DABCO catalyzed reaction of various nucleophiles with activated alkynes leading to the formation of alkenoic acid esters, 1,4-dioxane, morpholine, and piperazinone derivatives

Article abstract of DOI:10.1016/j.tet.2006.04.100

The reaction of acids, alcohols, acylamides, 1,2-diols, 1,2-diamines or amino alcohols with activated alkynes catalyzed by 1,4-diazabicyclo[2.2.2]octane (DABCO) was systematically investigated. A series of unsaturated alkenoic acid esters or heterocycles were formed in the reaction of monobasic or dibasic nucleophiles in excellent yields, respectively.

Full text of DOI:10.1016/j.tet.2006.04.100

Tetrahedron 62 (2006) 6782–6791
DABCO catalyzed reaction of various nucleophiles
with activated alkynes leading to the formation of
alkenoic acid esters, 1,4-dioxane, morpholine,
and piperazinone derivatives
Ming-Jin Fan,a Gao-Qiang Lia and Yong-Min Lianga,b,
*
aState Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
bLanzhou Institute of Chemical Physics, Chinese Academy of Science, Lanzhou 730000, PR China
Received 20 January 2006; revised 27 April 2006; accepted 29 April 2006
Available online 26 May 2006
Abstract—The reaction of acids, alcohols, acylamides, 1,2-diols, 1,2-diamines or amino alcohols with activated alkynes catalyzed by
1,4-diazabicyclo[2.2.2]octane (DABCO) was systematically investigated. A series of unsaturated alkenoic acid esters or heterocycles were
formed in the reaction of monobasic or dibasic nucleophiles in excellent yields, respectively.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
our continuing investigation on DABCO catalyzed organic
reactions, we decided to look closer into this type of the
reaction.5d,e A series of nucleophiles, such as alcohols, acyl-
amides, acids, 1,2-diols, 1,2-diamines, and amino alcohols
were selected to demonstrate the scope of the reaction and
excellent results were obtained. On one hand, the reaction
between DMAD and alcohols, acylamides or acids
proceeded smoothly and rapidly at room temperature to
give a,b-unsaturated carbonyl compounds in excellent
yields. On the other hand, using dibasic nucleophiles, such
as 1,2-diols, 1,2-diamines, and amino alcohols as the sub-
strates, different cycloaddition products were obtained under
the same conditions. Herein the full details of our research
including the scope of the reaction, suitable reaction condi-
tions, and selectivity optimization, along with the corre-
sponding possible reaction mechanisms were reported.
The organocatalytic carbon–carbon bond-forming reaction
involving the addition of nucleophiles to activated alkynes
has been drawing increasing attention.1 Several organic
catalysts have been investigated in detail in recent years.2
Among them, DABCO, a tertiary amine base with weak
basicity and moderate hindrance, has been widely used as
a potential catalyst in a broad range of organic reactions,
such as Hillman–Baylis reaction,3 cyclopropanation,4 het-
erocycle formation,5 and other transformations. In our recent
investigations on DABCO catalyzed reaction of a-halo car-
bonyl compounds with dimethyl acetylenedicarboxylate
(DMAD), it was found that the Michael addition product
rather than desired cyclization product was formed in
moderate yield using 2-chloroacetamide as the substrate
(Scheme 1).5e
2. Results and discussion
O
NH
H
DABCO (10 mol%)
CCO2CH3
CCO2CH3
Cl
ClCH CONH
+
In an initial experiment, the reaction of alcohols with
DMAD in the presence of a catalytic amount of DABCO
(10 mol %) was examined. In a typical procedure, DMAD
(0.5 mmol), DABCO (0.05 mmol), and alcohols (0.5 mmol)
in CH2Cl2 were stirred for 10 min at room temperature
and gave unsaturated alkenoic acid esters facilely by flash
on chromatography on silica column. The reaction appeared
to be general with a number of alcohols affording conjugate
addition products in excellent yields (Table 1, entries 1–5),
but it suffered from a drawback of stereoselectivity. Most
of the reactions gave the final products as a pair of (E)-
2
2
CH2Cl2, r.t.
60%
H3CO2C
CO2CH3
Scheme 1.
On the basis of this observation and previous investigations,6
we considered DABCO as a potential catalyst for the reac-
tion of nucleophiles with activated alkynes. As a part of
* Corresponding author. Tel.: +86 931 3904776; fax: +86 931 8912582;
e-mail: liangym@lzu.edu.cn
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.100

M.-J. Fan et al. / Tetrahedron 62 (2006) 6782–6791
Table 2. Reaction of acylamides with DMADa
6783
Table 1. Reaction of alcohols with DMADa
RO
H
RHN
H
CCO2CH3
CCO2CH3
DABCO (10 mol%)
CH2Cl2, r.t.
DABCO (10 mol%)
CH2Cl2, r.t.
CCO2CH3
CCO2CH3
ROH
+
RNH2
+
H3CO2C
CO2CH3
H3CO2C
CO2CH3
Entry
ROH
Product
Yield /%b
E/Zc
Entry
RNH2 (or NH)
Product
Yield /%b
E/Zc
1
2
3
4
CH3OH
ClCH2CH2OH
1
88
95
91
92
20:80
30:70
45:55
E
1
2
ClCH2CONH2
O
6
60
30
E
2
3
4
CH2OH
7
E
NH2
(Et)2NCH2CH2OH
CH2OH
CONH2
3
4
8
51
71
E
5
5
90
40:60
SO2NH2
a
All the reactions were performed at room temperature and completed
within 10 min.
Isolated yields.
The (E)- and (Z)-isomers were separated by silica gel column chromato-
graphy.
9
E
E
H3C
b
c
O
O
NH
5
10
85
and (Z)-isomers (Table 1, entries 1–3 and 5). These two iso-
mers can be easily separated by column chromatography. An
exception appeared when Et2NCH2CH2OH was used as the
substrate. The product 4 was obtained with dominant (E)-
selectivity (Table 1, entry 4). The structure and stereochem-
istry of the products were determined on the basis of their
elemental analysis, mass spectrometry (MS), 1H NMR,
a
All the reactions were performed at room temperature and the reaction
time was extended to 12 h.
Isolated yields.
b
c
Determined by 1H NMR (300 MHz) spectra.
13C NMR, and IR data. The H NMR spectral data of the
1
products exhibited two isomers (except for product 4) and
both of them displayed characteristic resonance pattern
with appropriate chemical shift. For example, the 1H NMR
spectrum of product 1 showed three single sharp lines at
3.76, 3.85, and 3.95 ppm for three methoxy groups in the
(Z)-isomer and three singlets at 3.71, 3.75, and 3.89 ppm
for the (E)-isomer. The olefinic proton in the (Z)-isomer
resonated at 6.19 ppm, while the olefinic proton in the (E)-
isomer resonated at 5.21 ppm. It was in agreement with
With an intention to expand the scope of this conjugate ad-
dition, we tested various acids in this reaction and got excel-
lent results surprisingly. In spite of longer reaction time
required, the present method seemed to be perfect in terms
of stereoselectivity. Only the (Z)-form isomers were isolated
in all the reactions of various acids with DMAD (Table 3,
entries 1–8). Moreover, the reaction had perfect selectivity
in cases of more than one nucleophilic groups presented in
the acids. For example, in the reaction of 2-hydroxybenzoic
acid, only COOH group participated and gave the desired
product with dominate (Z)-form (Table 3, entry 8). It should
be an acidity-controlled process and the selectivity was de-
termined by the pKa value of the nucleophile. Nucleophilic
groups with lower pKa value will participate in the reaction
first. The structure of the product was characterized by spec-
1
the values reported in the previous literature.7 In all the H
NMR spectra, (E)-isomer displayed a signal as a single sharp
resonance at about 5.21–5.37 ppm for the olefinic proton.
The 1H NMR chemical shift of the (Z)-form was similar to
that of the (E)-isomer, except for the olefinic proton, which
was at about 6.19–6.36 ppm (see Section 4).
1
troscopic analysis. In each H NMR spectrum of the prod-
Although amine reacted with activated alkynes quickly and
no base catalyst was needed,8 we found that the same reac-
tion of acylamides was very sluggish in the absence of a base
catalyst. However, in the presence of a catalytic amount of
DABCO (10 mol %), various acylamides could undergo
a smooth reaction with activated alkynes at room tempera-
ture and gave the corresponding unsaturated alkenoic acid
esters in moderate yields with excellent stereoselectivity.
Only the (E)-form isomers were isolated in all the reactions
of various acylamides with DMAD (Table 2, entries 1–5).
Though the reaction showed optimal stereoselectivity,
most of the yields were lower comparing to that of alcohols.
It could be attributed to the following two reasons: (i) The
reaction could not proceed completely even longer reaction
time (24 h) and higher temperature (reflux) were adopted;
(ii) complex side products were formed in company with
the generation of unsaturated alkenoic acid esters. In each
1H NMR spectrum of the products, a singlet was observed
at about 5.54–5.74 ppm for the olefinic proton (except for
product 10). These shifts were similar to those observed in
the previous literature.7
ucts, the olefinic proton resonated at 6.66–6.82 ppm
corresponding to the proposed (Z)-isomer. Furthermore,
the structure and stereoselectivity of the products were
established unambiguously by X-ray analysis of 17 as repre-
sentative example (Fig. 1).9 To the best of our knowledge,
there is no such nucleophilic conjugate addition process
involving acids to activated alkynes that has been reported
in the literature so far.
The reaction of other activated alkynes was also investi-
gated, such as benzyl propiolate, methyl propiolate with
acids, alcohols or acylamides. It was found that excellent re-
sults were obtained under the same conditions (0.5 mmol of
benzyl propiolate, 0.5 mmol of nucleophiles, and 0.05 mmol
of DABCO, CH2Cl2, at room temperature). The reaction
proceeded smoothly and rapidly (within 10 min) to give
conjugate addition products in excellent yields with better
stereoselectivities than that of DMAD (Table 4). Most of
the reaction gave (E)-form alkenoic acid esters as the main
product. The 1H NMR spectrum of (E)-form isomer
displayed two doublets with J¼12.3 Hz for the two olefinic

6784
M.-J. Fan et al. / Tetrahedron 62 (2006) 6782–6791
Table 4. Reaction of various nucleophiles with methyl or benzyl propiolatea
Table 3. Reaction of acids with DMADa
O
R2X
H
DABCO (10 mol%)
CH2Cl2, r.t.
R2XH
+
O
CO2CH3
H
HC CCO2R1
DABCO (10 mol%)
CH2Cl2, r.t.
CCO2CH3
CCO2CH3
RCOOH
+
H
CO2R1
R
H3CO2C
Entry
R1
R2XH
Product
Yield /%b
99
E/Zc
Entry
RCOOH
Product
Yield /%b
E/Zc
1
2
Bn
ClCH2CH2OH
COOH
19
20
95:5
1
2
CH3COOH
CH3(CH2)2COOH
11
12
94
99
Z
Z
Bn
98
E
CH2COOH
O
3
4
5
13
14
15
91
85
88
Z
Z
Z
CH2COOH
NH
3
Bn
21
22
99
90
E
O
ClCH2CH2OH
COOH
4
CH3
90:10
a
All the reactions were performed at room temperature and completed
within 10 min.
Isolated yields.
COOH
F
b
c
6
7
16
78
88
76
Z
Z
Z
Determined by 1H NMR (300 MHz) spectra.
COOH
17
3-phenylpropiolate should also perform the same reaction
with alcohols, acylamides or acids. However, the reaction
did not take place even when the reaction mixture was heated
to reflux or the reaction time was prolonged to 48 h.
F
COOH
OH
8
18d
a
All the reactions were performed at room temperature and completed
within 6 h.
Isolated yields.
R2X
R3
H
DABCO (10 mol%)
CH2Cl2, r.t.
R3C CCO2R1
DABCO
b
c
d
R2XH
+
Determined by 1H NMR (300 MHz) analysis.
The reaction time need to be extended to 24 h.
CO2R1
- DABCO
protons, while the chemical shift of the (Z)-form appeared
with J¼6.6 Hz. It was in agreement with the proposed (E)-
and (Z)-isomers, respectively.
R3
CO2R1
R3
CO2R1
H
R3
CO2R1
R2X
N
R2X
b
N
+
N
+
A proposed mechanism for this reaction was outlined in
Scheme 2 based on the previous investigation of Nozaki
Kyoko et al.10 Initially, the zwitterionic intermediate a,11
formed from DABCO and DMAD, deprotonated the nucleo-
phile to form the corresponding intermediates b and c.
Subsequent Michael addition of b to c gave intermediate
d, which then eliminated DABCO to afford the final product.
According to the proposed reaction mechanism, ethyl
H
N
+
R2XH
a
N
c
N
d
Scheme 2. Plausible mechanism for the reaction of various nucleophiles
with activated alkynes.
Further scope exploration revealed that 1,2-diols were
another class of suitable nucleophiles for this reaction.
Interestingly, 1,2-diols on treatment with DMAD in the pres-
ence of a catalytic amount of DABCO (10 mol %) in CH2Cl2
afforded 1,4-dioxane derivatives in good to excellent yields.
The reaction appeared to be general with a number of 1,2-
diols. The results using this mild and straightforward proce-
dure were shown in Table 5. The structure of the product was
revealed by H and 13C NMR analyses. In addition, the
1
NMR-based structure was confirmed by X-ray crystallo-
graphic analysis of 23 as representative example (Fig. 2).12
All the reactions proceeded extremely fast and completed
within 10 min. The formation of 1,4-dioxane derivatives
involved a Michael addition of 1,2-diol to DMAD and a
subsequent intramolecular esterification. Further study re-
vealed that this reaction did not take place in the absence
of DABCO, which suggested that the tertiary amine was
required as a catalyst in this procedure.
On the basis of the above encouraging results, we used this
concept to devise a new one-step approach to the synthesis
Figure 1. X-ray structure of 17.

M.-J. Fan et al. / Tetrahedron 62 (2006) 6782–6791
Table 6. Reaction of amino alcohols with DMADa
6785
Table 5. Reaction of 1,2-diols with DMADa
R1
O
O
H
N
R1
R2
OH
OH
R
DABCO (10 mol%)
CH2Cl2, r.t.
O
CCO2CH3
CCO2CH3
OH
NH2
CO2H
NH2
NaBH4-I2
DMAD
r.t.
+
*
*
*
R
R
R2
O
THF, reflux
O
CO2CH3
CO2CH3
Entry
1
1,2-Diol
OH
Product
Yield /%b
80
Entry Amino acid
Amino alcohol
Product
[a]2D0c
Yield /%b
23
HO
1
2
—
NH2CH2CH2OH
CH2OH
29 (80)
30 (96)
—
ꢀ58
OH
OH
2
3
24
25
96
60
HO
D-Valine
*
NH2
+109
3
L-Isoleucine
31 (60)
OH
OH
H2N * CH2OH
NH2
+70
+7
4
5
26
27
74
58
4
5
6
7
L-Leucine
32 (74)
33 (58)
34 (60)
35 (80)
CH2OH
*
OH
OH
NH2
L-Phenylalanine
D-Phenylalanine
D-Methionine
Ph
Ph
CH2OH
NH2
*
OH
OH
ꢀ7
OH
CH2OH
*
6
28
60
CH2OH
ꢀ56
MeS
HN
NH2
*
a
All the reactions were performed between DMAD (0.5 mmol), 1,2-diols
(3 mmol), and DABCO (0.05 mmol) at room temperature and completed
within 10 min.
Isolated yields.
b
8
DL-Tryptophane
36 (90)
37 (61)
—
CH2OH
*
NH2
of morpholine derivatives from amino alcohols. As we ex-
pected, excellent result was obtained in the reaction of equi-
molar amount of 2-aminoethanol with DMAD under above
conditions (Table 6, entry 1). The structure of the product
was deduced from its elemental analysis, mass spectrometry
ꢀ38
OH
NH2
*
9
—
*
a
All the reactions were performed between equimolar DMAD and amino
alcohols at room temperature and completed within 10 h.
Isolated yields.
[a]D in CHCl3 (c¼1).
(MS), and H and 13C NMR spectroscopic data. The H
NMR spectrum showed a sharp singlet at 3.71 ppm for three
methoxy group protons and a broad peak at 8.37 ppm for NH
group proton. The olefinic proton resonated at 5.66 ppm
corresponding to the proposed (Z)-isomer. On top of this, a
triplet at 4.50–4.54 ppm and a multiplet at 3.50–3.55 ppm
were readily attributable to CH2 bonding to oxygen and
CH2 bonding to NH group, respectively. It was worthy of
note that this reaction could take place in the absence of
DABCO. It was demonstrated that the NH2 group in the
amino alcohol played the same role as DABCO in this
1
1
b
c
reaction. It served not only as a reactant, but also as a catalyst
in this reaction. A series of amino alcohols, which were read-
ily prepared from commercial available amino acids,13 were
tested in this process to afford the corresponding morpho-
lines (Table 6, entries 2–8). The reaction was found to be
general with respect to various amino alcohols and morpho-
line derivatives were obtained in high yields. Moreover, we
were pleased to find that this technique could also be ex-
tended to provide bicyclic morpholine in good yield (Table
6, entry 9). An attractive feature of this synthetic approach
was that the incorporation of morpholine C3-substitution
was facilitated by the aide availability of natural and unnat-
ural a-amino acids. Similarly, 1,2-diamines, such as ethane-
1,2-diamine and cyclohexane-1,2-diamine, could also react
with DMAD in the absence of DABCO under the identical
conditions to afford piperazinone derivatives in excellent
yields (88% and 83%, respectively, Scheme 3). The present
process was more efficient with primary 1,2-diamine or
amino alcohol having primary NH2 group, while secondary
1,2-diamine or amino alcohol with secondary NH2 group did
not work in this manner. For example, treatment of N1,N2-
dimethylethane-1,2-diamine or L-prolinol with DMAD did
not give the expected products under the same conditions.
Figure 2. X-ray structure of 23.

6786
M.-J. Fan et al. / Tetrahedron 62 (2006) 6782–6791
H
H
N
R
N
O
O
CO2CH3
CO2CH3
NH2
NH2
DABCO (10 mol%)
CCO2CH3
CCO2CH3
R
CH2OH
*
*
+
CH2Cl2, r.t.
88%
N
H
O
+
NH2
CO2CH3
O
CO2CH3
38
-CH3OH
CO2CH3
H
N
H3CO2C
+
CO2CH3
NH2
NH2
DABCO (10 mol%)
CCO2CH3
CCO2CH3
O
+
*
CH2Cl2, r.t.
83%
R
NH2
+
N
H
H2N
HOH2C
H
A
CO2CH3
*
OCH3
O
39
R
i
Scheme 3. Reaction of 1,2-diamines with DMAD.
R
R
*
*
+
O
H3CO
H2N
H2N
CO2CH3
H
The mechanisms of these reactions have not been unequivo-
cally established, but two plausible explanations were pro-
posed in Schemes 4 and 5. In the reaction of 1,2-diol or
1,2-diamines with DMAD, it might also involve the initial
generation of a zwitterionic intermediate a between
DABCO and DMAD (Scheme 4), which was readily proton-
ated by one of the two protons of the nucleophile to yield
intermediates b and c. Subsequent Michael addition of b
to c formed intermediate d. It underwent the elimination
of DABCO to form intermediate e, which was followed by
intramolecular esterification in the presence of DABCO to
produce the corresponding 1,3-dioxane derivatives and
regenerate DABCO to accomplish the catalytic cycle. In
the reaction of amino alcohol with DMAD, similarly, zwit-
terionic intermediate A generated from the addition of
amino alcohol to DMAD (Scheme 5) underwent a second
Michael addition of the OH group, which was followed by
the leaving of NH2 group. Subsequent intramolecular amid-
ization led to the final morpholine derivatives. The slow
transformation step of h to i was assumed to be the rate
determining step, accounting for the longer reaction time
required for the final product.
O
CO2CH3
H
H3CO
O
O
g
h
Scheme 5. Plausible mechanism for the reaction of amino alcohols with
DMAD.
Further comparison studies demonstrated that DABCO was
the optimal catalyst for the addition of acids and cyclization
of 1,2-diols. Triphenylphosphine, which was commonly
employed in the traditional conjugate addition reaction,
was ineffective in promoting these reactions under the
same conditions. Triethylamine and 4-methylmorpholine
gave the lowered yields.
3. Conclusion
In the present work, we reported an excellent catalyst,
DABCO, for the reaction of nucleophiles with some acti-
vated alkynes. The procedure provided an easy access to
unsaturated alkenoic acid ester derivatives and various het-
erocycles in good to excellent yields under mild reaction
conditions. This process expanded not only the scope of
organocatalyst catalyzed carbon–carbon bond-forming
reaction but also unprecedented approaches to heterocycle
formations.
H3CO2C
CO2CH3
1,2-diols
CO2CH3
CO2CH3
N
N
N
N
+
a
4. Experimental
4.1. General
R
R2
HO
H3CO2C
CO2CH3
R1
R2
OH
O
All reagents were used directly as obtained commercially
unless otherwise noted. Melting points were determined on
a microscopic apparatus and were uncorrected. Column
O
N
CO2CH3
H3CO2C
H
N
N
H
b
1
c
chromatography was carried out on silica gel. H NMR
d
spectra were recorded at 300 MHz in CDCl3 and 13C NMR
spectra were recorded at 75 MHz in CDCl3 using TMS as
internal standard. Mass spectra were recorded by the EI
method. Nicolet AVATAR 360 FTIR spectrometer was used
for IR spectra. HRMS spectra were obtained with a Bruker
APEX II instrument.
N
R1
HO
H3CO
R2
O
R2
O
CO2CH3
CO2CH3
R1
HO
H
OCH3
H
O
O
e
f
4.2. Typical procedure for the reaction of various
nucleophiles with DMAD. Using alcohol as an example
R1
R2
O
O
O
DMAD (0.5 mmol), DABCO (0.05 mmol), and alcohol
(0.5 mmol, 3 mmol for 1,2-diol, 0.5 mmol for other nucleo-
philes) were stirred in CH2Cl2 (4 ml) at room temperature
for 10 min. (The reaction time needed to be extended
CO2CH3
Scheme 4. Plausible mechanism for the reaction of 1,2-diols or 1,2-
diamines with DMAD.

M.-J. Fan et al. / Tetrahedron 62 (2006) 6782–6791
6787
to 10 h for the reaction of amino alcohols and 6 h for acids.)
The solvent was evaporated under reduced pressure and the
residue was purified by flash chromatography on silica col-
umn to give final products.
(t, J¼7.2 Hz, 6H). 13C NMR (75 MHz, CDCl3): d¼166.1,
163.8, 161.7, 93.1, 68.7, 52.6, 51.3, 50.5, 47.6. MS (EI,
70 eV): m/z (%)¼259 (M+, 0.44), 244 (0.92), 100 (15.08),
86 (100). Anal. Calcd for C12H21NO5: C, 55.58; H, 8.16;
N, 5.40. Found: C, 55.37; H, 8.02; N, 5.56. IR (KBr):
2956, 2926, 2851, 1754, 1719, 1627, 1209, 1150.
4.2.1. Dimethyl 2-methoxyfumarate. Oil. 1H NMR
(300 MHz, CDCl3): d¼6.19 (s, 1H), 3.95 (s, 3H), 3.85 (s,
3H), 3.76 (s, 3H). 13C NMR (75 MHz, CDCl3): d¼164.9,
163.4, 155.0, 107.9, 61.2, 53.0, 51.9. MS (EI, 70 eV): m/z
(%)¼174 (M+, 2.58), 159 (20.46), 143 (48.67), 115
(67.41), 69 (100). Known compound.7a
1
4.2.8. Dimethyl 2-(benzyloxy) fumarate. Sticky oil. H
NMR (300 MHz, CDCl3): d¼7.31–7.45 (m, 5H), 6.25 (s,
1H), 5.19 (s, 2H), 3.81 (s, 3H), 3.73 (s, 3H). 13C NMR
(75 MHz, CDCl3): d¼164.5, 163.3, 153.6, 136.0, 128.4,
128.3, 128.1, 110.2, 74.9, 52.7, 51.6. MS (EI, 70 eV): m/z
(%)¼250 (M+, 0.55), 218 (0.63), 191 (1.33), 159 (2.20),
91 (100). Anal. Calcd for C13H14O5: C, 62.39; H, 5.64.
Found: C, 62.10; H, 5.22. IR (KBr): 2953, 2849, 1729,
1640, 1266, 742, 698.
4.2.2. Dimethyl 2-methoxymaleate. Oil. 1H NMR
(300 MHz, CDCl3): d¼5.21 (s, 1H), 3.89 (s, 3H), 3.75 (s,
3H), 3.71 (s, 3H). 13C NMR (75 MHz, CDCl3): d¼166.2,
163.9, 162.4, 93.0, 56.9, 52.9, 51.5. MS (EI, 70 eV): m/z
(%)¼174 (M+, 4.7), 159 (17.2), 143 (51.1), 115 (55), 69
(100). Known compound.7a
4.2.9. Dimethyl 2-(benzyloxy) maleate. Sticky oil. 1H
NMR (300 MHz, CDCl3): d¼7.36–7.38 (m, 5H), 5.29 (s,
1H), 4.91 (s, 2H), 3.88 (s, 3H), 3.69 (s, 3H). 13C NMR
(75 MHz, CDCl3): d¼166.2, 163.8, 161.5, 134.0, 128.7,
127.8, 94.0, 71.8, 52.9, 51.6. MS (EI, 70 eV): m/z
(%)¼250 (M+, 0.14), 218 (0.44), 191 (1.35), 159 (3.24),
91 (100). Anal. Calcd for C13H14O5: C, 62.39; H, 5.64.
Found: C, 62.39; H, 5.52. IR (KBr): 2954, 1752, 1725,
1637, 1203, 1131, 826.
4.2.3. Dimethyl 2-(2-chloroethoxy) fumarate. Oil. 1H
NMR (300 MHz, CDCl3): d¼6.30 (s, 1H), 4.34–4.38 (t,
J¼6 Hz, 2H), 3.85 (s, 3H), 3.77–3.81 (t, J¼6 Hz, 2H),
3.77 (s, 3H). 13C NMR (75 MHz, CDCl3): d¼164.3, 162.9,
153.3, 110.6, 73.2, 52.8, 51.7, 42.2. MS (EI, 70 eV): m/z
(%)¼222 (M+, 0.64), 207 (0.45), 191 (15.05), 163 (41.83),
127 (36.58), 101 (61.28), 69 (100). Anal. Calcd for
C8H11ClO5: C, 43.16; H, 4.98. Found: C, 43.34; H, 4.54.
IR (KBr): 2956, 2852, 1728, 1643, 1269.
4.2.10. Dimethyl 2-(2-chloroacetamido) maleate. Sticky
oil. 1H NMR (300 MHz, CDCl3): d¼11.03 (s, 1H), 5.64 (s,
1H), 4.14 (s, 2H), 3.83 (s, 3H), 3.77 (s, 3H). 13C NMR
(75 MHz, CDCl3): d¼168.0, 164.8, 163.9, 142.4, 104.3,
53.4, 52.4, 42.4. MS (EI, 70 eV): m/z (%)¼235 (M+, 5.36),
237 (1.85), 204 (11.46), 206 (3.76), 176 (100), 178
(30.74). Anal. Calcd for C8H10ClNO5: C, 40.78; H, 4.28;
N, 5.94. Found: C, 40.61; H, 4.01; N, 5.65. IR (KBr):
3285, 2956, 2851, 1746, 1694, 1638, 1295, 1223.
4.2.4. Dimethyl 2-(2-chloroethoxy) maleate. Oil. 1H NMR
(300 MHz, CDCl3): d¼5.22 (s, 1H), 4.09–4.13 (t, J¼6 Hz,
2H), 3.90 (s, 3H), 3.76–3.79 (t, J¼5.7 Hz, 2H), 3.71 (s,
1H). 13C NMR (75 MHz, CDCl3): d¼166.0, 163.5, 160.9,
94.2, 69.4, 53.0, 51.6, 40.3. MS (EI, 70 eV): m/z (%)¼222
(M+, 0.49), 207 (0.15), 191 (8.71), 163 (22.19), 127
(16.43), 101 (49.94), 69 (100). Anal. Calcd for
C8H11ClO5: C, 43.16; H, 4.98. Found: C, 43.12; H, 4.68.
IR (KBr): 2956, 2851, 1751, 1717, 1630, 1212, 1154.
4.2.11. Dimethyl 2-(acrylamido) maleate. White powder,
1
mp 57–58 ꢁC. H NMR (300 MHz, CDCl3): d¼10.45 (s,
4.2.5. Dimethyl 2-(prop-2-ynyloxy) fumarate. Sticky oil.
1H NMR (300 MHz, CDCl3): d¼6.36 (s, 1H), 4.91 (s, 2H),
3.85 (s, 3H), 3.77 (s, 3H), 2.58 (s, 1H). 13C NMR
(75 MHz, CDCl3): d¼164.4, 163.1, 151.9, 111.5, 77.1,
77.0, 60.2, 53.0, 51.8. MS (EI, 70 eV): m/z (%)¼198 (M+,
1.25), 183 (0.63), 167 (12.10), 139 (74.73), 111 (60.55),
69 (100). Anal. Calcd for C9H10O5: C, 54.55; H, 5.09.
Found: C, 54.32; H, 5.34. IR (KBr): 2958, 2852, 1733,
1633, 1256, 1116.
1H), 5.87–6.46 (m, 3H), 5.54 (s, 1H), 3.88 (s, 3H), 3.78 (s,
3H). 13C NMR (75 MHz, CDCl3): d¼168.4, 164.1, 162.9,
143.8, 130.2, 129.4, 101.5, 53.1, 51.9. MS (EI, 70 eV): m/z
(%)¼213 (M+, 3.39), 182 (3.63), 154 (35.25), 55 (100).
Anal. Calcd for C9H11NO5: C, 50.70; H, 5.20; N, 6.57.
Found: C, 50.51; H, 5.13; N, 6.65. IR (KBr): 3302, 2954,
2852, 1745, 1692, 1633, 1283, 1220.
1
4.2.12. Dimethyl 2-(benzamido) maleate. Sticky oil. H
NMR (300 MHz, CDCl3): d¼11.24 (s, 1H), 7.47–7.96 (m,
5H), 5.60 (s, 1H), 3.92 (s, 3H), 3.79 (s, 3H). 13C NMR
(75 MHz, CDCl3): d¼168.8, 164.5, 144.5, 133.1, 131.8,
128.9, 127.8, 101.2, 53.1, 51.9. MS (EI, 70 eV): m/z
(%)¼263 (M+, 5.55), 232 (4.71), 204 (82.65), 105 (100).
Anal. Calcd for C13H13NO5: C, 59.31; H, 4.98; N, 5.32.
Found: C, 59.19; H, 5.28; N, 5.20. IR (KBr): 3291, 2954,
2851, 1746, 1684, 1631, 1289, 1220, 774, 708.
4.2.6. Dimethyl 2-(prop-2-ynyloxy) maleate. Sticky oil. 1H
NMR (300 MHz, CDCl3): d¼5.37 (s, 1H), 4.60 (s, 2H), 3.89
(s, 3H), 3.72 (s, 3H), 2.66 (s, 1H). 13C NMR (75 MHz,
CDCl3): d¼165.8, 163.3, 159.7, 95.1, 77.8, 75.4, 57.4,
52.9, 51.6. MS (EI, 70 eV): m/z (%)¼198 (M+, 0.60), 183
(0.43), 167 (18.84), 139 (66.80), 111 (52.50), 69 (100).
Anal. Calcd for C9H10O5: C, 54.55; H, 5.09. Found: C,
54.57; H, 5.04. IR (KBr): 2954, 2853, 1748, 1714, 1630,
1144.
4.2.13. Dimethyl 2-(tosylamino) maleate. White powder,
1
mp 65–66 ꢁC. H NMR (300 MHz, CDCl3): d¼10.25 (s,
4.2.7. Dimethyl 2-(2-(diethylamino) ethoxy) maleate. Oil.
1H NMR (300 MHz, CDCl3): d¼5.21 (s, 1H), 3.90–3.95
(t, J¼6.6 Hz, 2H), 3.88 (s, 3H), 3.70 (s, 3H), 2.81–2.85
(t, J¼6.6 Hz, 2H), 2.54–2.61 (q, J¼7.2 Hz, 4H), 1.01–1.05
1H), 7.80–7.83 (d, J¼8.1 Hz, 2H), 7.32–7.35 (d,
J¼8.4 Hz, 2H), 5.74 (s, 1H), 3.81 (s, 3H), 3.75 (s, 3H),
2.44 (s, 3H). 13C NMR (75 MHz, CDCl3): d¼168.2, 162.9,
144.2, 143.6, 137.2, 129.4, 127.1, 103.4, 53.1, 52.1, 21.5.

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M.-J. Fan et al. / Tetrahedron 62 (2006) 6782–6791
MS (EI, 70 eV): m/z (%)¼313 (M+, 0.85), 282 (0.13), 189
(5.19), 164 (19.42), 155 (30.23), 91 (100). Anal. Calcd for
C13H15NO6S: C, 49.83; H, 4.83; N, 4.47. Found: C, 49.61;
H, 4.76; N, 4.17. IR (KBr): 3116, 2955, 2844, 1747, 1682,
1627, 1272, 1230, 1161, 837.
(0.11), 105 (100), 77 (42.36). Anal. Calcd for C13H12O6:
C, 59.09; H, 4.58. Found: C, 59.37; H, 4.34. IR (KBr):
2956, 2848, 1736, 1664, 1279, 1104, 707, 669.
4.2.20. Dimethyl 2-(2-fluorobenzoxy) fumarate. Sticky
1
oil. H NMR (300 MHz, CDCl3): d¼7.17–8.13 (m, 4H),
4.2.14. Dimethyl 2-(1,3-dioxoisoindolin-2-yl) maleate.
White powder, mp 104–105 ꢁC. 1H NMR (300 MHz,
CDCl3): d¼7.78–7.95 (m, 4H), 7.18 (s, 1H), 3.87 (s, 3H),
3.73 (s, 3H). 13C NMR (75 MHz, CDCl3): d¼165.5, 163.1,
162.3, 134.5, 132.0, 131.6, 128.6, 124.1, 53.5, 52.4. MS
(EI, 70 eV): m/z (%)¼289 (M+, 8.61), 258 (5.89), 230
(100), 104 (97.83), 76 (81.30). Anal. Calcd for C14H11NO6:
C, 58.13; H, 3.83; N, 4.84. Found: C, 58.36; H, 4.10;
N, 4.55. IR (KBr): 2956, 2924, 2853, 1732, 1659, 720.
6.80 (s, 1H), 3.87 (s, 3H), 3.73 (s, 3H). 13C NMR
(75 MHz, CDCl3): d¼164.1, 163.0, 161.4, 160.7, 146.4,
135.8, 135.7, 132.6, 124.2, 117.3, 116.9, 116.6, 116.5,
53.2, 52.1. MS (EI, 70 eV): m/z (%)¼282 (M+, 0.27), 251
(0.59), 223 (0.36), 123 (100), 95 (19.92). HRMS (EI) calcd
for C13H11FO6: (M+Na) 305.0432. Found: 305.0431. IR
(KBr): 2957, 1733, 1279, 756.
4.2.21. Dimethyl 2-(4-fluorobenzoxy) fumarate. White
powder, mp 69–70 ꢁC. 1H NMR (300 MHz, CDCl3):
d¼8.15–8.20 (m, 2H), 7.15–7.21 (t, J¼8.7 Hz, 2H), 6.79
(s, 1H), 3.86 (s, 3H), 3.72 (s, 3H). 13C NMR (75 MHz,
CDCl3): d¼168.0, 164.6, 163.0, 162.6, 161.5, 146.7,
133.2, 133.0, 124.3, 117.2, 116.0, 115.7, 53.2, 52.0. MS
(EI, 70 eV): m/z (%)¼282 (M+, 0.35), 251 (0.58), 223
(0.15), 123 (100), 95 (29.54). HRMS (EI) calcd for
C13H11FO6: (M+Na) 305.0432. Found: 305.0437. IR
(KBr): 2964, 1732, 1273, 856, 759.
4.2.15. Dimethyl 2-acetoxy fumarate. Oil. 1H NMR
(300 MHz, CDCl3): d¼6.69 (s, 1H), 3.86 (s, 3H), 3.77 (s,
3H), 2.32 (s, 3H). 13C NMR (75 MHz, CDCl3): d¼167.7,
163.1, 161.4, 146.5, 116.8, 53.1, 51.9, 20.2. MS (EI,
70 eV): m/z (%)¼202 (M+, 0.07), 171 (4.40), 143 (46.92),
101 (77.55), 69 (55.10), 43 (100). Anal. Calcd for
C8H10O6: C, 47.53; H, 4.99. Found: C, 47.59; H, 4.73. IR
(KBr): 2957, 2852, 1779, 1732, 1662, 1280, 1162.
1
4.2.16. Dimethyl 2-(butyryloxy) fumarate. Oil. H NMR
4.2.22. Dimethyl 2-(2-hydroxybenzoxy) fumarate. Sticky
1
(300 MHz, CDCl3): d¼6.68 (s, 1H), 3.84 (s, 3H), 3.76 (s,
3H), 2.54–2.59 (t, J¼6.9 Hz, 2H), 1.74–1.81 (m, 2H),
1.01–1.06 (t, J¼7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3):
d¼170.4, 163.1, 161.5, 146.6, 116.7, 53.0, 51.9, 35.3,
17.9, 13.3. MS (EI, 70 eV): m/z (%)¼230 (M+, 0.09), 199
(1.24), 171 (1.97), 129 (1.76), 71 (100). Anal. Calcd for
C10H14O6: C, 52.17; H, 6.13. Found: C, 51.93; H, 5.72. IR
(KBr): 2961, 2880, 1773, 1732, 1664, 1279, 1102.
oil. H NMR (300 MHz, CDCl3): d¼9.99 (s, 1H), 6.94–
8.01 (m, 4H), 6.82 (s, 1H), 3.88 (s, 3H), 3.74 (s, 3H). 13C
NMR (75 MHz, CDCl3): d¼167.1, 162.9, 162.0, 161.3,
146.0, 136.9, 130.8, 119.7, 117.8, 110.9, 53.4, 52.3. MS
(EI, 70 eV): m/z (%)¼280 (M+, 0.37), 249 (0.68), 221
(0.90), 121 (100). Anal. Calcd for C13H12O7: C, 55.72; H,
4.32. Found: C, 55.83; H, 4.48. IR (KBr): 3239, 2957,
2851, 1732, 1699, 1653, 1293, 1156, 759.
4.2.17. 13 Dimethyl 2-(2-phenylacetoyloxy) fumarate.
4.2.23. (E)-Benzyl 3-(2-chloroethoxy) acrylate. White
powder, mp 40–41 ꢁC. 1H NMR (300 MHz, CDCl3):
d¼7.59–7.63 (d, J¼12.3 Hz, 1H), 7.30–7.36 (m, 5H),
5.26–5.30 (d, J¼12.3 Hz, 1H), 5.15 (s, 2H), 4.03–4.07
(t, J¼6 Hz, 2H), 3.66–3.70 (t, J¼5.7 Hz, 2H). 13C NMR
(75 MHz, CDCl3): d¼167.0, 161.8, 136.2, 128.4, 128.0,
97.1, 70.5, 65.6, 41.2. MS (EI, 70 eV): m/z (%)¼240 (M+,
0.44), 195 (21.69), 160 (32.72), 133 (100), 91 (99.32).
Anal. Calcd for C12H13ClO3: C, 59.88; H, 5.44. Found: C,
59.69; H, 5.66. IR (KBr): 1709, 1627, 1132, 963, 751, 698.
1
Sticky oil. H NMR (300 MHz, CDCl3): d¼7.29–7.36 (m,
5H), 6.68 (s, 1H), 3.90 (s, 2H), 3.78 (s, 3H), 3.67 (s, 3H).
13C NMR (75 MHz, CDCl3): d¼168.5, 163.1, 161.4,
146.4, 132.5, 129.5, 128.5, 127.3, 117.1, 53.1, 52.0, 40.3.
MS (EI, 70 eV): m/z (%)¼278 (M+, 0.02), 247 (0.38), 219
(0.20), 118 (17.35), 91 (100). Anal. Calcd for C14H14O6:
C, 60.43; H, 5.07. Found: C, 60.39; H, 5.32. IR (KBr):
2953, 2924, 2853, 1773, 1729, 1664, 1279, 1102, 789, 689.
4.2.18. Dimethyl 2-(2-(naphthalen-6-yl) acetoyloxy) fu-
1
marate. Sticky oil. H NMR (300 MHz, CDCl3): d¼7.40–
4.2.24. (Z)-Benzyl 3-(2-chloroethoxy) acrylate. White
powder, mp 50–51 ꢁC. 1H NMR (300 MHz, CDCl3):
d¼7.26–7.40 (m, 5H), 6.56–6.59 (d, J¼6.9 Hz, 1H), 5.15
(s, 2H), 4.93–4.96 (d, J¼7.2 Hz, 1H), 4.24–4.28 (t,
J¼6 Hz, 2H), 3.72–3.76 (t, J¼6.3 Hz, 1H). 13C NMR
(75 MHz, CDCl3): d¼164.7, 158.9, 136.3, 128.4, 128.0,
127.9, 96.5, 96.4, 74.9, 65.4, 42.2. MS (EI, 70 eV): m/z
(%)¼240 (M+, 3.17), 195 (7.77), 160 (4.66), 133 (96.92),
91 (100). Anal. Calcd for C12H13ClO3: C, 59.88; H, 5.44.
Found: C, 59.67; H, 5.56. IR (KBr): 1709, 1634, 1157,
1134, 745, 697.
8.08 (m, 7H), 6.66 (s, 1H), 4.32 (s, 2H), 3.68 (s, 3H), 3.58
(s, 3H). 13C NMR (75 MHz, CDCl3): d¼168.4, 163.1,
161.4, 146.4, 133.7, 132.0, 129.1, 128.6, 128.3, 126.3,
125.8, 125.4, 123.8, 117.2, 53.0, 51.9, 38.2. MS (EI,
70 eV): m/z (%)¼328 (M+, 9.61), 297 (0.30), 168 (100),
141 (73.02), 115 (67.61). Anal. Calcd for C18H16O6: C,
65.85; H, 4.91. Found: C, 65.88; H, 4.95. IR (KBr): 2954,
2849, 1774, 1730, 1664, 1279, 1105, 789, 689.
4.2.19. Dimethyl 2-(benzoxy) fumarate. White powder, mp
1
40–42 ꢁC. H NMR (300 MHz, CDCl3): d¼8.14–8.16 (d,
J¼7.2 Hz, 2H), 7.61–7.65 (t, J¼7.5 Hz, 1H), 7.47–7.52
(t, J¼7.5 Hz, 2H), 6.79 (s, 1H), 3.84 (s, 3H), 3.70 (s, 3H).
13C NMR (75 MHz, CDCl3): d¼163.6, 163.0, 161.5,
146.8, 133.9, 130.3, 128.5, 128.0, 117.0, 53.1, 52.0. MS
(EI, 70 eV): m/z (%)¼264 (M+, 0.49), 2.33 (0.74), 205
4.2.25. (E)-2-((Benzyloxy) carbonyl) vinyl benzoate.
White powder, mp 79–81 ꢁC. 1H NMR (300 MHz,
CDCl3): d¼8.56–8.60 (d, J¼12.3 Hz, 1H), 7.32–8.11
(m, 10H), 5.93–5.97 (d, J¼12.6 Hz, 1H), 5.22 (s, 2H). 13C
NMR (75 MHz, CDCl3): d¼165.9, 162.4, 150.2, 135.8,

M.-J. Fan et al. / Tetrahedron 62 (2006) 6782–6791
6789
134.3, 130.3, 128.7, 128.5, 128.2, 127.6, 106.0, 66.2. MS
(EI, 70 eV): m/z (%)¼282 (M+, 0.02), 177 (1.49), 160
(2.76), 105 (100). Anal. Calcd for C17H14O4: C, 72.33; H,
5.00. Found: C, 72.15; H, 5.11. IR (KBr): 1744, 1708,
1655, 1261, 1106, 959, 755, 700, 679.
(46.37), 69 (100). Anal. Calcd for C11H14O5: C, 58.40; H,
6.24. Found: C, 58.28; H, 5.94. IR (KBr): 2949, 2869,
1720, 1643, 1237, 1174, 1073.
4.2.32. (Z)-Methyl 2-((4aR,7aR)-tetrahydro-2-oxo-2H-
cyclopenta[b][1,4]dioxin-3(4aH)-ylidene) acetate. White
powder, mp 68–70 ꢁC. 1H NMR (300 MHz, CDCl3):
d¼6.16 (s, 1H), 4.48–4.57 (m, 1H), 4.19–4.28 (m, 1H),
3.73 (s, 3H), 1.69–2.24 (m, 6H). 13C NMR (75 MHz,
CDCl3): d¼164.4, 160.0, 150.7, 105.2, 80.6, 79.4, 51.6,
24.3, 24.0, 17.4. MS (EI, 70 eV): m/z (%)¼212 (M+,
26.09), 181 (72.38), 69 (100). Anal. Calcd for C10H12O5:
C, 56.60; H, 5.70. Found: C, 56.58; H, 5.75. IR (KBr):
2924, 1721, 1642, 1233, 1105.
4.2.26. (E)-Benzyl 3-(1,3-dioxoisoindolin-2-yl) acrylate.
White powder, mp 108–109 ꢁC. 1H NMR (300 MHz,
CDCl3): d¼7.23–7.97 (m, 10H), 6.97–7.02 (d, J¼15 Hz,
1H), 5.22 (s, 2H). 13C NMR (75 MHz, CDCl3): d¼166.9,
165.4, 135.9, 135.2, 131.4, 128.5, 128.2, 124.2, 108.3,
66.3. MS (EI, 70 eV): m/z (%)¼307 (M+, 3.59), 261
(36.67), 200 (98.52), 91 (100). Anal. Calcd for
C18H13NO4: C, 70.35; H, 4.26; N, 4.56. Found: C, 70.18;
H, 4.39; N, 4.27. IR (KBr): 2956, 1751, 1717, 1630, 1212,
1153, 971, 764, 676.
4.2.33. (Z)-Methyl 2-((4aS,7aR)-tetrahydro-2-oxo-2H-
cyclopenta[b][1,4]dioxin-3(4aH)-ylidene) acetate. White
powder, mp 94–96 ꢁC. 1H NMR (300 MHz, CDCl3):
d¼6.27 (s, 1H), 4.85–4.88 (m, 1H), 4.67–4.70 (m, 1H),
3.75 (s, 3H), 1.76–2.18 (m, 6H). 13C NMR (75 MHz,
CDCl3): d¼164.4, 158.4, 148.0, 105.3, 80.1, 76.1, 51.5,
29.0, 27.8, 19.2. MS (EI, 70 eV): m/z (%)¼212 (M+,
24.02), 181 (100), 69 (59.28). Anal. Calcd for C10H12O5:
C, 56.60; H, 5.70. Found: C, 56.64; H, 5.90. IR (KBr):
2956, 1709, 1642, 1239, 1087.
1
4.2.27. (E)-Methyl 3-(2-chloroethoxy) acrylate. Oil. H
NMR (300 MHz, CDCl3): d¼7.58–7.62 (d, J¼12.9 Hz,
1H), 5.23–5.28 (d, J¼12.6 Hz, 1H), 4.09–4.13 (t,
J¼5.7 Hz, 2H), 3.73–3.77 (t, J¼5.7 Hz, 2H), 3.71 (s, 3H).
13C NMR (75 MHz, CDCl3): d¼167.7, 161.6, 97.1, 70.5,
51.2, 41.3. MS (EI, 70 eV): m/z (%)¼164 (M+, 17.0), 133
(100). Anal. Calcd for C6H9ClO3: C, 43.78; H, 5.51.
Found: C, 43.91; H, 5.11. IR (KBr): 2952, 1712, 1629, 1143.
4.2.28. (Z)-Methyl 2-(3-oxo-1,4-dioxan-2-ylidene) ace-
4.2.34. (Z)-Methyl 2-(3-oxomorpholin-2-ylidene) acetate.
White powder, mp 79–80 ꢁC. 1H NMR (300 MHz, CDCl3):
d¼8.37 (s, 1H), 5.66 (s, 1H), 4.50–4.54 (t, J¼4.8 Hz, 2H),
3.71 (s, 3H), 3.50–3.55 (m, 2H). 13C NMR (75 MHz,
CDCl3): d¼170.4, 160.3, 144.4, 89.9, 67.3, 51.0, 38.4. MS
(EI, 70 eV): m/z (%)¼171 (M+, 41.6), 140 (52.9), 68
(100). Anal. Calcd for C7H9NO4: C, 49.12; H, 5.30; N,
8.18. Found: C, 49.22; H, 5.75; N, 8.24. IR (KBr): 3326,
2923, 1744, 1663, 1619, 1287, 1233.
1
tate. White powder, mp 105–106 ꢁC. H NMR (300 MHz,
CDCl3): d¼6.19 (s, 1H), 4.60–4.63 (m, 2H), 4.37–4.40 (m,
2H), 3.75 (s, 3H). 13C NMR (75 MHz, CDCl3): d¼164.2,
158.5, 150.0, 104.7, 66.5, 64.2, 51.4. MS (EI, 70 eV): m/z
(%)¼172 (M+, 8.01), 141 (70.01), 69 (100). Anal. Calcd
for C7H8O5: C, 48.84; H, 4.68. Found: C, 48.79; H, 4.81.
IR (KBr): 2960, 1742, 1715, 1639, 1287, 1236, 1092.
4.2.29. (Z)-Methyl 2-(5,6-dimethyl-3-oxo-1,4-dioxan-2-
1
ylidene) acetate. White powder, mp 77–78 ꢁC. H NMR
4.2.35. (Z)-Methyl 2-((R)-5-isopropyl-3-oxomorpholin-2-
ylidene) acetate. Oil. 1H NMR (300 MHz, CDCl3): d¼8.51
(s, 1H), 5.56 (s, 1H), 4.26–4.46 (m, 2H), 3.66 (s, 3H), 3.22–
3.29 (m, 2H), 1.76–1.88 (m, 1H), 0.97–1.03 (m, 6H). 13C
NMR (75 MHz, CDCl3): d¼170.4, 160.3, 144.0, 89.1,
69.4, 53.7, 50.8, 29.6, 18.6, 18.4. MS (EI, 70 eV): m/z
(%)¼213 (M+, 16.3), 182 (8.9), 170 (100), 138 (97.9).
Anal. Calcd for C10H15NO4: C, 56.33; H, 7.09; N, 6.57.
Found: C, 56.43; H, 7.20; N, 6.19. IR (KBr): 3310, 2965,
1747, 1664, 1620, 1265, 1237.
(300 MHz, CDCl3): d¼6.14 (s, 1H), 4.41–4.46 (m, 1H),
4.06–4.11 (m, 1H), 3.72 (s, 3H), 1.37–1.42 (m, 6H). 13C
NMR (75 MHz, CDCl3): d¼164.7, 159.5, 150.2, 104.2,
78.7, 76.0, 51.7, 17.2, 16.5. MS (EI, 70 eV): m/z (%)¼200
(M+, 23.1), 169 (53.7), 69 (100). Anal. Calcd for C9H12O5:
C, 54.00; H, 6.04. Found: C, 54.24; H, 6.26. IR (KBr):
2959, 2917, 2850, 1734, 1701, 1646, 1279, 1237, 1070.
4.2.30. (Z)-Methyl 2-((4aR,8aR)-hexahydro-2-oxobenzo-
[b][1,4]dioxin-3 (2H)-ylidene) acetate. White powder,
mp 62–63 ꢁC. 1H NMR (300 MHz, CDCl3): d¼6.12 (s,
1H), 4.21–4.29 (m, 1H), 3.86–4.94 (m, 1H), 3.69 (s, 3H),
1.21–2.32 (m, 8H). 13C NMR (75 MHz, CDCl3): d¼164.4,
159.3, 150.6, 103.9, 79.5, 77.5, 51.4, 29.5, 29.1, 23.0,
22.8. MS (EI, 70 eV): m/z (%)¼226 (M+, 4.80), 195
(8.33), 101 (54.37), 69 (100). Anal. Calcd for C11H14O5:
C, 58.40; H, 6.24. Found: C, 58.64; H, 5.91. IR (KBr):
2947, 2865, 1742, 1712, 1641, 1259, 1188, 1072.
4.2.36. (Z)-Methyl 2-((S)-5-sec-butyl-3-oxomorpholin-2-
ylidene) acetate. Oil. 1H NMR (300 MHz, CDCl3):
d¼8.55 (s, 1H), 5.61 (s, 1H), 4.33–4.51 (m, 2H), 3.71
(s, 3H), 3.38–3.43 (m, 1H), 1.57–1.70 (m, 2H), 1.25–1.34
(m, 1H), 0.94–1.01 (m, 6H). 13C NMR (75 MHz, CDCl3):
d¼170.4, 160.3, 144.0, 88.9, 69.3, 52.3, 50.8, 35.8,
25.1, 14.6, 10.8. MS (EI, 70 eV): m/z (%)¼227 (M+, 16.0),
196 (7.8), 170 (100), 138 (92.0). Anal. Calcd for
C11H17NO4: C, 58.14; H, 7.54; N, 6.16. Found: C, 58.23;
H, 7.58; N, 5.82. IR (KBr): 3309, 2966, 1748, 1664, 1619,
1254, 1233.
4.2.31. (Z)-Methyl 2-((4aS,8aR)-hexahydro-2-oxobenzo-
[b][1,4]dioxin-3(2H)-ylidene) acetate. Sticky oil. 1H
NMR (300 MHz, CDCl3): d¼6.17 (s, 1H), 4.67–4.71 (m,
1H), 4.42–4.46 (m, 1H), 3.75 (s, 3H), 1.42–1.97 (m, 8H).
13C NMR (75 MHz, CDCl3): d¼164.6, 159.2, 149.2,
103.9, 76.0, 73.0, 51.5, 28.3, 27.4, 21.0, 20.3. MS (EI,
70 eV): m/z (%)¼226 (M+, 9.81), 195 (19.09), 101
4.2.37. Methyl 2-((S)-5-isobutyl-3-oxomorpholin-2-yl-
idene) acetate. Oil. H NMR (300 MHz, CDCl3): d¼8.46
1
(s, 1H), 5.61 (s, 1H), 4.17–4.46 (m, 2H), 3.71 (s, 3H),
3.66–3.69 (m, 1H), 1.32–1.80 (m, 3H), 0.97–1.01 (t,

6790
M.-J. Fan et al. / Tetrahedron 62 (2006) 6782–6791
J¼6.3 Hz, 6H). 13C NMR (75 MHz, CDCl3): d¼170.4,
160.2, 143.9, 89.2, 71.3, 50.8, 46.2, 39.7, 24.4, 22.8, 21.7.
MS (EI, 70 eV): m/z (%)¼227 (M+, 15.43), 196 (7.72),
170 (100), 138 (93.98). Anal. Calcd for C11H17NO4: C,
58.14; H, 7.54; N, 6.16. Found: C, 58.47; H, 7.15; N, 5.97.
IR (KBr): 3310, 2957, 1748, 1666, 1619, 1253, 1227.
CDCl3): d¼170.5, 159.1, 142.2, 89.7, 85.6, 55.4, 51.5,
50.9, 50.3, 47.5, 32.4, 25.4, 22.1, 19.7, 10.7. MS (EI,
70 eV): m/z (%)¼279 (M+, 17.22), 248 (3.55), 169
(17.17), 95 (100). Anal. Calcd for C15H21NO4: C, 64.50;
H, 7.58; N, 5.01. Found: C, 64.23; H, 8.01; N, 5.34. IR
(KBr): 3292, 2954, 1738, 1664, 1628, 1258.
4.2.38. (Z)-Methyl 2-((S)-5-benzyl-3-oxomorpholin-2-yl-
idene) acetate. White powder, mp 83–84 ꢁC. 1H NMR
(300 MHz, CDCl3): d¼8.36 (s, 1H), 7.20–7.39 (m, 5H),
5.65 (s, 1H), 4.22–4.43 (m, 2H), 3.74–3.80 (m, 1H), 3.68
(s, 3H), 2.85–2.87 (d, J¼7.2 Hz, 2H). 13C NMR (75 MHz,
CDCl3): d¼170.1, 160.3, 143.4, 135.3, 129.0, 128.9,
127.4, 90.2, 70.2, 51.0, 49.7, 38.0. MS (EI, 70 eV): m/z
(%)¼261 (M+, 6.51), 230 (2.83), 170 (100), 138 (89.10).
Anal. Calcd for C14H15NO4: C, 64.36; H, 5.79; N, 5.36.
Found: C, 64.61; H, 5.88; N, 5.09. IR (KBr): 3315, 2949,
1740, 1667, 1622, 1238, 772, 698.
4.2.43. (Z)-Methyl 2-(3-oxopiperazin-2-ylidene) acetate.
White powder, mp 169–170 ꢁC. 1H NMR (300 MHz,
CDCl3): d¼8.29 (s, 1H), 7.87 (s, 1H), 5.59 (s, 1H), 3.70 (s,
3H), 3.42–3.55 (m, 4H). 13C NMR (75 MHz, CDCl3):
d¼170.8, 161.6, 148.9, 86.3, 50.7, 40.1, 38.9. MS (EI,
70 eV): m/z (%)¼170 (M+, 92.2), 139 (100), 110 (75.4).
Anal. Calcd for C7H10N2O3: C, 49.41; H, 5.92; N, 16.46.
Found: C, 49.18; H, 5.85; N, 16.12. IR (KBr): 3328, 3203,
3073, 2948, 1698, 1657, 1621, 1218.
4.2.44. (Z)-Methyl 2-((4aR,8aR)-hexahydro-3-oxopipera-
zin-2(1H,2H,4H)-ylidene) acetate. White powder, mp 188–
189 ꢁC. 1H NMR (300 MHz, CDCl3): d¼8.08 (s, 1H), 7.63
(s, 1H), 5.59 (s, 1H), 3.69 (s, 3H), 3.10–3.25 (m, 2H),
1.37–1.98 (m, 8H). 13C NMR (75 MHz, CDCl3): d¼170.8,
161.6, 149.1, 86.0, 55.4, 54.9, 50.7, 29.5, 29.4, 23.7, 23.4.
MS (EI, 70 eV): m/z (%)¼224 (M+, 83.9), 193 (41.3), 41
(100). Anal. Calcd for C11H16N2O3: C, 58.91; H, 7.19; N,
12.49. Found: C, 59.01; H, 7.57; N, 12.26. IR (KBr): 3296,
3191, 3072, 2933, 1693, 1657, 1615, 1212.
4.2.39. (Z)-Methyl 2-((R)-5-benzyl-3-oxomorpholin-2-yl-
idene) acetate. White powder, mp 74–75 ꢁC. 1H NMR
(300 MHz, CDCl3): d¼8.36 (s, 1H), 7.20–7.39 (m, 5H),
5.65 (s, 1H), 4.22–4.42 (m, 2H), 3.77–3.79 (m, 1H), 3.68
(s, 3H), 2.84–2.87 (d, J¼7.2 Hz, 2H). 13C NMR (75 MHz,
CDCl3): d¼170.0, 160.3, 143.4, 135.3, 129.0, 128.9,
127.4, 90.1, 70.2, 50.9, 49.6, 38.0. MS (EI, 70 eV): m/z
(%)¼261 (M+, 5.17), 230 (2.67), 170 (91.84), 138 (100).
Anal. Calcd for C14H15NO4: C, 64.36; H, 5.79; N, 5.36.
Found: C, 64.52; H, 5.76; N, 4.97. IR (KBr): 3321, 2947,
1740, 1667, 1622, 1238, 772, 699.
Acknowledgements
4.2.40. (Z)-Methyl 2-((R)-5-(2-(methylthio) ethyl)-3-oxo-
morpholin-2-ylidene) acetate. Oil. H NMR (300 MHz,
We would like to thank the NSF-20021001, NSF-20172024,
and the ‘Hundred Scientist Program’ from the Chinese
Academy of Sciences for the financial support of this work.
1
CDCl3): d¼8.47 (s, 1H), 5.59 (s, 1H), 4.21–4.50 (m, 2H),
3.68–3.78 (m, 1H), 3.66 (s, 3H), 2.50–2.65 (m, 2H), 2.09
(s, 3H), 1.77–1.95 (m, 2H). 13C NMR (75 MHz, CDCl3):
d¼170.2, 160.1, 143.4, 89.9, 70.5, 50.9, 46.9, 30.5, 29.9,
15.4. MS (EI, 70 eV): m/z (%)¼245 (M+, 12.60), 214
(5.26), 170 (19.14), 138 (84.38), 61 (100). Anal. Calcd for
C10H15NO4S: C, 48.96; H, 6.16; N, 5.71. Found: C, 49.25;
H, 6.39; N, 5.44. IR (KBr): 3307, 2949, 1745, 1666, 1619,
1269, 1240.
References and notes
1. (a) Inanaga, J.; Baba, Y.; Hanamoto, T. Chem. Lett. 1993, 241;
(b) Trost, B. M.; Li, C. J. Am. Chem. Soc. 1994, 116, 3167; (c)
Rychnovsky, S. D.; Kim, J. J. Org. Chem. 1994, 59, 2659; (d)
Trost, B. M.; Li, C. J. Am. Chem. Soc. 1994, 116, 10819; (e)
Avalos, M.; Babiano, R.; Bravo, J. L.; Cintas, P.; Jimenez,
J. L.; Palacios, J. C.; Silva, M. A. Green Chem. 2001, 3, 26;
(f) Mosslemin, M. H.; Yavari, I.; Anary-Abbasinejad, M.;
Nateghi, M. R. Synthesis 2004, 1029; (g) Islami, M. R.;
Abedini-Torghabeh, J.; Fatemi, S. J.; Hassani, Z.; Amiry, A.
Synlett 2004, 1707; (h) Yavari, I.; Souri, S.; Sirouspour, M.;
Djahaniani, H.; Nasiri, F. Synthesis 2005, 1761; (i)
Hanedanian, M.; Loreau, O.; Sawicki, M.; Taran, F.
Tetrahedron 2005, 61, 2287; (j) Skouta, R.; Varma, R. S.; Li,
C.-J. Green Chem. 2005, 7, 571.
2. (a) Matsuya, Y.; Hayashi, K.; Nemoto, H. J. Am. Chem. Soc.
2003, 125, 646; (b) Nair, V.; Pillai, A. N.; Menon, R. S.;
Suresh, E. Org. Lett. 2005, 7, 1189; (c) Du, Y.; Feng, J.; Lu,
X. Org. Lett. 2005, 7, 1987; (d) Ding, H.; Ma, C.; Yang, Y.;
Wang, Y. Org. Lett. 2005, 7, 2125; (e) Zhu, X.; Schaffner,
A. P.; Li, R. C.; Kwon, O. Org. Lett. 2005, 7, 2977; (f) Zhao,
G.; Shi, Y.; Shi, M. Org. Lett. 2005, 7, 4527.
4.2.41. (Z)-Methyl 2-(5-((1H-indol-3-yl) methyl)-3-oxo-
morpholin-2-ylidene) acetate. Yellow powder, mp 59–
1
61 ꢁC. H NMR (300 MHz, CDCl3): d¼8.40 (s, 1H), 8.31
(s, 1H), 7.54–7.56 (d, J¼7.8 Hz, 1H), 7.36–7.39 (d,
J¼8.4 Hz, 1H), 7.13–7.25 (m, 3H), 5.65 (s, 1H), 4.27–4.49
(m, 2H), 3.88–3.91 (m, 1H), 3.67 (s, 3H), 2.90–3.11 (m,
2H). 13C NMR (75 MHz, CDCl3): d¼170.3, 160.5, 143.6,
136.4, 126.7, 123.1, 122.5, 119.8, 118.2, 111.5, 109.3,
89.8, 70.8, 51.0, 48.4, 27.7. MS (EI, 70 eV): m/z (%)¼300
(M+, 3.02), 269 (0.42), 241 (2.00), 138 (4.20), 130 (100).
Anal. Calcd for C16H16N2O4: C, 63.99; H, 5.37; N, 9.33.
Found: C, 63.76; H, 5.55; N, 9.12. IR (KBr): 3407, 2948,
1742, 1664, 1616, 1260, 1237, 744.
4.2.42. (Z)-Methyl 1,7,7-trimethylbicyclo[2.2.1]hepta-
[c]2-((4aS,8aR)-3-oxomorpholin-2-ylidene) acetate.
White powder, mp 87–90 ꢁC. 1H NMR (300 MHz,
CDCl3): d¼8.44 (s, 1H), 5.75 (s, 1H), 4.42–4.45
(d, J¼8.7 Hz, 1H), 3.71 (s, 3H), 3.59–3.62 (dd, J¼8.4 Hz,
J¼3 Hz, 1H), 0.82–1.91 (m, 14H). 13C NMR (75 MHz,
3. (a) Faltin, C.; Fleming, E. M.; Connon, S. J. J. Org. Chem.
2004, 69, 6496; (b) Saxena, R.; Patra, A.; Batra, S. Synlett
2003, 1439; (c) Lee, K. Y.; Kim, J. M.; Kim, J. N. Synlett
2003, 357; (d) Yu, C.; Liu, B.; Hu, L. J. Org. Chem. 2001,

M.-J. Fan et al. / Tetrahedron 62 (2006) 6782–6791
6791
66, 5413; (e) Kaye, P. T.; Nocanda, X. W. J. Chem. Soc., Perkin
Trans. 1 2000, 1331; (f) Rafel, S.; Leahy, J. W. J. Org. Chem.
1997, 62, 1521; (g) Kaye, P. T.; Robinson, R. S. Synth.
Commun. 1996, 26, 2085; (h) Drewes, S. E.; Emslie, N. D.;
Karodia, N. Synth. Commun. 1990, 20, 1915.
G. C. B.; Chi, S.; Zhang, M.; Crowe, A.; Bennett, R. A.;
Parsons, I. Tetrahedron Lett. 2003, 44, 3659.
9. Crystal data for 17 have been deposited in CCDC as deposi-
tion number 604540: C13H11FO6, MW¼282.22, T¼294
˚
(2) K, l¼0.71073 A, triclinic space group P1, a¼5.4716
ꢁ
˚
˚
˚
4. (a) Papageorgiou, C. D.; Ley, S. V.; Gaunt, M. J. Angew. Chem.,
Int. Ed. 2003, 42, 828; Angew. Chem. 2003, 115, 852; (b)
Bremeyer, N.; Smith, S. C.; Ley, S. V.; Gaunt, M. J. Angew.
Chem. 2004, 116, 2735; Angew. Chem., Int. Ed. 2004, 43,
2681; (c) Shi, L.; Wang, P.; Liu, X.; Liu, W.; Liang, Y.
Synthesis 2004, 2342.
(2) A, b¼10.9415 (3) A, c¼12.4742 (4) A, a¼113.7600
3
˚
ꢁ
ꢁ
(10), b¼100.6690 (10), g¼92.6020 (10), V¼665.68 (4) A ,
Z¼2, Dc¼1.408 mg/m3, m¼0.121 mmꢀ1, F (000)¼292, crystal
size 0.40ꢂ0.33ꢂ0.30 mm, independent reflections 2557
[R (int)¼0.0088], reflections collected 3746, refinement
method, full-matrix least-squares on F2, goodness-of-fit on
F2 2.828, final R indices [I>2s(I)] R1¼0.0550, wR2¼0.0656,
R indices (all data) R1¼0.0440, wR2¼0.0638, extinction
coefficient 0.0131 (17), largest diff. peak and hole 0.215
5. (a) Shi, Y.; Shi, M. Org. Lett. 2005, 7, 3057; (b) Lesch, B.;
Torang, J.; Vanderheiden, S.; Brase, S. Adv. Synth. Catal.
¨
¨
2005, 347, 555; (c) Yang, Z.; Fan, M.; Mu, R.; Liang, Y.
Tetrahedron 2005, 61, 9140; (d) Fan, M.; Guo, L.; Liu, X.;
Liu, W.; Liang, Y. Synthesis 2005, 391; (e) Fan, M.; Yan, Z.;
Liang, Y. J. Org. Chem. 2005, 70, 8204; (f) Zhao, G.; Shi, M.
J. Org. Chem. 2005, 70, 9975.
ꢀ3
˚
and ꢀ0.171 eA
.
10. Nozaki, K.; Sato, N.; Ikeda, K.; Takaya, H. J. Org. Chem. 1996,
61, 4516.
11. Nair, V.; Bindu, S.; Sreekumar, V.; Rath, N. P. Org. Lett. 2003,
5, 665.
6. (a) Adib, M.; Mollahosseini, M.; Yavari, H.; Sayahi, M. H.;
Bijanzadeh, H. R. Synthesis 2004, 861; (b) Winterfeldt, E.
Chem. Ber. 1964, 97, 1952; (c) Winterfeldt, E. Chem. Ber.
1965, 98, 3537.
7. (a) Winterfeldt, E.; Preuss, H. Chem. Ber. 1966, 99, 450; (b)
Huisgen, R.; Herbig, K.; Siegl, A.; Huber, H. Chem. Ber.
1966, 99, 2526.
8. (a) Lappin, G. R. J. Org. Chem. 1961, 26, 2350; (b) Huisgen,
R.; Giese, B.; Huber, H. Tetrahedron Lett. 1967, 1883; (c)
Nair, M. D.; Mehta, S. R. Indian J. Chem. 1968, 6, 490; (d)
Nair, M. D. Indian J. Chem. 1969, 7, 229; (e) Gudi, M. N.;
Hiriyakkanavar, J. G.; George, M. V. Indian J. Chem. 1969,
12. Crystal data for 23 have been deposited in CCDC as deposition
number 295603: C7H8O5, MW¼172.13, T¼296 (2) K, l¼
˚
˚
0.71073 A, orthorhombic space group Pnma, a¼9.581 (2) A,
b¼6.582 (1) A, c¼12.534 (2) A, a¼90.00ꢁ, b¼90.00ꢁ,
˚
˚
3
3
ꢁ
˚
g¼90.00 , V¼790.43 (26) A , Z¼4, Dc¼1.446 mg/m , m¼
0.125 mmꢀ1
,
F
(000)¼360, crystal size 0.58ꢂ0.46ꢂ
0.38 mm, independent reflections 941 [R (int)¼0.0181], reflec-
tions collected 1179, refinement method, full-matrix least-
squares on F2, goodness-of-fit on F2 1.023, final R indices
[I>2s(I)] R1¼0.0489, wR2¼0.1025, R indices (all data)
R1¼0.0339, wR2¼0.0982, extinction coefficient 0.079 (8),
ꢀ3
.
˚
´
7, 971; (f) Prie, G.; Richard, S.; Parrain, J. L.; Duchene, A.;
Abarbri, M. J. Fluorine Chem. 2002, 117, 35; (g) Harriman,
ˆ
largest diff. peak and hole 0.204 and ꢀ0.140 eA
13. Mckennon, M. J.; Meyers, A. I. J. Org. Chem. 1993, 58, 3568.