Highly enantioselective Michael addition of diethyl malonate to chalcones catalyzed by cinchona alkaloids-derivatived bifunctional tertiary amine-thioureas bearing multiple hydrogen-bonding donors

Article abstract of DOI:10.1039/c4ob00203b

Chalcones are still challenge substrates in Michael reactions, and only limited success has been achieved. This work describes a highly enantioselective Michael addition of diethyl malonate with chalcones catalyzed by cinchona alkaloids-derivatived bifunctional tertiary amine-thioureas bearing multiple hydrogen-bonding donors.

Full text of DOI:10.1039/c4ob00203b

Volume 12 Number 20 28 May 2014 Pages 3139–3312
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Wei He et al.
Highly enantioselective Michael addition of diethyl malonate to chalcones
catalyzed by cinchona alkaloids-derivatived bifunctional tertiary
amine-thioureas bearing multiple hydrogen-bonding donors

Organic &
Biomolecular Chemistry
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COMMUNICATION
Highly enantioselective Michael addition of
diethyl malonate to chalcones catalyzed by
cinchona alkaloids-derivatived bifunctional
tertiary amine-thioureas bearing multiple
hydrogen-bonding donors†
Cite this: Org. Biomol. Chem., 2014,
12, 3163
Received 26th January 2014,
Accepted 20th February 2014
DOI: 10.1039/c4ob00203b
www.rsc.org/obc
Yulong Liu, Xie Wang, Xiaoyun Wang and Wei He*
Chalcones are still challenge substrates in Michael reactions, and
only limited success has been achieved. This work describes a
highly enantioselective Michael addition of diethyl malonate with
chalcones catalyzed by cinchona alkaloids-derivatived bifunctional
tertiary amine-thioureas bearing multiple hydrogen-bonding
donors.
The formation of carbon–carbon bonds by the Michael
addition of appropriate carboanionic reagents to α,β-unsatu-
rated carbonyl compounds is one of the most useful methods
of remote functionalization in organic synthesis.1 Therefore,
their catalytic asymmetric version has been studied exten-
sively.2 2-(3-Oxo-1,3-arylpropyl)malonic acids, prepared from
the Michael adducts of malonates to chalcones, are allosteric
modulators for the protein kinase C-related kinase 2 (PRK2)-
interacting fragment (PIF) pocket of phosphoinositide-depen-
dent kinase-1 (PDK1), and targeting the PIF pocket is possibly
a novel approach for the treatment of type 2 diabetes.3 Many
kinds of catalysts, such as chiral phase transfer catalysts,4
chiral ionic liquids,5 chiral N,N′-dioxide–Sc complexes,6 chiral
bis-sulfonamide–Sr complexes,7 chiral bisphosphazide–Li
complexes,8 chiral SIPAD–Co complexes,9 DPEN/NAP-MgO,10
and organocatalysts,11 have been developed for enantio-
selective Michael addition of malonates with chalcones.
However, some of these catalysts could not give satisfactory
enantioselectivity; chalcones are still challenging substrates
in Michael reactions with malonates. Moreover, the scope
of chalcones in reported asymmetric Michael additions is very
limited.
Fig. 1 The cinchona alkaloids-based bifunctional tertiary amine-
thioureas bearing multiple hydrogen-bonding donors.
biocatalysis, the advantages of organocatalysis include their
operational simplicity and employment of readily available,
low-cost, and low toxic oganocatalysts. Previously, we developed
a series of cinchona alkaloids-based bifunctional tertiary
amine-thioureas bearing multiple hydrogen-bonding donors
1–4 (Fig. 1) for highly enantioselective aza-Henry reactions,
Michael additions of acetylacetone and acetone to nitro-
olefins.13 The additional hydroxyl group in 1–4 might facilitate
the formation of more hydrogen bonds and thereby
Asymmetric organocatalysis has emerged as one of the
most rapidly growing and promising areas in synthetic organic
chemistry.12 Compared to traditional metal catalysis and
Department of Chemistry, School of Pharmacy, Fourth Military Medical University,
Xi’an 710032, P. R. China. E-mail: weihechem@fmmu.edu.cn; Fax: +86 29 84774470;
Tel: +86 29 84774470
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob00203b
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Table 1 Catalyst 4b and its diastereoisomers in the asymmetric Michael
reaction of chalcone with diethyl malonatea
Entry
Catalyst
Yieldb (%)
eec,d (%)
1
2
3
4
4b
5
6
35
30
30
35
87 (R)
8 (R)
7 (S)
7
84 (S)
a Reaction conditions: 0.1 mmol of chalcone, 0.12 mmol of diethyl
malonate, 10 mol% of catalyst 4b and 100 mol% of Na2CO3 as base
additive in 0.5 mL of CHCl3 at room temperature for 48 h. b Isolated
yield. c Determined by chiral HPLC analysis. d Absolute configuration
was determined by comparison of the optical rotation with the value
previously reported.7
Fig. 2 Plausible transition state for the enantioselective Michael
reaction.
significantly enhance the catalytic activity as well as the rigidity
of the transition state, leading to high enantioselectivity and
activity.14 Extending the interest of these organocatalysts in
asymmetric catalysis, herein, we describe a highly enantio-
selective Michael addition of diethyl malonate with chalcones
catalyzed by cinchona alkaloids-derivatived bifunctional tertiary
amine-thioureas bearing multiple hydrogen-bonding donors.
Initially, the Michael addition of chalcone (8a) with diethyl
malonate (9) was chosen as model reaction for the screening
of catalysts and reaction conditions. After extensive screening
(see ESI†), to our delight, among the catalysts tested, 4b
showed a promising result. Thus, using 10 mol% of 4b as cata-
lyst, 1 equivalent of Na2CO3 as additive and CHCl3 as solvent,
chalcone 8a reacted with diethyl malonate (9) at room temp-
erature to give the adduct (R)-10a in 35% yield and 87% ee.
Another three diastereoisomers 5, 6 and 7 (Fig. 2) were then
synthesized. Diastereomers 5 (from quinine and L-phenyl-
glycine) and 6 (from quinidine and D-phenylglycine) are
mismatched, giving almost a racemate in the reaction. 7 (from
quinidine and L-phenylglycine), a pseudo-enantiomer of 4b,
gave the product in similar enantioselectivity to 4b but with
opposite asymmetric induction (Table 1).
Table 2 Effects of the base and temperature on the asymmetric
Michael reaction catalyzed by catalyst 4ba
Entry Base (mol%)
Temp. (°C) Time (h) Yieldb (%) eec,d (%)
1
2
3
4
5
6
7
8
—
25
25
25
25
25
25
25
25
0
48
8
8
0
99
99
99
32
20
35
99
99
99
99
99
ND
0
0
0
8
13
87
10
44
78
85
94
K2CO3 (100)
Cs2CO3 (100)
KOH (100)
Mg(OH)2 (50)
Ca(OH)2 (50)
Na2CO3 (100)
NaOH (20)
NaOH (20)
NaOH (20)
NaOH (10)
NaOH (5)
8
48
48
48
8
8
8
9
10
11
12
−20
−20
−20
8
8
a Reaction conditions: 0.1 mmol of chalcone, 0.12 mmol of diethyl
malonate, 10 mol% of catalyst 4b and 100 mol% of Na2CO3 as base
additive in 0.5 mL of CHCl3 at room temperature for 48 h. b Isolated
yield. c Determined by chiral HPLC analysis. d Absolute configuration
was determined by comparison of the optical rotation with the value
previously reported.7
Considering the significant effects of basic additives15 and
reaction temperature on the enantioselectivity of Michael
addition, the reaction conditions were optimized. As depicted
in Table 2, without a basic additive, the reaction cannot be
promoted by a catalyst (entry 1). Then a variety of bases were
tested as additives. When 1 equivalent K2CO3, CS2CO3 and
KOH was added respectively, the reaction proceeded rapidly at optimized (entries 11–12). To our delight, high yield and excellent
room temperature and gave the adduct in almost quantitative enantioselectivity were achieved when the reaction was
yield but as a racemate (entries 2–4). Low activity and low performed in CHCl3 at −20 °C using 10 mol% of 4b as catalyst
chiral induction were observed when 0.5 equivalent Mg(OH)2 and 5 mol% of NaOH as additive (entry 12).
and Ca(OH)2 were used (entries 5–6). High enantioselectivity
Under the optimized reaction conditions, the substrate
but low yield were obtained with Na2CO3 as additive (entry 7). scope was subsequently investigated for this enantioselective
When NaOH was added, high activity was achieved, even in a Michael addition. A variety of substituted chalcones 8 reacted
lower loading (entry 8). Then, the effect of reaction tempera- smoothly with diethyl malonate (9) to afford the corresponding
ture on the reaction was investigated. Lowering the tempera- products (R)-10 in high yields (83–99%) and excellent enantio-
ture significantly improved the enantioselectivity (entries selectivities (90–97% ee) in the presence of 10 mol% of catalyst
8–10). Finally, at −20 °C, the amount of base was further 4b at −20 °C within 8 h (Table 3, entries 1–20). It appears that
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excellent chiral environment of the cinchona alkaloid backbone
and the matched amino alcohol moiety enable diethyl malo-
nate to attack the activated chalcone from the Si-face,
affording the R-configured product. While in transition state
B, the Michael reactions of chalcone 8a and diethyl malonate
(9) was catalyzed by 7, and a Re-face attack is favored, giving
the S-configured product.
Table 3 The asymmetric Michael reaction of chalcones with diethyl
malonate catalyzed by catalyst 4b and 7a
Entry
Ar1
Ar2
Yieldb,d (%)
eec,d (%)
Conclusions
1
2
3
4
5
6
7
8
Ph
Ph (8a)
Ph (8b)
Ph (8c)
Ph (8d)
Ph (8e)
Ph (8f)
Ph (8g)
Ph (8h)
Ph (8i)
Ph (8j)
Ph (8k)
Ph (8l)
Ph (8m)
Ph (8n)
Ph (8o)
4-CH3C6H4 (8p)
4-CH3OC6H4 (8q)
4-CF3C6H4 (8r)
4-ClC6H4 (8s)
4-FC6H4 (8t)
Ph (8a)
99 (97)
95 (95)
97 (98)
98 (99)
94 (93)
95 (96)
98 (98)
96 (95)
98 (99)
99 (94)
97 (99)
89 (90)
99 (99)
87 (85)
80 (83)
96 (95)
98 (96)
99 (98)
96 (97)
99 (99)
99 (97)
94 (−94)
92 (−92)
94 (−94)
92 (−94)
94 (−90)
93 (−96)
95 (−94)
96 (−96)
92 (−99)
94 (−90)
90 (−90)
93 (−90)
92 (−90)
91 (−91)
94 (−95)
94 (−94)
96 (−94)
95 (−90)
96 (−92)
95 (−90)
93 (−92)
3-CH3C6H4
4-CH3C6H4
2-CH3OC6H4
4-CH3OC6H4
2-CF3C6H4
4-CF3C6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
3-BrC6H4
4-BrC6H4
4-FC6H4
2-Furyl
1-Naphthyl
Ph
In summary, the bifunctional chiral tertiary amine-thioureas
bearing multiple hydrogen-bonding donors 4b and 7, easily
prepared from natural cinchona alkaloids and chiral amino
alcohols, are highly effective in asymmetric Michael additions
of diethyl malonate to chalcones. Notably, catalyst 4b and 7
showed similar catalytic activities and enantioselectivities,
giving the R and S enantiomers of the adducts easily in up to
99% yield and 99% ee. Further detailed catalytic mechanism
and catalytic performance in other asymmetric reactions using
this type of bifunctional tertiary amine-thioureas are currently
underway in our laboratory.
9
10
11
12
13
14
15
16
17
18
19
20
21e
Ph
Ph
Ph
Ph
Acknowledgements
Ph
We thank the National Natural Science Foundation of China
(NSFC 21272272) for financial support. And we also would
like to express our great thanks to Professor Weiping Chen for
valuable discussions and kind help.
a Unless otherwise specified, the reactions were performed with
0.1 mmol of chalcone, 0.12 mmol of diethyl malonate, 10 mol% of 4b
and 5 mol% of NaOH in 0.5 mL of CHCl3 at −20 °C for 8 h. b Isolated
yield. c Determined by chiral HPLC analysis. d The data in parentheses
were obtained by replacement of 4b with 7 at −50 °C for 10 h. e 5 mol
% of catalyst was used.
Notes and references
the position and the electronic property of the substituents on
the aromatic rings have a very limited effect on the enantio-
selectivities. The heteroaryl and naphthyl derived α,β-unsatu-
rated ketones also gave high yields and enantioselectivities
(entries 14–15). Importantly, replacement of 4b with its
pseudo-enantiomer 7 gave the adduct (S)-10 (with opposite
configuration) in similar yields and enantioselectivities
(entries 1–20, the data in parentheses). More importantly, the
catalysts 4b and 7 are highly active for the Michael addition as
well. Almost identical results were obtained when the catalyst
loading was reduced from 10 mol% to 5 mol% (entry 1 vs. 21).
It is worth noting that some adducts and their enantiomers
are unknown compounds, such as 10b, 10d, 10f, 10g, 10i, 10k,
10l and 10m.
To explain the stereochemical outcome, plausible transition
state (TS) models for the Michael reactions of chalcone 8a and
diethyl malonate (9) catalyzed by 4b (TS A) and 7 (TS B) are
proposed (Fig. 2). In transition state A, the carbonyl group of
chalcone is activated by the multiple hydrogen bonding inter-
actions between the oxygen atom of the carbonyl with the
thiourea moiety and the extra hydroxyl group of 4b. Meanwhile
diethyl malonate (9) is deprotonated by the basic nitrogen
atom of the quinuclidine in cinchona alkaloid moiety. The
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