Rhodium-Catalyzed Asymmetric Hydrogenation of Tetrasubstituted Cyclic Enamides: Efficient Access to Chiral Cycloalkylamine Derivatives

Article abstract of DOI:10.1002/adsc.201601135

An efficient rhodium-catalyzed asymmetric hydrogenation of challenging tetrasubstituted cyclic enamides has been developed, affording cyclic chiral amides with high yields and excellent enantioselectivities (up to 99% yield and >99% ee). This novel method

Full text of DOI:10.1002/adsc.201601135

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DOI: 10.1002/adsc.201601135
Rhodium-Catalyzed Asymmetric Hydrogenation of
Tetrasubstituted Cyclic Enamides: Efficient Access to Chiral
Cycloalkylamine Derivatives
Xiuxiu Li,+a Cai You,+a Hailong Yang,a Jinteng Che,a Pengyu Chen,a
Yusheng Yang,a Hui Lv,a,* and Xumu Zhanga,b,*
a
College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, Peopleꢀs Republic of China
Fax : (+86)-27-6875-5925; e-mail: huilv@whu.edu.cn
Department of Chemistry, South University of Science and Technology of China, Shenzhen, Guangdong 518055, Peopleꢀs
b
Republic of China
Fax : (+86)-755-8801-8300; e-mail: zhangxm@sustc.edu.cn
+
Xiuxiu Li and Cai You contributed equally to this work.
Received: October 13, 2016; Revised: November 19, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201601135.
Abstract: An efficient rhodium-catalyzed asymmet-
ric hydrogenation of challenging tetrasubstituted
cyclic enamides has been developed, affording
cyclic chiral amides with high yields and excellent
enantioselectivities (up to 99% yield and >99%
ee). This novel methodology provides an efficient
and concise synthetic route to chiral cycloalkyl-
ACHTUNGTRENNUNGamines with two contiguous stereogenic centers.
The potential utility of this protocol in the synthesis
of bioactive molecules is also disclosed.
tracted considerable attention. Typically synthetic
methods include dynamic kinetic resolution,[7] asym-
metric conjugate addition to nitroalkenes,[8] and other
transformations.[9] Among the successful strategies de-
veloped for obtaining chiral cycloalkylamine deriva-
tives, those that lead to substrates containing certain
functional groups are of great significance. We envi-
sioned that a direct asymmetric reduction of the C=C
double bond in the corresponding enamides would be
the most straightforward way to construct chiral cy-
cloalkylamine derivatives.
Keywords: amines; asymmetric synthesis; enantio-
selectivity; hydrogenation; rhodium
In the past decades, transition metal-catalyzed
asymmetric hydrogenation of enamides has been de-
veloped as a powerful and environmentally friendly
Chiral cycloalkylamines and their derivatives are val-
uable intermediates in organic synthesis. In particular,
cycloalkylamines with a substitution at the 2-position
are important motifs in many bioactive molecules and
drugs. For example, Tofacitinib (A),[1] a janus kinase
(JAK) inhibitor, is used to treat rheumatoid arthritis
(RA) and B[2] is a PDE IV inhibitor. Molecules such
as (+)-(2S,3S)-CP-99994 (C)[3] and (+)-(2S,3S)-CP-
122721 (D)[4] are known to be non-peptide antagonists
of neurokinin-1 (NK-1) substance
P
receptor
(Figure 1). In addition, chiral cycloalkylamines are
also important building blocks for the synthesis of
enantiopure indoline skeletons, such as E[5] and F
(WAY-163909),[6] neuroleptic agents in many types of
antidepressants. Consequently, the asymmetric synthe-
Figure 1. Structures of biologically active compounds con-
sis of cycloalkylamines and their derivatives has at- taining a chiral cycloalkylamine moiety.
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methodology to obtain chiral amine derivatives.[10] Al- of 0.5 mol% Rh(COD)2BF4/(R)-Binapine complex.
though great success has been achieved in enantiose- To our delight, when dichloromethane was used as
lective hydrogenation of di- and trisubstituted enam- the solvent, 91% conversion and >99% ee were ob-
ides, the hydrogenation of tetrasubstituted enamides tained (Table 1, entry 1). Subsequently, we investigat-
is generally more difficult, and fewer successful results ed the solvent effects and found that different sol-
have been reported.[11] In this context, our group was vents have a great influence on the conversions, but
devoted to develop new catalytic systems to achieve almost no effect on the enantioselectivities (Table 1,
this transformation and some methods for the asym- entries 2–8). Solvent screening shows that dichlorome-
metric hydrogenation of tetrasubstituted enamides thane was the best solvent, and when the catalyst
have been developed.[12] In addition, as in the asym- loading was increased to 1 mol%, full conversion and
metric hydrogenation of tetrasubstituted cyclic enam- >99% ee were achieved (Table 1, entry 9).
ides, the substrates are limited to cyclic (b-amido)
Inspired by these promising results, a variety of
acrylates, other types of tetrasubstituted cyclic enam- chiral diphosphine ligands developed in our group
ides generally give the corresponding reduction prod- and some commercially available chiral ligands
uct with poor enantioselectiviy. Therefore, methods (Figure 2) were screened. Besides (R)-Binapine,
for the asymmetric hydrogenation of tetrasubstituted (Sc,Rp)-DuanPhos also showed almost the same reac-
cyclic enamides are far less established. Herein, we titity and enantioselectivity (Table 2, entries 1 and 2),
disclose an efficient rhodium-catalyzed asymmetric while (Rc,Sp)-TangPhos showed excellent reactivity
hydrogenation of tetrasubstituted cyclic enamides for but with only moderate stereoselectivity (Table 2,
the concise synthesis of chiral cycloalkylamine deriva- entry 3). Other chiral ligands with stereogenic P cen-
tives with excellent enantioselectivities (90% to ters, such as (R)-QuinoxP* and (S,S)-Me-Duphos,
>99% ee).
showed bad to good conversions with poor enantiose-
Initially,
N-(3,4,5,6-tetrahydro-[1,1’-biphenyl]-2- lectivities (Table 2, entries 4 and 5). Some chiral biar-
yl)acetamide (1a) was chosen as the model substrate ylbisphosphorus ligands with axial chirality, such as
to assay the best reaction conditions for asymmetric (S)-BINAP, (S)-DTBM-SegPhos, and (R)-MeO-
hydrogenation, and the reactions were carried out Biphep, were also investigated, but either low enan-
with 30 atm H2 at room temperature in the presence tioselectivities or bad conversions were obtained
Table 1. Solvent screening for the Rh-catalyzed asymmetric
hydrogenation of 1a.[a]
Entry
Solvent
Conversion [%][b]
ee [%][c]
1
2
3
4
5
6
7
CH2Cl2
MeOH
EtOH
CF3CH2OH
EtOAc
THF
dioxane
toluene
CH2Cl2
91
31
80
62
86
85
34
40
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
8
9[d]
[a]
Unless otherwise mentioned, all reactions were carried
out with a [Rh(COD)2]BF4/(R)-Binapine/substrate ratio
of 1:1.1:200, in 1 mL of solvent, at room temperature,
under hydrogen (30 atm) for 20 h.
[b]
[c]
1
Determined by H NMR spectroscopy.
Determined by HPLC analysis using a chiral stationary
phase. The absolute configuration was assigned by com-
paring the sign of the optical rotation of the product 2a,
N-[(1S,2S)-2-phenylcyclohexyl]acetamide, with that re-
ported in the literature; see Ref.[8]
[d]
Figure 2. Structures of the phosphine ligands for hydrogena-
tion of 1a.
Carried out with a [Rh(COD)2]BF4/(R)-Binapine/sub-
strate ratio of 1:1.1:100.
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Table 2. Ligand screening for the Rh-catalyzed asymmetric
hydrogenation of 1a.[a]
(Table 2, entries 6–8). When chiral ferrocenyl ligands
were employed, low enantioselectivities were ob-
tained, albeit with full conversions (Table 2, entries 9
and 10).
Under the optimized reaction conditions, a series of
tetrasubstituted cyclic enamides was examined to
evaluate the substrate scope and generality of this cat-
alytic reaction (Table 3). Many functional groups,
such as methyl (2b), methoxy (2c), trifluoromethyl
(2d), methyl ester (2e) and halides (2f and 2g), at the
para position of the phenyl group are compatible with
this transformation. Substrates with ortho-substitution
on the phenyl group are also tolerated, but slightly
compromised ee values were obtained (2h and 2i),
presumably because of the added steric hindrance. In
comparison, the meta-methyl adduct 2j was produced
with 94% ee. Moreover, the product 2k with 3,4-dime-
thoxy groups was obtained with >99% ee. Further-
more, good yields and enantioselectivities were ob-
tained with a range of substrates containing other aro-
matic fragments, including naphthalenes, furans and
indoles (2l, 2m and 2n). Notably, when the substituent
was changed to a benzyl group, high enantioselectivity
(93% ee) was produced as well (2o). The tetrasubsti-
tuted cycloheptene enamide was also found to be
Entry Ligand
Conversion [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
10
(R)-Binapine
(Sc,Rp)-Duanphos
Tangphos
(R)-QuinoxP*
(S,S)-Me-Duphos
(S)-BINAP
(S)-DTBM-SegPhos >99
(R)-MeO-Biphep
JosiPhos
>99
>99
>99
18
>99
>99
66
À7
86
35
35
99
79
38
3
>99
>99
À61
WalPhos
À25
[a]
All reactions were carried out with a [Rh(COD)2]BF4/
ligand/substrate ratio of 1:1.1:100, in 1 mL of dichlorome-
thane, at room temperature, under hydrogen (30 atm) for
20 h.
Determined by H NMR spectroscopy.
Determined by HPLC analysis using a chiral stationary
phase.
[b]
[c]
1
Scheme 1. Synthetic transformations: a) Gram-scale reaction for AH of 1k; b) the derivatization of 2h; c) creative synthesis
of biologically active product E.
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Table 3. Rh-catalyzed asymmetric hydrogenation of various tetrasubstituted cyclic enamides.
[a]
Unless otherwise mentioned, all reactions were carried out with a [Rh(COD)2]BF4/(R)-Binapine/substrate ratio of
1:1.1:100, in 1 mL of dichloromethane, at room temperature, under hydrogen (30 atm) for 20 h.
Yield of the isolated product.
Determined by HPLC analysis using a chiral stationary phase.
2 mol% catalyst were used.
40 atm H2 were used.
Methanol was used as the solvent.
The reaction was carried out under 5 atm H2 for 1 hour.
S/C=200.
[b]
[c]
[d]
[e]
[f]
[g]
[h]
[i]
(R,S)-t-Bu-JosiPhos was used instead of (R)-Binapine.
a suitable substrate for the reaction, affording the cor- report.[5] In addition, a direct and efficient method to
responding product in up to 96% ee (2p). For cyclo- synthesize the chiral indoline skeleton was developed.
pentene enamides, (R,S)-t-Bu-JosiPhos was used in- Through a Buchwald–Hartwig cross-coupling,[13] the
stead of (R)-Binapine and good enantioselectivities product 2h was successfully converted to the chiral in-
were achieved (2r and 2s).
doline skeleton 3a without enantioselectivity loss
To demonstrate the potential utility of this method- (Scheme 1b). When (S)-Binapine was used as the
olgy, the synthesis of the chiral cycloakylamide on chiral ligand for the asymmetric hydrogenation of N-
a gram scale was achieved, and applications of this (2’-bromo-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)benz-
methodolgy in concise synthesis of several bioactive
ACHTUNGTRENaNGNU mide (1h), N-[(1R,2R)-2-(2-bromophenyl)cyclohex-
molecules are also disclosed. As shown in Scheme 1, yl]benzamide (2q) was obtained with 93% ee. After
when the asymmetric hydrogenation of N-(3’,4’-di- the cross-coupling, 3b was produced with the same ee
A
value (Scheme 1c). Starting from the key intermediate
mide (1k) was carried out on a gram scale, there was 3b, the enantiopure indoline skeleton derivative E,
no loss in the yield and enantioselecltivity. More im- a neuroleptic agent in many types of antidepressants,
portantly, the product 2k can be easily transfomed to can be readily synthesized following the literature
B, a PDE IV inhibitor, according to a literature procedure.[14]
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In conclusion, we have developed a highly enantio-
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ACHTUNGTRENNUNGamides using a commercially available Rh-Binapine
catalyst. With the mild conditions, a variety of sub-
strates was converted to the cycloalkylamides with ex-
cellent enantioselectivities (up to >99% ee). This
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of functionalized enamides are underway in our labo-
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Experimental Section
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General Procedure for the Asymmetric
Hydrogenation of Various Tetrasubstituted Cyclic
Enamides
A stock solution was made by mixing [Rh(COD)2]BF4 with
(R)-Binapine in a 1:1.1 molar ratio in dichloromethane at
room temperature for 30 min in a nitrogen-filled glovebox.
An aliquot of the catalyst solution (0.1 mL, 0.001 mmol) was
transferred by syringe into the vials charged with different
substrates (0.1 mmol for each) in anhydrous dichlorome-
thane (1.0 mL). The vials were subsequently transferred into
an autoclave into which hydrogen gas was charged. The re-
action mixture was then stirred under H2 (30 atm) at room
temperature for 20 h. The hydrogen gas was released slowly
and carefully. The solution was concentrated and passed
through a short column of silica gel (eluent: ethyl acetate)
to remove the metal complex. The ee values of all com-
pounds 2 were determined by HPLC analysis on a chiral sta-
tionary phase.
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Acknowledgements
We are grateful for the grant from Wuhan University
(203273463, 203410100064), the support of the Important Sci-
Tech Innovative Project of Hubei Province (2015ACA058),
the Youth Chen-Guang Science and Technology Project of
Wuhan City (2015071704011640), Natural Science Founda-
tion of Hubei Province (2014CFB181), “111” Project of the
Ministry of Education of China and the National Natural Sci-
ence Foundation of China (Grant No. 21372179, 21432007,
21402145).
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Rhodium-Catalyzed Asymmetric Hydrogenation of
Tetrasubstituted Cyclic Enamides: Efficient Access to
Chiral Cycloalkylamine Derivatives
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Adv. Synth. Catal. 2017, 359, 1 – 7
Xiuxiu Li, Cai You, Hailong Yang, Jinteng Che,
Pengyu Chen, Yusheng Yang, Hui Lv,* Xumu Zhang*
Adv. Synth. Catal. 0000, 000, 0 – 0
7
ꢁ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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