Chemoselective phosphine-catalyzed cascade annulations between two different activated alkenes: Highly diastereoselective syntheses of polysubstituted cyclohexanes and cyclopentenes

Article abstract of DOI:10.1039/c0cc02817g

Chemoselective phosphine-catalyzed cascade [2 + 2 + 2] and [2 + 2 + 1] annulations between two molecules of 2-arylmethylidene cyanoacetates or malononitriles and one molecule of α,β-unsaturated ketones have been developed. Under the nucleophilic catalysis

Full text of DOI:10.1039/c0cc02817g

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Chemoselective phosphine-catalyzed cascade annulations between
two different activated alkenes: highly diastereoselective syntheses
of polysubstituted cyclohexanes and cyclopentenesw
Lingchao Cai, Bo Zhang, Guiping Wu, Haibin Song and Zhengjie He*
Received 26th July 2010, Accepted 15th October 2010
DOI: 10.1039/c0cc02817g
Chemoselective phosphine-catalyzed cascade [2 + 2 + 2] and [2
+ 2 + 1] annulations between two molecules of 2-arylmethylidene
cyanoacetates or malononitriles and one molecule of a,
b-unsaturated ketones have been developed. Under the
nucleophilic catalysis of PPh3 or PBu3 (10 mol%), a highly
diastereoselective synthesis of polysubstituted cyclohexanes or
cyclopentenes has been successfully achieved, respectively.
hetero-coupling, as seen in the intermolecular Rauhut–Currier
reaction.7 Encouragingly, significant progress has been recently
made in this area by Shi and other groups.8
Most recently, we reported a highly diastereoselective
tertiary amine-catalyzed cascade Michael–Michael–Henry
reaction between nitromethane, doubly activated alkenes and
a,b-unsaturated carbonyl compounds, giving densely
functionalized cyclohexanes and some bicyclic compounds.8g
Further investigations gratifyingly unveiled that, under
the catalysis of tertiary phosphines, multi-component cascade
[2 + 2 + 2] and [2 + 2 + 1] annulations could be
chemoselectively realized between two molecules of
2-arylmethylidene cyanoacetate or malononitrile and one
molecule of a,b-unsaturated ketones. These annulations
represent two novel organocatalytic multi-component
cascade reactions,9 and also provide efficient syntheses of
polysubstituted cyclohexanes and cyclopentenes (vide infra).
Optimization of the reaction conditions was initially
conducted using the reaction of 2-phenylmethylidene
cyanoacetate (1a, 1.0 mmol) with methyl vinyl ketone (2a,
0.75 mmol) as the model (Table 1). Under the catalysis of PPh3
(0.1 mmol, 10 mol% referred to 1a), the cascade [2 + 2 + 2]
annulation product 3a from two molecules of 1a and one
molecule of 2a was exclusively produced in modest to good
yields with the best yield (84%) given in 1,4-dioxane (Table 1,
entries 1–4). Other electron-deficient triarylphosphines also
solely mediated the formation of 3a in moderate yields
(entries 5 and 6). In sharp contrast with the results obtained
with the catalyst triarylphosphine, relatively electron-rich
PPh2Me (10 mol%) could catalyze both [2 + 2 + 2] and
[2 + 2 + 1] annulations between 1a and 2a, giving the
corresponding cyclohexane 3a and cyclopentene 4a in 34%
and 45% yields, respectively (entry 7). Compared with PPh3,
much electron-richer PBu3 (10 mol%), however, mediated the
exclusive formation of the [2 + 2 + 1] annulation product 4a
in 50% yield after short time (10 min) (entry 8). Lowering the
catalyst loading of PBu3 or running the PBu3-mediated
reaction in other solvents (THF, toluene, CH2Cl2) all
resulted in inferior yields of 4a (entries 9–12). In the PBu3-
catalyzed reactions, the formation of oligomers from the
activated alkenes was observed in substantial amounts.
Addition of hydroquinone (0.5 mmol, 50 mol% referred to
1a) as an inhibitor for polymerization brought about a
dramatic increase in the yield of 4a (Table 1, entry 13).
Lowering the amount of hydroquinone to 25 mol% led to an
obvious decrease of the yield of 4a (entry 14). Amine Lewis
bases such as DABCO, Et3N, and imidazole proved ineffective
in either [2 + 2 + 2] or [2 + 2 + 1] annulation of 1a and 2a
During the past decade, nucleophilic phosphine organocata-
lysis has attracted much research interest.1 As a result, a
number of highly efficient synthetic reactions, particularly
including many new annulations to form carbocycles and
heterocycles, have been developed.2,3 As a class of popular
nucleophilic organocatalysts, the superior activity of tertiary
phosphines may be primarily attributable to their excellent
nucleophilicity as a nucleophile trigger and decent cleaving
ability as a leaving group in the catalytic process. The electro-
nic and steric properties of phosphines can not only exert
significant influence on the catalytic efficiency as usual, but also
in some cases on the reaction chemoselectivity as well. For
example, Kwon et al.4 reported that the use of small-size
phosphine catalyst PMe3 led to the formation of dioxane
products, while bulky phosphines like PCyp3 (Cyp = cyclo-
pentyl) produced pyrones exclusively in the phosphine-
catalyzed reactions of 2,3-butadienoates with aldehydes.5 Also
by the same research group, a complete reversal of regioselec-
tivity was realized by employing electron-rich P(NMe2)3
instead of P(4-FC6H4)3 in the phosphine-catalyzed [4 + 2]
annulation between a-substituted allenoates and activated
alkenes.6 As a new example of phosphine-induced chemoselec-
tivity, herein we wish to report phosphine-catalyzed cascade
[2 + 2 + 2] and [2 + 2 + 1] annulations between two different
activated alkenes, which could be chemoselectively achieved by
choosing appropriate phosphines.
The Lewis base-catalyzed cross-coupling between different
activated alkenes provides a straightforward and efficient
protocol to construct densely functionalized building blocks.
However, this type of coupling remains challenging due to the
inherent preference of the homo-coupling over the desired
The State Key Laboratory of Elemento-Organic Chemistry and
Department of Chemistry, Nankai University, 94 Weijin Road,
Tianjin 300071, China. E-mail: zhengjiehe@nankai.edu.cn;
Tel: +86 22-23501520
w Electronic supplementary information (ESI) available: Experimental
details, spectroscopic and analytical data and 1H, 13C NMR spectra for
3 and 4, ORTEP drawings for 3a and 4a. CCDC 782770 (3a) and
782771 (4a). For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c0cc02817g
c
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Chem. Commun., 2011, 47, 1045–1047 1045

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Table 1 Optimization of reaction conditions on the model reactiona
Table 2 PPh3-catalyzed [2 + 2 + 2] annulations of 1 and 2aa
Entry Solvent
Catalyst
Time
3ab,c (%) 4ab,c (%)
Entry
R1
Ar in 1
Yield of 3b (%)
1
2
3
4
5
6
7
8
THF
Toluene
CH2Cl2
1,4-Dioxane PPh3
1,4-Dioxane P(4-ClC6H4)3
PPh3
PPh3
PPh3
24 h
24 h
24 h
24 h
24 h
43
73
72
84
67
59
0
0
0
0
0
0
45
50
30
33
41
31
95
66
0
1
2
3
4
5
6
7
8
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CN
Ph (1a)
3a, 84
3b, 78
3c, 84
3d, 95
3e, 71
3f, 88
3g, 91
3h, 93
3i, 80
3j, 85
3k, 38
p-CH3C6H4 (1b)
m-CH3C6H4 (1c)
m-FC6H4 (1d)
p-ClC6H4 (1e)
p-BrC6H4 (1f)
p-CF3C6H4 (1g)
m-CF3C6H4 (1h)
2-Furyl (1i)
1,4-Dioxane P(4-CF3C6H4)3 24 h
1,4-Dioxane PPh2Me
1,4-Dioxane PBu3
1,4-Dioxane PBu3 (5 mol%) 20 min
THF
Toluene
CH2Cl2
1,4-Dioxane PBu3
1,4-Dioxane PBu3
1,4-Dioxane DABCO
1,4-Dioxane Et3N
1,4-Dioxane Imidazole
30 min 34
10 min
0
0
0
0
0
0
0
0
0
0
9
9
10
11
10
11
12
13d
14e
15
16
17
PBu3
PBu3
PBu3
15 min
15 min
15 min
15 min
30 min
24 h
2-Thienyl (lj)
Ph (1k)
a
Typical procedure: under N2 atmosphere, to a stirred solution of
the activated alkenes 1 (1.0 mmol) and 2a (0.75 mmol) in 1,4-dioxane
(3.0 mL) was added PPh3 (0.1 mmol). The resulting mixture was stirred
b
at rt for 24 h. Isolated yield as a single diastereomer based on 1.
24 h
24 h
0
0
a
Reactions were performed on a 1.0 mmol scale of 1a using 1.5 equiv. of
2a and 10 mol% catalyst in 3 mL solvent under other specified
Table 3 PBu3-catalyzed [2 + 2 + 1] annulations of 1 and 2a
b
conditions. Only one diastereomer obtained. Isolated yield based on 1a.
d
c
e
Additive hydroquinone (0.5 mmol) was added. Hydroquinone
(0.25 mmol) added.
(Table 1, entries 15–17), although imidazole was reported to be
an effective catalyst for the [2 + 2 + 2] annulation between
2-arylmethylidene malononitriles and nitro alkenes.8e The
structures of the annulation products 3a and 4a were
confirmed by HRMS-ESI, 1H and 13C NMR, and X-ray
crystallographic analyses.w
Entry R1
Ar in 1
R2 in 2 t/min Yield of 4b (%)
1
2
3
CO2Me Ph (1a)
CO2Me p-CH3C6H4 (1b)
CO2Me m-CH3C6H4 (1c)
Me (2a) 15 4a, 95
Me (2a) 10 4b, 96
Me (2a) 15 4c, 92
Under the optimized conditions, the scope of the PPh3-
catalyzed cascade [2 + 2 + 2] annulation was briefly
evaluated by varying the structure of doubly activated
4
5
CO2Me p-CH3OC6H4 (1l) Me (2a) 15 4d, 72
CO2Me m-CH3OC6H4 (1m) Me (2a) 15 4e, 90
6
7
8
9
CO2Me m-FC6H4 (1d)
CO2Me p-ClC6H4 (1e)
CO2Me m-CF3C6H4 (1h)
CO2Me 2-Furyl (1i)
Me (2a) 30 4f, 78
Me (2a) 15 4g, 89
Me (2a) 30 4h, 59
Me (2a) 20 4i, 90
Me (2a) 15 4j, 99
Me (2a) 30 4k, 51
Me (2a) 15 4l, 90
Me (2a) 15 4m, 96
Ph (2b) 60 4n, 52
alkenes 1. For 2-arylmethylidene cyanoacetate 1 (R1
=
CO2Me), when aryl in 1 was phenyl or substituted phenyl
bearing either electron-donating or -withdrawing group, its
PPh3-catalyzed annulation with methyl vinyl ketone (2a)
readily furnished the corresponding polysubstituted
cyclohexanes 3a–h in good to excellent yield (Table 2, entries
1–8). Heteroaryl substituted 1i and 1j were also effective, giving
the annulation products 3i and 3j in good yields (entries 9
and 10). However, for 2-phenylmethylidene malononitrile 1k
(R1 = CN, Ar = Ph), its annulation product 3k was only
obtained in 38% yield (Table 1, entry 11). In all cases of the
[2 + 2 + 2] annulation listed in Table 2, the cyclohexanes 3
were isolated as a single diastereomer. Obviously, the PPh3-
10
11
12
13
14
15
CO2Me 2-Thienyl (1j)
CN
CN
CN
m-FC6H4 (1n)
2-Furyl (1o)
2-Thienyl (1p)
CO2Me Ph (1a)
CO2Me m-CH3OC6H4 (1m) Ph (2b) 120 4o, 86
a
Typical procedure: under N2 atmosphere, to a stirred solution of
the activated alkenes 1 (1.0 mmol), 2 (0.75 mmol), and hydroquinone
(0.5 mmol) in 1,4-dioxane (3.0 mL) was slowly added PBu3 (23 mL,
0.1 mmol) by means of microsyringe. The resulting mixture was stirred
b
at rt for specified time. Isolated yield as a single diastereomer based on
1.
catalyzed cascade [2
+
2
+
2] annulation between
annulations with methyl vinyl ketone (2a) quickly completed
within 30 min, affording the corresponding cyclopentenes
4a–m in modest to excellent yields (Table 3, entries 1–13).
Phenyl vinyl ketone (2b) was also effective in the [2 + 2 + 1]
annulation with aryl-substituted 2-methylidene cyanoacetates
(1a, 1m) to form the expected cyclopentenes (4n, 4o) in good
yields, although elongated reaction times were required (entries 14
and 15). In all of the tested cases listed in Table 3, the PBu3-
catalyzed [2 + 2 + 1] annulation proved to be highly
2-arylmethylidene cyanoacetate or malononitrile
1 and
methyl vinyl ketone 2a is highly diastereoselective.
Following the optimized conditions for the PBu3-catalyzed
annulation between 1a and 2a (Table 1), the substrate scopes
of the PBu3-catalyzed [2 + 2 + 1] annulation of doubly
activated alkenes 1 and a,b-unsaturated ketones 2 were also
explored (Table 3). For various aryl-substituted 2-methylidene
cyanoacetates and malononitriles, their PBu3-catalyzed [2 + 2 + 1]
c
1046 Chem. Commun., 2011, 47, 1045–1047
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In summary, two novel phosphine-catalyzed cascade [2 + 2 + 2]
and [2 + 2 + 1] annulations between 2-arylmethylidene
cyanoacetates or malononitriles and a,b-unsaturated ketones
have been successfully developed by choosing appropriate
phosphines with different leaving group abilities. These
annulations provide highly efficient and diastereoselective
syntheses for polysubstituted cyclohexanes
3
and
cyclopentenes 4 respectively. Future efforts in our laboratory
will be directed toward further expanding their scopes and
developing the asymmetric versions of these two annulations.
Financial support from National Natural Science
Foundation of China (Grant nos. 20872063; 21072100) is
gratefully acknowledged.
Notes and references
1 For leading reviews on nucleophilic phosphine organocatalysis, see:
(a) X. Lu, C. Zhang and Z. Xu, Acc. Chem. Res., 2001, 34, 535;
(b) J. L. Methot and W. R. Roush, Adv. Synth. Catal., 2004, 346,
1035; (c) A. Marinetti and A. Voituriez, Synlett, 2010, 174.
2 For important reviews, see: (a) L.-W. Ye, J. Zhou and Y. Tang,
Chem. Soc. Rev., 2008, 37, 1140; (b) B. J. Cowen and S. J. Miller,
Chem. Soc. Rev., 2009, 38, 3102.
Scheme
1
A plausible mechanism to account for the cascade
annulations.
diastereoselective, giving the annulation product 4 as a single
diastereomer.
3 For most recent examples, see: (a) Z. Lu, S. Zheng, X. Zhang and
X. Lu, Org. Lett., 2008, 10, 3267; (b) M. Schuler, D. Duvvuru,
P. Retailleau, J.-F. Betzer and A. Marinetti, Org. Lett., 2009, 11,
4406; (c) N. Pinto, N. Fleury-Bregeot and A. Marinetti, Eur. J. Org.
Chem., 2009, 146; (d) S. Zheng and X. Lu, Org. Lett., 2009, 11,
3978; (e) Y. Liang, S. Liu and Z.-X. Yu, Synlett, 2009, 905;
(f) X. Meng, Y. Huang and R. Chen, Org. Lett., 2009, 11, 137;
(g) S. Xu, L. Zhou, R. Ma, H. Song and Z. He, Chem.–Eur. J.,
2009, 15, 8698; (h) H. Liu, Q. Zhang, L. Wang and X. Tong, Chem.
Commun., 2010, 46, 312; (i) Q. Zhang, L. Yang and X. Tong, J. Am.
Chem. Soc., 2010, 132, 2550; (j) H. Xiao, Z. Chai, C.-W. Zheng,
Y.-Q. Yang, W. Liu, J.-K. Zhang and G. Zhao, Angew. Chem., Int.
Ed., 2010, 49, 4467.
4 X.-F. Zhu, C. E. Henry, J. Wang, T. Dudding and O. Kwon, Org.
Lett., 2005, 7, 1387.
5 X.-F. Zhu, A.-P. Schaffner, R. C. Li and O. Kwon, Org. Lett.,
2005, 7, 2977.
6 Y. S. Tran and O. Kwon, J. Am. Chem. Soc., 2007, 129, 12632.
7 J. D. McClure, J. Org. Chem., 1970, 35, 3045.
8 (a) X. Sun, S. Sengupta, J. L. Petersen, H. Wang, J. P. Lewis and
X. Shi, Org. Lett., 2007, 9, 4495; (b) Y. Chen, C. Zhong,
J. L. Petersen, N. G. Akhmedov and X. Shi, Org. Lett., 2009, 11,
2333; (c) Y. Chen, C. Zhong, X. Sun, N. G. Akhmedov,
J. L. Petersen and X. Shi, Chem. Commun., 2009, 5150;
(d) C. Zhong, Y. Chen, J. L. Petersen, N. G. Akhmedov and
X. Shi, Angew. Chem., Int. Ed., 2009, 48, 1279; (e) X.-G. Liu and
M. Shi, Eur. J. Org. Chem., 2008, 6168; (f) V. Nair, B. P. Babu,
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Lett., 2009, 11, 2507; (g) B. Zhang, L. Cai, H. Song, Z. Wang and
Z. He, Adv. Synth. Catal., 2010, 352, 97.
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(a) D. Enders, C. Grondal and M. R. M. Huttl, Angew. Chem.,
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A plausible mechanism is depicted in Scheme 1 to account for
the chemoselective occurrence of the phosphine-catalyzed
cascade [2 + 2 + 2] and [2 + 2 + 1] annulations between
two different activated alkenes 1 and 2 although a precise
mechanism remains unclear. The catalytic process is
presumably initiated with the nucleophilic attack of the
catalyst PR3 at the a,b-unsaturated ketone 2 to produce a
zwitterionic phosphonium enolate intermediate 5, which
subsequently undergoes a Michael addition with the doubly
activated alkene 1 to form the intermediate 6. Another Michael
addition of 6 to the alkene 1 furnishes the double Michael
adduct intermediate 7. When the catalyst PR3 is the relatively
electron-poor triphenylphosphine (R = Ph), the intermediate 7
is prone to a ring-closure via an intramolecular SN2 replacement
between 1- and 6-carbons, leading to the formation of the
[2 + 2 + 2] annulation product cyclohexane 3 and the
regeneration of the catalyst phosphine. It is believed that the
stereochemistry outcome in 3 is governed by a preferred
six-membered chair-like conformation of the transition state 8.
In another scenario, when PR3 is the electron-rich
tributylphosphine (R
=
n-Bu), the intermediate
7
consequently tends to undertake a proton transfer between 1-
and 6-carbons giving the intermediate 9, rather than an SN2
replacement due to the inferior leaving group ability of PBu3.10
Subsequently, an intramolecular SN2 replacement between
1- and 5-carbons in 9 results in the formation of the
cyclopentane intermediate 11 and the release of the stabilized
carbanion 10. Under the influence of the generated carbanion 10
as a base, 11 undergoes an E2 elimination involving Ha and PR3
moiety, leading to the regiospecific formation of the [2 + 2 + 1]
annulation product cyclopentene 4 and the release of the
phosphine catalyst (Scheme 1).
10 It is believed that electron-rich PBu3 has an inferior leaving group
ability to that of electron-poor PPh3, although a comprehensive
search using SciFinder revealed that no previous evaluation on the
leaving group ability of tertiary phosphines was reported in the
literature.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 1045–1047 1047