The N,N,N′,N′-tetramethylethylenediamine mediated Baylis-Hillman reaction

Article abstract of DOI:10.1081/SCC-200046521

The Baylis-Hillman reaction of aromatic aldehydes with various activated alkenes catalyzed by N,N,N′,N′-Tetramethylethylenediamine (TMEDA) in aqueous medium were reported. The efficiency of this catalyst was examined in comparison with DABCO. It was demon

Full text of DOI:10.1081/SCC-200046521

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The
N,N,N′,N′–Tetramethylethylenediam
Mediated Baylis‐Hillman
Reaction
a
a
Sanhu Zhao & Zhaobin Chen
a
School of Chemistry and Chemical Engineering ,
Shanxi University , Taiyuan, 030006, P.R. China
Published online: 22 Jun 2006.
To cite this article: Sanhu Zhao & Zhaobin Chen (2005) The
N,N,N′,N′–Tetramethylethylenediamine Mediated Baylis‐Hillman Reaction, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 35:1, 121-127, DOI: 10.1081/SCC-200046521
To link to this article: http://dx.doi.org/10.1081/SCC-200046521
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Synthetic Communications , 35: 121–127, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200046521
0
0
The N,N,N ,N –Tetramethylethylenediamine
Mediated Baylis-Hillman Reaction
Sanhu Zhao and Zhaobin Chen
School of Chemistry and Chemical Engineering, Shanxi University,
Taiyuan, P.R. China
Abstract: The Baylis-Hillman reaction of aromatic aldehydes with various activated
0
0
alkenes catalyzed by N,N,N ,N –Tetramethylethylenediamine (TMEDA) in aqueous
medium were reported. The efficiency of this catalyst was examined in comparison
with DABCO. It was demonstrated that this amine is not only a very efficient
catalyst for the Baylis-Hillman reaction, it also outperforms the most widely used
catalyst DABCO.
0
0
Keywords: N,N,N ,N –Tetramethylethylenediamine, catalyze, Baylis-Hillman
reaction
INTRODUCTION
The Baylis-Hillman reaction is an atom-economical and extremely useful C-C
[
bond-forming reaction in organic synthesis. Numerous catalytic systems,
1]
[
2–7]
[8,9]
[10]
[11]
such as tertiary amines,
etc, were used as catalyst to mediate this reaction. 1,4-Diazabicyclo [2.2.2]
phosphines
and chalcogenides,
TiCl4
[
12]
octane (DABCO, 1), first introduced by Baylis and Hillman,
still the most widely used one. We are surprised to find, however, that other
is arguably
0
0
related tertiary amines such as the very readily available N,N,N ,N –Tetra-
methylethylenediamine (TMEDA, 2) has never been used as a catalyst in
this context. We now wish to report our preliminary findings that, not only
Received in Japan August 19, 2004
Address correspondence to Zhaobin Chen, School of Chemistry and Chemical
Engineering, Shanxi University, Taiyuan 030006, P.R. China. Fax: 86351-7011688;
E-mail: zchen@sxu.edu.cn

122
S. Zhao and Z. Chen
this inexpensive and user-friendly amine can be successfully used in the
Baylis-Hillman reaction, it also outperforms the classical 1.
RESULTS AND DISCUSSION
For evaluating the influence of TMEDA on the Baylis-Hillman reaction,
we examined the reaction of 2-nitrobenzaldehyde with butyl acrylate in a
1
: 1(v/v) mixture of 1,4-dioxane and water in the presence of TMEDA.
The good result was obtained when a mixture of 2-nitrobenzaldehyde
3 mmol), butyl acrylate (9 mmol), H O (5 ml), 1,4-dioxane (5 ml), and
(
2
TMEDA (1 mmol) was stirred at ambient temperature. The main emphasis
was here given to aromatic aldehydes, because they are harder to react in
[
13]
Baylis-Hillman reaction than aliphatic one.
For comparing the effect of
TMEDA with DABCO, the similar reaction of 2-nitrobenzaldehyde with
butyl acrylate in the presence of DABCO was also conducted (Table 1).
Encouraged by this result, we then carried out the TMEDA or DABCO
catalyzed Baylis-Hillman coupling of 2-nitrobenzaldehyde with acrylonitrile.
It was found that the reaction medium catalyzed by DABCO became dark
and dirty after 4 hrs. Furthermore, the formation of Baylis-Hillman adducts
could be only detected in very low yields (by TLC,GC). As compared
with DABCO, the reaction medium catalyzed by TMEDA was very clean
in all reaction times, and a better result (fast reaction rate, higher yield)
was obtained.
We also successfully carried out the TMEDA-induced Baylis-Hillman
reaction of the other aldehydes with activated alkenes, as shown in Table 1.
Considering the results presented in Table 1, it was observed that the use of
stoichiometric amounts of TMEDA as a promoter not only reduces the
reaction time but also gives a high yield.
In conclusion, we have demonstrated that the rather inexpensive, readily
0
0
available and user-friendly N,N,N ,N –Tetramethylethylenediamine 2 can be
used as a new and efficient catalyst for Baylis-Hillman reaction. Its activity is
even superior to that of the most widely used catalyst DABCO 1. Further
investigation in optimizing the reaction conditions is being actively pursued
in our laboratory.

Baylis-Hillman Reaction
123
Table 1. TMEDA and DABCO mediated the Baylis-Hillman reactions
Time
(h)
Yield
a
(%)
Entry
R
EWG
Cat.
Product
1
2
3
4
5
6
7
8
9
2-O NC H
COOC H
4
DABCO
TMEDA
DABCO
TMEDA
DABCO
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
36
12
8
3a
3a
3b
3b
3c
3c
3d
3e
3f
59
68
2
2
2
6
6
6
4
4
4
4
4
4
4
9
2-O
2-O
NC
NC
H
H
COOC
CN
CN
4 9
H
b
N/A
90
2-O NC H
8
2
2
2
2
6
6
6
6
2-O
2-O
2-O
NC
NC
NC
H
H
H
CONH
CONH
2
36
12
10
8
45
2
70.5
86
COOCH
COOCH3
CONH
COOCH
3
2-pyridin
2-pyridin
91
78
2
10
36
8
1
1
1
1
1
0
1
2
3
4
4-ClC
4-O NC H
6
H
4
3
3g
3h
3i
62
COOCH3
CN
CN
89.5
61
2
6
4
C
6
H
5
48
72
72
4-OHC
CH3
6
H
4
3j
3k
56
27
COOCH3
a
b
Isolated yield based on aldehyde.
Only trace amount of product was detected and its yield not determined.
EXPERIMENTAL
All melting points were recorded by capillary melting point apparatus and
uncorrected. The IR spectra were determined on an IR-408 Infrared Spec-
1
trometer by dispersing samples in KBr disks. H NMR spectra were
measured on a DRX300 NMR Spectrometer with CDCl as solvent. Analyti-
3
cal thin-layer chromatography (TLC) was carried out using MN Kieselgel
G/UV254 (Art. 816320) glass-backed plates. All products are already
[
6,13–17]
reported in the literature.
General Procedure
A solution of aromatic aldehyde (3 mmol) and activated alkene (9 mmol) in
0 mL of 1,4-dioxane/water (1 : 1, v/v) was stirred at room temperature in
1
the presence of DABCO (1 mmol) or TMEDA (1 mmol) and the reaction
progress was monitored by TLC. Upon completion, the reaction mixture
was acidified dropwise with 1.5N aqueous HCl, then partitioned with ether

124
S. Zhao and Z. Chen
(
(
50 mL) and water (30 mL). The organic phase was washed with brine
2 ꢀ 30 mL), dried over anhydrous Na SO , and removal of solvent on a
2
4
rotary vacuum evaporator afforded the crude product. The crude product
obtained after work-up was purified by flash column chromatography on
silica gel (300–400 mesh).
3
-Hydroxy-2-methylene-3-(2-nitrophenyl) propanoic acid, n-butyl
ester (3a). This compound was prepared in the same manner as that
described above, the crude material obtained on workup was purified by
column chromatography. Elution with petroleum ether-ethyl acetate (5 : 1)
2
1
afforded pure product 3a as a pale yellow oil; IR (neat): n (cm ) 3434
1
OH), 2960, 1731(C 55 O), 1536, 1357; H NMR(300 MHz, CDCl ): d 8.04
(
(
3
d, 1H, J ¼ 8.05Hz, Ar), 7.74(d, J ¼ 8.05Hz,1H, Ar), 7.60 (t, J ¼ 7.56Hz, 1H,
Ar), 7.44(t, J ¼ 7.56Hz, 1H, Ar), 5.92(s, 1H), 5.62(s, 1H), 5.20(s, 1H, CHOH),
4
3
.10(t, 2H), 2.62(br s, 1H, OH), 1.12–1.36(m, 4H), 0.94(t, J ¼ 7.4 Hz,
H, CH ).
3
3
-Hydroxy-2-methylene-3-(2-nitrophenyl) propanenitrile (3b). This
compound was prepared in the same manner as that described above, the
crude material obtained on workup was purified by column chromatography.
Elution with petroleum ether-ethyl acetate (7 : 1) afforded pure 3b as a yellow
2
1
solid; mp 418C; IR (KBr): n (cm ) 3462.0 (OH), 2229.6, 1610.5, 1344.3;
1
H NMR (300MHz,CDCl ): d 8.03 (d, J ¼ 8.06Hz, 1H, Ar), 7.84
3
(
d, J ¼ 8.06Hz, 1H, Ar), 7.73 (t, J ¼ 7.71Hz, 1H, Ar), 7.56 (t, 1H,
J ¼ 7.71Hz, Ar), 6.15 (s, 1H), 6.12 (s, 1H), 5.96 (d, J ¼ 5.56Hz 1H, CHOH),
.27 (br s, 1H, OH).
-Hydroxy-2-methylene-3-(2-nitrophenyl) propionamide (3c). This
3
3
compound was prepared in the same manner as that described above, the
crude material obtained on workup was purified by column chromatography.
Elution with petroleum ether-ethyl acetate (3 : 1) afforded pure 3c as a yellow
2
1
1
crystal; mp 598C; IR (KBr): n (cm ) 3360 (OH), 1662, 1640, 1346.2; H NMR
(
300MHz, CDCl ): d 10.43(s, 1H, OH), 8.13(d, J ¼ 8.09Hz, 1H, Ar),
3
7
1
2
.96(d, J ¼ 8.09Hz, 1H, Ar), 7.80(t, J ¼ 7.76Hz, 1H, Ar), 7.76 (t, J ¼ 7.76Hz
H, Ar), 6.19 ꢀ 6.34(m, 2H), 5.73(d, J ¼ 5.52 Hz 1H, CHOH), 5.53(br s,
H, NH ).
2
3
-Hydroxy-2-methylene-3-(2-nitrophenyl) propanoic acid, methyl ester
3d). This compound was prepared in the same manner as that described above,
(
material obtained on workup was purified by column chromatography, Elution
with petroleum ether-ethyl acetate (9: 2) afforded pure 3d as a yellow oil; IR
(
21
1
neat): n (cm ) 3449.4 (OH), 1714.1(C 55 O), 1530.9, 1352; H NMR
(
300MHz, CDCl ): d 7.96 (d, J ¼ 8.01Hz 1H, Ar), 7.76 (d, 1H, J ¼ 8.01Hz,
3
Ar), 7.66 (t, J ¼ 7.41Hz, 1H, Ar), 7.48(t, 1H, J ¼ 7.41Hz, Ar), 6.38(s, 1H),
6
.21(s, 1H), 5.74(s, 1H, CHOH), 3.77(s, 3H, CH ), 3.25(br s, 1H, OH).
3
3
-Hydroxy-2-methylene-3-(pyridin-2-yl) propanoic acid, methyl ester
3e). This compound was prepared in the same manner as that described
above, the crude material obtained on workup was purified by column
(

Baylis-Hillman Reaction
125
chromatography. Elution with petroleum ether-ethyl acetate (9 : 2) afforded
21
pure 3e as a yellow oil; IR (neat): n (cm ) 3418 (OH), 3012, 2952,
1
1
725(C 55 O), 1593. H NMR (300 MHz,CDCl ): d 8.48(d, J ¼ 4.82 Hz, 1H,
3
pyridine), 7.60–7.55(m, 1H, pyridine), 7.36(d, 1H, J ¼ 7.36 Hz, pyridine),
7
.15(t, 1H, J ¼ 6.15 Hz, pyridine), 6.33(s, 1H), 5.90(s, 1H), 5.61(d, 1H,
J ¼ 5.31 Hz, CHOH), 4.83(br s, 1H, OH), 3.68(s, 3H, CH ).
3
3
-Hydroxy-2-methylene-3-(pyridin-2-yl) propionamide (3f). This
compound was prepared in the same manner as that described above, the
crude material obtained on workup was purified by column chromatography.
Elution with petroleum ether-ethyl acetate (5 : 2) afforded pure 3f as a pale
2
1
1
yellow oil; IR (neat): n (cm ) 3380 (OH), 1675; H NMR (300 MHz,
CD Cl ): d 8.3–8.18(m, 1H, pyridine), 7.52(d, J ¼ 7.6 Hz, 1H, pyridine),
3
3
7
5
.27(d, J ¼ 8.4 Hz, 1H, pyridine), 7.05–6.96(m, 1H, pyridine), 5.76(s, 1H),
.68(s, 2H, NH ), 5.32(s, 1H), 5.38(s, 1H, CHOH), 3.29(br s, 1H, OH).
2
3
-Hydroxy-2-methylene-3-(4-chlorophenyl) propanoic acid, methyl
ester (3g). This compound was prepared in the same manner as that
described above, the crude material obtained on workup was purified by
column chromatography. Elution with petroleum ether-ethyl acetate (7 : 3)
[
15]
21
afforded pure 3g as a white solid; mp 428C, Lit,
428C; IR (KBr): n (cm )
1
500 (OH), 2985, 1725; H NMR (300MHz,CDCl ): d 7.82(s, 2H, Ar),
.30(s, 2H, Ar), 6.35(s, 1H), 5.85(s, 1H), 5.52(d, J ¼ 5.82Hz, 1H,CHOH),
3
7
3
3
.72(s, 3H, CH ), 3.15(d, J ¼ 5.84,1H,OH).
3
3
-Hydroxy-2-methylene-3-(4-nitrophenyl) propanoic acid, methyl
ester (3h). This compound was prepared in the same manner as that
described above, the crude material obtained on workup was purified by
column chromatography. Elution with petroleum ether-ethyl acetate (5 : 1)
[
13]
afforded pure 3h as a yellow solid; mp 738C, Lit.
(
73–748C; IR (KBr): n
2
1
1
cm ) 3510 (OH), 2992, 1724, 1634, 1359; H NMR (300 MHz, CDCl ): d
3
8
5
1
.70(d, J ¼ 8.76 Hz, 2H, Ar), 7.56(d, J ¼ 8.76 Hz, 2H, Ar), 6.40(s, 1H),
.88(s, 1H), 5.64(d, J ¼ 5.87 Hz, 1H, CHOH), 3.75(s, 3H, CH ), 3.40(br s,
3
H, OH).
3
-Hydroxy-2-methylene-3-phenylpropanenitrile (3i). This compound
was prepared in the same manner as that described above, the crude
material obtained on workup was purified by column chromatography.
Elution with petroleum ether-ethyl acetate (4 : 1) afforded pure 3i as a
2
1
1
yellow oil; IR (neat): n (cm ) 3445.0 (OH), 2229.5, 1605.8, 1340.3; H
NMR (300MHz, CDCl ): d 7.40–7.16 (m, 5H, C H ), 6.15 (s, 1H), 6.12
3
6 5
(
s, 1H), 5.96 (d, J ¼ 5.56 Hz 1H,CHOH), 2.87 (br s, 1H, OH).
3
-Hydroxy-2-methylene-3-(4-hydroxyphenyl) propanenitrile (3j).
This compound was prepared in the same manner as that described above,
the crude material obtained on workup was purified by column chromato-
graphy. Elution with petroleum ether-ethyl acetate (5 : 1) afforded pure 3j as
2
1
1
a colourless oil; IR (neat): n (cm ) 3460.0 (OH), 2228.5, 1620; H NMR
(
300 MHz, CDCl ): d 7.42 (d, J ¼ 8.40 Hz, 2H, Ar), 6.75 (d, J ¼ 8.06 Hz,
3

126
S. Zhao and Z. Chen
2
H, Ar), 6.05 (s, 1H), 5.80(s, 1H), 4.75 (s, 1H,CHOH), 4.52 (s, 1H), 3.64
br s, 1H, OH).
-Hydroxy-2-methylene-butanoic acid, methyl ester (3k). This
(
3
compound was prepared in the same manner as that described above,
material obtained on workup was purified by column chromatography.
Elution with petroleum ether-ethyl acetate (4 : 1) afforded pure 3k as a
2
1
1
yellow oil; IR (neat): n (cm ) 3469.4 (OH), 1714.1(C 55 O), 1630.9; H
NMR (300 MHz,CDCl ): d 6.20 (d, J ¼ 1.35 Hz, 1H,C 55 CH), 5.83 (d, 1H,
3
J ¼ 1.1 Hz, C 55 CH), 4.59 (m, 1H, CH), 3.79(s, 3H, OCH ), 2.70 (s, 1H,
3
OH), 1.35(d, J ¼ 6.42 Hz, 3H, CH ) .
3
ACKNOWLEDGMENTS
The present work was supported by the Natural Science Foundation of China
(30000112); Laboratory of Organic Solid, Chinese Academy of Sciences, and
The Returned Student Science Foundation of Shanxi Province of China.
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