Tandem Knoevenagel-Michael addition of aryl sulfonimines with diethyl malonate for synthesis of arylidene dimalonates

Article abstract of DOI:10.1021/jo070726e

(Chemical Equation Presented) A highly efficient, one-flask tandem Knoevenagel-Michael addition reaction of sulfonimines with diethyl malonate in the presence of a catalytic amount of base affords the corresponding arylidene dimalonates in good to excellent yields.

Full text of DOI:10.1021/jo070726e

in organic synthesis.7 They are conveniently prepared in various
methods,8 and are employed as electrophiles in a wide variety
of addition conditions,9 which provide a useful route to
sulfonamides. We report herein an efficient method for the
synthesis of arylidene dimalonates from a one-flask tandem
Knoevenagel-Michael addition of aryl sulfonimines with
diethyl malonate in the presence of a catalytic amount of base.
Compared to the extensive studies on the nucleophilic
addition of sulfonimines, the Mannich-type reaction of sulfon-
imines with malonates, which can be used to synthesize â-amino
acid derivatives,10 has received much less scrutiny.11 During
the course of our studies on the reactivity of imines,12 we found
that the treatment of sulfonimine 1a with diethyl malonate at
room temperature gave the expected addition product 3a in 89%
yield. However, when the reaction was run at a higher
temperature (50 °C), a dual-addition product,13 benzylidene
dimalonate 2a, was isolated in 75% yield (eq 1). Gong and Kato
Tandem Knoevenagel-Michael Addition of Aryl
Sulfonimines with Diethyl Malonate for Synthesis
of Arylidene Dimalonates
Renhua Fan,* Weizi Wang, Dongming Pu, and Jie Wu*
Department of Chemistry, Fudan UniVersity, 220 Handan Road,
Shanghai, 200433, China
rhfan@fudan.edu.cn
ReceiVed April 7, 2007
A highly efficient, one-flask tandem Knoevenagel-Michael
addition reaction of sulfonimines with diethyl malonate in
the presence of a catalytic amount of base affords the
corresponding arylidene dimalonates in good to excellent
yields.
Arylidene dimalonate has the potential to serve as a bone-
affinity agent in the treatment of bone disease,1 and as the
precursor for the synthesis of 3-Ar-glutaric acid.2 Usually it is
synthesized in two steps: the Knoevenagel condensation3 of
aromatic aldehydes with malonate or bromomalonate to form
arylidene malonate followed by the Michael addition4 of
arylidene malonate with malonate to produce arylidene dima-
lonate.5 Mori has reported a tandem Knoevenagel-Michael
addition of alkyl aldehyde with malonate in the presence of
stoichiometric piperidinium acetate;6 however, to our know-
ledge, no efficient one-flask synthesis of arylidene dimalonate
has been reported. On the other hand, sulfonimines are of
increasing importance due to their versatility as intermediates
have also observed the dual-addition product in the NaH-induced
addition of diethyl malonate to 4-methoxy-N-(2,2,2-trifluoro-
(7) Weinreb, S. M. Top. Curr. Chem. 1997, 190, 131.
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Chem. 1991, 56, 6468. (c) Georg, G. I.; Harriman, G. C. B.; Peterson, S.
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Ferrara, M.; Spey, S. E. J. Org. Chem. 2002, 67, 2335. (j) Yamanaka, M.;
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Y.; Hou, X. L.; Dai, L. X. J. Org. Chem. 1999, 64, 4233. (m) Zhang, W.
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47, 8391. (n) Shi, M.; Chen, L. H.; Li, C. Q. J. Am. Chem. Soc. 2005, 127,
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see: (a) Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048.
(b) Shou, W. G.; Yang, Y. Y.; Wang, Y. G. Tetrahedron Lett. 2006, 47,
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K. A. Chem. Eur. J. 2003, 9, 2359. (d) Martin, S. F. Acc. Chem. Res. 2002,
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Chem. Soc., Perkin Trans. 1 1999, 681. (f) Lounasmaa, M.; Miettinen, J.;
Hanhinen, P.; Jokela, R. Tetrahedron Lett. 1997, 38, 1455. (g) Shida, N.;
Kubota, Y.; Fukui, H.; Asao, N.; Kadota, I.; Yamamoto, Y. Tetrahedron
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10.1021/jo070726e CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/22/2007
J. Org. Chem. 2007, 72, 5905-5907
5905

TABLE 1. The Condition Screening Experiments
SCHEME 1
entry
base (equiv)
solvent
3a
2a
happens to be an excellent Michael acceptor, was generated from
the elimination reaction, and underwent the subsequent Michael
addition with the anion of malonate to give the dual-addition
intermediate B. After a proton exchange with the malonate,
benzylidene dimalonate 2a was formed as the product, and the
anion of malonate was regenerated at the same time. During
the reaction, 3a could be observed by TLC, but only trace
Knoevenagel product 4a was detected. So it was supposed
that the elimination reaction was the rate-limiting step to the
reaction.
1
2
3
4
5
6
7
8
9
t-BuOK (2)
t-BuOK (1)
t-BuOK (0.5)
t-BuOK (0.1)
t-BuOK (1)
t-BuOK (1)
t-BuOK (1)
t-BuOK (1)
NaH (1)
t-BuOH
t-BuOH
t-BuOH
t-BuOH
DMF
DMSO
DCE
H2O
0
0
0
89
88
91
18
75
81
52
7
65
10
8
15
12
10
16
56
t-BuOH
t-BuOH
t-BuOH
85
72
5
10
11
K2CO3 (1)
Et3N (1)
The scope of the base-catalyzed tandem Knoevenagel-
Michael addition of sulfonimines with diethyl malonate
was examined (Table 2). For aryl and heteroaryl sulfon-
imines, the reactions proceeded smoothly to produce the de-
sirable arylidene dimalonate in good to excellent yields.
The presence of an electron-donating group slightly de-
ethylidene)aniline.14 However, in that case, 1.1 equiv of Lewis
acid (ZnCl2) and high temperature (90-110 °C) were required
to form the dual-addition product.
As a control experiment, the reaction of benzaldehyde with
diethyl malonate under the same condition only gave a trace
amount of product 2a (e5%). In the following condition
screening experiments (Table 1), the yield of 2a increased to
89% while 3 equiv of ethyl malonate was used. It is noteworthy
that a catalytic amount of t-BuOK (0.5 equiv) was enough to
finish the reaction and to produce 2a in excellent yield (91%).
However, when the amount of t-BuOK decreased to 0.1 equiv,
the reaction became sluggish and gave 3a as the major product.
t-BuOH as solvent and t-BuOK as base were proved to be the
optimal condition for the tandem reaction, while the combination
of other organic solvents and bases gave rise to a mixture of 2a
and 3a. Although sulfonimines are generally stable, they were
hydrolyzed to aldehydes and TsNH2 when the reaction was
carried out in water.
When 1 equiv of ethyl malonate was used, the reaction not
only gave product 3a (18% yield) and 2a (25% yield), but also
a benzylidene malonate 4a in 14% yield. 3a could not be
converted into 2a by treatment with 1 equiv of ethyl malonate
in t-BuOH at 50 °C unless 0.5 equivof t-BuOK was present in
the system. 4a could also be generated from the reaction of 3a
with t-BuOK, and converted into 2a by the Michael addition
with ethyl malonate (Scheme 1).
FIGURE 1. A plausible pathway.
TABLE 2. Synthesis of Arylidene Dimalonates
The above results suggested that the reaction might proceed
via a tandem Knoevenagel-Michael addition pathway as shown
in Figure 1. The Knoevenagel condensation of sulfonimine 1a
with diethyl malonate was catalyzed by the anion of malonate
via an intermediate A, which was formed from the Mannich-
type reaction. At a lower temperature (25 °C), the elimination
reaction of the intermediate A could not occur, and then 3a
was obtained as the reaction product. At a higher temperature
(50 °C), the Knoevenagel condensation product 4a, which
entry
Ar
2 (%)
1
2
3
4
5
6
7
8
9
Ph
2a (91)
2b (80)
2c (78)
2d (75)
2e (88)
2f (92)
2g (86)
2h (89)
2i (93)
2j (88)
2k (92)
2l (93)
p-CH3O-C6H4
p-CH3-C6H4
o,m-(CH3O)2-C6H3
p-F-C6H4
p-NO2-C6H4
p-I-C6H4
o-CF3-C6H4
o-Cl-C6H4
1-naphthyl
2-furan
(11) Rudolf, A.; Guenter, K.; Bogdan, M. Chem. Ber. 1964, 97, 483.
(12) Fan, R. H.; Pu, D. M.; Qin, L. H.; Wen, F. Q.; Yao, G. P.; Wu, J.
J. Org. Chem. 2007, 72, 3149.
(13) Baris Temelli. B.; Unaleroglu, C. Tetrahedron 2006, 62, 10130.
(14) Gong, Y. F.; Kato, K. J. Fluorine Chem. 2001, 111, 77.
10
11
12
2-thiophen
5906 J. Org. Chem., Vol. 72, No. 15, 2007

creased its reactivity toward the tandem Knoevenagel-
Michael addition. As a consequence, some monoaddition
products 3 (e10% yield) were observed in these cases. The
N-substituent of imines played an important role in the
reaction. When N-phenyl and N-benzyl imines were used as
the substrates, no expected product was obtained from the
reactions.
Experiment Section
Typical Procedure for the Tandem Knoevenagel-Michael
Addition of Sulfonimines with Diethyl Malonate. A solution of
sulfonimine (1 mmol) in anhydrous t-BuOH (2 mL) was treated
with t-BuOK (0.5 mmol). This mixture was stirred at 50 °C under
N2 for 4 h (determined by TLC), then quenched with saturated
NH4Cl, extracted by CH2Cl2, and dried by anhydrous Na2SO4, and
the crude product was purified by flash column chromatography
to provide the corresponding product.
Decarboxylation of the benzylidene dimalonate 2a was
promoted by heating with hydrochloric acid to give rise to
3-phenylglutaric acid 5 (eq 2).
Tetraethyl 2-phenylpropane-1,1,3,3-tetracarboxylate (2a): 1H
NMR (400 MHz, CDCl3) δ 0.97 (t, J ) 7.3 Hz, 6H), 1.21 (t, J )
7.3 Hz, 6H), 3.91 (m, 4H), 4.05-4.24 (m, 7H), 7.21 (m, 3H), 7.32
(d, J ) 8.8 Hz, 2H). The spectral data are consistent with those
reported in the literature.2a
Acknowledgment. We thank Dr. Wen Ling for his invalu-
able advice during the course of this research. Financial support
from National Natural Science Foundation of China (20642006,
20502004), the Science and Technology Commission of Shang-
hai Municipality (05ZR14013), and Fudan University is grate-
fully acknowledged.
In summary, we found that arylidene dimalonates
could be synthesized in high yields from a one-flask tan-
dem Knoevenagel-Michael addition of sulfonimines with
diethyl malonate in the presence of a catalytic amount of
t-BuOK. A plausible mechanism for this convenient reac-
tion system is presented. The suitable reaction substrates
are also tested. Further investigation of the scope, mecha-
nism, and synthetic applications of this reaction is currently
underway.
Supporting Information Available: General experimental
information, characterization data of the isolated compounds, and
1H and 13C NMR spectra for 2a-l. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO070726E
J. Org. Chem, Vol. 72, No. 15, 2007 5907