Phosphine-catalyzed [3 + 2] and [3 + 3] annulations of azomethine imines with ethyl 2-butynoate

Article abstract of DOI:10.1246/cl.2012.218

The phosphine-catalyzed [3 + 2] and [3 + 3] annulation reactions of azomethine imines and ethyl 2-butynoate were developed, providing 1,2-dinitrogen-containing heterocycles tetrahydropyrazolopyrazolones and tetrahydropyrazolopyridazinones in moderate to good yields.

Full text of DOI:10.1246/cl.2012.218

doi:10.1246/cl.2012.218
218
Published on the web February 18, 2012
Phosphine-catalyzed [3 + 2] and [3 + 3] Annulations of Azomethine Imines
with Ethyl 2-Butynoate
Jun Liu,1,2 Honglei Liu,1 Risong Na,1 Guiyong Wang,1 Zhen Li,1 Hao Yu,1
Min Wang,1 Jiangchun Zhong,*1 and Hongchao Guo*1
1Department of Applied Chemistry, China Agricultural University,
2 West Yuanmingyuan Road, Beijing 100193, P. R. China
2Chemical Industry Press, 13 Qingnianhu South St., Beijing 100011, P. R. China
(Received November 8, 2011; CL-111089; E-mail: hchguo@cau.edu.cn)
The phosphine-catalyzed [3 + 2] and [3 + 3] annulation
O
O
reactions of azomethine imines and ethyl 2-butynoate were
developed, providing 1,2-dinitrogen-containing heterocycles
tetrahydropyrazolopyrazolones and tetrahydropyrazolopyridazi-
nones in moderate to good yields.
O
N
PBu3 (20 mol%)
CH2Cl2, rt
N
+
N
+
N N
N
CO2Et
CO2Et
2
R
R
R
1
CO2Et
4
3
Over the last twenty years, nucleophilic phosphine catalysis
has been successfully developed as one of the most powerful
tools for convergent synthesis of a broad range of carbo- and
heterocycles from simple starting materials.1 Under the nucleo-
philic phosphine catalysis conditions, activated allenes have
often been used as versatile synthons and exhibited diverse
reactivity toward a variety of electrophilic partners including
aldehydes, activated alkenes, imines, or aziridines, furnishing
all kinds of formal cycloaddition reactions.1 Most recently, we
reported the first phosphine-catalyzed [3 + 2], [3 + 3], [4 + 3],
and [3 + 2 + 3] annulation reactions of allenoates with azo-
methine imines, providing generally applicable routes toward
dinitrogen-fused heterocycles, such as tetrahydropyrazolo-pyr-
azolone, -pyridazinone, -diazepinone, and -diazocinone,2 which
are key units in or building blocks of many pharmaceuticals,
agrochemicals, biologically active compounds, and other useful
chemicals.3 Using phosphine as the catalyst, ethyl 2,3-butadi-
enoate, served as a two- or three-carbon component to undergo
the [3 + 2] or [3 + 3] annulation reactions with azomethine
imine (1-(p-nitrobenzylidene)-3-oxopyrazolidin-1-ium-2-ide),
giving tetrahydropyrazolo-pyrazolone and -pyridazinone.2 It is
known that ethyl 2-butynoate could undergo the same annulation
processes as ethyl 2,3-butadienoate under the phosphine
catalysis conditions.4 As ethyl 2-butynoate is commercially
available and very cheap, and tetrahydropyrazolo-pyrazolone
and -pyridazinone are important biologically active com-
pounds,3 we attempted to investigating the cycloaddition
reaction of various azomethine imines with ethyl 2-butynoate.
Herein, we described the [3 + 2] and [3 + 3] cycloaddition of
azomethine imines with ethyl 2-butynoate to furnish function-
alized 1,2-dinitrogen-fused heterocycles (Scheme 1).
Scheme 1. The [3 + 2] and [3 + 3] annulation of azomethine
imine 1 with ethyl 2-butynoate (2).
Table 1. Phosphine-catalyzed annulations of the azomethine
imine 1a with ethyl 2-butynoate (2)a
O
O
O
N
N N
PR3 (20 mol%)
CH2Cl2, rt
N
+
N
+
N
CO2Et
R
CO2Et
R
R = 4-NO2C6H4
R
CO2Et
4a
1a
2
3a
3a yield
/%b
4a yield
/%b
Entry
PR3
Time/h
1
2
3
4
5
PBu3
PMe3
MePPh2
Me2PPh
HMPT
12
24
72
24
24
49
34
30
65
®
b
34
6
3
14
Trace
a1.2 equiv of ethyl 2-butynoate was used. Isolated yield.
a single (E)-isomer and the tetrahydropyrazolopyridazinone
4a as a single trans diastereoisomer in 49 and 34% yields,
respectively (Table 1, Entry 1).6 Considering that the efficiency
of nucleophilic phosphine catalysis was often influenced by the
nature of the tertiary-phosphine catalyst, several phosphines with
different nucleophilicity had been screened for improving the
yield and chemoselectivity (Entries 2-5). When phosphines
PMe3, MePPh2, and Me2PPh were utilized as catalysts, the
[3 + 2] cycloaddition product 3a was obtained as the major
product in 34, 30, and 65% yield, respectively, and the [3 + 3]
product 4a was produced with 6, 3, and 14% yield, respectively
(Entries 2, 3, and 4). Dimethylphenylphosphine achieved the
best overall reaction efficiency, providing 65% yield of 3a and
14% yield of 4a (Entry 4). Methyldiphenylphosphine demon-
strated the best chemoselectivity toward [3 + 2] product,
affording 30% yield of 3a and 3% yield of 4a (Entry 3),
however, its overall yield (33%) was somewhat bad. Hexameth-
ylphosphorous triamide (HMPT) was quite sluggish, producing
no product 3a, and trace amount of product 4a (Entry 5). In this
Initially, the annulation reactions of ethyl 2-butynoate (2)
with 1-(p-nitrobenzylidene)-3-oxopyrazolidin-1-ium-2-ide (1a)
were performed to screen the appropriate reaction conditions
(Table 1). The azomethine imines have been extensively
employed as efficient 1,3-dipoles in a variety of metal-catalyzed
or organocatalytic cycloadditions5 and can easily be prepared
from the reaction of pyrazolidin-3-one with aldehydes.2,5b-5d In
the presence of 20 mol % PBu3, azomethine imine 1a was treated
with ethyl 2-butynoate (2) in dichloromethane at room temper-
ature for 12 h to provide the tetrahydropyrazolopyrazolone 3a as
Chem. Lett. 2012, 41, 218-220
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

219
research, both tetrahydropyrazolopyrazolone 3 and the tetra-
hydropyrazolopyridazinone 4 were desired to be obtained in
reasonable yield, therefore, tributylphosphine was chosen as the
catalyst.
Using 20 mol % of tributylphosphine as the catalyst, the
[3 + 2] and [3 + 3] annulation reactions of ethyl 2-butynoate (2)
with a range of azomethine imines 1 were carried out in
dichloromethane at room temperature within a given time period
(Table 2). A variety of aromatic azomethine imines 1 underwent
the [3 + 2] and [3 + 3] cycloaddition, providing the anticipated
tetrahydropyrazolopyrazolone and tetrahydropyrazolopyridazi-
none products in moderate to good yields (Entries 1-11).7
A wide range of aryl groups with electron-donating and
-withdrawing substituents on the benzene ring could be tolerated
in the process. In general, the azomethine imines bearing strong
electron-withdrawing groups such as nitro and cyano on the
ortho- or para-position of the benzene ring afforded much higher
yields of the corresponding cyclization products than the imines
with phenyl and bearing electron-donating and weak electron-
withdrawing groups on benzene did (Entry 1 in Table 1, Entries
6 and 8 in Table 2 versus Entries 1-5 in Table 2), but the
chemoselectivities of the former toward [3 + 2] product were
much lower than that of the latter (Entry 1 in Table 1, Entries 6
and 8 in Table 2 versus Entries 1-5 in Table 2). Interestingly,
the azomethine imines bearing nitro on the meta-position were
not very active to give a moderate yield of the cycloadduct
(Entry 9). The phenomenon could be attributed to the weak
electron-withdrawing effect of a nitro group at the meta-position
of a benzene ring. The azomethine imines bearing 1-naphthyl
(Entry 10) and 2-naphthyl (Entry 11) also underwent the cy-
clization reaction with 2-butynoate 2, affording the correspond-
ing pyrazolidinone derivatives in sound yields. Alkylimine
could also carry out the annulation with ethyl 2-butynoate (2) to
give only [3 + 2] product, albeit in low yield (Entry 12). In all
reactions, the [3 + 2] annulation products were always obtained
as the major product in a single (E)-isomer (Entries 1-12), and
the [3 + 3] cycloadduct were obtained as the minor product in a
single trans diastereoisomer.
The reaction of ethyl 2-pentynoate with azomethine imine
1a has also been checked, unfortunately, no cycloaddition
product could be isolated after the reaction was carried out in
dichloromethane at room temperature for 72 h.
According to the reported mechanistic studies on nucleo-
philic phosphine-catalyzed reactions,2 a plausible mechanism for
the [3 + 2] and [3 + 3] cycloaddition of azomethine imines 1
with ethyl 2-butynoate (2) is proposed (Scheme 2). The addition
of the Lewis-basic phosphine to the electrophilic ¢-carbon of
ethyl 2-butynoate (2), results in the formation of a zwitterionic
intermediate A. The conversion of vinyl anion A to ¢-phospho-
Table 2. PBu3-catalyzed [3 + 2] and [3 + 3] cycloadditions of
azomethine imines 1 with ethyl 2-butynoate (2)a
O
O
O
+
N
PBu3 (20 mol%)
CH2Cl2, rt
N
N
+
N N
N
CO2Et
CO2Et
R
R
R
CO2Et
1
2
3
4
Time
/h
Yield
/%b
Entry
R
Product
3:4
1
2
3
4
5
6
7
8
9
C6H5 (1b)
36
72
72
72
72
24
72
72
72
72
72
72
3b + 4b
3c + 4c
3d + 4d
3e + 4e
3f + 4f
3g + 4g
3h + 4h
3i + 4i
3j + 4j
3k + 4k
3l + 4l
3m
44
60
51
54
64
76
44
78
52
60
61
27
82:18
90:10
97:3
4-MeC6H4 (1c)
4-i-PrC6H4 (1d)
4-FC6H4 (1e)
95:5
4-BrC6H4 (1f)
4-CNC6H4 (1g)
4-CF3C6H4 (1h)
2-NO2C6H4 (1i)
3-NO2C6H4 (1j)
1-naphthyl (1k)
2-naphthyl (1l)
cyclohexyl (1m)
82:18
51:49
86:24
68:32
57:43
96:4
10
11
12
90:10
100:0
b
a1.2 equiv of ethyl 2-butynoate was used. Isolated yield.
O
O
O
PBu3
E
PBu3
N
N
N
PBu3
1
E
E
N
N
N
E
E
PBu3
PBu3
A
PBu3
E
2, E = CO2Et
R
B
R
D
R
E
3
O
O
O
N
N
E
N
N
N
N
PBu3
E
1
E
PBu3
2', E = CO2Et
R
PBu3
O
R
PBu3
R
PBu3
C
E
E
O
G
H
F
O
N
N
N
N
N N
PBu3
R
R
R
E
1
4
I
E
Scheme 2. Proposed mechanism for the [3 + 2] and [3 + 3] annulation of azomethine imines with ethyl 2-butynoate.
Chem. Lett. 2012, 41, 218-220
© 2012 The Chemical Society of Japan
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220
nium enoate B § C should be thermodynamically favorable.
In the case of using ethyl 2,3-butadienoate (2¤), ¢-phosphonium
enoate B and C can directly be generated by the addition of
phosphine to the ¢-carbon of 2¤.2 The £-carbon anion of ¢-
phosphonium enoate B attacks azomethine imine 1 leading to
the formation of the amide D. Intramolecular conjugate addition
of amide to the ¢-phosphonium enoate motif of intermediate D
accomplishes the [3 + 2] cyclization to give ¢-phosphonium
ester E, which undergoes a facile ¢-elimination to regenerate the
catalyst and form the final tetrahydropyrazolopyrazolone prod-
ucts 3, which are (E)-trisubstituted exocyclic alkylidenes. The
distribution of the geometric isomers of [3 + 2] product would
be thermodynamically controlled by the action of the phos-
phine.2 Thus, the equilibrium between the intermediates E and
the products 3 can support the exclusive formation of the more
stable (E)-isomer 3. Following another competing pathway, the
¡-carbon anion of zwitterion C attacks azomethine imine 1 to
give the phosphonium amide F, which carries out the 6-endo
cyclization to deliver the ylide G. The ¢-phosphonium ester H
formed by proton transfer from G expels phosphine and
provides the tetrahydropyrazolopyridazinone I, which isomer-
izes into [3 + 3] annulation product 4.
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In summary, we have developed phosphine-catalyzed
[3 + 2] and [3 + 3] cycloaddition reactions of azomethine
imines with ethyl 2-butynoate. Reactions are operationally
simple and proceed smoothly under very mild reaction con-
ditions, providing a broad range of tetrahydropyrazolo-pyrazo-
lones and -pyridazinones in moderate to good yield.
This study was supported by the National Natural Science
Foundation of China (No. 21172253), the startup research
funding from China Agricultural University, Chinese Univer-
sities Scientific Fund (Nos. 2011JS029 and 2011JS031), the
National Scientific and Technology Supporting Program of
China (No. 2011BAE06B05-5), the Key Technologies R&D
Program of China (No. 2012BAK25B03), and Nutrichem Co.
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6
The structures of 3a and 4a have been established by NMR
spectroscopy and X-ray crystallography. For the structures,
also see ref. 2. Crystallographic data for 3a and 4a have
been deposited with the Cambridge Crystallographic Data
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data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12, Union Road,
Cambridge, CB2 1EZ, U.K.; fax: +44 1223 336033.
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Chem. Lett. 2012, 41, 218-220
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/