Organocatalytic and direct asymmetric vinylogous Michael addition of 3-cyano-4-methylcoumarins to α,β-unsaturated ketones

Article abstract of DOI:10.1016/j.tetlet.2010.10.055

The first highly regio-, chemo-, and enantio-selective direct vinylogous Michael addition of 3-cyano-4methylcoumarin derivatives to α,β- unsaturated ketones is described, employing readily available 9amino-9-deoxy-epiquinine as the iminium organocatalyst.

Full text of DOI:10.1016/j.tetlet.2010.10.055

Tetrahedron Letters 51 (2010) 6637–6640
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Tetrahedron Letters
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Organocatalytic and direct asymmetric vinylogous Michael addition
of 3-cyano-4-methylcoumarins to a,b-unsaturated ketones
⇑
Xiong Huang, Yi-Hang Wen, Fei-Ting Zhou, Ce Chen, Dong-Cheng Xu, Jian-Wu Xie
Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry and Life Science, Zhejiang Normal University, 321004 Jinhua, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The first highly regio-, chemo-, and enantio-selective direct vinylogous Michael addition of 3-cyano-4-
Received 24 August 2010
Revised 25 September 2010
Accepted 12 October 2010
Available online 19 October 2010
methylcoumarin derivatives to
amino-9-deoxy-epiquinine as the iminium organocatalyst.
a,b-unsaturated ketones is described, employing readily available 9-
Ó 2010 Elsevier Ltd. All rights reserved.
Development of novel synthetic methods for the construction of
new and optically active analogs of bioactive heterocyclic com-
pounds represents a major challenge in synthetic organic and
medicinal chemistry. The Michael reactions have been employed
as one of the most powerful synthetic tools to afford optically ac-
tive compounds from simple and easily available starting materials
and catalysts.1 Moreover, the Michael addition of nucleophiles to
envisaged that the acidity of c-C–H might be greatly enhanced
when strong electron withdrawing groups are attached to C@C
bond, which allows the easy generation of nucleophilic species
by in situ deprotonation under mild conditions. Thus, as illustrated
in Scheme 1, facile deprotonation of 2a could occur to generate the
vinylogous carbanion under mild basic conditions. It is interesting
that high regioselectivity was observed when the reaction was car-
ried out between 3-cyano-4-methylcoumarin 2a and benzylidene-
acetone 3a in the presence of catalytic BnNH2 and DIPEA. The
vinylogous Michael addition proceeded smoothly to afford the
product 4aa and no product 5aa was observed. Moreover, organo-
catalytic direct vinylogous Michael reactions have attracted
increasing attention over the past five years.8,9 Herein we present
such an advance and its direct application in an atom-economic
synthesis of optically active coumarins derivatives based on the
development of a new organocatalytic enantioselective vinylogous
a,b-unsaturated ketones is a challenging benchmark for such a
development owing to its potential for the construction of C–C,
C–N, C–O, C–S bonds with simultaneous generation of up to three
adjacent stereogenic centers and because of the pivotal importance
of the carbonyl group as a precursor to many functionalities.2–4
Therefore, the development of enantioselective catalytic protocols
for this reaction has been the subject of intensive research.2–4
Coumarins are important heterocycles, widely present in natu-
ral products exhibiting a broad range of biological and therapeutic
activities, which have been the subject of intensive research.5–7
During our ongoing studies of 3-cyano-4-methylcoumarin 2a, we
Michael addition of 3-cyano-4- methylcoumarins to
rated ketones.
a,b-unsatu-
O
H
O
γ
NC
β
O
O
CN
CN
Ph
base
α
3a
γ
-selectivity
O
O
O
O
4aa
2a
O
O
CN
O
CN
Ph
Ph
O
O
O
5aa
Scheme 1. Regioselectivity in the C–C bond formation reaction of 3-cyano-4-methylcoumarin under mild basic conditions.
⇑
Corresponding author. Fax: +86 579 82282610.
E-mail address: xiejw@zjnu.cn (J.-W. Xie).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.055

6638
X. Huang et al. / Tetrahedron Letters 51 (2010) 6637–6640
Table 2
Asymmetric vinylogous Michael addition of 3-cyano-4- methylcoumarins 2 to
a,b-
OMe
N
O
unsaturated ketones 3.a
N
N
O
O
P
O
OH
NC
O
NH2
NH2
O
O
R
R
CN
+
O
20 mol% 1a
DCM, rt, 96h
N
Ar
Ar
(R)-BDHP
1c
H
O
1a
1b
2a R=H
2b R=Cl
3
4
Figure 1. The structure of amine catalysts and 1c.
Entry
2
Ar (3)
Yield of 4b (%)
eec(%)
1
2
3
4
5
6
7
8
9
2a
Ph (3a)
82 (4aa)
61 (4ab)
51 (4ac)
86 (4ad)
76 (4ae)
75 (4af)
91 (4ba)
88 (4bb)
75 (4bc)
82 (4bd)
87 (4be)
73 (4bf)
91
91
91
95
93
92
91
91
85
93
92
92
Recently, amines and amino acids were investigated and
established as effective organocatalysts in asymmetric catalysis10
and many exciting discoveries have been made in the amine/amino
acid-catalyzed multi-catalysis reactions, such as multi-compo-
nent,11 organo-click reactions,12 and domino reactions.13 More-
over, we have reported the Michael addition of some
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
p-Me-Ph (3b)
p-MeO-Ph (3c)
p-Cl-Ph (3d)
p-Br-Ph (3e)
2-furanyl (3f)
Ph (3a)
p-Me-Ph (3b)
p-MeO-Ph (3c)
p-Cl-Ph (3d)
p-Br-Ph (3e)
2-furanyl (3f)
nucleophiles to
a,b-unsaturated ketones by employing primary
aminocatalyst 1a14 (Fig. 1) and the primary amine 1a has been
used successfully in the asymmetric Michael reactions by many
groups.15,16 Inspired by the recent reports on iminium activation
10
11
12
a
All the reactions were performed with 0.1 mmol of 2, 0.15 mmol of 3, 20 mol%
of 1a in 1 mL DCM at room temperature for 96 h.
of
a,b-unsaturated ketones by chiral primary aminocatalyst 1a,
we envisioned that the organocatalyst 1a would be an efficient cat-
alyst for the Michael reaction of 3-cyano-4-methylcoumarins to
b
Isolated yield.
Determined by chiral HPLC analysis
c
a,b-unsaturated ketones. Table 1 shows some screening results
for the reaction of 2a with 3a. In the course of our screening studies
of organocatalytic vinylogous Michael addition of 3-cyano-4-
methylcoumarin 2a to benzylideneacetone 3a, the effects of acidic
additives were very evident. The 9-amino-9-deoxy-epiquinine 1a
(Fig. 1, 20 mol %) in combination with TFA (40 mol %) that has been
successfully used in the asymmetric Michael reactions,14–16 was
inert in the reaction of 3-cyano-4-methylcoumarin 2a to benzyli-
deneacetone 3a (Table 1, entry 1). The ee and yield were dramati-
cally increased when the TFA was reduced to 10 mol %. To our
surprise, 9-amino-9-deoxy-epiquinine 1a exhibited excellent cata-
lytic activity when no acidic additives were added, and high
enantioselectivity (91% ee) and good yield (82% yield) were ob-
tained (entry 4). Subsequently we investigated the effects of other
acidic additives and solvents with 1a. The same enantioselectivity
was obtained while the yield was decreased in the presence of
other acidic additives (entries 5 and 6). Good yields were obtained
in THF and DMF but the ees were reduced (entries 9 and 10). Both
reactivity and enantioselectivity were decreased in toluene or
methanol (entries 7 and 8). It is worthy of note that 9-Amino-9-
deoxyepicinchonine 1b gave the same enantioselectivity while
the adduct with opposite configuration was obtained (entry 11).
With the optimal reaction conditions in hand, we then exam-
ined a variety of
a,b-unsaturated ketones and 3-cyano-4-methyl-
Table 1
coumarin derivatives to establish the general utility of the
catalytic transformation.17 The vinylogous Michael reaction was
generally conducted with 20 mol % of 1a at 25 °C for 96 h. As illus-
trated in Table 2, the electronic effect of 3 was very marginal and
remarkable enantioselectivity was achieved (entries 2–6). High
enantioselectivities were achieved in the reaction of 2a with vari-
Screening studies of organocatalytic vinylogous Michael addition of 3-cyano-4-
methylcoumarin 2a to benzylideneacetone 3a.a
O
NC
O
20 mol% 1a
O
O
CN
+
O
10 mol% additive
solvent, rt, 96h
H
O
ous
a,b-unsaturated ketones 3b–3f having an electron-rich, elec-
tron-deficient aromatic group or heteroaromatic group (entries
2–6). Up to 95% ee was obtained in the reaction of 2a with 4-chlo-
robenzylideneacetone 3d. On the other hand, an electron-with-
drawing substituent on aryl ring of 3-cyano-4-methylcoumarin
2b has little effect on the asymmetric vinylogous Michael
2a
3a
4aa
Entry
solvent
additive
Yieldb (%)
eec (%)
1d
2e
3
DCM
DCM
DCM
DCM
DCM
DCM
MeOH
Toluene
DMF
TFA
TFA
TFA
—
(R)-1c
HCl
—
—
—
—
—
0
—
—
Trace
33
82
60
43
45
53
77
70
81
91
91
91
88
63
71
69
78
ꢀ91
4
5f
6
7
8
9
Br
10
THF
DCM
11g
a
Otherwise noted, reactions performed with 0.1 mmol of 2a, 0.15 mmol of 3a,
20 mol % catalyst 1a, 10 mol % additive, in 1 mL solvent at room temperature for
96 h.
(S)
O
b
Isolated yield.
Determined by chiral HPLC analysis.
40 mol % TFA was added.
20 mol % TFA was added.
10 mol % additive was added.
Catalyzed by 1b.
H
Cl
CN
O
c
d
e
O
f
g
Figure 2. Molecular structure of enantiopure 4be (ellipsoids with 30% probability).

X. Huang et al. / Tetrahedron Letters 51 (2010) 6637–6640
6639
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Ar
Figure 3. Proposed mechanism for the vinylogous Michael reaction.
reactions. Similarly, excellent enantioselectivities were also
achieved in the reaction of 2b with various
tones 3b–3f bearing an electron-rich, electron-deficient aromatic
group or heteroaromatic group.
a,b-unsaturated ke-
To determine the absolute configuration of the vinylogous
Michael addition products, single crystal suitable for X-ray crystal-
lographic analysis was fortunately obtained from enantiopure 4be
that bears a bromine atom. As shown in Figure 2, it composes of
(C12S) configuration.18
The stereochemical outcome in the Michael addition reaction
can be rationalized by the following plausible mechanism
(Fig. 3). According to the previous literature,14–16 chiral primary
amine 1a is an effective catalyst for the formation of iminium with
2-hydroxy-benzalacetone 3, while the 3-cyano-4-methylcoumarin
2 would be deprotonated by the amino group of 1a, furnishing the
corresponding vinylogous carbanion, then a subsequent Michael
addition reaction affords the desired product 4.
In conclusion, we have successfully demonstrated the first
asymmetric direct vinylogous Michael addition reaction of
electron-deficient 3-cyano-4-methylcoumarins to a,b-unsaturated
ketones with excellent enantioselectivity, employing readily avail-
able 9-amino-9-deoxy-epiquinine as the iminium organocatalyst.
This methodology provides facile access to various enantioen-
riched multifunctional compounds that, to date, have not been re-
ported in the literature. The novel and chiral coumarins derivatives
might have important biological and pharmaceutical activities in
the future. Current studies are actively and well underway to ex-
pand the synthetic utility of this new reaction, as well as of this
catalytic system in other asymmetric transformations.
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Acknowledgments
We are grateful for the financial support from the National Nat-
ural Science Foundation of China (20902083), Natural Science
Foundation of Zhejiang Province (Y4090082) and Zhejiang Normal
University.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.10.055.
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temperature for 96 h, then flash column chromatography on silica gel was
performed (monitored by TLC, 10% ethyl acetate/petroleum ether as eluent)
gave 4aa as a pale yellow solid (82% yield). Mp 120–122 °C; 1H NMR (400 MHz,
CDCl3) d (ppm) 8.32 (d, J = 8.0 Hz, 1H), 7.71 (t, J = 7.2 Hz, 1H), 7.51 (t, J = 8.0 Hz,
1H), 7.36 (d, J = 8.3 Hz, 1H), 7.27–7.22 (m, 3H), 7.05 (d, J = 8.0 Hz, 2H), 3.65–
3.59 (m, 2H), 3.25–3.10 (m, 2H), 3.04–2.98 (m, 1H), 2.21 (s, 3H); 13C NMR
(100 MHz, CDCl3) d (ppm) 207.2, 163.9, 156.5, 153.4, 140.4, 135.0, 128.9, 127.8,
127.4, 127.0, 125.7, 117.7, 117.4, 113.4, 102.8, 49.4, 41.1, 39.0, 30.5; IR (KBr)
cmꢀ1 3069, 2956, 2223, 1723, 1700, 1601, 1543, 1268, 809, 716; ESI-HRMS:
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calcd for C21H17NO3+Na 354.11061, found 354.11006; ½a D25
ꢀ45.0 (c 0.7, ethyl
ꢁ
acetate), 91% ee; The enantiomeric ratio was determined by HPLC on Chiralpak
AS column (30% 2-propanol/hexane, flow rate 1 mL/min, k = 254 nm),
tmajor = 12.867 min, tminor = 17.596 min.
18. Crystal data for 4be
C21H15BrClNO3 (444.70), orthorhombic, space group
P2(1)2(1)2(1),
a = 8.93930(10),
b = 11.8849(2),
c = 18.7529(3) Å,
U = 1992.36(5) Å3, Z = 4, specimen 0.554 ꢂ 0.304 ꢂ 0.053 mm3, T = 296(2) K,
SIEMENS P4 diffractometer, absorption coefficient 2.218 mmꢀ1
, reflections
collected 31275, independent reflections 4598 [R(int) = 0.0431], refinement by
17. Typical experimental procedure for asymmetric vinylogous Michael addition of
full- matrix least-squares on F2, data/restraints/parameters 4598/0/244,
3-cyano-4-methylcoumarins
methylcoumarin 2a (0.1 mmol),
primary amine 1a 6.5 mg (0.02 mol) were stirred in DCM (1.5 mL) at room
2
to
a
,b-unsaturated ketones 3. 3-cyano-4-
goodness-of-fit on
F
2 = 1.011, final
R
indices [I > 2sr(I)] R1 = 0.0317,
a
,b–unsaturated ketone (0.15 mmol),
wR2 = 0.0664, R indices (all data) R1 = 0.0518, wR2 = 0.0718, largest diff. peak
and hole 0.297 and ꢀ0.284 e Åꢀ3
.