Reactions of Arylaldehydes and N-Sulfonated Imines with Dimethyl Acetylenedicarboxylate Catalyzed by Nitrogen and Phosphine Lewis Bases

Article abstract of DOI:10.1021/ol0354324

(Equation presented) In the reaction of arylaldehydes or N-sulfonated imines (0.5 mmol) with dimethyl acetylenedicarboxylate (DMAD) (0.6 mmol) catalyzed by pyridine or DMAP (20 mol %), we found that (E)-2-aryl-but-2- enedioic acid dimethyl ester 1 or (E)-2-[aryl-(toluene-4-sulfonylimino)methyl]- but-2-enedioic acid dimethyl ester 2 was formed in good yields at 60°C in THF. A plausible mechanism has been proposed.

Full text of DOI:10.1021/ol0354324

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4273-4276
Reactions of Arylaldehydes and
N-Sulfonated Imines with Dimethyl
Acetylenedicarboxylate Catalyzed by
Nitrogen and Phosphine Lewis Bases
Chao-Qun Li and Min Shi*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
mshi@pub.sioc.ac.cn
Received July 30, 2003
ABSTRACT
In the reaction of arylaldehydes or N-sulfonated imines (0.5 mmol) with dimethyl acetylenedicarboxylate (DMAD) (0.6 mmol) catalyzed by
pyridine or DMAP (20 mol %), we found that (E)-2-aryl-but-2-enedioic acid dimethyl ester 1 or (E)-2-[aryl-(toluene-4-sulfonylimino)methyl]-but-
2-enedioic acid dimethyl ester 2 was formed in good yields at 60 °C in THF. A plausible mechanism has been proposed.
Recently, Nair and co-workers published a very interesting
paper on the pyridine-catalyzed reaction of arylaldehydes
with dimethyl acetylenedicarboxylate (DMAD) leading to
2-oxo-3-benzylidene succinates.1 In this paper, they sug-
gested that a 1,4-zwitterionic intermediate is generated from
the pyridine and DMAD, and that this adds onto arylalde-
hydes in a formal [2 + 2] manner, resulting in the facile
synthesis of 2-oxobenzylidenesuccinates (Scheme 1). We
were very curious about this reaction because it is hard to
conceive of a [2 + 2] reaction of the type proposed by Nair
being triggered by a weak Lewis base.2 Therefore, we
decided to reexamine this interesting reaction in the presence
of various nitrogen Lewis bases (20 mol %). To our surprise,
we found that in this process, (E)-2-aryl-but-2-enedioic acid
dimethyl esters 1 were actually produced, rather than
2-oxobenzylidenesuccinates (Tables 1 and 2).
We first reexamined the Nair reaction under various
reaction conditions to develop the optimal reaction conditions
Scheme 1. Formal [2 + 2] Reaction Mechanism in the
Reaction of Arylaldehydes with DMAD Catalyzed by Pyridine
(1) Nair, V.; Sreekanth, A. R.; Vinod, A. U. Org. Lett. 2001, 3, 3495
and references therein.
(2) (a) Shi, M.; Xu, Y.-M. Chem. Commun. 2001, 1876. (b) Shi, M.;
Xu, Y.-M. Eur. J. Org. Chem. 2002, 696. (c) Shi, M.; Xu, Y.-M.; Zhao,
G.-L.; Wu, X.-F. Eur. J. Org. Chem. 2002, 3666. (d) Shi, M.; Xu, Y.-M.
J. Org. Chem. 2003, 68, 4784.
10.1021/ol0354324 CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/17/2003

9-11). It should be noted that the reaction conditions shown
in entry 1 are exactly the same as those reported by Nair’s
group.1 Therefore, we believe that they misassigned this
Table 1. Reaction of p-Nitrobenzenealdehyde (0.5 mmol) with
DMAD (0.6 mmol) Catalyzed by Nitrogen Lewis Bases (20 Mol
%) in Various Solvents
1
product in their paper (see H and 13C and HMBC NMR
spectra of 1a in Supporting Information).1
Using pyridine as a Lewis base (20 mol %) under the
optimized reaction conditions, we next examined the reaction
of other arylaldehydes (0.5 mmol) with DMAD (0.6 mmol)
in THF. The results are summarized in Table 2. As can be
seen from Table 2, the corresponding products 1 are
stereoselectively obtained in moderate to good yields with
(E)-configuration (Table 2, entries 1-8). Their structures
have been determined by H and 13C NMR spectroscopic
data and HRMS or microanalyses (see Supporting Informa-
tion) and X-ray diffraction. The X-ray crystal structure of
1d is shown in Figure 1.3
1
nitrogen
temp
[°C]
timea yield of 1a
entry Lewis base solvent
[h]
[%]b
1
2
3
4
5
6
7
8
9
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
DMAP
DME
THF
THF
DCEc
MeCN
DMSO
PhMe
THF
-10 to ∼20
40
40
12
12
12
12
12
12
12
12
12
81
85
86
85
80
86
85
85
20
60
60
60
60
60
60
60
60
60
DBU
DABCO
Et3N
THF
THF
THF
trace
trace
trace
10
11
a Reaction time for consuming all of the starting materials. b Isolated
yields. c DCE ) 1,2-dichloroethane.
using p-nitrobenzaldehyde as the substrate. The results are
summarized in Table 1. Although a prolonged reaction time
was required to get high yield of 1a at low reaction
temperature (Table 1, entries 1 and 2), 1a could be obtained
in high yields in various solvents using pyridine as a Lewis
base at 60 °C (Table 1, entries 3-7). DMAP has catalytic
activity similar to that of pyridine (Table 1, entry 8). In the
presence of other nitrogen Lewis bases such as DABCO,
DBU, or Et3N, only a trace of 1a is formed (Table 1, entries
Figure 1. X-ray crystal structure of 1d.
Replacing arylaldehydes with N-tosyl arylimines in the
same reaction demonstrated that the corresponding (E)-2-
[aryl-(toluene-4-sulfonylimino)methyl]-but-2-enedioic acid
dimethyl esters 2 were formed in good yields. Using N-(m-
nitrobenzylidene)-4-methylbenzenesulfonamide as a sub-
strate, we examined the effect of various nitrogen Lewis
bases (20 mol %) in mediating this reaction in THF.4 We
found that pyridine or DMAP was a good Lewis base, the
reaction being complete within 7 h at 60 °C. Other nitrogen
Lewis bases such as DABCO, DBU, and Et3N gave 2a in
poor yields under the same conditions.
Table 2. Reactions of Arylaldehydes (0.5 mmol) with DMAD
(0.6 mmol) Catalyzed by Pyridine (20 Mol %)
Using DMAP (20 mol %) as a Lewis base under the
optimized reaction conditions, we next examined the reaction
time
[h]
yield of 1
[%]a
entry
Ar
(3) X-ray data of 1d has been deposited in CCDC as deposition number
208176. Empirical formula: C13H11O5Br. Formula weight: 327.13. Crystal
color, habit: colorless, prismatic. Crystal dimensions: 0.506 × 0.435 ×
0.367 mm. Crystal system: orthorhombic. Lattice type: primitive. Lattice
parameters: a ) 8.9139(10) Å, b ) 11.3686(12) Å, c ) 13.6725(15) Å, R
) 90°, â ) 90°, γ ) 90°, V ) 1385.6(3) Å3. Space group: P2(1)2(1)2(1).
Z value ) 4. Dcalcd ) 1.568 g/cm3. F000 ) 656. Diffractometer: Rigaku
AFC7R. Residuals: R ) 0629, Rw ) 0.1751.
(4) Phosphine Lewis base-catalyzed [3 + 2] cycloaddition of acetylene-
dicarboxylate with N-tosylated imines has been reported. Please see: (a)
Xu, Z.; Lu, X. Tetrahedron Lett. 1997, 38, 3461. (b) Xu, Z.; Lu, X. J. Org.
Chem. 1998, 63, 5031. (c) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001,
34, 535.
1
2
3
4
5
6
7
8
m-NO2C6H4
o-NO2C6H4
p-BrC6H4
p-ClC6H4
m-ClC6H4
o,p-Cl2C6H3
p-MeC6H4
C6H5
12
12
12
12
24
24
48
48
1b, 89
1c, 85
1d , 72
1e, 64
1f, 71
1g, 83
1h , 50
1i, 43
a Isolated yields.
4274
Org. Lett., Vol. 5, No. 23, 2003

For other arylaldehydes, no reaction occurred under the
same conditions.
Table 3. Reaction of N-Tosylated Imines (0.5 mmol) with
On the basis of the above results, it is clear that the Lewis
base catalysts play a very important role in determining the
outcome of this reaction. A careful investigation of the Lewis
base character should be carried out before such Lewis base-
catalyzed reactions are performed.
DMAD (0.6 mmol) Catalyzed by DMAP (20 Mol %)
Using diethyl acetylenedicarboxylate to replace DMAD
under the same conditions afforded similar results (Scheme
3).
time
[h]
yield of 2
[%]a
entry
Ar
1
2
3
4
5
6
7
8
m-NO2C6H4
p-NO2C6H4
p-BrC6H4
p-ClC6H4
m-ClC6H4
m-FC6H4
p-MeOC6H4
C6H5
7
7
7
7
7
7
7
7
2a , 83
2b, 85
2c, 86
2d , 79
2e, 76
2f, 82
2g, 70
2h , 70
Scheme 3. Reaction of p-Nitrobenzaldehyde (0.5 mmol) and
N-(p-Chlorobenzylidene)-4-methylbenzenesulfonamide (0.5
mmol) with Diethyl Acetylenedicarboxylate (0.6 mmol) in the
Presence of Pyridine (20 Mol %)
a Isolated yields.
of various N-tosylated imines (0.5 mmol) with DMAD (0.6
mmol). The results are summarized in Table 3. As can be
seen from Table 3, the corresponding reaction products 2
were stereoselectively obtained in good yields with (E)-
configuration (Table 3, entries 1-8). Their structures have
also been determined by 1H and 13C NMR spectroscopic data
and HRMS or microanalyses (see Supporting Information)
and X-ray diffraction. The X-ray crystal structure of 2h is
shown in Supporting Information.5
Using other electron-deficient alkynes such as phenyl-
acetylene, methyl propiolate, 3-butyn-2-one, and phenyl-
propynoic acid ethyl ester as alkyne partners in these
reactions with RCHO gave poor results (Scheme 4).8
Since the [3 + 2] cycloaddition of acetylenedicarboxylate
with N-tosylated imines in the presence of phosphine Lewis
bases has been disclosed before,4,6 we examined the reaction
of arylaldehydes (0.5 mmol) with DMAD (0.6 mmol) in the
presence of a stronger Lewis base such as PPh3 or PBu3
(20 mol %). We observed that arylaldehydes having a
strongly electron-withdrawing group on the benzene ring
such as nitrobenzaldehyde give the [3 + 2] cycloaddition
product (4-methoxy-5-oxo-2-nitrophenyl-2,5-dihydrofuran-
3-carboxylic acid methyl ester 3a or 3b) in moderate yield
along with the formation of 1a or 1b, respectively (Scheme
2). The structures of 3a and 3b have been determined by 1H
Scheme 4. Reaction of Other Electron-Deficient Alkynes with
p-Nitrobenzaldehyde in the Presence of Pyridine (20 Mol %) in
THF
Scheme 2. Reaction of Arylaldehydes (0.5 mmol) with DMAD
(0.6 mmol) in the Presence of Triphenylphosphine (20 Mol %)
On the basis of our results, a plausible mechanism for the
conversion of arylaldehydes and imines into 1 and 2 is
(5) X-ray data of 2h has been deposited in CCDC as deposition number
208176. Empirical formula: C13H11O5Br. Formula weight: 327.13. Crystal
color, habit: colorless, prismatic. Crystal dimensions: 0.506 × 0.435 ×
0.367 mm. Crystal system: orthorhombic. Lattice type: primitive. Lattice
parameters: a ) 8.9139(10) Å, b ) 11.3686(12) Å, c ) 13.6725(15) Å, R
) 90°, â ) 90°, γ ) 90°, V ) 1385.6(3) Å3. Space group: P2(1)2(1)2(1).
Z value ) 4. Dcalcd ) 1.568 g/cm3. F000 ) 656. Diffractometer: Rigaku
AFC7R. Residuals: R ) 0629, Rw ) 0.1751.
and 13C NMR spectroscopic data and HRMS or micro-
analyses as well (see Supporting Information) and X-ray
diffraction. The X-ray crystal structure of 3a is shown in
Supporting Information.7
Org. Lett., Vol. 5, No. 23, 2003
4275

imines to form the zwitterionic intermediate B or C.
Repulsion between the aryl group and pyridine means that
the zwitterionic intermediate C is thermodynamically more
stable. Therefore, the formation of products 1 and 2 with
(E)-configuration is favored. Two consecutive proton-transfer
steps shuffle the proton on the â′-carbon to the â-carbon
through intermediate D to E to F. The expulsion of pyridine
or DMAP generates the product and reproduces the nucleo-
philic promoter.1,4,6
Scheme 5. Plausible Reaction Mechanism in the Reaction of
Arylaldehydes and N-Sulfonated Imines with DMAD Catalyzed
by Pyridine
In conclusion, we have found that weak Lewis bases such
as pyridine or DMAP catalyze the reaction of arylaldehydes
or N-tosylated imines with DMAD to give (E)-2-aryl-but-
2-enedioic acid dimethyl esters 1 or (E)-2-[aryl-(toluene-4-
sulfonylimino)methyl]-but-2-ene-dioic acid dimethyl esters
2 in moderate to good yields. 2-Oxobenzylidenesuccinates
are not formed in the former reaction as proposed by Nair.
Using stronger Lewis bases such as PPh3 as the promoter
leads to [3 + 2] annulations taking place to give products 3
in moderate yields along with the formation of 1. A plausible
mechanism has been proposed on the basis of the above
experiments and previous reports. Efforts are underway to
elucidate the mechanistic details of this reaction and to
disclose the scope and limitations of this reaction. Work
along this line is currently in progress.
outlined in Scheme 5. Pyridine or DMAP acts as a nucleo-
philic promoter to initiate the reaction and produces zwit-
terionic intermediate A, which is actually an allenic enolate.
The central carbon of A adds to aldehydes or N-tosylated
Acknowledgment. We thank the State Key Project of
Basic Research (Project 973) (No. G2000048007), Shanghai
Municipal Committee of Science and Technology, and the
National Natural Science Foundation of China for financial
support (20025206, 203900502, and 20272069).
(6) Tertiary phosphine-catalyzed lactone formation from electron-deficient
carbonyl compounds and DMAD has been reported. Nozaki, K.; Sato, N.;
Ikeda, K.; Takoya, H.J. Org. Chem. 1996, 61, 4516.
(7) X-ray data of 3a has been deposited in CCDC as deposition number
208177. Empirical formula: C20H19NO6S. Formula weight: 401.42. Crystal
color, habit: colorless, prismatic. Crystal dimensions: 0.267 × 0.251 ×
0.189 mm. Crystal system: triclinic. Lattice type: primitive. Lattice
parameters: a ) 8.0459(10) Å, b ) 9.8127(12) Å, c ) 12.9141(15) Å, R
) 84.189(2)°, â ) 74.524(2)°, γ ) 82.746(3)°, V ) 972.3(2) Å3. Space
group: P-1. Z value ) 2. Dcalcd ) 1.371 g/cm3; F000 ) 420. Diffractom-
eter: Rigaku AFC7R. Residuals: R ) 0457, Rw ) 0.0637.
Supporting Information Available: Spectroscopic data
(1H and 13C NMR spectra data) and analytic data of the
compounds shown in Tables 1-3 and Schemes 1-3 and
detailed description of experimental procedures. This material
is available free of charge via the Internet at http://pubs.acs.org.
(8) These electron-deficient alkynes such as phenylacetylene, methyl
propiolate, and 3-butyn-2-one are labile at 60 °C in THF. Therefore, these
reactions were carried out at room temperature.
OL0354324
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Org. Lett., Vol. 5, No. 23, 2003