
different substituted functionalized enamides. Intrigued by the
γ,
δ
-
unsaturated
substituted allylic amines,12 α-amino
γ
-
2 | J. Name., 2012, 00, 1-3
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and Technology Project of Wuhan City (2015071704011640),
Natural Science Foundation of Hubei Province (2014CFB181),
Scheme 3 Investigation of potential application of asymmetric
mono-hydrogenation of 2-acetamido-1,3-dienes.
“111” Project of the Ministry of Education of China and the
National Natural Science Foundation of China (Grant No.
21372179, 21432007, 21402145).
Notes and references
aAll reactions were carried out with a catalyst/substrate in a
ratio of 1:100, in MeOH at rt under 1 atm H2. bThe yield of
isolated product based on consumed starting material .
cDetermined by HPLC analysis using a chiral stationary phase.
1
2
3
(a) Y. Nakamura, A. M. Burke, S. Kotani, J. W. Ziller and S. D.
Rychnovsky, Org. Lett. 2009, 12, 72; (b) T. L. Suyama and W.
H. Gerwick, Org. Lett. 2008, 10, 4449; (c) A. D. Brosius, L. E.
Overman and L. Schwink, J. Am. Chem. Soc. 1999, 121, 700;
(d) B. M. Trost and D. J. Van Vranken, J. Am. Chem. Soc.
1993, 115, 444.
(a) C. Dai and C. R. J. Stephenson, Org. Lett. 2010, 12, 3453;
(b) C. Gnamm and G. Helmchen, Synthesis. 2008, 3331; (c) Y.-
K. Chen and P. J. Walsh, J. Am. Chem. Soc. 2002, 124, 12225;
(d) k. Burgess, L.-T. Liu, and B. Pal, J. Org. Chem. 1993, 58,
4758; (e) T. Hayashi, A. Yamamoto, Y. Ito, E. Nishioka, H.
Miura and K. Yanagi, J. Am. Chem. Soc. 1989, 111, 6301.
(a) T. Ohmura and J. F. Hartwig, J. Am. Chem. Soc. 2002, 124
dReaction time under condition a. eS/C = 20, 20 atm H2. f 2a
2c 2g were obtained by using (Sc,Rp)-DuanPhos as lignd, 2d-2f,
2h-2m were obtained by using (Rc,Sp)-DuanPhos as ligand.
no over-reduction product was observed in all cases.
, 2b,
,
g
3
for 24 hours, the full reduction product 3d was obtained with
high yield and moderate diastereoselectivity. Moreover,
asymmetric hydrogenation of 1l with low catalyst loading was
evaluated. We found that there was no effect on the yield and
enantioselectivity when the catalyst loading was decreased to
0.1 mol%. (Scheme 3).
,
15164; (b) C. A. Kiener and J. F. Hartwig, J. Am. Chem. Soc.
2003, 125, 14272; (c) C. Shu, A. Leitner and J. F. Hartwig,
Angew. Chem. Int. Ed. 2004, 43, 4797; (d) J. W. Faller and J. C.
Wilt, Org. Lett. 2005,
7, 633; (e) D. Polet, A. Alexakis, K.
Tissot-Croset, C. Corminboeuf and K. Ditrich, Chem.-Eur. J.
2006, 12, 3596; (f) O. V. Singh and H. Han, J. Am. Chem. Soc.
2007, 129, 774; (g) T. Nagano and S. Kobayashi, J. Am. Chem.
Soc. 2009, 131, 4200; (h) M. Roggen, E. M. Carreira, J. Am.
Chem. Soc. 2010, 132, 11917; (i) E. M. Vieira, M. L. Snapper
and A. H. Hoveyda, J. Am. Chem. Soc. 2011, 133, 3332; (j) S. T.
In conclusion, we have developed a new strategy to
synthesize β-substituted chiral allylic amines by Rh/DuanPhos
catalyzed asymmetric hydrogenation under very mild reaction
conditions. The protocol exhibited high regioselectivity and
good to excellent enantioselectivity with broad substrate
scope, which suggests that this approach has potential
applications in organic synthesis. Further efforts to expand the
substrate scope and applications are underway in our lab.
We are grateful for the financial support by a grant from
Wuhan University (203273463), the Youth Chen-Guang Science
Madrahimov and J. F. Hartwig, J. Am. Chem. Soc. 2012, 134
,
8136; (k) S. Breitler and E. M. Carreira J. Am. Chem. Soc. 2015,
137, 5296; (l) B. W. H. Turnbull and P. A. Evans, J. Am. Chem.
Soc. 2015, 137, 6156.
4
(a) R. B. Grossman, W. M. Davis and S. L. Buchwald, J. Am.
Chem. Soc. 1991, 113, 2321; (b) S. J. Patel and T. F. Jamison,
Angew. Chem. Int. Ed. 2004, 43, 3941; (c) E. Skucas, J. R.
Kong and M. J. Krische, J. Am. Chem. Soc. 2007, 129, 7242; (d)
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

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Page 4 of 4
View Article Online
DOI: 10.1039/C6CC06047A
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Journal Name
M. Y. Ngai, A. Barchuk and M. J. Krische, J. Am. Chem. Soc.
2007, 129, 12644; (e) M. McLaughlin, M. Takahashi and G. C.
1154; (h) H.-L. Yang, N.-N. Huo, P. Yang, H. Pei, H. Lv and X.-
M. Zhang, Org. Lett. 2015, 17, 4144.
Micalizio, Angew. Chem. Int. Ed. 2007, 46, 3912; (f) K. Brak 11 M. Gao, J.-J. Meng, H. Lv and X.-M. Zhang, Angew. Chem. Int.
and J. A. Ellman, J. Am. Chem. Soc. 2009, 131, 3850; (g) Y. Ed. 2015, 54, 1885.
Fukumoto, M. Daijo and N. Chatani, J. Am. Chem. Soc. 2012, 12 (a) T.-L. Liu, C.-J. Wang and X.-M. Zhang, Angew. Chem. Int.
134, 8762; (h) L.-J. Zhou, Z.-M. Li, Y. Zou, Q.-R. Wang, I. A. Ed. 2013, 52, 8416; (b) M. Zhou, T.-L. Liu, M. Cao, Z.-J. Xue, H.
Sanhueza, F. Schoenebeck and A. Goeke, J. Am. Chem. Soc. Lv and X.-M. Zhang, Org. Lett. 2014, 16, 3484.
2012, 134, 20009; (i) H. Wu, F. Haeffner and A. H. Hoveyda, J. 13 (a) T. Sun, G.-H. Hou, X.-F. Ma and X.-M. Zhang, Adv. Synth.
Am. Chem. Soc. 2014, 136, 3780; (j) Y. Huang, R.-Z. Huang
and Y. Zhao, J. Am. Chem. Soc. 2016, 138, 6571.
Catal. 2011, 353, 253; (b) W.-C. Gao, Q.-L. Wang, H. Lv abd
X.-M. Zhang, Chem. Asian J. 2016, , 231.
See review: M. Johannsen and K. A. Jorgensen, Chem. Rev. 14 Absolute configuration of compound 2a has been
2
5
6
1998, 98, 1689.
(a) L. E. Overman, Acc. Chem. Res. 1980, 13, 218; (b) C. E.
established by comparison with literature data.
ref. 7
[α] D20 = -30 (c = 0.3, CHCl3, 83% ee), our experiment
result of 2a: [α]D = -26 (c = 0.5, CHCl3, 95% ee)
other configurations are uncertain and based on the
assumption that the configuration follows that of 2a
( for S-2a in
:
20
Anderson and L. E. Overman, J. Am. Chem. Soc. 2003, 125
12412; (c) L. E. Overman, C. E. Owen, M. M. Pavan and C.
Richards, J. Org. Lett. 2003, , 1809; (d) S. F. Kirsch, L. E.
,
). All the
5
.
Overman and M P. Watson, J. Org. Chem. 2004, 69, 8101; (e)
A. G. Jamieson and A. Sutherland, Org. Biomol. Chem. 2005,
3
, 735; (f) C. E. Anderson, Y. Donde, C. J. Douglas and L. E.
Overman, J. Org. Chem. 2005, 70, 648; (g) R. Peters, Z.-Q. Xin,
D. F. Fischer and W. B. Schweizer, Organometallics, 2006, 25
2917; (h) A. G. Jamieson and A. Sutherland, Org. Biomol.
Chem. 2006, , 2932; (i) M. Weiss, D. F. Fischer, Z. Q. Xin, S.
,
4
Jautze, W. B. Schweizer and R. Peters, Angew. Chem. Int. Ed.
2006, 45, 5694; (j) S. Jautze, P. Seiler and R. Peters, Angew.
Chem. Int. Ed. 2007, 46, 1260.
7
8
A. Kolleth, M. Cattoen, S. Arseniyadis and J. Cossy, Chem.
Commun. 2013, 49, 9338.
(a) K. Matsui, S. Takizawa and H. Sasai, J. Am. Chem. Soc.
2005, 127, 3680; (b) R. Gausepohl, P. Buskens, J. Kleinen, A.
Bruckmann, C. W. Lehmann, J. Klankermayer and W. Leitner,
Angew. Chem. Int. Ed. 2006, 45, 3689; (c) V. Declerck, J.
Martinez and F. Lamaty, Chem. Rev. 2009, 109, 1; (d) T.
Yukawa, B. Seelig, Y.-J. Xu, H. Morimoto, S. Matsunaga, A.
Berkesse and M. Shibasaki, J. Am. Chem. Soc. 2010, 132
,
11988; (e) K. Hyodo, S. Nakamura and N. Shibata, Angew.
Chem. Int. Ed. 2012, 51, 10337.
9
Selective books on asymmetric hydrogenation, see: (a) The
Handbook of Homogeneous Hydrogenation; Vries, J. G., de
Elsevier, C. J., Eds.; Wiley- VCH: Weinheim, 2007; (b)
Asymmetric Catalysis: New Concepts and Methods, K.-L. Ding,
Q.-H. Fan, Eds; Chemical industry press: Beijing, 2008; (c)
Transition Metal-Catalyzed Homogeneous Asymmetric
Hydrogenation. In Catalytic Asymmetric Synthesis, 3rd ed,;
John Wiley & Sons, Inc,: Hoboken, NJ, 2009; PP 343-436W.
Selective reviews on asymmetric hydrogenation, see: (d) S.
Knowles, Acc. Chem. Res. 1983, 16, 106; (e) Q.-H. Fan, Y.-M.
Li and A. S.-C. Chan, Chem. Rev. 2002, 102, 3385; (f) W.-J.
Tang and X.-M. Zhang, Chem. Rev. 2003, 103, 3029; (g) S. J.
Roseblade and A. Pfaltz, Acc. Chem. Res. 2007, 40, 1402; (h)
Y.-G. Zhou, Acc. Chem. Res. 2007, 40, 1357. (i) H. Shimizu, I.
Nagasski, K. Matsumura, N. Sayo and T. Saito, Acc. Chem. Res.
2007, 40, 1385; (j) W. Zhang, Y. Chi, X.-M. Zhang, Acc. Chem.
Res. 2007, 40, 1278; (k) J.-H. Xie, S.-F. Zhu and Q.-L. Zhou,
Chem. Rev. 2011, 111, 1713; (l) Y. Liu, Z. Wang and K.-L. Ding,
Acta Chim. Sin. 2012, 70, 1464; (m) J.-H. Xie and Q.-L. Zhou,
Acta Chim. Sin. 2012, 70, 1427.
10 (a
2003, 125, 9570; (
) W.-J. Tang, S.-L. Wu and X.-M. Zhang, J. Am. Chem. Soc.
) D. Liu, W.-Z. Gao, C.-J. Wang and X.-M.
b
Zhang, Angew. Chem. Int. Ed. 2005, 44, 1687; Angew. Chem.
2005, 117, 1715; (c) G. Liu, X. Liu, Z. Cai, G. Xu and W.-J. Tang,
Angew. Chem. Int. Ed. 2013, 52, 4235; Angew. Chem. 2013,
125, 4329; (d) M. Zhou, D.-J. Dong, Y. Wang and X.-M. Zhang,
Org. Lett. 2013, 15, 5524; (e) J. Jiang, Y. Wang and X.-M.
Zhang, ACS Catal. 2014,
Lv and X.-M. Zhang, J. Am. Chem. Soc. 2014, 136, 16120; (g) J.
Jiang, W.-X. Lu, H. Lv and X.-M. Zhang, Org. Lett. 2015, 17
4, 1570; (f) Q.-L. Wang, W. Huang, H.
,
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