Enantioselective synthesis of diarylcyclopropanecarboaldehydes by organocatalysis

Article abstract of DOI:10.1016/j.tetlet.2016.10.097

An efficient synthetic method for chiral trisubstituted diarylcyclopropanecarboaldehydes has been developed from substituted benzyl chloride and α,β-unsaturated aldehydes. The reactions were catalyzed by chiral amine catalyst under mild condition to afford the chiral diarylcyclopropanecarboaldehydes in good to high yields and up to excellent enantioselectivities.

Full text of DOI:10.1016/j.tetlet.2016.10.097

Accepted Manuscript
Enantioselective Synthesis of Diarylcyclopropanecarboaldehydes by Organo-
catalysis
Xuyun Chen, Yang Yu, Ziyang Liao, Hao Li, Wei Wang
PII:
S0040-4039(16)31419-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.10.097
TETL 48267
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
27 August 2016
23 October 2016
25 October 2016
Please cite this article as: Chen, X., Yu, Y., Liao, Z., Li, H., Wang, W., Enantioselective Synthesis of
Diarylcyclopropanecarboaldehydes by Organocatalysis, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/
j.tetlet.2016.10.097
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Tetrahedron Letters
Enantioselective Synthesis of Diarylcyclopropanecarboaldehydes by Organocatalysis
Xuyun Chena, Yang Yua, Ziyang Liaoa, Hao Lia,, and Wei Wanga,b,
a State Key Laboratory of Bioengineering Reactor, Shanghai Key Laboratory of New Drug Design, and School of Pharmacy, East China University of Science
and Technology, 130 Mei-long Road, Shanghai 200237, China
bDepartment of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, NM 87131-0001, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient synthetic method for chiral trisubstituted diarylcyclopropanecarboaldehydes has
been developed from substituted benzyl chloride and -unsaturated aldehydes. The reactions
were catalyzed by chiral amine catalyst under mild condition to afford the chiral
diarylcyclopropanecarboaldehydes in good to high yields and up to excellent
enantioselectivities.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Diarylyclopropane
Enantioselective
Organocatalysis
Benzyl chloride
Cinnamaldehyde
———
 Corresponding author. Tel./fax: +86 (21) 6425 3299 (H.L.); tel.: +1 (505) 277 0756; fax: +1 (505) 277 2609 (W.W.).
E-mail addresses: hli77@ecust.edu.cn (H. Li), wwang@unm.edu (W. Wang).

2
Cyclopropane, particular chiral cyclopropane, is one of the
most important privileged core structures in natural products and
biologically active compounds,1 which has inspired extensive
synthetic effect for obtaining asymmetric multi-substituted
cyclopropanations.2 Simmons-Smith cyclopropanation with
chiral promoters could afford substituted cyclopropanes with
high enantioselectivities.3,4 However, the methods rely
significantly on metal catalysis, including Rh,5 Te ylide,6 Cu,7
Zn,8 Co,9 and Ru.10 In the last decade, organocatalysis, which is
more environmental friendly than metal catalysis, has emerged as
a new methodology to afford asymmetric cyclopropanes. For
example, ammonium ylides was converted to cyclopropanes
catalyzed by cinchona alkaloid.11 Iminium catalyzed
cyclopropanation between enals and ylides could afford chiral
trisubstituted cyclopropanes.12 Cyclopropanation of nitrostyrenes,
enals or 2-arylidene-1,3-indandiones with halomalonates
generated asymmetric cyclopropanes with good to high
enatioselectivities.13-15
2). The reaction yield was further improved to 51% as well as
good enantioselectivities for both 3a and 4a (92% and 81% ee,
respectively, entry 3) when 1a was added in four portions and
reaction was performed under N2 atmosphere. When this reaction
was performed at different solvents, it generally afforded two
diasteromeric cyclopropane products in moderate yields and high
enantioselectivities (entries 3-6). Reaction in diethyl ether gave
the highest reaction yield but with compromised
enantioselectivities (entry 7), while in toluene or dioxane, no
cyclopropane products were separated (entries 8 and 9). For all
solvents tested, 1,2-dichloroethane (DCE) seemed to give the
best
combination
of
yield,
enantioselectivity
and
diastereoselectivity (entry 4). Therefore, DCE was chosen as the
best reaction solvent. In terms of organocatalyst, four catalysts
were screened. The more steric catalysts II and III afforded
much higher yields while still retaining good enantioselectivities
(entries 10 and 11). The enhanced yield was likely caused by the
minimized nucleophilic substitution side reaction due to
increased steric effects. By increasing the amount of 1a to 2
equiv., the reaction catalyzed by III gave the products in good
yields with excellent enantioselectivities (entry 12). However, the
reaction catalyzed by more steric catalyst IV gave much lower
enantioselectivities (entry 13). Other bases such as 2,6-lutidine
and NaOAc could not afford the product.
Among cyclopropanes, trisubstituted diarylcyclopropanes
present special biological activities. For example, trisubstituted
diphenyl cyclopropane amide derivative A is a potent inhibitor of
purified
renin
(Scheme
1).16
Trisubstituted
has been
diarylcyclopropanehydroxamic acid derivative
B
developed as potent and selective class IIa histone deacetylase
(HDAC) inhibitor for potential treatment of Huntington’s
disease.17 Trisubstituted diarylcyclopropane urea derivative C has
been reported as potent orally available soluble epoxide
hydrolase (sEH) inhibitor.18 However, efficient synthetic methods
for constructing trisubstituted diarylcyclopropanes were still very
rare. Recently, an improved Zn-catalyzed Simmons-Smith
reaction was developed to synthesize 1,2,3-trisubstituted
diarylcyclopropanes.19 Very recently, asymmetric synergistic
catalysis of the cis-cyclopropanation of benzoxazoles has been
reported.20
Table 1. Screening of the reaction conditionsa
Scheme 1. Trisubstituted diphenyl cyclopropane derivatives
with biological activities.
entry
cat.
solvent
yield%b
(3a+4a)
ee%
dr
(3a/4a)c
(3a:4a)d
1e,f
2f
3
I
CH3CN
CH3CN
CH3CN
trace
32
-
-
-
I
-
I
51
92/81
92/89
93/75
95/87
68/67
-
2:1
2:1
1:1
1:1
3:2
-
4
I
Cl(CH2)2Cl 55
Our research focuses on the development of efficient
methodology for construction of chiral scaffolds. For chiral
cyclopropane synthesis, in 2007, we reported cascade Michael-
alkylation reaction of -unsaturated aldehydes with
bromomalonates for synthesis of chiral diester substituted
cyclopropanes.21 Later on, electron-deficient arylmethanes were
also demonstrated to react with -unsaturated aldehydes and
form cyclopropanes.22 Based on our previous work, we
envisioned that chiral trisubstituted diarylcyclopropanes could be
constructed from electron-deficient benzyl chloride and -
unsaturated aldehydes.23
5
I
CHCl3
THF
42
54
66
-
6
I
7
I
Et2O
8
I
toluene
dioxane
9
I
-
-
-
10
11
12g
13
II
III
III
IV
Cl(CH2)2Cl 75
Cl(CH2)2Cl 72
Cl(CH2)2Cl 74
Cl(CH2)2Cl 65
85/82
88/85
96/94
25/39
1:1
2:1
2:1
3:2
To test out our hypothesis, we initially tried reaction between
1-(bromomethyl)-2,4-dinitrobenzene 1a’ (0.33 mmol) and
cinnamaldehyde 2a (0.28 mmol) in CH3CN using
diphenylprolinol TMS ether I (30 mol%) as the organo-catalyst
and trimethylamine (TEA) as base under ambient air and
temperature. Interestingly, the reaction for 11 h gave mainly a
mixture of 2,4-dinitrobenzaldehyde from hydrolysis and
oxidation of 1a’ and a nucleophilic substitution product formed
between 1a’ and amine catalyst I. (table 1, entry 1). To avoid
side reactions due to substitution and oxidation, the less reactive
benzyl chloride 1a was used instead at same condition. To our
delight, cyclopropane products (3a and 4a) were isolated in 32%
yield with some 2,4-dinitrobenzaldehyde obtained as well (entry
a Reaction conditions: unless specified, a mixture of 2a (0.33 mmol), TEA
(0.56 mmol) and catalyst (0.084 mmol) in 1.6 mL solvent was added the
solution of 1a (0.28 mmol) in 4 mL solvent for 4 times and stirred for 11 h at
rt.
b Isolated yield.
cDetermined by chiral HPLC analysis.
d Determined by 1H NMR.
e 2,4-Nitro benzyl bromide 1a’ was used.
f 1 was added in one port under air.
g 2a (0.56 mmol) was used.

Table 2. Scope of the synthesis of chiral cyclopropanesa
smoothly to afford two products (entries 4 and 5). For 4-
methoxycinnamaldehyde, diastereoselectivity was decreased to
1:1 (entry 5). The reaction yield could reach to 81% when 3-
fluorocinnamaldehyde was used (entry 6).
Interestingly, when 2-substituted cinnamaldehydes reacted
with 1-(chloromethyl)-2,4-dinitrobenzene 1a, the third
diastereomer 5 was detected as the minor product (Table 3). -
Unsaturated aldehydes with electron-withdrawing groups at the
ortho- position of the phenyl ring gave all three products in good
yields and enantioselectivities (entry 1 and 2). For 2-methoxy
cinnamaldehyde, cyclopropane products were obtained in a high
yield of 86% with high enantioselectivities for only two products:
3i and 4i. The enantioselectivity of the other product 5i dropped
entry
R
yield%b (3+4) ee% (3/4)c
dr (3:4)d
2:1
1
2
3
4
5
6
Ph (a)
74
66
74
76
68
81
96/94
90/95
95/90
95/94
93/86
91/92
4-BrC6H4 (b)
4-ClC6H4 (c)
4-MeC6H4 (d)
4-MeOC6H4 (e)
3-FC6H4 (f)
2:1
1.5:1
2:1
significantly (39% ee, entry 3). When
withdrawing methoxycarbonyl group replaced one nitro group in
disubstituted benzylchlorides reacted with 2-
a less electron-
1:1
methoxycinnamaldehyde, no cyclopropane products were
obtained. To our delight, for these less reactive disubstituted
1.7:1
benzylchlorides
including
1-(chloromethyl)-2-nitro-4-
a
Reaction conditions: unless specified, a mixture of 2 (0.56 mmol), TEA
(trifluoromethyl)benzene 1j, methyl 2-(chloromethyl)-5-
nitrobenzoate 1k, and methyl 4-(chloromethyl)-3-nitrobenzoate
1l, 4-chlorocinnamaldehyde reacted smoothly to give acceptable
reaction yields and high enantioselectivities, though extended
reaction time up to several days were needed (entries 4-6).
However, the reactions between benzylchloride and alkyl
substituted -unsaturated aldehydes could not proceed under
these reaction conditions, presenting a limitation for this method.
(0.56 mmol) and catalyst (0.084 mmol) in 1.6 mL DCE was added the
solution of 1a (0.28 mmol) in 4 mL DCE for 4 times and stirred for 11 h at rt.
b Isolated yield.
c Determined by chiral HPLC analysis.
d Determined by 1H NMR.
With the optimal reaction condition in hand, we then focused
on exploration of reactant scope of -unsaturated aldehydes for
this asymmetric cyclopropanation reaction (Table 2). The results
showed that -unsaturated aldehydes with substituted group at
para- and meta- position of the phenyl ring afforded
cyclopropane products 3 and 4 in modest to good yields and
Scheme 2. The absolute configurations of 3c and 4h.
excellent
enantioselectivities.
Unfortunately,
the
diastereoselectivities of cyclopropanation products were not so
attractive due to high structural similarity between two aromatic
groups on the cyclopropane ring. Electron-withdrawing groups at
para- position of the phenyl ring gave similar results as the
unsubstituted cinnamaldehyde (entries 2 and 3). Electron-
donating groups at para- position of the phenyl ring also reacted
Table 3. Scope of the synthesis of chiral cyclopropanesa
Entry R’, R’’
R
yield%b
(3+4+5) (3/4/5)c
Ee%
dr
(3:4:5)d
1
NO2, NO2
2-BrC6H4
(g)
70
96/94/86
90/95/94
95/94/39
96/90/85
88/91/70
96/90/80
2.5:1:1.5
3.4:2.4:1
3:1:1.3
2
NO2, NO2
NO2, NO2
NO2, CF3
2-ClC6H4
(h)
74
3
2-MeOC6H4 86
(i)
The absolute configurations of product 3 and 4 were
determined by single crystal X-ray diffraction analysis based on
compound 3c and 4h (Scheme 2). Unfortunately, we were not
able to get good crystal of product 5 and solve its absolute
configuration.
4e
5e
6f
4-ClC6H4
(j)
76
61
1.5:1.3:1
1:1.7:1.1
1.9:1.5:1
CO2Me,
NO2
4-ClC6H4
(k)
NO2,
4-ClC6H4 (l) 61
The proposed mechanism is described in Scheme 3.
CO2Me
Activation of -unsaturated aldehyde
2
by a chiral
a
Reaction conditions: unless specified, a mixture of 2 (0.56 mmol), TEA
(0.56 mmol) and catalyst (0.084 mmol) in 1.6 mL DCE was added the
solution of 1 (0.28 mmol) in 4 mL DCE for 4 times and stirred for 11 h at rt.
organocatalyst III produces iminium A. Conjugate addition of a
nucleophilic anion from 1, to the resulting active iminium A,
triggers a Michael process to afford intermediate B. Then a
nucleophilic substitution results in cyclopropane intermediate C.
Probably, the nucleophilic substitution can happen from both
directions due to chloride at achiral  position to give poor
diastereoselectivities. Finally, water enters to recycle the catalyst
III and afford products 3, 4 and 5.
b Isolated yield.
c Determined by chiral HPLC analysis.
d Determined by 1H NMR.
e The reaction was stirred for 7 d at rt.
f The reaction was stirred for 4 d at rt.

4
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Scheme 3. The proposed mechanism.
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In summary, we have developed an efficient method for the
synthesis
of
chiral
trisubstituted
diarylcyclopropanecarboaldehydes from substituted benzyl
chloride and -unsaturated aldehydes. The reactions were
catalyzed by chiral diphenylprolinol TBDMS ether under mild
condition to give chiral diarylcyclopropanecarboaldehydes in
good to high yields and overall excellent enantioselectivities. For
-unsaturated aldehydes with substitutions at both para- and
meta- position of the phenyl ring reacting with 1-(chloromethyl)-
2,4-dinitrobenzene afforded only two cyclopropane products,
while the reactions of cinnamaldehyde with substitution at ortho-
position or other disubstituted benzylchlorides generated three
diastereomers. Further exploration of this methodology in
synthetic applications towards biologically relevant molecules
are under investigation in our laboratory.
Acknowledgments
Financial support of this research from the National Science
Foundation of China (21372073, 21572054 and 21572055), the
Fundamental Research Funds for the Central Universities and
East China University of Science and Technology, and the China
111 Project (Grant B07023) is gratefully acknowledged.
Supplementary Material
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
CCDC 1500758 and 1500817. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.UK). All experimental procedures,
spectroscopic data associated with this article can be found, in
the online version. at http://dx.doi.org/
.
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Highlights
Chiral trisubstituted diarylcyclopropanecarboaldehydes have been synthesized by organocatalysis.
The enantioselectivities of trisubstituted diarylcyclopropanecarboaldehydes are very high.
The reactions can be proceeded under the mild conditions.