Novel pyridine-catalyzed reaction of dimethyl acetylenedicarboxylate with aldehydes and N-tosylimines: Efficient synthesis of 2-benzoylfumarates and 1-azadienes

Article abstract of DOI:10.1055/s-2003-41000

A novel reaction of 1,4-dipolar intermediate 3, generated from pyridine and dimethyl acetylenedicarboxylate, with aromatic aldehydes, resulted in the facile synthesis of 2-benzoylfumarates via the elimination of pyridine, whereas with N-tosylimines as dipolarophiles the reaction afforded highly substituted 1-azadienes. The reaction of pyridine and dimethyl acetylenedicarboxylate with N-substituted isatins, resulted in a novel three component condensation, affording spiropyrido[2,1-b][1,3]oxazino derivatives in high yields via 1,4-dipolar cycloaddition.

Full text of DOI:10.1055/s-2003-41000

PAPER
1895
Novel Pyridine-Catalyzed Reaction of Dimethyl Acetylenedicarboxylate with
Aldehydes and N-Tosylimines: Efficient Synthesis of 2-Benzoylfumarates and
1
-Azadienes
a
a
a
a
a
a
b
S
V
ynthesis of 2-Ben
i
zoylfum
j
arates
a
and 1-Aza
y
dienes Nair,* A. R. Sreekanth, N. Abhilash, A. T. Biju, B. Rema Devi, Rajeev. S. Menon, Nigam P. Rath,
c
R. Srinivas
a
Organic Chemistry Division, Regional Research Laboratory (CSIR), Trivandrum 695 019, India
Fax +91(472)2491712; E-mail: vijaynair_2001@yahoo.com
b
c
Department of Chemistry, University of Missouri-St. Louis, Missouri-63121-4499, USA
National Center for Mass Spectrometry, Indian Institute of Chemical Technology (CSIR), Hyderabad 500 007, India
Received 4 November 2002; revised 2 June 2003
This paper is dedicated with best wishes to Professor Dr. Andrea Vasella on the occasion of his 60th birthday.
3
duct. Nevertheless, elucidation of the structure of the
adduct as 4H-quinolizine 4 occurred and evidence for the
existence of a 1,4-dipolar intermediate 3 was provided
Abstract: A novel reaction of 1,4-dipolar intermediate 3, generated
from pyridine and dimethyl acetylenedicarboxylate, with aromatic
aldehydes, resulted in the facile synthesis of 2-benzoylfumarates via
the elimination of pyridine, whereas with N-tosylimines as dipo-
only decades later, largely by the extensive investigations
4
larophiles the reaction afforded highly substituted 1-azadienes. The of Acheson and co-workers (Scheme 1).
reaction of pyridine and dimethyl acetylenedicarboxylate with N-
The intermediacy of 1,4-dipolar species 3 was established
substituted isatins, resulted in a novel three component condensa-
tion, affording spiropyrido[2,1-b][1,3]oxazino derivatives in high
yields via 1,4-dipolar cycloaddition.
by its intramolecular trapping with carbonyl groups.1
c,5
Isolated reports of intermolecular trapping of the 1,4-di-
6
7
pole with carbon dioxide and phenyl isocyanate are also
known. It is especially noteworthy that there has been no
attempt at trapping the dipole with aldehydes or ketones.
In the context of our general interest in heterocyclic con-
struction via dipoles generated by nucleophilic addition to
Key words: aldehyde, pyridine, nucleophilic additions, dimethyl
acetylenedicarboxylate, 1,4-dipolar cycloadditions
The reaction of nucleophiles with activated acetylenes has
attracted the attention of organic chemists for a long time,
especially from the vantage point of heterocyclic synthe-
8
activated alkynes, we have recently reported our prelim-
inary results on the unusual reactivity of the 1,4-dipole
generated from pyridine and DMAD towards aldehydes.9
The products of this reaction were initially misconstructed
as 2-oxo-3-benzylidenesuccinates. Subsequent studies
and single crystal X-ray analysis have shown that the
products are indeed 2-benzoylfumarates. The error has
been corrected and the structures of the products have
1
sis. Of special interest in this area is the reaction of nitro-
gen containing heterocycles with activated alkynes, which
2
has been thoroughly investigated. As early as 1932, Diels
and Alder showed that pyridine reacts smoothly with dim-
ethyl acetylenedicarboxylate (DMAD) to form an ad-
CO2Me
+
N
N
N
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
1
2
3
3a
DMAD
CO2Me
CO2Me
CO2Me
CO2Me
[
1,5] H Shift
N
N
CO2Me
CO2Me
CO2Me
CO2Me
4
Scheme 1
Synthesis 2003, No. 12, Print: 02 09 2003. Web: 07 08 2003.
Art Id.1437-210X,E;2003,0,12,1895,1902,ftx,en;T11502SS.pdf.
DOI: 10.1055/s-2003-41000
©
Georg Thieme Verlag Stuttgart · New York

1
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V. Nair et al.
PAPER
1
0
Table 1 Preparation of 2-Benzoylfumaratesa
been revised. The results of our detailed investigation of
the pyridine-catalyzed reaction of aromatic aldehydes and
DMAD are presented in this paper. Analogous results ob-
tained in the pyridine-catalyzed reaction of DMAD and N-
tosylimines are also presented here.
Entry Aldehyde
Product
Yield
b
(
%)
1
O
CO Me
44
CHO
2
Our studies were initiated by the reaction of 3-nitrobenz-
aldehyde with DMAD in the presence of a catalytic
amount of pyridine (20 mol%) in DME, which led to a
synthesis of the 2-benzoylfumarate 6 in excellent yield
H
CO2Me
7
14
2
3
4
CHO
O
CO Me
84
2
(
Scheme 2).
H
O
CO2Me
H
CHO
CO2Me
CO2Me
Cl
Cl
Pyridine (20 mol%)
DME
Cl
Cl
+
CO2Me
8
15
–10 °C- RT, 3 h
NO2 CO Me
2
85%
CHO
O
CO2Me
H
72
43
84
NO2
5
2
6
Scheme 2
CO Me
2
O2N
NO2
1
6
The product was characterized based on spectroscopic da-
9
1
ta. In the H NMR spectrum, the two methoxycarbonyl
CHO
O
CO Me
2
groups were observed at = 3.68 and 3.81 ppm as two sin-
H
glets and the olefinic proton resonated as a singlet at
=
1
3
CO Me
7
.14 ppm. The C signal for the benzoyl group was ob-
2
H3C
served at = 189.95 ppm and the ester carbonyls were dis-
cernible from the signals at = 162.83 and 164.04 ppm.
Finally the structure and stereochemistry of the compound
was established unambiguously by single crystal X-ray
CH3
17
1
0
5
CHO
O
CO Me
2
1
1
analysis (Figure 1).
H
CO2Me
F3C
CF3
O
1
8
1
1
1
2
6
7
CO Me
61
43
2
CHO
CHO
H
O
O
CO2Me
1
9
CO Me
2
O
H
CO2Me
1
3
Figure 1 ORTEP diagram of compound 6
2
0
The reaction was found to be generally applicable to a va-
riety of substituted aromatic aldehydes affording the 2-
benzoylfumarates in low to good yields (Table 1).
a
Reaction conditions: pyridine (20 mol%), 1,2-dimethoxyethane
(DME), –10 °C to r.t., 3 h.
b
Isolated yield.
Since benzoylfumarates are important intermediates for
1
2
13
agrochemicals and drugs, a number of methods have
been developed for their synthesis using patented proce-
dures. A general method for the synthesis of 2-benzoyl-
fumarates involving the sensitized photooxygenation of
arations. Novelty of the mechanism (Scheme 3),
stereoselectivity and the atom economy feature of the re-
action are also particularly noteworthy. The compounds
1
4
2
-methoxyfurans followed by the reductive work-up of
16
15
1
4
and 17 were already known in the literature and
the hydroperoxide has been reported by Scarpati and co-
they were identified by comparison of their spectroscopic
data with those reported. The structures for the new com-
pounds 15, 16 and 18–20 were assigned on the basis of
spectroscopic data.
1
5
workers as part of their extensive investigations on the
photosensitized oxidation of furans. In comparison to the
existing methods, the process described herein is experi-
mentally much simpler and adaptable to large-scale prep-
Synthesis 2003, No. 12, 1895–1902 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Benzoylfumarates and 1-Azadienes
1897
A mechanistic rationale for the reaction along the follow-
ing lines may be invoked. The initial event can be consid-
ered as an addition of pyridine to DMAD to generate the
CO2Me
O
CO2Me
Ph
Pyridine (20 mol%) Ph
CHO
+
H
DME
-10 °C - RT
1
,4-dipolar intermediate 3, which can react with the alde-
Ph
Ph
2
CO Me
CO2Me
32%
hyde to form the zwitterionic intermediate 21. The latter
can easily undergo a [1,3]-hydrogen shift, followed by the
elimination of pyridine to afford the product (Scheme 3).
23
2
24
Scheme 5
Another plausible mechanism for this transformation via
a [4+2] cycloadduct 22 is shown in Scheme 4.
The structure of the products was elucidated by spectro-
scopic techniques; the ratio of diastereomers was discern-
ible from H NMR spectra. The major diastereomer 26
was separated by crystallization and characterized. The
characteristic signals for methoxycarbonyl groups for ma-
Aliphatic aldehydes were found to be ineffective as di-
polarophiles; the only exception being diphenylacetalde-
hyde which gave the expected product 24 albeit in low
yield (Scheme 5).
1
The reaction of 1,4-dipolar intermediate from pyridine jor diastereomer of 26 were observed at = 3.29 and 3.96
and DMAD with N-substituted isatins, resulted in a novel ppm. The ring junction proton appeared as a doublet at
13
three-component condensation, affording a [4+2] cy-
= 6.37 ppm. In C NMR, the spiro carbon was discern-
cloadduct. In a prototype experiment, the reaction of pyri- ible at = 78.8 ppm, while the ester carbonyls were ob-
dine and DMAD with N-benzylisatin 25 led to the served at = 163.3 and 163.4 and the amide carbonyl at
efficient synthesis of the novel spiropyrido[2,1-b][1,3]ox-
azino derivatives 26 and 27 in excellent yield and dia- of the major diastereomer 26 was established unambigu-
= 174.0 ppm. Finally, the structure and stereochemistry
1
7
stereoselectivity. The reaction seems to be applicable to ously by single crystal X-ray analysis (Figure 2).
other N-substituted isatins, affording the cycloadducts
(
Scheme 6).
H
O
O
Ar
Ar-CHO
N
N
OMe
•
CO2Me
CO2Me
N
CO2Me
CO2Me
CO2Me
3
21
[
1,3] H Shift
O
CO2Me
H
O
N
Ar
Ar
-
Py
CO2Me
CO2Me
CO2Me
Scheme 3
Ar
O
H
H
O
H
Ar
O
Ar
N
N
N
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
22
3
[
1,3] H Shift
O
CO2Me
H
O
Ar
N
Ar
-
Py
CO2Me
CO2Me
CO2Me
Scheme 4
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PAPER
O
H
O
H
O
N
N
CO2Me
CO2Me
N
N
CO2Me
CO2Me
DME
1
+ 2 +
O
+
RT, 6 h
N
R
O
O
2
5
R
2
6
27
R
2
2
2
5, R = Bn, 88% (5:1) of 26 and 27
8, R = Ph, 90% (7:1)
9, R = Me, 84% (5:1)
Scheme 6
Figure 3 ORTEP diagram of compound 31
The reaction seems to be general, from its application to a
number of aromatic N-tosylimines, affording the 1-aza-
dienes in high yields (Table 2). Mechanistically the reac-
tion can be considered to proceed via a pathway
analogous to that outlined for the carbonyl compounds in-
volving the intermediacy of a zwitterion or a six mem-
bered cycloadduct (cf. Scheme 3 and Scheme 4). It is
noteworthy that 1-azadiene 38 on treatment with NaBH4
in methanol afforded a novel enamino diester 44
Figure 2 ORTEP diagram of compound 26
Intrigued by the possibility that an analogous reaction of
DMAD with N-tosylimines would occur under the influ-
ence of pyridine, we exposed a solution of 30 in DME to
that of DMAD in the presence of catalytic amount of py-
ridine. As expected an efficient reaction occurred to yield
(
Scheme 8) which can be considered as a dehydroamino
1
9
acid; the latter are synthetic precusors of saturated ami-
no acids.
3
1, thus constituting a novel 1-azadiene synthesis
Ts
Ts
(
Scheme 7).
NH CO Me
N
CO2Me
H
2
NaBH4
NTs
CO Me
Ts
MeOH, RT
83%
2
N
CO2Me
H
CO Me
CO2Me
2
Cl
Cl
Pyridine (20 mol%)
DME
+
38
44
-10 °C-RT, 3 h, 66%
CO2Me
CO2Me
Scheme 8
30
31
2
We have uncovered a novel reaction of the 1,4-dipole de-
rived from pyridine and DMAD with aldehydes resulting
in a facile one-pot synthesis of 2-benzoylfumarates, which
are important intermediates for drugs and agrochemicals.
Analogous reaction with N-tosylimines leads to the effi-
cient synthesis of highly substituted 1-azadienes. The lat-
ter, besides being useful dienes in hetero Diels–Alder
Scheme 7
The product was characterized by spectroscopic methods
and finally the stereochemistry was confirmed unambigu-
ously by single crystal X-ray analysis (Figure 3).18
Synthesis 2003, No. 12, 1895–1902 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Benzoylfumarates and 1-Azadienes
1899
2
0
reactions, can serve as intermediates for the synthesis of were recorded on a Nicolet Impact 400D FT-IR spectrophotometer.
2
1
Elemental analyses were obtained on a Perkin-Elmer-2400 elemen-
tal analyser. Dimethyl acetylenedicarboxylate was purchased from
Aldrich Chemical Co. and was used without further purification. N-
Tosylimines 30, 32–38 were prepared according to the reported pro-
-
amino acids. The experimental simplicity and the mild
reaction conditions, stereoselectivity and atom economy
of the process described are especially noteworthy.
2
2
cedure.
Table 2 Preparation of 1-Azadienesa
2
-Benzoylfumarates; Dimethyl (E)-2-(3-Nitrobenzoyl)but-2-
Entry N-Tosylimines
Product
Yield
enedioate (6); Typical Procedure
A solution of DMAD (75 mg, 0.53 mmol) and 3-nitrobenzaldehyde
b
(
%)
(
80 mg, 0.53 mmol) in anhyd DME (10 mL) was cooled to –10 °C
1
2
3
4
86
65
70
76
NTs
Ts
N
CO2Me
H
under argon. Pyridine (20 mol%) was then added and the reaction
mixture was stirred for 3 h at r.t. The solvent was removed under
vaccum, and the residue on chromatographic separation on silica
gel using hexane–EtOAc (80:20) gave the product 6 in 85% yield;
colorless crystalline solid; mp 97–99 °C (for yields of products 14–
CO2Me
Cl
Cl
38
2
0, see Table 1).
3
3
3
2
3
4
–
1
IR (KBr): 2959, 1719, 1686, 1533, 1440, 1261, 1202, 1016 cm .
NTs
Ts
N
CO2Me
H
1
H NMR (CDCl –CCl , 3:1): = 8.62 (s, 1 H), 8.45 (d, J = 8.1 Hz,
3
4
1
H), 8.21 (d, J = 7.7 Hz, 1 H), 7.71 (t, J = 7.9 Hz, 1 H), 7.14 (s, 1
1
3
H), 3.82 (s, 3 H), 3.69 (s, 3 H). C NMR (CDCl –CCl , 3:1):
189.9, 164.0, 162.9, 144.3, 137.1, 133.8, 131.4, 130.0, 127.9, 123.5,
53.4, 52.7.
=
CO2Me
3
4
H3C
CH3
3
9
Anal Calcd for C H NO : C, 53.25; H, 3.78; N, 4.78. Found: C,
5
1
3
11
7
NTs
Ts
3.4; H, 3.79; N, 4.91.
N
CO2Me
H
1
4
Colorless crystalline solid; mp 80–82 °C.
CO2Me
MeO
–
1
IR (KBr): 2957, 1726, 1685, 1590, 1420, 1255 cm .
OMe
40
1
H NMR (CDCl –CCl , 3:1): = 7.86 (d, J = 7.7 Hz, 2 H), 7.62–
3
4
7
13
.45 (m, 3 H), 7.08 (s, 1 H), 3.78 (s, 3 H), 3.63 (s, 3 H).
NTs
Ts
N
CO2Me
H
C NMR (CDCl –CCl , 3:1): = 191.9, 164.1, 163.5, 145.3, 135.7,
3
4
1
33.8, 130.4, 128.9, 128.8, 53.2, 52.4.
CO2Me
Anal. Calcd for C H O : C, 62.90; H, 4.87. Found: C, 63.22; H,
1
3
12
5
F3C
4
.88.
CF3
4
1
3
5
15
Colorless crystalline solid; mp 68–70 °C.
5
6
NTs
Ts
78
77
N
CO2Me
H
–
1
IR (KBr): 2955, 1721, 1681, 1438, 1249, 1196 cm .
O
O
1
H NMR(CDCl –CCl , 3:1): = 7.93 (s, 1H), 7.66 (d, J = 8.1 Hz, 1
3
4
CO2Me
H), 7.56 (d, J = 8.2 Hz, 1 H), 7.09 (s, 1 H), 3.80 (s, 3 H), 3.69 (s, 3
H).
O
O
42
1
3
C NMR (CDCl –CCl , 3:1): = 189.8, 164.0, 163.0, 144.5, 138.5,
3
4
36
1
35.3, 133.7, 131.1, 131.0, 130.4, 127.6, 53.3, 52.6.
NTs
2
CO Me
Anal.Calcd for C H Cl O : C, 49.24; H, 3.18. Found: C, 49.49, H,
N
H
13 10
2
5
Ts
3
.36.
CO2Me
1
6
37
Pale yellow crystalline solid; mp 115–117 °C.
4
3
IR (KBr): 2959, 1732, 1686, 1520, 1348, 1275, 1202 cm–1.
a
1
Reaction conditions: pyridine (20 mol%), DME, –10 °C to r.t., 3 h.
Isolated yield.
H NMR (CDCl –CCl , 3:1): = 8.33 (d, J = 8.3 Hz, 2 H), 8.03 (d,
3
4
b
J = 8.4 Hz, 2 H), 7.12 (s, 1 H), 3.81 (s, 3 H), 3.68 (s, 3 H).
1
3
C NMR (CDCl –CCl , 3:1): = 190.4, 164.1, 162.9, 150.7, 144.5,
3
4
1
39.9, 131.3, 129.6, 124.1, 119.8, 104.8, 53.4, 52.7.
Melting points were recorded on a Büchi melting point apparatus
Anal. Calcd for C H NO : C, 53.25; H, 3.78; N, 4.78. Found: C,
1
3
11
7
1
and are uncorrected. NMR spectra were recorded at 300 ( H) and 75
5
3.46; H, 4.13; N 4.98.
1
3
(
C) MHz on a Bruker DPX-300 MHz NMR spectrometer. The
spectra were run in CDCl –CCl (3:1) and chemical shifts are re-
3
4
17
Colorless crystalline solid; mp 85–87 °C.
1
13
ported ( ) relative to TMS ( H) and CDCl ( C) as the internal stan-
3
dards. Mass spectra were recorded under EI/HRMS (at 5000)
resolution using an Auto Spec. M mass spectrometer. IR spectra
–
1
IR (KBr): 2955, 1728, 1670, 1600, 1431, 1344, 1263 cm .
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V. Nair et al.
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1
H NMR (CDCl –CCl , 3:1): = 7.75 (d, J = 8.1 Hz, 2 H), 7.26 (d,
26
3
4
J = 7.9 Hz, 2 H), 7.05 (s, 1 H), 3.77 (s, 3 H), 3.62 (s, 3 H), 2.42 (s,
Yellow crystalline solid.
3
H).
IR (KBr): 2948, 1748, 1715, 1607, 1566, 1438, 1351, 1270, 1229,
1155, 1007 cm .
1
3
–1
C NMR (CDCl –CCl , 3:1): = 191.3, 164.0, 163.5, 145.3, 144.6,
3
4
1
33.2, 130.1, 129.5, 128.8, 53.0, 52.2, 21.8.
1
H NMR (CDCl –CCl , 3:1): = 7.40–7.14 (m, 7 H), 6.94 (t,
3
4
HRMS (EI): m/z Calcd for C H O : 262.0841. Found: 262.0831.
J = 7.5 Hz, 1 H), 6.69 (d, J = 7.1 Hz, 2 H), 6.38 (d, J = 7.5 Hz, 1 H),
.25 (dd, J = 6.1, 9.9 Hz, 1 H), 5.64 (dd, J = 3.1, 9.9 Hz, 1 H), 5.35–
1
4
14
5
6
1
8
5.28 (m, 1 H), 5.07 (d, J = 15.5 Hz, 1 H), 4.72 (d, J = 15.6 Hz, 1 H),
Pale yellow crystalline solid; mp 52–54 °C.
3.96 (s, 3 H), 3.29 (s, 3 H).
–
1
13
IR (KBr): 2956, 1725, 1682, 1502, 1437, 1408 cm .
C NMR (CDCl –CCl , 3:1): = 174.0, 163.4, 163.3, 145.5, 144.5,
3
4
1
135.8, 130.2, 130.0, 128.8, 128.5, 127.7, 125.2, 124.6, 123.2, 123.0,
16.6, 116.0, 109.3, 101.7, 79.5, 78.8, 53.3, 51.6, 44.0.
H NMR (CDCl –CCl , 3:1): = 7.98 (d, J = 7.9 Hz, 2 H), 7.75 (d,
3
4
1
J = 7.9 Hz, 2 H), 7.11 (s, 1 H), 3.80 (s, 3 H), 3.66 (s, 3 H).
1
3
HRMS (EI): m/z calcd for C26 , 458.1477; found, 458.1491.
H N O
22 2 6
C NMR (CDCl –CCl , 3:1): = 190.9, 164.0, 163.1, 144.7, 138.2,
3
4
1
34.7, 131.0, 128.9, 125.9, 125.8, 121.7, 53.3, 52.5.
2
8
Anal. Calcd for C H F O : C, 53.17; H, 3.51. Found: C, 53.32; H,
3
14
11
3
5
Yellow crystalline solid.
.71.
IR (KBr): 2948, 1748, 1708, 1607, 1573, 1499, 1330, 1270, 1243,
1
–
1
155 cm .
1
9
1
Colorless crystalline solid; mp 98–100 °C.
H NMR (CDCl –CCl , 3:1): = 7.55–7.46 (m, 6 H), 7.26–7.18 (m,
3 4
–
1
2 H), 7.01 (t, J = 7.5 Hz, 1 H), 6.77 (d, J = 7.8 Hz, 1 H), 6.67 (d,
J = 2.3 Hz, 1 H), 6.39 (d, J = 7.5 Hz, 1 H), 6.26 (dd, J = 6.0, 9.9 Hz,
1 H), 5.66 (dd, J = 3.2, 10.1 Hz, 1 H), 5.35 (t, J = 6.6 Hz, 1 H), 3.97
IR (KBr): 2952, 1725, 1653, 1467, 1394, 1275, 1215 cm .
1
H NMR (CDCl –CCl , 3:1): = 7.60 (s, 1 H), 7.20 (d, J = 3.5 Hz,
H), 7.05 (s, 1 H), 6.58 (d, J = 1.6 Hz, 1 H), 3.81 (s, 3 H), 3.68 (s,
3
4
1
3
(
s, 3 H), 3.53 (s, 3 H).
H).
1
3
C NMR (CDCl –CCl , 3:1): = 173.3, 163.3, 163.2, 145.5, 134.4,
3
4
1
3
C NMR (CDCl –CCl , 3:1): = 176.1, 164.0, 163.3, 152.0, 147.1,
3
4
130.0, 129.6, 129.5, 128.1, 126.6, 126.5, 125.6, 125.2, 124.6, 123.6,
23.4, 116.6, 109.6, 106.5, 101.8, 78.9, 53.3, 51.8.
1
43.5, 131.1, 118.3, 112.9, 112.7, 53.2, 52.4.
1
Anal. Calcd for C H O : C, 55.47; H, 4.23. Found: C, 55.80; H,
11
10
6
HRMS (EI): m/z calcd for C H N O , 444.1321; found, 444.1330.
25 20 2 6
4
.45.
2
9
2
0
Yellow crystalline solid.
Colorless crystalline solid; mp 134–136 °C.
IR (KBr): 2955, 1742, 1721, 1613, 1566, 1472, 1351, 1270, 1229,
1
–1
IR (KBr): 2948, 1728, 1667, 1506, 1580, 1438, 1276 cm .
–1
034 cm .
1
H NMR (CDCl –CCl , 3:1): = 9.19 (d, J = 8.6 Hz, 1 H), 8.01 (d,
1
3
4
H NMR (CDCl –CCl , 3:1): = 7.29–7.26 (m, 1 H), 7.15 (d,
3 4
J = 8.1 Hz, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.77 (d, J = 6.7 Hz, 1 H),
7
1
J = 6.6 Hz, 1 H), 6.96 (uneven t, J = 7.5 Hz, 1 H), 6.79 (d, J = 7.6
Hz, 1 H), 6.63–6.61 (m, 1 H), 6.36 (d, J = 7.5 Hz, 1 H), 6.22 (dd,
J = 6.1, 9.9 Hz, 1 H), 5.58 (dd, J = 3.3, 9.9 Hz, 1 H), 5.31 (t, J = 6.8
Hz, 1 H), 3.93 (s, 3 H), 3.43 (s, 3 H), 3.20 (s, 3 H).
.65 (t, J = 7.4 Hz, 1 H), 7.55 (t, J = 7.0 Hz, 1 H), 7.43 (t, J = 7. Hz,
H), 7.04 (s, 1 H), 3.77 (s, 3 H), 3.52 (s, 3 H).
1
3
C NMR (CDCl –CCl , 3:1): = 193.1, 164.2, 163.9, 146.4, 134.7,
34.0, 132.0, 131.9, 130.8, 129.5, 128.8, 128.4, 126.8, 126.3, 124.1,
3.2, 52.4.
3
4
1
5
13
C NMR (CDCl –CCl , 3:1): = 173.6, 163.0, 162.9, 145.2, 144.9,
3
4
1
1
2
29.9, 128.2, 125.3, 125.2, 124.9, 124.4, 123.9, 122.8, 122.6, 122.3
16.2, 115.6, 108.1, 106.2, 101.5, 101.2, 79.2, 53.0, 51.6, 51.5,
6.4, 25.9.
HRMS (EI): m/z calcd for C H O , 298.0841; found, 298.0830.
1
7
14
5
2
4
HRMS (EI): m/z calcd for C H N O , 382.1164; found, 382.1168.
2
0
18
2
6
Yellow viscous oil.
–
1
1-Azadienes; General Procedure
IR (film): 2956, 1738, 1632, 1445, 1270, 1183, 1033 cm .
A solution of DMAD (75 mg, 0.53 mmol) and the appropriate N-to-
sylimine (0.53 mmol) in anhyd DME (10 mL) was cooled to –10 °C
under argon. Pyridine (20 mol%) was then added and the reaction
mixture was stirred for 3 h at r.t. The solvent was removed under
vacuum, and the residue on chromatographic separation on silica
gel using hexane–EtOAc (80:20) gave the product 1-azadienes
1
H NMR (CDCl –CCl , 3:1): = 7.47 (d, J = 8.2 Hz, 2 H), 7.35–
3
4
7
.24 (m, 8 H), 6.65 (s, 1 H), 6.36 (s, 1 H), 3.85 (s, 3 H), 3.72 (s, 3 H).
1
3
C NMR (CDCl –CCl , 3:1): = 191.3, 163.8, 162.4, 151.2, 140.8,
3
4
1
1
39.3, 136.4, 130.2, 128.6, 128.5, 128.3, 128.2, 128.1, 127.9, 127.3,
27.2, 124.7, 111.1, 53.0, 51.8, 29.7.
(Table 2).
HRMS (EI): m/z calcd for C H O , 338.1154; found, 338.1150.
2
0
18
5
3
1
2H,9aH-Pyrido[2,1-b][1,3]oxazino Derivatives; General Proce-
Colorless crystalline solid; mp 128–130 °C.
dure
–
1
To a solution of DMAD (75 mg, 0.53 mmol) and N-substituted isat-
in 25 (125 mg, 0.53 mmol) in anhyd DME (10 mL) was added py-
ridine (0.043 mL, 0.53 mmol) under argon at r.t. The reaction
mixture was stirred for 6 h, the solvent was removed under vacuum,
and the residue on chromatographic separation on silica gel using
hexane–EtOAc (80:20) gave 2H,9aH-pyrido[2,1-b][1,3]oxazino
derivatives as inseparable mixture of diastereomers. Spectroscopic
data of the major diastereomers 26, 28 and 29 are provided.
IR (KBr): 2955, 1748, 1719, 1553, 1317, 1243, 1162, 1088 cm .
1
H NMR (CDCl –CCl , 3:1): = 7.86–7.80 (m, 4 H), 7.54–7.49 (m,
H), 7.41–7.22 (m, 4 H), 7.18 (s, 1 H), 3.83 (s, 3 H), 3.59 (s, 3 H),
.43 (s, 3 H).
3
4
1
2
1
3
C NMR (CDCl –CCl , 3:1): = 172.5, 163.7, 162.7, 143.8, 142.4,
37.2, 135.1, 133.6, 130.7, 129.4, 128.9, 128.7, 127.7, 53.2, 52.3,
1.6.
3
4
1
2
Synthesis 2003, No. 12, 1895–1902 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Benzoylfumarates and 1-Azadienes
1901
1
3
Anal. Calcd for C H NO S: C, 59.84; H, 4.77; N, 3.49; S, 7.99.
C NMR (CDCl –CCl , 3:1): = 171.2, 163.7, 162.7, 152.8, 148.5,
2
0
19
6
3
4
Found: C, 59.54; H, 5.15; N, 3.71; S, 8.25.
143.6, 142.4, 137.5, 130.5, 129.7, 129.4, 127.6, 126.0, 108.1, 108.0,
02.1, 53.2, 52.2, 21.6.
1
3
8
Anal. Calcd for C H NO S: C, 56.62; H, 4.30; N, 3.14; S, 7.20.
Found: C, 56.78; H, 4.32; N, 3.34; S, 7.33.
2
1
19
8
Colorless crystalline solid; mp 165–167 °C.
IR (KBr): 2948, 1728, 1580, 1553, 1438, 1270, 1162, 1088, 1013
–
1
cm .
43
1
Colorless crystalline solid; mp 144–146 °C.
H NMR (CDCl –CCl , 3:1): = 7.84 (d, J = 8.1 Hz, 2 H), 7.76 (d,
3
4
–
1
J = 8.5 Hz, 2 H), 7.38–7.31 (m, 4 H) 7.18 (s, 1 H), 3.85 (s, 3 H), 3.63
IR (KBr): 2955, 1724, 1582, 1328, 1249, 1162, 1094 cm .
(
1
s, 3 H), 2.45 (s, 3 H).
1
H NMR (CDCl –CCl , 3:1): = 8.87 (d, J = 9.5 Hz, 1 H), 7.95–
3
4
3
C NMR (CDCl –CCl , 3:1): = 171.5, 163.6, 162.5, 142.1, 140.2,
7.89 (m, 3 H), 7.83–7.80 (m, 1 H), 7.60 (d, J = 7.3 Hz, 1 H), 7.53–
7.49 (m, 2 H), 7.40 (t, J = 7.7 Hz, 1 H), 7.32 (d, J = 8.1 Hz, 2 H),
3
4
1
33.6, 130.9, 130.1, 129.5, 129.1, 127.8, 53.4, 52.5, 21.7.
7
.18 (s, 1 H), 3.87 (s, 3 H), 3.54 (s, 3 H), 2.44 (s, 3 H).
Anal. Calcd for C H ClNO S: C; 55.11, H; 4.16, N; 3.21; S; 7.36.
Found: C, 55.31; H, 4.39; N, 3.48; S, 7.70.
20
18
6
1
3
C NMR (CDCl –CCl , 3:1): = 172.4, 163.9, 163.2, 144.0, 143.9,
3
4
1
37.3, 134.2, 134.1, 132.6, 131.2, 131.0, 130.3, 129.5, 128.5, 128.2,
3
9
127.8, 126.5, 126.4, 124.1, 53.3, 52.5, 21.7.
Colorless crystalline solid; mp 117–119 °C.
Anal. Calcd for C H NO S: C, 63.85; H, 4.69; N, 3.10; S, 7.10.
Found: C, 64.17; H, 4.68; N, 3.32; S, 7.28.
2
4
21
6
–1
IR (KBr): 2955, 1735, 1580, 1553, 1317, 1256, 1088 cm .
1
H NMR (CDCl –CCl , 3:1): = 7.85 (d, J = 8.3 Hz, 2 H), 7.72 (d,
3
4
Enamino Diester 44
To a solution of 1-azadiene 38 (1 equiv) in anhyd MeOH at r.t. was
J = 8.3 Hz, 2 H), 7.31–7.26 (m, 2 H), 7.19 (d, J = 8.3 Hz, 2 H), 7.17
(
s, 1 H), 3.83 (s, 3 H), 3.62 (s, 3 H), 2.43 (s, 3 H), 2.35 (s, 3 H).
added NaBH (1 equiv). The reaction mixture was stirred for 5 h, the
4
1
3
C NMR (CDCl –CCl , 3:1): = 172.4, 163.7, 162.8, 144.8, 143.7,
3
4
solvent was removed under vacuum, and the residue on chromato-
graphic separation on silica gel using hexane–EtOAc (80:20) gave
the enamino ester 44 in 83% yield; colorless crystalline solid; mp
1
5
42.5, 137.4, 132.5, 130.5, 129.6, 129.5, 129.4, 129.0, 127.7, 53.3,
2.3, 21.8, 21.6.
1
56–158 °C.
Anal. Calcd for C H NO S: C, 60.71; H, 5.09; N, 3.37; S, 7.72.
2
1
21
6
Found: C, 60.64; H, 5.03; N, 3.71; S, 7.73.
IR (KBr): 3117, 2955, 1742, 1674, 1613, 1492, 1344, 1276, 1169,
–
1
1
088, 1007 cm .
4
0
1
H NMR (CDCl –CCl , 3:1): = 11.52 (s, 1 H), 7.32 (d, J = 8.1 Hz,
3
4
Colorless crystalline solid; mp 132–134 °C.
2
3
H), 7.19–7.15 (m, 4 H), 6.92 (d, J = 8.2 Hz, 2 H), 3.78 (s, 3 H),
.53 (s, 3 H), 2.89 (s, 2 H), 2.42 (s, 3 H).
–
1
IR (KBr): 2955, 1742, 1560, 1420, 1244, 1152, 1086, 1015 cm .
1
H NMR (CDCl –CCl , 3:1): = 7.84–7.74 (m, 4 H), 7.29 (d,
13
3
4
C NMR (CDCl –CCl , 3:1): = 171.5, 169.1, 151.7, 143.9, 137.2,
3 4
J = 8.1 Hz, 2 H), 7.14 (s, 1 H), 6.86 (d, J = 8.9 Hz, 2 H), 3.82 (s, 6
H), 3.56 (s, 3 H), 2.39 (s, 3 H).
1
2
35.9, 130.9, 129.9, 129.3, 128.1, 127.5, 103.9, 52.2, 51.8, 33.6,
1.6.
1
3
C NMR (CDCl –CCl , 3:1): = 171.5, 164.3, 163.6, 162.8, 143.5,
3
4
Anal. Calcd for C H ClNO S: C, 54.86, H; 4.60; N, 3.20; S, 7.32.
20 21 6
Found: C, 54.66; H, 4.75; N, 3.43; S, 7.62.
1
5
42.4, 137.5, 131.2, 130.2, 129.3, 127.6, 127.5, 114.1, 55.4, 53.1,
2.1, 21.5.
Anal. Calcd for C H NO S: C, 58.46; H, 4.91; N, 3.25; S, 7.43.
Found: C, 58.68; H, 5.08; N, 3.35; S, 7.74.
2
1
21
7
Acknowledgments
S.A.R., B.A.T. and R.S.M thank Council of Scientific and Industrial
Research, New Delhi and A.N. thanks Indo-French Center for the
Promotion of Advanced Research (IFCPAR), for financial assi-
stance. Authors also thank Ms. Saumini Mathew for high resolution
NMR spectra and Mrs. S. Viji for CHN analysis. Thanks are also
due to Professor M. V. George for useful discussions on the mecha-
nism of the reactions reported in this paper.
4
1
Colorless crystalline solid; mp 175–177 °C.
IR (KBr): 2954, 1723, 1598, 1570, 1329, 1267, 1164, 1129, 1020
cm .
–
1
1
H NMR (CDCl –CCl , 3:1): = 7.93 (d, J = 8.3 Hz, 2 H),7.85 (d,
3
4
J = 8.2 Hz, 2 H), 7.65 (d, J = 8.3 Hz, 2 H), 7.33 (d, J = 8.1 Hz, 2 H),
.20 (s, 1 H), 3.85 (s, 3 H), 3.64 (s, 3 H), 2.45 (s, 3 H).
7
1
3
C NMR (CDCl –CCl , 3:1): = 171.4, 163.7, 162.4, 144.3, 141.9, References
3
4
1
1
38.3, 136.7, 134.9, 134.4, 131.1, 129.6, 129.3, 129.1, 128.5, 127.8,
26.4, 125.7, 125.6, 53.4, 52.5, 21.6.
(
1) (a) Dickstein, J. I.; Miller, S. I. In The Chemistry of
Functional Group. The Chemistry of Carbon–Carbon Triple
Bond, Part 2; Patai, S., Ed.; Wiley: Chichester, 1978, Chap.
19, 813–955. (b) Winterfeldt, E. In Chemistry of Acetylenes;
Viehe, H. G., Ed.; Dekker: New York, 1969, 267.
Anal. Calcd for C H F NO S: C, 53.73, H, 3.86, N, 2.98, S, 6.83.
Found: C, 54.02; H, 3.99; N, 3.21; S, 7.10.
2
1
18
3
6
4
2
(c) Winterfeldt, E. Angew. Chem., Int. Ed. Engl. 1967, 6,
4
Colorless crystalline solid; mp 187–189 °C.
23.
(2) (a) Acheson, R. M. Adv. Heterocycl. Chem. 1963, 1, 125.
b) Acheson, R. M.; Elmore, N. F. Adv. Heterocycl. Chem.
978, 23, 263.
–
1
IR (KBr): 2955, 1728, 1553, 1492, 1445, 1270, 1148, 1034 cm .
(
1
1
H NMR (CDCl –CCl , 3:1): = 7.83 (d, J = 8.2 Hz, 2 H), 7.43 (s,
3
4
1
6
H), 7.31–7.26 (m, 3 H), 7.15 (s, 1 H), 6.76 (d, J = 8.3 Hz, 1 H),
.02 (s, 2 H), 3.84 (s, 3 H), 3.61 (s, 3 H), 2.43 (s, 3 H).
(
3) Diels, O.; Alder, K. Liebigs Ann. Chem. 1932, 498, 16.
Synthesis 2003, No. 12, 1895–1902 © Thieme Stuttgart · New York

1
902
V. Nair et al.
PAPER
(14) (a) Chosakon, Y.; Yamamoto, N. Jpn. Kokai 63104940,
(
4) (a) Acheson, R. M.; Plunkett, A. O. J. Chem. Soc., Perkin
Trans. 1 1975, 438. (b) Acheson, R. M.; Taylor, G. A. Proc.
Chem. Soc. 1959, 186. (c) Acheson, R. M.; Taylor, G. A. J.
Chem. Soc. 1960, 1691. (d) Acheson, R. M.; Gagan, J. M.
F.; Taylor, G. A. J. Chem. Soc. 1963, 1903.
1988; Chem. Abstr. 1988, 109, 230551. (b) Ikeda, T.;
Hirano, H.; Aoki, K. Jpn. Kokai 63130564, 1989; Chem.
Abstr. 1989, 110, 7866. (c) Takahashi, S.; Ueda, Y.;
Yanagida, Y.; Namito, Y.; Ohaska, T.; Watanabe, K.
European Patent Appl. EP 204286, 1986; Chem. Abstr.
1987, 106, 84179.
(
(
(
5) Winterfeldt, E. Chem. Ber. 1965, 98, 3537.
6) Acheson, R. M.; Plunkett, A. O. J. Chem. Soc. 1964, 2676.
7) Huisgen, R.; Morikawa, M.; Herbig, K.; Brunn, E. Chem.
Ber. 1967, 100, 1094.
(15) (a) Iesce, M. R.; Cermola, F.; Piazza, A.; Graziano, M. L.;
Scarpati, R. Synthesis 1995, 439. (b) Iesce, M. R.; Cermola,
F.; Graziano, M. L.; Scarpati, R. Synthesis 1994, 944.
(16) Winterfeldt, E.; Dillinger, H. J. Chem. Ber. 1966, 99, 1558.
(17) Crystal data for 26: C H N O , M 458.46, Monoclinic,
(8) (a) Nair, V.; Vinod, A. U. Chem. Commun. 2000, 1019.
(
b) Nair, V.; Vinod, A. U.; Nair, J. S.; Sreekanth, A. R.; Rath,
N. P. Tetrahedron Lett. 2000, 41, 6675. (c) Nair, V.; Vinod,
A. U.; Rajesh, C. J. Org. Chem. 2001, 66, 442. (d) Nair, V.;
Bindu, S.; Balagopal, L. Tetrahedron Lett. 2001, 42, 2043.
9) Nair, V.; Sreekanth, A. R.; Vinod, A. U. Org. Lett. 2001, 3,
2
6
22
2
6
space group = P2 /n, unit cell diamensions a = 11.2763(2)
1
Å, = 90°, b = 9.28570(10) Å, = 99.1180(10)°,
(
c = 20.7237(3) Å, = 90°, R indices (all data) R1 = 0.1003,
3
3
495.
10) Nair, V.; Sreekanth, A. R.; Vinod, A. U. Org. Lett. 2002, 4,
807.
11) Crystal Data for 6: C H O , M 293.23, Monoclinic, space
wR2 = 0.1131, volume, Z = 2142.52(5) Å , 4, Dcalc = 1.421
3
–1
(
(
Mg/m , absorption coefficient = 0.102 mm , = 0.71073
Å, reflections collected = 56111.
2
(18) Crystal data for 30: C H NO S, M 401.42, Triclinic, space
4
0
32
2
20 19
6
group P2 /c, unit cell dimensions a = 12.4082(9) Å, = 90°;
group P-1, unit cell diamensions a = 7.9631(3) Å,
= 83.827(2)°, b = 9.7212(3) Å, = 74.064(2)°,
1
b = 12.1843(9) Å, = 91.974(5)°, c = 8.6733(6) Å, = 90°,
R indices (all data) R1 = 0.1341, wR2 = 0.1335, volume,
c = 12.8578(4) Å, = 83.132(2)°, R indices (all data)
R1 = 0.0643, wR2 = 0.1155, volume, Z = 947.30(5) Å3, 2,
3
3
Z = 1310.50(16) Å , 4, D = 1.486 Mg/m , absorption
calc
–
1
3
–1
coefficient = 0.123 mm , = 0.71073 Å, reflections
collected 22288.
Dcalc = 1.407 Mg/m , absorption coefficient = 0.209 mm ,
= 0.71073 Å, reflections collected 14301.
(
12) For example, see: (a) Nippon Synthetic Chemical Industry ;
Jpn. Kokai 5838302, 1983; Chem. Abstr. 1983, 99, 1818.
(19) (a) Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1988,
159. (b) Trost, B. M.; Dake, G. R. J. Am. Chem. Soc. 1997,
119, 7595.
(20) Hetero Diels–Alder Methodology in Organic Synthesis;
Boger, D. L.; Weinreb, S. M., Eds.; Academic Press: San
Diego, 1987.
(
8
b) Nippon Synthetic Chemical Industry , Jpn. Kokai
1127302, 1981; Chem. Abstr. 1982, 96, 2180.
(13) Yamada, K.; Ino, K.; Takahashi, S.; Ohashi, T.; Watanabe,
K. European Pat. Appl. EP 239062, 1987; Chem. Abstr.
1988, 109, 110904.
(21) (a) Juaristi, E. Enantioselective Synthesis of -Amino Acids;
Wiley-VCH: New York, 1997. (b) Gellman, S. H. Acc.
Chem. Res. 1998, 31, 173.
(
22) Proctor, G. R.; McKay, W. R. J. Chem. Soc., Perkin Trans.
1981, 2435.
1
Synthesis 2003, No. 12, 1895–1902 © Thieme Stuttgart · New York