Efficient synthesis of β-enaminoesters via highly stereoselective Reformatsky reaction with disubstituted formamides as novel electrophiles

Article abstract of DOI:10.1016/j.tetlet.2009.01.003

An efficient synthesis of various β-enaminoesters has been achieved via Reformatsky reaction with disubstituted formamides as novel electrophiles. The exclusive β-enaminoester E-isomers were obtained in 60-72% yield.

Full text of DOI:10.1016/j.tetlet.2009.01.003

Tetrahedron Letters 50 (2009) 1389–1391
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Tetrahedron Letters
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Efficient synthesis of b-enaminoesters via highly stereoselective
Reformatsky reaction with disubstituted formamides as novel electrophiles
*
Yi-Yin Ke, Yu-Jin Li, Jian-Hong Jia, Wei-Jian Sheng, Liang Han, Jian-Rong Gao
State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou 310032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of various b-enaminoesters has been achieved via Reformatsky reaction with disub-
stituted formamides as novel electrophiles. The exclusive b-enaminoester E-isomers were obtained in
60–72% yield.
Received 30 October 2008
Revised 25 December 2008
Accepted 6 January 2009
Available online 9 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
b-Enaminoesters
Reformatsky reaction
Disubstituted formamides
Stereoselective
b-Enaminoesters,1 a class of versatile intermediates for the syn-
thesis of the heterocycles,2 are common pharmacophores in a
number of important medicinal agents. Many of their derivatives,
including anticonvulsant,3 anti-inflammatory,4 and particularly
the antibacterial fluorinated quinolone,5 possess a wide range of
biological activities. Despite the importance of enaminones as
valuable biologically active compounds, their synthesis has re-
ceived little attention so far. b-Enaminoesters are generally pre-
pared by condensation of amines with b-ketoesters or alkynes.6,7
However, the drawbacks are well documented including incom-
plete reaction, long reaction time, and discrimination between E
and Z double-bond geometric isomers.8
uct in low yield, and the nonpolar solvent toluene led to
uncompleted reaction (entry 3). As shown in Table 1, THF was
the better solvent, and the corresponding product was obtained
in 62% yield (entry 4). Because of the low reactivity of ethyl chlo-
roacetate, no product was detected at all in THF (entry 5), but 3b
was obtained in 43% yield in toluene because of higher reaction
temperature (entry 6). Similarly, ethyl iodoacetate gave the same
product in 65% yield (entry 7) (Scheme 2).
DMF could be appropriate as a solvent in some specific Refor-
matsky reactions when more reactive electrophiles such as alde-
hydes and ketones are used.10 We found that DMF also could be
used as an electrophile, but 2 equiv of Reformatsky reagent were
needed to make sure that DMF was absolutely transformed. Gener-
ally, the reaction was monitored by TLC and GC–MS.
Reformatsky reagents and disubstituted formamides formed
the dehydrated adducts spontaneously to afford enaminoesters
3a–h in 60–72 yield. The results are summarized in Table 2. Among
all the formamides tested, N-methyl-N-phenylformamide gave the
best yields of about 70% (entries 10–12). Methyl bromoacetate (2a)
gave methyl b-enaminoesters. Also, the reaction of ethyl iodoace-
tate 2c gave the desired products in a little better yield.
The Reformatsky reaction is one of the fundamental reactions in
organic synthesis.9,10 It is well recognized10–13 that the Reformat-
sky reagents as nucleophiles reacted with a number of electro-
philes including aldehydes, ketones, nitriles, amides, and imides
affording b-hydroxy or
a,b-unsaturated products. However, there
have been few studies on disubstituted formamides as electro-
philes in the Reformatsky reaction. In this Letter, we report an effi-
cient method to synthesize b-enaminoesters via Reformatsky
reaction with disubstituted formamides as novel electrophiles for
the first time. The afforded b-enaminoesters were E-isomers exclu-
sively (Scheme 1).
The solvent of this reaction was studied with ethyl bromoace-
tate and DMF as the model substrates, and the reaction was carried
out with Zn dust. Results are summarized in Table 1. The ether sol-
vents such as Et2O and 1,4-dioxane (entries 1 and 2) gave the prod-
O
O
O
Zn
X
+
H
N
OEt
N
OEt
X = Cl, Br, I
THF
* Corresponding author. Tel.: +86 0571 88320890; fax: +86 0571 88320544.
E-mail address: gdzjut@163.com (J.-R. Gao).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.003

1390
Y.-Y. Ke et al. / Tetrahedron Letters 50 (2009) 1389–1391
Table 1
Table 2
Reaction of haloacetates with DMF
Reaction
a-haloesters with disubstituted formamides
Entrya
X
Solvent(reflux)
Yieldb
Entry
1
2
Product
Yielda (%)
65
Ref.
14
1
2
3
4
5
6
7
Br
Br
Br
Br
Cl
Cl
I
Et2O
41
45
50
62
0
O
O
O
1,4-Dioxane
Toluene
THF
THF
Toluene
THF
1
2
2a
N
H
1a
N
OMe
OEt
3a
43
65
1a
1a
2b
2c
2a
2b
2c
2a
2b
2c
2a
2b
2c
62
65
61
60
67
63
61
64
72
70
72
15
15
16
17
17
16
18
18
19
20
20
N
3b
a
Reaction condition: 10 mmol of a-haloacetate, 5 mmol DMF, 15 mmol Zn dust,
0.1 mmol I2, and 10 mL THF were refluxed for 5 h.
b
Isolated yield of pure compound.
3
3b
The structures of b-enaminoesters were confirmed by 1H NMR
spectra. The characteristic coupling constant of the two protons
on the double bond is about 13 Hz, which indicates that the prod-
ucts are E-isomers instead of the Z isomers.
In summary, the first synthetically useful, convenient, and cost-
effective Reformatsky reaction of disubstituted formamides and
haloacetates is presented here. The exclusive b-enaminoester E-
isomers were prepared from different formamides and
tates in 60–72% yield via Reformatsky reaction.
General procedure: The reagents were obtained from commer-
cial sources. THF, DMF, diethyl ether, toluene, and 1,4-dioxane
were dehydrated with Na or CaH2. Zinc dust was activated by tri-
methyl chlorosilane. The 1H and 13C NMR spectra were recorded
at 500 and 125 MHz, respectively, in CDCl3 with a Bruker AM
500 spectrometer.
General procedure for synthesis of ethyl b-(N-methyl-N-phenylami-
no)-acrylate (3h): Under dry nitrogen atmosphere, a mixture of
ethyl bromoacetate (1.7 g, 10 mmol) and N-methyl-N-phenyl
formamide (0.68 g, 5 mmol) in anhydrous THF (20 mL) was added
to the mixture of Zn dust (3 equiv) and I2 (cat 0.1 equiv) over
30 min. The mixture was refluxed in THF until the staring material
was consumed, as determined by GC and TLC. The reaction mixture
was poured into 20 mL saturated aqueous ammonium chloride and
was extracted (3 Â 20 mL) with Et2O. The combined ether extracts
were washed with brine (60 mL) and dried over MgSO4. The sol-
vent was removed under vacuum, and the resulting crude product
was purified by chromatography on silica gel eluted with EtOAc–
petroleum ether to get ethyl b-(N-methyl-N-phenylamino)-acry-
late in 70% yield.
O
O
O
4
N
H
N
OMe
OEt
1b
3c
a
-
5
1b
1b
N
3d
a-haloace-
6
3d
O
O
7
O
N
H
O
N
N
OMe
OEt
1c
3e
O
8
1c
O
3f
9
1c
3f
O
O
O
10
11
H
OMe
OEt
N
N
N
1d
3g
1d
1d
3h
Methyl b-dimethylamino acrylate (3a): 1HNMR (CDCl3, 500 MHz)d
7.44 (d, J = 13 Hz, 1H), 4.51 (d, J = 13 Hz, 1H), 3.66 (s, 3H), 2.89 (s, 6H).
Ethyl b-dimethylamino acrylate (3b): 1H NMR (CDCl3, 500 MHz) d
7.44 (d, J = 13 Hz, 1H), 4.51 (d, J = 13 Hz, 1H), 4.13 (q, J = 7.0 Hz,
2H), 2.89 (s, 6H), 1.26 (t, J = 7.0 Hz, 3H). MS (m/z): 143, calcd for
C7H13NO2 [M] 143.18.
12
3h
a
Isolated yield of pure compound.
3.69–3.71 (m, 4H), 1.57–1.62 (m, 6H), 3.21 (t, J = 5 Hz, 4H), 1.26
(t, J = 7 Hz, 3H).
Methyl b-piperdinoacrylate (3c): 1HNMR (CDCl3, 500 MHz) d 7.39
(d, J = 13 Hz, 1H), 4.62 (d, J = 13 Hz, 1H), 3.66 (s, 3H), 3.18–3.20 (m,
4H), 1.56–1.66 (m, 6H).
Methyl b-(N-methyl-N-phenylamino)-acrylate (3g): 1H NMR
(CDCl3, 500 MHz) d 7.94 (d, J = 13 Hz, 1H), 7.12–7.37 (m, 5H),
4.94 (d, J = 13 Hz, 1H), 3.71 (s, 3H), 3.24 (s, 3H).
Ethyl b-piperdinoacrylate (3d): 1H NMR (CDCl3, 500 MHz) d 7.39
(d, J = 13 Hz, 1H), 4.62 (d, J = 13 Hz, 1H), 4.12 (q, J = 7.0 Hz, 2H),
3.19 (t, J = 5 Hz, 4H), 1.57–1.62 (m, 6H), 1.25 (t, J = 7 Hz, 3H).
Methyl b-morphinoacrylate (3e): 1H NMR (CDCl3, 500 MHz) d
7.36 (d, J = 13 Hz, 1H), 4.70 (d, J = 13 Hz, 1H), 3.70–3.72 (m, 4H),
3.67 (s, 3H), 3.20–3.22 (t, J = 5 Hz, 4H).
Ethyl b-(N-methyl-N-phenylamino)-acrylate (3h): 1H NMR
(CDCl3, 500 MHz) d 7.94 (d, J = 13 Hz, 1H), 7.10–7.37 (m, 5H),
4.94 (d, J = 13 Hz, 1H), 4.18 (q, J = 7.0 Hz, 2H), 3.24 (s, 3H), 1.29
(t, J = 7 Hz, 3H). 13C NMR (CDCl3, 125 MHz) d 169.20 (1C), 148.45
(1C), 146.60 (1C), 129.44 (2C), 124.14 (1C), 119.84 (2C), 90.45
(1C), 59.31 (1C), 36.55 (1C), 14.57 (1C). MS (m/z): 206 [M+1], calcd
for C12H15NO2 [M+H+] 206.11.
Ethyl b-morphinoacrylate (3f): 1H NMR (CDCl3, 500 MHz) d 7.36
(d, J = 13 Hz, 1H), 4.69 (d, J = 13 Hz, 1H), 4.13 (q, J = 7.0 Hz, 2H),
O
R1, R2 = alkyl, aryl
O
O
Zn
R1
R2
R1
R2
Acknowledgments
OR3
N
3 = Me
3 = Et
3 = Et
X
OR3
2a: X = Br
2b: X = Br
2c: X = I
R
N
H
THF
R
R
3
2
1
We gratefully acknowledge the financial support from the Nat-
ural Science Foundation of China (20876148) and the National Nat-
ural Science Foundation of Zhejiang (Y407306).
Scheme 2.

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1391
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