Phosphine-catalyzed asymmetric [4+1] annulation of Morita-Baylis-Hillman carbonates with dicyano-2-methylenebut-3-enoates

Article abstract of DOI:10.1039/c2cc34619b

A novel asymmetric [4+1] annulation of MBH carbonates with dicyano-2-methylenebut-3-enoates has been developed for the first time, providing an efficient and enantioselective synthesis of highly functionalized cyclopentenes bearing one all-carbon quaternary stereogenic center.

Full text of DOI:10.1039/c2cc34619b

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COMMUNICATION
Phosphine-catalyzed asymmetric [4+1] annulation of
Morita–Baylis–Hillman carbonates with
dicyano-2-methylenebut-3-enoatesw
Xiao-nan Zhang,a Hong-Ping Deng,b Long Huang,a Yin Weib and Min Shi*ab
Received 28th June 2012, Accepted 12th July 2012
DOI: 10.1039/c2cc34619b
A novel asymmetric [4+1] annulation of MBH carbonates with
dicyano-2-methylenebut-3-enoates has been developed for the
first time, providing an efficient and enantioselective synthesis
of highly functionalized cyclopentenes bearing one all-carbon
quaternary stereogenic center.
Scheme 1 A research proposal.
Over the past decade, nucleophilic phosphine catalysis has attracted
much research effort.1 At the present stage, phosphine-mediated
reactions have become a powerful tool in producing carbo- and
heterocycles.2 In particular, phosphine-catalyzed [3+2] and [4+2]
annulations3 of allenoates and imines/alkenes have been applied in
the synthesis of several natural products.4 Recently, Morita–
Baylis–Hillman (MBH) acetates and carbonates as complementary
and versatile substrates have emerged in nucleophilic phosphine
catalysis since Lu and co-workers first reported a series of intra- and
intermolecular [3+n] annulations (n = 2, 4, 6) using MBH
carbonates as 1,3-dipoles with various electron-deficient olefins
catalyzed by a tertiary phosphine under mild conditions.5 Then,
several reports on asymmetric [3+2] annulations of MBH carbo-
nates with electron-deficient olefins have been disclosed.6 More
recently, Zhang, Huang and He and their co-workers have also
developed several MBH adducts involved in [4+1] annulations to
give the annulation products in high yields, respectively, in which
the MBH adducts served as a new kind of 1,1-dipolar synthon.7
However, to the best of our knowledge, there is no report on
the asymmetric version of this reaction. On the basis of these
studies and our ongoing investigations on the phosphine catalyzed
asymmetric annulations,8 we envisioned that chiral phosphine-
mediated [4+1] cyclization may be utilized to construct densely
functionalized optically active cyclopentenes (Scheme 1).
the first enantioselective [4+1] annulation of MBH acetates and
carbonates with dicyano-2-methylenebut-3-enoates, providing a
facile protocol to construct highly functionalized cyclopentenes
bearing one all-carbon quaternary stereogenic center in good
yields with excellent enantioselectivities.10
Based on our previous work on chiral phosphines as nucleo-
philic catalysts in asymmetric catalysis,11 we initiated the study
Table 1 Screening of chiral phosphine catalystsa
The electron-deficient diene compounds necessary for the
annulation reactions can be conveniently prepared from alkyl
propiolates and a,a-dicyanoolefins.9 Herein we wish to report
a Key Laboratory for Advanced Materials and Institute of Fine
Chemicals, East China University of Science and Technology,
130 MeiLong Road, Shanghai 200237, P. R. China
b State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, P. R. China.
E-mail: mshi@mail.sioc.ac.cn
a
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for new compounds. CCDC
872182. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2cc34619b
Reactions were performed with 1a (0.10 mmol) and 2a (0.15 mmol) in
the presence of 20 mol% of CP in toluene (1 mL) at room temperature.
c
Isolated yields. Determined by chiral HPLC analysis.
b
c
8664 Chem. Commun., 2012, 48, 8664–8666
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With the identification of the best catalyst in this reaction, we
next attempted to further optimize reaction conditions by screening
the solvent (Table S1, ESIw). The reaction outcomes revealed that
using 20 mol% CP9 as the catalyst with 4 A MS as the additive
(40 mg for 0.1 mmol of 1a and 0.15 mmol of 2a) and carrying out
the reaction in toluene at room temperature for 2 days gave 3a in
84% yield with 90% ee value, which served as the best reaction
conditions in this reaction (Scheme 2). Using 10 mol% of CP9
gave 3a in 72% yield and 88% ee under identical conditions.
Having determined the optimal reaction conditions for the highly
enantioselective formation of 3a, we turned our attention to the
substrate scope of this multifunctional chiral-phosphine-catalyzed
asymmetric [4+1] annulation of dicyano-2-methylenebut-3-enoates
with MBH carbonates and the results are summarized in Table 2.
All reactions proceeded smoothly to give the corresponding
products 3 in moderate to good yields with excellent enantio-
selectivities under the optimal reaction conditions (Table 2).
Whether R1 is an electron-rich or -deficient aromatic ring,
the reactions proceeded smoothly to give the corresponding
annulation products 3b–3i in good yields with 77–90% ee
values, respectively (Table 2, entries 1–8). Only in the case of
ortho-MeOC6H4 dicyano-2-methylenebut-3-enoate 1b, the corre-
sponding adduct 3b was obtained in good yield along with
relatively lower ee value (77% ee), perhaps due to the steric
influence (Table 2, entry 1). When R1 is a heteroaromatic group
(R1 = funan-2-yl) or a sterically more bulky 2-naphthalene moiety
or a more substituted aromatic group (R1 = 3,4,5-(MeO)3C6H2),
the reactions also proceeded efficiently to afford the corresponding
Scheme 2 Optimization of the reaction conditions.
by investigating the reaction between dicyano-2-methylenebut-3-
enoate 1a and MBH carbonate 2a in the presence of multifunc-
tional chiral thiourea–phosphine CP1 (20 mol%) derived from
L-phenylalanine in toluene at room temperature. To our delight, the
desired annulation indeed took place, giving the corresponding
product 3a in 84% ee, albeit in only 39% yield (Table 1). Increasing
the steric bulkiness of multifunctional thiourea–phosphines derived
from natural amino acids, we consecutively examined the catalysts
CP2 and CP3, and identified that CP3 was the more efficient
catalyst, producing 3a in 38% yield along with 90% ee value.
Subsequently we examined several multifunctional chiral phos-
phines CP4–CP9 having an axially chiral binaphthyl scaffold.
Using CP4 as the chiral phosphine 3a was produced in 42% yield
with 15% ee value. Notably, both yields and ee values of the
product 3a increased when multifunctional thiourea–phosphines
CP5–CP7 were employed, and revealed that CP7 was the more
effective catalyst, affording 3a in 90% yield with 80% ee. Gratify-
ingly, an improvement was possible through a slight structural
modification of catalyst CP7 to give CP8 and CP9, which could
produce 3a in better results. Finally, we found that 3a could be
obtained in 80% yield with 89% ee using CP9 as catalyst (Table 1).
Table 2 The substrate scope of [4+1] annulation of dienes 1 with MBH carbonates 2a
Entry
R1
R2
R3
Time (d)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1b (o-MeOC6H4)
1c (m-MeOC6H4)
1d (p-MeC6H4)
1e (p-FC6H4)
1f (p-ClC6H4)
1g (p-BrC6H4)
1h (Ph)
2a (p-NO2C6H4)
2a (p-NO2C6H4)
2a (p-NO2C6H4)
2a (p-NO2C6H4)
2a (p-NO2C6H4)
2a (p-NO2C6H4)
2a (p-NO2C6H4)
2a (p-NO2C6H4)
2a (p-NO2C6H4)
2a (p-NO2C6H4)
2a (p-NO2C6H4)
2b (m-NO2C6H4)
2c (p-ClC6H4)
2d (Ph)
2e (3-Br,4-FC6H3)
2f (CH3)
2g (p-NO2C6H4)
2h (p-NO2C6H4)
2i (m-NO2C6H4)
2j (p-CF3C6H4)
2k (p-FC6H4)
2a (OEt)
2a (OEt)
2a (OEt)
2a (OEt)
2a (OEt)
2a (OEt)
2a (OEt)
2a (OEt)
2a (OEt)
2a (OEt)
2a (OEt)
2b (OEt)
2c (OEt)
2d (OEt)
2e (OEt)
2f (OEt)
2g (OtBu)
2h (OBn)
2i (CH3)
2j (CH3)
2k (CH3)
2l (CH3)
2m (CH3)
2n (CH3)
2o (CH3)
2p (CH3)
2
2
2
2
2
2
2
2
2
2
2
2
7
7
7
7
5
2
2
2
2
4
3
4
3
3
3b, 80
3c, 82
3d, 86
3e, 80
3f, 79
3g, 70
3h, 85
3i, 75
3j, 81
3k, 84
3l, 70
3m, 76
3n, 42
3o, 39
3p, 69
3q, 29
3r, 70
3s, 80
3t, 90
3u, 86
3v, 88
3w, 41
3x, 90
3y, 86
3z, 92
3aa, 91
77
87
90
89
90
90
89
87
91
90
90
92
85
85
89
66
90
90
90
92
94
93
93
98
90
97
1i (p-CF3C6H4)
1j (furan-2-yl)
1k (naphtha-2-yl)
1l (3,4,5-(MeO)3C6H2)
1d (p-MeC6H4)
1d (p-MeC6H4)
1d (p-MeC6H4)
1d (p-MeC6H4)
1d (p-MeC6H4)
1d (p-MeC6H4)
1d (p-MeC6H4)
1d (p-MeC6H4)
1d (p-MeC6H4)
1d (p-MeC6H4)
1d (p-MeC6H4)
1d (p-MeC6H4)
1d (p-MeC6H4)
1d (p-MeC6H4)
1d (p-MeC6H4)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
2l (o-ClC6H4)
2m (p-ClC6H4)
2n (p-MeC6H4)
2o (3,4-Cl2C6H3)
2p (thiophen-2-yl)
a
Reactions were performed with 1 (0.10 mmol) and 2 (0.15 mmol) in the presence of 20 mol% of CP9 in toluene (1 mL) at room temperature.
c
Isolated yields. Determined by chiral HPLC analysis.
b
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 8664–8666 8665

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Financial support from the National Basic Research Program of
China (973)-2010CB833302, the Shanghai Municipal Committee
of Science and Technology (11JC1402600), the Fundamental
Research Funds for the Central Universities and the National
Natural Science Foundation of China (20902019, 20872162,
20672127, 21121062, 20732008, 20772030 and 20702059) is
greatly acknowledged.
Notes and references
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Scheme 3 Possible reaction mechanism for the formation of 3.
products 3j–3l in 70–84% yields with 90–91% ee values
(Table 2, entries 9–11). Next, the investigation of the MBH
carbonates was continued by using 1d as a substrate (Table 2,
entries 12–26). The reaction tolerated different aromatic moieties R2
in the MBH carbonates 2. Due to their lower reactivities, substrates
with no substituent or halogen atom substituent on the aromatic
ring of MBH carbonates resulted in reduced yields with high ee
values upon prolonging the reaction time to 7 days (Table 2,
entries 13–15). However, using MBH carbonate 2f as a substrate,
the reaction also proceeded efficiently, affording the cycloadduct 3q
in 29% yield along with 66% ee value. The reactions also worked
well upon changing the ester groups in the MBH carbonates,
providing the corresponding products 3r and 3s in 70% and 80%
yields with identical 90% ee values, respectively (Table 2, entries 17
and 18). Notably, taking MBH carbonates derived from methyl
vinyl ketone (MVK) as substrates, whether R2 is an electron-rich
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or -deficient aromatic ring or a heteroaromatic group (R2
=
thiophen-2-yl), the reactions proceeded smoothly to give the corre-
sponding annulation products 3t–3aa in moderate to excellent
yields (41–92%) with 90–98% ee values, respectively (Table 2,
entries 19–26). Only in the case of ortho-ClC6H4 MBH carbonate
2l, the corresponding adduct 3w was obtained in 93% ee along with
relatively lower yields (41% yield), perhaps due to the steric
influence (Table 2, entry 22). The absolute configuration of 3d
has been assigned by X-ray diffraction as R-configuration. The
ORTEP drawing and the CIF data are summarized in the ESI.w
On the basis of the above experimental results and previous
work,5a,c,12 a plausible reaction mechanism has been outlined in
Scheme 3. The reaction might be initiated with the in situ formation
of the phosphorus ylide I from 2 via an addition–elimination–
deprotonation process. Then the nucleophilic attack of phosphorus
ylide I to dicyano-2-methylenebut-3-enoate 1 with its C-1-terminal
results in intermediate II, which isomerizes to intermediate III
through a hydrogen transfer. Intermediate III produces the desired
highly functionalized cyclopentene 3 and regenerates the chiral-
phosphine catalyst via an intramolecular Michael addition followed
by the elimination of catalyst. The possible transition state of this
asymmetric [4+1] annulation is illustrated in Fig. S1 in the ESI.w
In conclusion, the asymmetric [4+1] annulation reactions
utilizing MBH carbonates as C1 synthons have been developed
for the first time, which provide an efficient and enantioselective
synthesis of highly functionalized cyclopentenes bearing one
all-carbon quaternary stereogenic center. Further efforts are in
progress to develop the use of this reaction in organic synthesis.
8 (a) X.-Y. Guan and M. Shi, J. Org. Chem., 2009, 74, 1977;
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9 X. Jiang, D. Fu, X. Shi, S. Wang and R. Wang, Chem. Commun.,
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10 For reviews on the construction of quaternary carbon center, see:
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11 For reviews on chiral phosphorus compounds as catalysts
in organocatalytic reactions, see: (a) Y. Wei and M. Shi, Acc.
Chem. Res., 2010, 43, 1005; For selected references of chiral
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L.-H. Chen, Chem. Commun., 2003, 1310; (c) M. Shi, L.-H. Chen
and C.-Q. Li, J. Am. Chem. Soc., 2005, 127, 3790; (d) K. Matsui,
S. Takizawa and H. Sasai, Synlett, 2006, 761; (e) B. J. Cowen and
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Chem., 2011, 9, 3349; (h) H.-P. Deng, Y. Wei and M. Shi, Eur. J.
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12 R. Zhou, C. Wang, H. Song and Z. He, Org. Lett., 2010, 12, 976.
c
8666 Chem. Commun., 2012, 48, 8664–8666
This journal is The Royal Society of Chemistry 2012