Rhodium/bisphosphine-thiourea-catalyzed enantioselective hydrogenation of α,β-unsaturated: N -acylpyrazoles

Article abstract of DOI:10.1039/c6cc04987g

We successfully extended our Rh/bisphosphine-thiourea (ZhaoPhos) catalytic system to asymmetric hydrogenation of α,β-unsaturated N-acylpyrazoles affording products with high yields and excellent enantioselectivities (up to 97% yield, 99% ee). The pyrazole

Full text of DOI:10.1039/c6cc04987g

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DOI: 10.1039/C6CC04987G
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Rhodium/Bisphosphine-Thiourea-Catalyzed Enantioselective
Hydrogenation of -Unsaturated N-Acylpyrazoles
Pan Li,a,b Xinquan Hu,*b Xiu-Qin Dong,*a Xumu Zhang*a,c
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
We successfully extended our Rh/bisphosphine-thiourea electrophilic substrate in an organocatalytic Michael
(ZhaoPhos) catalytic system to asymmetric hydrogenation of α,β- addition.7a More recently, Wu developed an enantioselective
unsaturated N-acypyrazoles affording the products with high vinylogous aldol-cyclization cascade reaction of allyl
yields and excellent enantioselectivities (up to 97% yield, 99% ee). pyrazoleamides with isations.9 Inspired by these results and
The pyrazole moiety played an important role in providing H-bond our ongoing research interest in the field of asymmetric
acceptor site, which is critical for achieving high reactivities and hydrogenation, we herein successfully developed asymmetric
enantioselectivities.
hydrogenation of a series of α,β-unsaturated N-acylpyrazoles
catalyzed by rhodium/bisphosphine-thiourea (ZhaoPhos) with
excellent enantioselectivities (up to 99% ee). We envisioned
that thiourea could activate α,β-unsaturated N-acylpyrazoles
through forming hydrogen bonds (Scheme 1). Moreover, the
resulting hydrogenation products could be readily transformed
to other valuable chiral acids and their derivatives, which are
important intermediates for the construction of biologically
active compounds.10
The combination of transition-metal catalysis and
organocatalysis as a promising strategy has been introduced to
promote challenging and unprecedented asymmetric
reactions.1 This great catalytic strategy has drawn increasing
attention owing to the excellent catalytic efficiency during the
last decades. Until now some effective catalytic methodologies
have been established, such as cooperative catalysis,2
sequential/relay catalysis3 and synergistic catalysis.4 Recently,
our group have successfully developed another powerful
strategy, which cooperated both activation modes of
transition-metal catalysis and organocatalysis into one
bifunctional molecule.5 With this newly developed strategy,
some challenging asymmetric hydrogenation reactions were
accomplished smoothly through multiple activation in our
catalytic system.5a-5c
α, β-Unsaturated N-acylpyrazoles have been proved to be
a valuable scaffold and widely applied in asymmetric catalysis.6
The pyrazole moiety was revealed to play an important role in
Scheme 1. Application of Rh/ZhaoPhos catalytic system to asymmetric
providing H-bond acceptor sites for better chelation to hydrogenation of α,β-unsaturated N-acylpyrazoles.
improve activities and enantioselectivities.7 In addition, it is
We began our investigation by evaluating the asymmetric
also an excellent leaving group for subsequent transformation
to construct chiral molecules.8 Sibi and Itoh applied pyrazole
moiety as a H-bond acceptor sites to facilitate activation of the
hydrogenation of (E)-3-phenyl-1-(1H-pyrazol-1-yl)but-2-en-1-one
(1a)7d as the model substrate in dichloromethane at room
temperature with the catalyst generated in situ by mixing
Rh(COD)2BF4 and bisphosphine-thiourea ligands L1-L3. To our
delight, ZhaoPhos L3 furnished the best result in terms of reactivity
and enantioselectivity (>99 % conversion, 88% ee, Table 1, entry 3).
The ligand L1 without thiourea scaffold provided very poor result
(19 % conversion, 43% ee, Table 1, entry 1), it exhibited that the
thiourea motif can activate the substrate efficiently as an excellent
directing role. Another ligand L2 without CF3 group on the 3,5-
(trifluoromethyl)-phenyl ring provided the same enantioselectivity
but with low conversion (40% conversion, 88% ee, Table 1, entry 2).
a College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei,
430072, P. R. China
b College of Chemical Engineering, Zhejiang University of Technology, Hangzhou,
Zhejiang, 310014, P.R. China.
c Department of Chemisty, South University of Science and Technology of China,
Shenzhen, 518000, P.R. China.
*Corresponding author. E-mail address: xumu@whu.edu.cn;
xiuqindong@whu.edu.cn; xinquan@zjut.edu.cn.
‡ Electronic supplementary information (ESI) available: Experimental procedures, NMR
spectra of compounds. See DOI: 10.1039/x0xx00000x
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Scheme 2. Asymmetric hydrogenation of (Z)-1a-1 and terminal olefin substrate
1a-2 catalyzed by Rh/ZhaoPhos catalytic system.
enylbut-3-en-1-one (1a-2) didn’t performed well, full conversion
and only 7% ee was achieved (Scheme 2).
Subsequently, an array of various (E)-β-arylbut-2-enoic
pyrazolamides were employed as substrates to exam the generality
of this asymmetric hydrogenation to produce the desired 3-
arylbutanoic pyrazolamides under the optimized reaction
conditions. As shown in Table 2, electron-neutral (1a), electron-rich
(1b-1e, 1i), and electron-deficient (1f-1h) β-arylbut-2-enoic
pyrazolamides with different substitution groups on the phenyl ring
could be smoothly hydrogenated with excellent enantioselectivities
(90%-96% ee) and high yields (93%-97% yields). The substitution
pattern and position of the phenyl ring had little effect on the
reaction.
And then the solvent screening revealed that EtOH and THF gave
excellent enantioselectivities (91%-96% ee, Table 1, entries 4-5).
However, esterification of product (2a) was observed in EtOH and
MeOH, especially there is no corresponding hydrogenation product
in MeOH (Table 1, entry 6). In order to suppress the esterification of
product, mixed solvents were investigated and a mixture solvent of
EtOH/CH2Cl2 (V/V = 5:1) showed to be the best reaction solvents of
choice (>99 % conversion, 96% ee, Table 1, entry 8). When the
catalyst loading was reduced from 12 mol% to 4 mol%, a similar
result with excellent enantioselectivity and conversion was
obtained (>99 % conversion, 96% ee, Table 1, entry 9 vs entry 8). In
addition, we investigated other bisphosphine ligands in this
asymmetric hydrogenation, such as Me-Duphos, Josiphos, Binapine
(Table 1, entries 10-12). Poor results were observed in Rh/Me-
Duphos and Rh/Josiphos catalytic system (Table 1, entries 10-11).
Full conversion and 90% ee were obtained by Rh/Binapine (Table 1,
entry 12).
The Rh/ZhaoPhos catalytic system has also been extended
to the asymmetric hydrogenation of β-substituted methacrylic
pyrazolamides. However, the hydrogenation of (E)-2-methyl-3-
phenyl-1-(1H-pyrazol-1-yl)prop-2-en-1-one (3a) afforded the
desired product (4a) with 89 % ee under the above reaction
conditions (Table 3, entry 1). When the reaction was
We also applied (Z)-3-phenyl-1-(1H-pyrazol-1-yl)but-2-en-1-
one (1a-1) to be hydrogenated in this transformation, affording the
product (2a’) with opposite configuration and poor
enantioselectivity (Scheme 2, 31% ee, 94% yield, >99% conversion).
The terminal olefin substrate 1-(3,5-dimethyl-1H-pyrazol-1-yl)-3-ph
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performed in the solvent of dichloromethane, the similar
result was obtained (Table 3, entry 2 vs entry 1). In addition,
the metal precursor was changed from Rh(COD)2BF4 to
Rh(NBD)2BF4, the enantioselectivity wasn’t improved (Table 3,
entry 3). In order to enhance the enantioselectivity, further
investigation was focused on the effect of the substituent
groups in pyrazole ring. It was found that enantioselectivity
was strongly related to the pyrazole structure. When the
amide functional group switched from pyrazole (3a) to 3,5-
dimethylpyrazole (3b) and 4-halogenated 3,5-dimethylpyrazol
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DOI: 10.1039/C6CC04987G
(
3c
-
3d) (Table 3, entries 3-6). Gratifyingly, β-substituted
3b was successfully
methacrylic pyrazolamide
(
)
hydrogenated with the best result (97% ee, >99% conversion,
Table 3, entry 4). Moreover, when the catalyst loading was
decreased to 4 mol%, there was no influence on the reactivity
and enantioselectivity (Table 3, entry 7). Remarkably, similar
result can be obtained when the catalyst loading was further
decreased to 2 mol% (97% ee, >99% conversion, Table 3, entry
8).
We investigated the challenging tetra-substituted
substrate
1-(3,5-dimethyl-1H-pyrazol-1-yl)-2-methyl-3-
phenylbut-2-en-1-one (5a) in this asymmetric hydrogenation
(Scheme 3). The reactivity was very low, and the reaction
wasn’t proceeded efficiently with trace conversion.
Scheme 3. Asymmetric hydrogenation of tetra-substituted substrate (5a)
catalyzed by Rh/ZhaoPhos catalytic system.
In order to evaluate the role that the pyrazole motif
played in this transformation, control experiments were
11
carried out using trans-
(E)-3-phenyl-1-(1H-pyrazol-1-yl)but-2-en-1-one

-substituted acryl pyrrole (7a
1a
)
and
(
)
as the
substrates under the optimized reaction conditions (Scheme 4):
replacing the acryl pyrrole with acyl pyrazole not only seriously
affected reactivity but also led to much higher
enantioselectivity with the same sense of asymmetric
induction (2a: >99% conversion, 88% ee; 8a: 20% conversion,
71% ee). This indicated that introducing the pyrazole moiety
plays an important role in providing H-bond acceptor site for
higher reactivity and enantioselectivity.
Encouraged by these results, we turned our attention to
the scope of the hydrogenation of a series of 3,5-dimethyl-1-
(3-butanonyl)pyrazoles in Rh-ZhaoPhos catalytic system. These
results were summarized in Table 4. Substrates bearing
electron-donating substituents
(
3e-
3h)
or electron-
withdrawing substituents (3i 3j) at the different positions of
-
the phenyl group were hydrogenated well with full Scheme 4. Control experiments for the investigation of the role of pyrazole
conversions and excellent enantioselectivities (91-98% ee, moiety.
92%-97% yield). Remarkably, the heteroaromatic product was
obtained with excellent result (4k, 99% ee, >99% conversion,
As the synthetic utility of this asymmetric catalytic
95% yield). The less reactive alkyl substrate cyclohexyl 3,5- methodology, further application was performed for the
dimethyl-1-(3-butanonyl)pyrazole (3l) was hydrogenated with construction of optical active drug molecule (Scheme 5). The
full conversion but low enantioselectivity (Table 4, entry 9, 33% substrate 1b was easily hydrogenated to obtain chiral product
ee, >99% conversion, 92% yield).
2b (>99% conversion, 95% yield, 95% ee). The N-acylpyrazole
group of 2b can be efficiently cleaved to corresponding chiral
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acid
Journal Name
9
without any lost of ee value,12 which is very important
Am. Chem. Soc. 2004, 126, 7559; d) J. K. Myers, E. N. Jacobsen,
J. Am. Chem. Soc. 1999, 121, 8959; e)DAO. IB:a10sc.1h0i3e9Vri/ie,CwL6.ACrBtCiec0lre4nO9an8rl7dinGie,
A. Ricci, S. Suresh, M. P. A. Adamo, Angew. Chem. Int. Ed.
2009, 48, 9342; f) D. A. Evans, J. S. Johnson, J. Am. Chem. Soc.
1998, 120, 4895; g) D. A. Evans, K. R. Fandrick, H.-J. Song, J.
Am. Chem. Soc. 2005, 127, 8942.
a) M. P. Sibi and K. Itoh, J. Am. Chem. Soc., 2007, 129, 8064; b)
K. Ishihara and M. Fushimi, Org. Lett., 2006, 8, 1921. c) X.-Q.
Dong, X. Fang, H.i-Y. Tao, X. Zhou, and C.-J. Wang, Adv. Synth.
Catal. 2012, 354, 1141; d) X.-Q. Dong, X. Fang, H.i-Y. Tao, X.
Zhou, and C.-J. Wang, Chem. Commun., 2012, 48, 7238.
A. B. Smith III, T. Bosanac and K. Basu, J. Am. Chem. Soc., 2009,
131, 2348.
intermediate for the synthesis of (R)-Turmerone.13
7
8
9
T.-Z. Li, Y. Jiang, Y.-Q. Guan, F. Sha, X.-Y. Wu, Chem. Commun.,
2014, 50, 10790.
10
For a review, see: a) D. Lednicer, L. A. Mitscher, In the Organic
Chemistry of Drug Synthesis; Wiley: New York, 1977 and 1980;
Vols. 1 and 2. For selected examples, see: b) Y. Lu, T. M.-D.
Nguyen, G. Weltrowska, I. Berezowska, C. Lemieux, N. N.
Chung, P. W. Schiller, J. Med. Chem., 2001, 44, 3048; c) I.
Churcher, K. Ashton, J. W. Butcher, E. E. Clarke, T. Harrison, H.
D. Lewis, A. P. Owens, M. R. Teall, S. Williams, J. D. Wrigley, J.
Bioorg. Med. Chem. Lett. 2003, 13, 179; d) B. R. Henke, J. Med.
Chem. 2004, 47, 4118; e) J. Kasuga, M. Makishima, Y.
Hashimoto, H. Miyachi, Bioorg. Med. Chem. Lett. 2006, 16,
554.
Scheme 5. Appliaction of hydrogenation product to optical active drug
intermediate.
In conclusion, we successfully extended our Rh/bisphosphine-
thiourea ZhaoPhos catalytic system to asymmetric hydrogenation of
α,β-unsaturated pyrazolamides to furnish the corresponding
products with excellent enatioselectivities. The pyrazole moiety
played an important role in providing H-bond acceptor site, which is
critical for achieving high enantioselectivity. Moreover, the pyrazole
group of enantioenriched hydrogenation products can be easily
cleaved to construct the corresponding chiral carboxylic acid
derivatives, which are important intermediates in many
pharmaceuticals.
11 T. Maehara, R. Kanno, S. Yokoshima, T. Fukuyama, Org. Lett.,
2012, 14, 1946.
12 X.-Q. Dong, X. Fang, H.-Y. Tao, X. Zhou, C.-J. Wang, Chem.
Commun. 2012, 48 (58), 7238.
13 K. Mori, Tetrahedron: Asymmetry 2005, 16 (3), 685.
We thank the grant from Wuhan University (203273463,
203410100064), and “111” Project of the Ministry of Education of
China for financial support and the National Natural Science
Foundation of China (Grant No. 21372179, 21432007, 21502145).
Notes and references
1
For an account on metal–organic cooperative catalysis, see: a)
Y. J. Park, J.-W. Park and C.-H. Jun, Acc. Chem. Res.,2008, 41,
222; b) Z. Shao and H. Zhang, Chem. Soc. Rev., 2009, 38, 2745;
c) C. Zhong and X. Shi, Eur. J. Org. Chem., 2010, 2999; d) C. C. J.
Loh and D. Enders, Chem. – Eur. J., 2012, 18, 10212.
2
3
Recent examples of cooperative catalysis: a) L. Stegbauer, F.
Sladojevich and D. J. Dixon, Chem. Sci., 2012, 3, 942; b) Tang,
W.; Johnston, S.; Iggo, J. A.; Berry, N. G.; Phelan, M.; Lian, L.;
Bacsa, J.; Xiao, J., Angew. Chem., Int. Ed., 2013, 52, 1668.
Recent example of sequential/relay catalysis: a) F. Shi and L.-Z.
Gong, Angew. Chem., Int. Ed., 2012, 51, 11423; b) N. T. Patil, V.
S. Shinde and B. Gajula, Org. Biomol. Chem., 2012, 10, 211; c)
D.-F. Chen, Z.-Y. Han, X.-L. Zhou and L.-Z. Gong, Acc. Chem.
Res., 2014, 47, 2365.
4
5
Recent examples of synergistic catalysis: a) A. E. Allen and D.
W. C. MacMillan, Chem. Sci., 2012, 3, 633; b) M. T. Pirnot, D. A.
Rankic, D. B. C. Martin and D. W. C. MacMillan, Science, 2013,
339, 1593.
a) Q. Zhao, S. Li, K. Huang, R. Wang, X. Zhang, Org. Lett. 2013,
15, 4014; b) Q. Zhao, J. Wen, R. Tan, K. Huang, P. Metola, R.
Wang, E. V. Anslyn, X. Zhang, Angew. Chem., Int. Ed. 2014, 53,
8467; c) P. Li, M. Zhou, Q. Zhao, W. Wu, X. Hu, X.-Q. Dong, X.
Zhang, Org. Lett. 2016, 18, 40; d) X.-Q. Dong, Q. Zhao, P. Li, C.
Chen, X. Zhang, Org. Chem. Front. 2015, 2, 1425.
For selected examples, see; a) D. A. Evans, K. R. Fandrick, H.-J.
Song, K. A. Scheidt, R. Xu, J. Am. Chem. Soc. 2007, 129, 10029;
b) M. P. Sibi, K. Itoh, J. Am. Chem. Soc. 2007, 129, 8064; c) S.
Matsunaga, T. Kinoshita, S. Okada, S. Harada, M. Shibasaki, J.
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