Phosphine-catalyzed [3+3] annulation reaction of modified tert-butyl allylic carbonates and substituted alkylidenemalononitriles

Article abstract of DOI:10.1016/j.tetlet.2009.05.085

A phosphine-catalyzed [3+3] annulation reaction of modified tert-butyl allylic carbonates with various alkylidenemalononitriles to form cyclohexenes was developed. The use of protic solvent is crucial in this reaction. When non-polar solvent, toluene or x

Full text of DOI:10.1016/j.tetlet.2009.05.085

Tetrahedron Letters 50 (2009) 4532–4535
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Phosphine-catalyzed [3+3] annulation reaction of modified tert-butyl allylic
carbonates and substituted alkylidenemalononitriles
*
Suqing Zheng, Xiyan Lu
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A phosphine-catalyzed [3+3] annulation reaction of modified tert-butyl allylic carbonates with various
alkylidenemalononitriles to form cyclohexenes was developed. The use of protic solvent is crucial in this
reaction. When non-polar solvent, toluene or xylene, was used, only non-cyclized product was obtained.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 15 April 2009
Revised 18 May 2009
Accepted 22 May 2009
Available online 27 May 2009
Keywords:
Phosphine
Cyclopentenes
[3+3] Annulation
tert-Butyl allylic carbonates
Alkylidenemalononitriles
Recently, reports of phosphines as nucleophilic catalysts have
grown significantly.1,2 For example, phosphine-catalyzed reaction
of allenoates and butynoates has proven to be efficient for the
synthesis of polyfunctionalized structures,2 especially the cyclo-
pentene derivatives. Recently we reported an unexpected phos-
phine-catalyzed [3+2] reaction of allenoates with substituted
alkylidenemalononitriles in which the allenoates acted as the
two-carbon unit in the formed cyclopentenes instead of the
three-carbon unit in general.2q This is due to the acidity of the
hydrogen atom of the substituted methyl group in alkylidenemal-
ononitriles (Scheme 1).
fied allylic compounds with 3-substituted 1,1-dicyanoalkenes via a
catalytic carbon–phosphorus ylide reaction to form substituted
cyclohexenes.
In our initial study, we examined the reaction of the tert-butyl
allylic carbonate (1a) and 2-(10-phenylethylidene)malononitrile
(2a) with PPh3 (10 mol %) in toluene under reflux. Unfortunately,
a non-cyclized product 3aa was obtained (Scheme 2). From the
structure of 3aa, it is clear that the basicity of the phosphine was
insufficient to promote the intramolecular conjugate addition to
complete the cyclization. Then the reaction was carried out in dif-
ferent solvents. In non-polar solvents, for example, toluene and
On the other hand, we also developed the phosphine-catalyzed
[3+2] and [3+6] annulation reactions of carbon-phosphorus ylides
with electron-deficient olefins3 and imines.4 In these reactions,
simple allylic compounds, which can be easily obtained by one-
step transformation of the product of Morita–Baylis–Hillman reac-
tion, can be used as three-carbon unit instead of the complex
alkynoates or allenoates.3–5 On detailed study, we found that the
reaction of allylic compounds has some different results as com-
pared with the allenoates,3,4 which stimulated us to study the reac-
tion of the modified tert-butyl allylic carbonates and substituted
alkylidenemalononitriles.
CN
CN
CO2Et
PPh3
CO2Et
CN
+
CN
Scheme 1. Phosphine-catalyzed [3+2] reaction of allenoates and substituted
alkylidenemalononitriles.
NC
Ph
CN
Compared with [3+2] and [4+2] annulation reactions, relatively
little was known about the [3+3] cycloaddition.6 No [3+3] annula-
tion in phosphine-catalyzed reaction was reported.7 Herein, we
wish to report our recent results on the [3+3] annulation of modi-
OBoc
PPh3 (10 mol%)
CN
NC
Ph
CO2Et
+
Ph
toluene, reflux
95%
CO2Et
Ph
1a
2a
3aa
* Corresponding author. Tel.: +86 21 54925158; fax: +86 21 64166128.
E-mail address: xylu@mail.sioc.ac.cn (X. Lu).
Scheme 2.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.085

S. Zheng, X. Lu / Tetrahedron Letters 50 (2009) 4532–4535
4533
Table 1
Table 3
Effect of solvents on the formation of 3aa and 4aa from phosphine-catalyzed reaction
Reaction of 2a and 1 with different substituentsa
of 1a and 2aa
NC CN
OBoc
NC
Ph
CN
PPh3 (20 mol %)
Ph
NC
Ph
CN
CO2R1
NC CN
PPh3
+
R
Ph
+
CO2Et
OBoc
i-PrOH
reflux
NC
Ph
CN (10 mol %)
CO2R1
CO2Et
+
Ph
R
1a-1k: R1 = Et
solvent
CO2Et
2a
Ph
4aa-4la
1l: R1 = t-Bu
Ph
1a
2a
3aa
4aa
Entry
R
Product
Yieldb (%)
trans:cisc
Entry
Solvent
Temp.
3aab (%)
4aab (%) (trans:cis)c
1
2
3
4
Ph
p-MeC6H4
p-MeOC6H4
p-ClC6H4
4aa
4ba
4ca
4da
89
88
84
91
5.1:1
3.9:1
4:1
1
2
3
4
5
6
7
8
9
Toluene
Xylene
ClCH2CH2Cl
Dioxane
CH3CN
EtOH
i-PrOH
t-BuOH
PEG (200–300)
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
90 °C
95
79
42
51
48
17
16
39
—
Trace
Trace
52 (2.7:1)
28 (1.6:1)
42 (3.4:1)
44 (5.2:1)
75 (4.8:1)
56 (5:1)
45 (4.8:1)
5.5:1
Cl
Cl
5
4ea
70
5.8:1
6
7
p-NO2C6H4
4fa
74
61
>10:1
4:1
a
Reaction conditions: Under Ar, a mixture of 1a (73 mg, 0.24 mmol), 2a (33.6 mg,
0.2 mmol), and PPh3 (5.3 mg, 0.02 mmol) in solvents (2 mL) was stirred at the
temperature indicated.
O
4ga
b
Isolated yields.
c
Diastereoisomeric ratio was determined by 1H NMR.
8
9
10
11
12
CH3
n-Pr
i-Pr
i-Bu
4ha
4ia
4ja
4ka
4la
87
84
37
54
87
>10:1
>10:1
>10:1
>10:1
5:1
Ph
xylene, 3aa was the only product (Table 1, entries 1 and 2). In polar
solvents, both products 3aa and 4aa were obtained (Table 1,
entries 3–9). Encouragingly, the [3+3] addition product 4aa was
obtained as mixture of a 4.8:1 (trans:cis) stereoisomers in 75%
yield with 16% of product 3aa when 2-propanol was used as sol-
vent (Table 1, entry 7).8 The assignment of the trans stereochemis-
try of the major isomer 4aa was confirmed by 1H NMR spectra and
X-ray crystallography.9 On further reaction of 3aa and PPh3 in 2-
propanol, 4aa could also be produced. Thus, 2-propanol was se-
lected as the optimal solvent in this reaction. The use of 2-propanol
as solvent to promote the intramolecular conjugate addition in
phosphine-catalyzed reaction has been reported recently.10
Many phosphines could be used as catalyst in this reaction
(Table 2). Using 20 mol % of triphenylphosphine provided optimal
reactivity, giving the cyclization product 4aa as 5:1 mixture of dia-
stereoisomers in 89% yield (Table 2, entry 2). No product was
obtained when the strong nucleophilic phosphine PBu3 was used
(Table 2, entry 5).
(R1 = t-Bu)
a
Reaction conditions: Under Ar, a mixture of 1a (73 mg, 0.24 mmol), 2a (33.6 mg,
0.2 mmol), and PPh3 (11.6 mg, 0.04 mmol) in 2-propanol (2 mL) was stirred at
reflux.
b
Isolated yields.
Diastereoisomeric ratio was determined by 1H NMR.
c
the aryl substituted substrates with both electron-donating and
electron-withdrawing groups. When the aryl group was changed
to alkyl, the yield was high (Table 3, entries 8 and 9) and the dia-
stereoselectivities were improved (Table 3, entries 8–11). The
yields were decreased as the substituents became bulky (Table 3,
entries 10 and 11). When a bulky t-butyl ester was used, similar
yield was obtained (Table 3, entry 12).
To further establish the scope of the reaction, the reaction of
substrates 2 with different substitutes in aryl group with 1h was
also tried. Electronic effect was found to be very important. The
compounds with electron-withdrawing group gave better yields
Under these optimized conditions, the scope of the phosphine-
catalyzed [3+3] cycloaddition was studied (Table 3). The reaction
was general and was found to occur with 2a and different substi-
tuted tert-butyl allylic carbonates. Good yields were obtained for
Table 4
Reaction of 1h and 2 with different substituentsa
NC CN
Table 2
R2
OBoc
Formation of 4aa from 1a and 2a using different catalystsa
NC
CN
PPh3 (20 mol %)
CO2Et
+
i-PrOH
reflux
NC CN
R2
2b-f
CO2Et
Ph
OBoc
NC
Ph
CN
catalyst
1h
CO2Et
4hb-hf
+
Ph
i-PrOH
CO2Et
reflux
Ph
4aa
Entry
R2
Product
Yieldb (%)
trans:cisc
1d
2e
3
4
5
p-MeC6H4
p-MeOC6H4
p-BrC6H4
p-NO2C6H4
t-Bu
4hb
4hc
4hd
4he
4hf
59
58
100
67
>10:1
>10:1
>10:1
>10:1
>10:1
1a
2a
Entry
Catalyst
Yieldb (%)
trans:cisc
1
2
3
4
5
PPh3 (10 mol %)
PPh3 (20 mol %)
PPh2Et (20 mol %)
PPhEt2 (20 mol %)
PBu3 (20 mol %)
75
89
76
76
—
4.8:1
5.2:1
5.9:1
4.5:1
—
75
a
Reaction conditions: Under Ar, a mixture of 1a (73 mg, 0.24 mmol), 2a (33.6 mg,
0.2 mmol), and PPh3 (11.6 mg, 0.04 mmol) in 2-propanol (2 mL) was stirred in
reflux.
b
a
Isolated yields.
Reaction conditions: Under Ar, a mixture of 1a (73 mg, 0.24 mmol), 2a (33.6 mg,
Diastereoisomeric ratio was determined by 1H NMR.
c
0.2 mmol), and catalyst in 2-propanol (2 mL) was stirred at reflux.
d
b
Non-cyclized product 3hb was isolated in 29% yield.
Non-cyclized product 3hc was isolated in 25% yield.
Isolated yields.
e
c
Diastereoisomeric ratio was determined by 1H NMR.

4534
S. Zheng, X. Lu / Tetrahedron Letters 50 (2009) 4532–4535
that a high yield of 4ah occurred when a carboxylate group was
introduced into the ethyl group (substrate 2h) (Scheme 3).
The possible mechanism of this [3+3] cyclization reaction was
shown in Scheme 4. As elucidated in our previous paper, the phos-
phonium salt A was formed from PPh3 and the allylic substrate
first.5,6 The methyl group of 2 was believed to be deprotonated
by the tert-butoxy anion generated in situ because of its acidic
property. The formed carbanion could attack the intermediate A
and PPh3 was eliminated giving the non-cyclized product 3aa.
Conjugate addition of the phosphine to 3aa generated a phospho-
nium-substituted carbanion B. This carbanion may serve as the
base for the intramolecular conjugate addition.11 The intermediate
B is possible to attract the proton from 3aa to form C making the
intramolecular cyclization possible. In the presence of 2-propanol,
protonation of B may occur easily to form the alkoxide ion which
can serve as the base in the intramolecular cyclization of 3aa to
improve the reaction yield.10
NC
Ph
CN
OBoc
NC
Ph
CN
PPh3 (20 mol %)
CO2Et
+
Ph
i-PrOH
CO2Et
reflux
Ph
3ag
1a
89 %
2g
NC CN
Ph
i-PrO2C
OBoc
NC
CN
PPh3 (20 mol %)
CO2Et
+
i-PrOH
88 %
Ph
CO2i-Pr
CO2Et
Ph
Ph
1a
2h
4ah (trans:cis=5.5:1)
Scheme 3.
(Table 4, entries 3 and 4). For the compounds with electron-donat-
ing group, the non-cyclized products 3 could also be obtained
(Table 4, entries 1 and 2). When the aryl group was changed to
tert-butyl group, the reaction can still occur with similar yield.
When the methyl group of substrate 2 was changed to ethyl (sub-
strate 2g), the cyclization could not proceed and only non-cyclized
product 3ag was obtained (Scheme 3), which might be due to the
lower acidity of the ethyl group. This can be supported by the fact
In conclusion, we developed a novel phosphine-catalyzed [3+3]
annulation reaction of modified allylic tert-butyl carbonates
and substituted alkylidenemalononitriles yielding functionalized
cyclohexene derivatives in moderate to excellent yield with mod-
erate to good diastereoselectivity. The use of protic solvent is cru-
cial in this reaction. Detailed study of the mechanism is underway.
OBoc
NC
Ph
CN
CO2Et
Ph
PPh3
1a
CO2Et
NC
Ph
3aa
CN
Ph
CO2Et
Ph
A
CO2Et
PPh3
Ph
t-BuO
A
PPh3
NC
CN
Ph
H
t-BuOH
2a
CN
NC
NC
Ph
CN
NC
Ph
CN
PPh3
CO2Et
i-PrOH
+
i-PrO
Ph
CO2Et
CO2Et
Ph
Ph
Ph
B
PPh3
3aa
PPh3
3aa
CN
CN
CN
NC
Ph
CN
NC
Ph
CN
H
NC
Ph
Ph
i-PrO
H
CO2Et
CO2Et
i-PrOH
CO2Et
CO2Et
Ph
Ph
i-PrOH
Ph
3aa
Ph
C
NC CN
Ph
NC CN
Ph
Ph
CO2Et
CO2Et
i-PrO
Ph
4aa
Scheme 4. Possible mechanism of the [3+3] annulation reaction.

S. Zheng, X. Lu / Tetrahedron Letters 50 (2009) 4532–4535
4. Zheng, S.; Lu, X. Org. Lett. 2008, 10, 4481.
4535
Acknowledgments
5. Reports on tertiary amines or phosphines-catalyzed reactions of allylic
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We thank the National Natural Science Foundation of China
(20572121) and Chinese Academy of Sciences for financial support.
Supplementary data
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Supplementary data (Experimental procedure, characterization
data, and copies of 1H and 13C NMR spectra for new compounds)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2009.05.085.
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8. Control experiment showed that no transesterificaton was found between 1
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9. The structure of the product 4aa was confirmed by X-ray crystallography.
Deposit number of compound 4aa from Crystallographic Data Centre: CCDC
234945. Copies of the data can be obtained free of charge on application to
CCDC, 12, Union Road, Cambridge CB21EZ, UK; fax: +44-1223-336-033; e-mail:
deposit@ccdc.cam.ac.uk.
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