Access to Chiral Seven-Member Cyclic Amines via Rh-Catalyzed Asymmetric Hydrogenation

Article abstract of DOI:10.1021/acs.orglett.7b01726

A highly efficient asymmetric hydrogenation of azepine/oxazepine-type seven-member cyclic imine hydrochlorides was successfully developed using Rh/bisphosphine-thiourea ligand ZhaoPhos, affording various chiral seven-member cyclic amines with full conversions, high yields, and excellent enantioselectivities (up to 96% yield, >99% ee). Additionally, this asymmetric hydrogenation can proceed well on gram scale with excellent ee value. Moreover, control experimental results displayed that the anion-bonding interaction between the chloride ion of the substrate and thiourea motif of the ZhaoPhos played an important role to obtain excellent enantioselectivity.

Full text of DOI:10.1021/acs.orglett.7b01726

Letter
pubs.acs.org/OrgLett
Access to Chiral Seven-Member Cyclic Amines via Rh-Catalyzed
Asymmetric Hydrogenation
Pan Li,†,‡ Yi Huang,‡ Xinquan Hu,*,† Xiu-Qin Dong,*,‡ and Xumu Zhang*,§,‡
†College of Chemical Engineering, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, P. R. China
‡College of Chemistry and Molecular Sciences, Wuhan University, 430072, Wuhan, P. R. China
§Department of Chemistry, South University of Science and Technology of China, Shenzhen, 518000, P. R. China
S
* Supporting Information
ABSTRACT: A highly efficient asymmetric hydrogenation of azepine/oxazepine-type seven-member cyclic imine hydro-
chlorides was successfully developed using Rh/bisphosphine-thiourea ligand ZhaoPhos, affording various chiral seven-member
cyclic amines with full conversions, high yields, and excellent enantioselectivities (up to 96% yield, >99% ee). Additionally, this
asymmetric hydrogenation can proceed well on gram scale with excellent ee value. Moreover, control experimental results
displayed that the anion-bonding interaction between the chloride ion of the substrate and thiourea motif of the ZhaoPhos
played an important role to obtain excellent enantioselectivity.
hiral macrocyclic amines and derivatives have attracted
derivatives for the construction of chiral seven-member cyclic
Cmuch attention due to their wide application in the amine 2,3-dihydro-1H-benzo[b]azepines with excellent enan-
tioselectivities.6b In 2011, Tian reported an asymmetric Pictet−
synthesis of numerous natural products and medicinal
compounds.1 Among these chiral macrocyclic amines, chiral
Spengler-type reaction of 4-(2-aminoaryl)indoles with imines
catalyzed by chiral phosphoric acid to afford various structurally
diverse indolo[3,4-cd][1]benzazepines.6c In 2014, Nguyen and
co-workers developed a Rh-catalyzed sequential allylic amina-
tion−olefin hydroacylation reaction to access chiral seven-
member cyclic amines.6d The catalytic asymmetric hydro-
genation of cyclic imines emerged as one of the most
straightforward synthetic methodologies to prepare corre-
sponding chiral cyclic amines.7 Recently, Zhou and co-workers
successfully realized Ir/C3*-TunePhos-catalyzed asymmetric
hydrogenation of fused benzodiazepinones and benzodiaze-
pines to provide seven-member cyclic amines.7f Despite the
great advances that have been achieved, it is still highly
desirable to develop effective synthetic methods to construct
valuable chiral seven-member cyclic amines. Recently, we
developed chiral bifunctional bisphosphine-thiourea ligands
(ZhaoPhos) based on the synergistic activation strategy via
cooperating transition metal catalysis and organocatalysis.8
Some challenging asymmetric hydrogenation reactions were
accomplished smoothly by the activation modes of hydrogen-
bonding catalysis8a,c−f,h and anion-binding catalysis.8b,g Herein,
we believed that the asymmetric hydrogenation of 11H-
dibenzo[b,e]azepine/oxazepine hydrochlorides can be success-
seven-member cyclic amines are important and powerful motifs
of biologically active molecules and pharmaceuticals.2 For
example, Cephalotaxine possessed excellent anticancer activity,3
Stemonine displayed potent antibechic effect on clinical
evaluation,4 and (R)-Mianserin acted as a kind of antiulcer
drug and antidepressant5 (Figure 1).
Figure 1. Examples of biologically active compounds and
pharmaceuticals with chiral seven-member cyclic amine motifs.
Owing to the remarkable importance of chiral seven-member
cyclic amines, great efforts have been made to develop
asymmetric catalytic synthetic methods to construct these
compounds.6 In 2002, Hoveyda and co-workers described Mo-
catalyzed asymmetric ring-closing metathesis to synthesize
chiral seven-member cyclic amines.6a In 2010, You and co-
workers developed an Ir/phosphoramidite-catalyzed asymmet-
ric tandem allylic vinylation and amination reaction of (E)-but-
2-ene-1,4-diyl dimethyl dicarbonate with ortho-amino styrene
Received: June 7, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01726
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
fully achieved by Rh/ZhaoPhos with high reactivity and
excellent enantioselectivity through forming anion-bonding
interaction (Scheme 1).
enantioselectivity (94% ee, Table 1, entry 6). And the ligand
L2 without a thiourea motif provided a very poor ee value (27%
ee, Table 1, entry 7). The reaction results displayed that the
thiourea motif of our ligand ZhaoPhos can activate the
substrate 6-methyl-11H-dibenzo[b,e]azepine hydrochloride 1a
through anion-bonding interaction.
Scheme 1. Synthesis of Chiral Seven-Member Cyclic Amines
Subsequently, we investigated the solvent effect in the
asymmetric hydrogenation of 6-methyl-11H-dibenzo[b,e]-
azepine hydrochloride 1a with the ZhaoPhos as the ligand.
High reactivities and excellent enantioselectivities can be
achieved in DCM, ethanol, isopropanol, 1,4-dioxane, and
tetrahydrofuran (THF) (>99% conversions, 94%−96% ee,
Table 2, entries 1−3, 6−7). Poor to moderate enantioselectiv-
Table 2. Screening Solvents for Asymmetric Hydrogenation
a
of 6-Methyl-11H-dibenzo[b,e]azepine Hydrochloride (1a)
Initially, we began our investigation by evaluating chiral
diphosphine ligands for the asymmetric hydrogenation of
model substrate 6-methyl-11H-dibenzo[b,e]azepine hydro-
chloride 1a9 with the catalyst generated in situ by mixing
[Rh(COD)Cl]2 with ligand at room temperature. As shown in
Table 1, several diphosphine ligands, such as (RC, SP)-DuanP-
b
c
entry
solvent
DCM
conv (%)
ee (%)
1
2
3
4
5
6
7
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
96
94
96
83
27
96
96
96
95
93
EtOH
iPrOH
MeOH
CF3CH2OH
1,4-dioxane
THF
Table 1. Screening Ligands for Asymmetric Hydrogenation
a
of 6-Methyl-11H-dibenzo[b,e]azepine Hydrochloride (1a)
d
8
e
DCM
9
DCM
f
10
DCM
b
c
entry
ligand
conv (%)
ee (%)
a
Unless otherwise noted, all reations were carried out with a Rh/
ZhaoPhos/1a (0.1 mmol) ratio of 6/6.6/100 in solvent under 5 MPa
of H2. Conversion was determined by H NMR analysis. Ee was
determined by chiral HPLC analysis. The catalyst loading is 1.0 mol
%. The reaction was carried out with a Rh/ZhaoPhos/1a (0.1
mmol)/tetrabutylammonium bromide ratio of 6/6.6/100/100. The
reaction was carried out with a Rh/ZhaoPhos/1a (0.1 mmol)/
tetrabutylammonium iodide ratio of 6/6.6/100/100.
1
2
3
4
5
6
7
(Rc,Sp)-DuanPhos
Josiphos
Binapine
(S)-SegPhos
ZhaoPhos
L1
>99
>99
>99
>99
>99
>99
>99
35
60
37
40
96
94
27
b
c
1
d
e
f
L2
a
Unless otherwise noted, all reations were carried out with a Rh/
ZhaoPhos/1a (0.1 mmol) ratio of 6/6.6/100 in DCM under 5 MPa of
ities were obtained when the hydrogenations were performed
in methanol and trifluoroethanol (>99% conversions, 27%−
83% ee, Table 2, entries 4−5). We finally selected DCM as the
best choice, because the substrate 1a exhibited better solubility
in DCM, and it is much cheaper and more easily available than
other solvents. When the catalyst loading was reduced to 1.0
mol %, the same reaction result was attained (>99% conversion,
96% ee, Table 2, entry 8). Different counterions were also
investigated. The addition of bromide counterion from
tetrabutylammonium bromide (TBAB) and iodide counterion
from tetrabutylammonium iodide (TBAI) provided slightly
lower enantioselectivities.
b
c
H2. Conversion was determined by 1H NMR analysis. Ee was
determined by chiral HPLC analysis.
With the optimized reaction conditions in hand, we focused
on the substrate scope of the asymmetric hydrogenation of
seven-member cyclic imine hydrochlorides 11H-dibenzo[b,e]-
azepine hydrochlorides 1. As summarized in Scheme 2, a series
of chiral seven-member cyclic amines were obtained in high
yields and excellent enantioselectivities. Whether R1 is an
electron-withdrawing group (1b−1c) or R2 is an electron-
donating group (1d−1e), 92%−98% ee and 94%−96% yields
were obtained. In addition, the substrate bearing naphthyl ring
1f was hydrogenated well with 92% yield and 98% ee. When the
hos, JosiPhos, (S)-Segphos, and Binapine, displayed poor
enantioselectivities (35−60% ee, > 99% conversions, Table 1,
entries 1−4). The bisphosphine-thiourea ligand ZhaoPhos can
provide full conversion and excellent enantioselectivity (96%
ee, >99% conversion, Table 1, entry 5). Another chiral
bisphosphine-thiourea ligand L1 afforded slightly lower
B
DOI: 10.1021/acs.orglett.7b01726
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dibenzo[b,e]azepine 3 as the substrate into this asymmetric
hydrogenation. Much lower enantioselectivity was observed
(Scheme 4). This result implied that the chloride ion of the 6-
Scheme 2. Substrate Scope Study for Asymmetric
Hydrogenation of 11H-Dibenzo[b,e]azepine/oxazepine
a
Hydrochlorides (1)
Scheme 4. Control Experiment
methyl-11H-dibenzo[b,e]azepine hydrochloride 1a played an
important role to achieve excellent enantioselectivity in this
catalytic system.
In summary, we successfully developed a highly efficient
asymmetric hydrogenation of azepine/oxazepine-type seven-
member cyclic imine hydrochlorides catalyzed by Rh/bi-
sphosphine-thiourea ligand ZhaoPhos. A series of chiral
seven-member cyclic amines were obtained with excellent
results (up to 96% yield, >99% ee). In addition, this asymmetric
hydrogenation of 6-methyl-11H-dibenzo[b,e]azepine hydro-
chloride 1a proceeded well on gram scale with excellent
enantioselectivity. Moreover, control experiments were con-
ducted and the results demonstrated that the anion-bonding
interaction between the chloride ion of the substrate and
thiourea motif of the ZhaoPhos played an important role in
obtaining excellent enantioselectivity in this asymmetric
hydrogenation.
a
1 (0.1 mmol) and a Rh/ZhaoPhos/1 ratio of 1/1.1/100 in DCM
1
under 5 atm of H2; conversion was determined by H NMR analysis;
yield of isolated product; ee was determined by chiral HPLC analysis.
The configuration of 2 was determined as (S) by comparing the
optical rotation data with those reported by the literature.7b,9
R3 group was changed from a methyl group (1a) to an ethyl
group (1g), moderate enantioselectivity was observed in the
asymmetric hydrogenation (71% ee). Encouraged by these
excellent results in the asymmetric hydrogenation of 11H-
dibenzo[b,e]azepine hydrochlorides, we turned our attention to
exploring the asymmetric hydrogenation of various oxazepine-
type seven-member cyclic imine hydrochlorides.7a The
asymmetric hydrogenation of the substrates with different
substituents, such as a methyl group (2i), haloid (2j−2k), and
naphthyl group (2l), proceeded smoothly with high yields and
excellent enantioselectivities (93%−96% yields, 94%−99% ee).
In addition, the asymmetric hydrogenation of 6-methyl-11H-
dibenzo[b,e]azepine hydrochloride 1a proceeded efficiently on
gram scale under the optimized reaction conditions. And the
desired product chiral seven-member cyclicamine (2a) can be
obtained with 99% conversion, 94% yield, and 92% ee (Scheme
3).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01726.
General procedure and spectroscopic data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xumu@whu.edu.cn.
*E-mail: xiuqindong@whu.edu.cn.
*E-mail: xinquan@zjut.edu.cn.
In order to further evaluate the role of anion-bonding
interaction between the chloride ion of the substrate and
thiourea motif of the ZhaoPhos, we applied 6-methyl-11H-
ORCID
Xumu Zhang: 0000-0001-5700-0608
Notes
Scheme 3. Asymmetric Hydrogenation of 6-Methyl-11H-
dibenzo[b,e]azepine Hydrochloride 1a on Gram Scale
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support of the Important Sci-Tech
Innovative Project of Hubei Province (2015ACA058), the
National Natural Science Foundation of China (Grant Nos.
21372179, 21432007, 21502145), and Natural Science
Foundation of Hubei Province (Grant No. 2016CFB449).
C
DOI: 10.1021/acs.orglett.7b01726
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Letter
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