Reaction of cyclic imidates with α,β-unsaturated esters: Synthesis of new pyrrolo[2,1-b]-1,3-oxazine and pyrido[2,1-b]-1,3-oxazine derivatives

Article abstract of DOI:10.1002/jhet.539

The cycloaddition reaction of cyclic imidates, 2-benzyl-5,6-dihydro-4H-1,3- oxazines 1a-f, with dimethyl acetylenedicarboxylate 2, trimethyl ethylenetricarboxylate 4, or dimethyl 2-(methoxymethylene)malonate 6 afforded new fused heterocyclic compounds, su

Full text of DOI:10.1002/jhet.539

May 2011
Reaction of Cyclic Imidates with a,b-Unsaturated Esters:
Synthesis of New Pyrrolo[2,1-b]-1,3-oxazine and Pyrido[2,1-b]-
1,3-oxazine Derivatives
577
Shogo Ihara,* Takashi Soma, Daigo Yano, Shunichi Aikawa,
and Yasuhiko Yoshida*
Department of Applied Chemistry, Faculty of Science and Engineering, Toyo University, Kujirai,
Kawagoe, Saitama 350-8585, Japan
*E-mail: iharayh@toyonet.toyo.ac.jp or yoshida_y@toyonet.toyo.ac.jp
Received October 29, 2009
DOI 10.1002/jhet.539
Published online 4 March 2011 in Wiley Online Library (wileyonlinelibrary.com).
The cycloaddition reaction of cyclic imidates, 2-benzyl-5,6-dihydro-4H-1,3-oxazines 1a-f, with dimethyl
acetylenedicarboxylate 2, trimethyl ethylenetricarboxylate 4, or dimethyl 2-(methoxymethylene)malonate 6
afforded new fused heterocyclic compounds, such as methyl (6-oxo-3,4-dihydro-2H-pyrrolo[2,1-b]-1,3-oxa-
zin-7-ylidene)acetates 3a-f (71–79%), dimethyl 2-(6-oxo-3,4,6,7-tetrahydro-2H-pyrrolo[2,1-b]-1,3-oxazin-7-
yl)malonates 5b-f (43–71%), or methyl 6-oxo-3,4-dihydro-2H,6H-pyrido[2,1-b]-1,3-oxazine-7-carboxylates
7a-f (32–59%), respectively. In these reactions, 1a-f (cyclic imidates, iminoethers) functioned as their N,C-
tautomers (enaminoethers) 10 to a,b-unsaturated esters 2, 4, and 6 to give annulation products 3, 5, and 7
following to the elimination of methanol, respectively.
J. Heterocyclic Chem., 48, 577 (2011).
respectively. On a C-alkylation of enaminoether, Trost
et al. [3] reported the reaction of 6-methoxy-1-methyl-
1,2,3,4-tetrahydropyridine with 3-buten-2-one to afford
conjugate addition product. To our best knowledge,
however, there is no report to use cyclic imidates as
their N,C-tautomers, which reacted with a,b-unsaturated
esters to form fused heterocycles.
In this study, we expected the synthesis of novel
fused heterocycles, which shared a common molecular
skeleton, consisting of fused oxazine and pyrrolidine
hetercycles. Herein, we report the easy and efficient
synthesis of new N-bridged fused heterocycles, methyl
INTRODUCTION
In 1972, Toke et al. [1] first described an existence of
tautomerism by the chemical terms of iminoether-enami-
noether tautomerism for N,C-tautomerism of substituted
acetimidates in their report. The existence of N,C-tau-
tomerism of cyclic imidates was demonstrated by Pfau
1
et al. [2] on the basis of H NMR technique, in which
2-(benzylimino)-3-methyltetrahydropyran or 2-(benzyli-
mino)-3-methyltetrahydrofuran reacted with a,b-unsatu-
rated esters or 3-buten-2-one to give conjugate addition
products combined at a-carbon relative to imino group,
C
V
2011 HeteroCorporation

578
S. Ihara, T. Soma, D. Yano, S. Aikawa, and Y. Yoshida
Vol 48
Scheme 1
(6-oxo-3,4-dihydro-2H-pyrrolo[2,1-b]-1,3-oxazin-7-ylidene)
acetates 3, dimethyl 2-(6-oxo-3,4,6,7-tetrahydro-2H-pyr-
rolo[2,1-b]-1,3-oxazin-7-yl)malonates 5 and methyl 6-oxo-
3,4-dihydro-2H,6H-pyrido[2,1-b]-1,3-oxazine-7-carboxylates
7 from the cycloaddition reaction of the cyclic imidates, 2-
means of HMBC in NMR technique. As shown in Table
1, the reaction of 2-benzyl-5,6-dihydro-4H-1,3-oxazines
1 with a,b-unsaturated esters 4 or 6 provided 2-(6-oxo-
3,4,6,7-tetrahydro-2H-pyrrolo[2,1-b]-1,3-oxazin-7-
yl)malonates 5a-f in good yields (43–71%) or 6-oxo-
3,4-dihydro-2H,6H-pyrido[2,1-b]-1,3-oxazine-7-carboxy-
lates 7a-f in moderate yields (32–59%), respectively, by
the similar reaction path giving compounds 3. It was
difficult for the compound 5a to be purified by means of
distillation, crystallization or silica gel chromatography.
Also, N-alkylation-cyclization products were not found
in these cycloaddition reactions. It was concluded that
their enaminoethers 10 as N,C-tautomer of the imi-
noether (cyclic imidates) 1 reacted with a,b-unsaturated
benzyl-5,6-dihydro-4H-1,3-oxazines
1 with dimethyl
acetylenedicarboxylate 2, trimethyl ethylenetricarboxy-
late 4 or dimethyl 2-(methoxymethylene)malonate 6,
respectively.
RESULTS AND DISCUSSION
The reaction of the cyclic imidates 1a-f with dimethyl
acetylenedicarboxylate 2 at room temperature afforded
(6-oxo-3,4-dihydro-2H-pyrrolo[2,1-b]-1,3-oxazin-7-ylidene)
acetates 3a-f in good yields (71–79%). As shown in
Scheme 1, cyclic imidates (imino ether) 1a-f isomerized
to their enaminoethers 10 and attacked to dimethyl ace-
tylenedicarboxylate 2 to yield the Michael adducts. The
adducts isomerized to enaminoethers again, followed by
cyclization with elimination of methanol to yield 3a-f.
Table 1
Yields of compounds 3, 5, and 7.
Compounds
R1
R2
3 (%)
5 (%)
7 (%)
a
b
c
d
e
f
Ph
Ph
H
Me
H
74
76
75
79
71
74
54a
69
43
59
46
71
38
55
40
59
32
49
1
The compounds, 3a-f, were characterized by H NMR,
13C NMR, MALDI-TOF-MS spectral, and elemental
analysis data. E-Forms of 3a-f were identified by the
characteristic signals for the olefinic hydrogen atoms on
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
Me
H
Me
1
the acetate moieties at d 6.15–6.19 in H NMR spectrum
[4]. In addition, the compounds, 5a-f, were analyzed by
a Crude product.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2011
Reaction of Cyclic Imidates with a,b-Unsaturated Esters: Synthesis of
New Pyrrolo[2,1-b]-1,3-oxazine and Pyrido[2,1-b]-1,3-oxazine Derivatives
579
3.67 (2H, t, J ¼ 1.1 Hz, OCH2), 3.78 (3H, s, OCH3), 6.84
(2H, d, J ¼ 8.7 Hz, ArAH), 7.21 (2H, d, J ¼ 8.7 Hz, ArAH).
General procedure for the synthesis of methyl (6-oxo-3,4-
dihydro-2H-pyrrolo[2,1-b]-1,3-oxazin-7-ylidene)acetates 3. To
a stirred solution of 2-benzyl-5,6-dihydro-4H-1,3-oxazines 1
(30 mmol) in methanol (15 mL) was added dropwise a solu-
tion of dimethyl acetylenedicarboxylate 2 (45 mmol) in metha-
nol (15 mL) over 30 min at room temperature. After the reac-
tion mixture was maintained for 15 min at room temperature
the precipitated materials were collected by filtration and
washed with methanol.
esters 2, 4, and 6 to give new C-alkylation-cyclization
products 3, 5, and 7, respectively.
EXPERIMENTAL
All melting points were provided with uncorrected measure-
ment. IR spectra were recorded on a Horiba FT-720 spectrom-
1
eter as potassium bromide pellets. H and 13C NMR data were
obtained using a JEOL JNM-ECX500M (500 MHz) spectrom-
eter in CDCl3 or DMSO-d6 with tetramethylsilane (0.03%) as
an internal standard. For compounds 3, 5, and 7 MALDI-TOF-
MS spectra were recorded on a Bruker AutoFlex II TOF/TOF
mass spectrometer equipped with a nitrogen laser (k ¼ 337
nm), a pulsed ion extraction and a reflector. The operation was
performed at an accelerating potential of 20 kV for a reflector
positive ion mode. Samples for the MALDI analysis were pre-
pared by mixing volumes of the matrix solution b-methyl-
trans-cinnamylidenemalononitrile, called as BMCM [5] (10
mg/mL in THF), sample solution (2 mg/mL in CHCl3), and
cationization reagent solution (2 mg/mL in THF) to obtain a
20:1:8 ratio (BMCM/sample/TFANa) v/v. Elemental analyses
were performed using a Perkin-Elmer 2400 II CHN Analyzer.
Starting materials. 2-Benzyl-5,6-dihydro-4H-1,3-oxazines
1a-f were prepared by modifying the literature procedure [6].
A mixture of arylacetoimidates [7] and corresponding 3-ami-
nopropanols in diglyme was refluxed at 120ꢀC (oil bath), and
then distilled under reduced pressure.
Methyl (E)-(6-oxo-8-phenyl-3,4-dihydro-2H-pyrrolo[2,1-b]-
1,3-oxazin-7-ylidene)acetate (3a). The product was obtained
as red powder; mp 185–187ꢀC; IR: 1716, 1637 cmꢂ1 1H
;
NMR: d 2.22 (1H, t, J ¼ 6.3 Hz, CHAHB), 2.24 (1H, t, J ¼
6.3 Hz, CHAHB), 3.77 (3H, s, OCH3), 4.04 (2H, t, J ¼ 6.3 Hz,
OCH2), 4.54 (1H, d, J ¼ 5.4 Hz, NCHAHB), 4.57 (1H, d, J ¼
5.4 Hz, NCHAHB), 6.18 (1H, s, CH), 7.13 (1H, t, J ¼ 7.5 Hz,
ArAH), 7.32 (2H, t, J ¼ 8.3 Hz, ArAH), 7.84 (2H, d, J ¼ 8.5
Hz, ArAH); 13C NMR: d 21.7, 43.2, 52.0, 67.6, 93.5, 99.6,
125.2, 125.8, 128.1, 130.8, 142.6, 165.9, 172.1, 180.3;
MALDI-TOF MS: 285.1 (Mþ); Anal. Calcd. for C16H15NO4:
C, 67.36; H, 5.30; N, 4.91. Found: C, 67.37; H, 5.35; N, 4.88.
Methyl (E)-(3,3-dimethyl-6-oxo-8-phenyl-3,4-dihydro-2H-
pyrrolo[2,1-b]-1,3-oxazin-7-ylidene)acetate (3b). The product
was obtained as red powder; mp 173–174ꢀC; IR: 1716, 1645
1
cmꢂ1; H NMR: d 1.16 (6H, s, 2 ꢁ CH3), 3.74 (2H, s, OCH2),
3.78 (3H, s, OCH3), 4.20 (2H, s, NCH2), 6.19 (1H, s, CH),
7.14 (1H, t, J ¼ 7.5 Hz, ArAH), 7.33 (2H, t, J ¼ 7.5 Hz,
ArAH), 7.86 (2H, d, J ¼ 8.3 Hz, ArAH); 13C NMR: d 23.0,
29.5, 52.0, 54.9, 76.5, 93.4, 99.5, 125.2, 125.9, 128.2, 130.8,
142.9, 165.9, 171.0, 180.4; MALDI-TOF MS: 313.1 (Mþ);
Anal. Calcd. for C18H19NO4: C, 68.99; H, 6.11; N, 4.47.
Found: C, 69.05; H, 6.24; N, 4.49.
2-Benzyl-5,6-dihydro-4H-1,3-oxazine (1a) [8]. The product
was collected as colorless oil; 78% yield; bp 100–112ꢀC (1.2
Torr); 1H NMR: d 1.82 (2H, quin, J ¼ 5.7 Hz, CH2), 3.37 (2H, t, J
¼ 5.7 Hz, NCH2), 3.43 (2H, s, ArACH2), 4.10 (2H, t, J ¼ 5.6 Hz,
OCH2), 7.20–7.25 (1H, m, ArAH), 7.28–7.30 (4H, m, ArAH).
2-Benzyl-5,5-dimethyl-5,6-dihydro-4H-1,3-oxazine (1b). The
product was collected as colorless oil; 78% yield; bp 97ꢀC
Methyl (E)-[6-oxo-8-(4-methylphenyl)-3,4-dihdro-2H-pyr-
rolo[2,1-b]-1,3-oxazin-7-ylidene]acetate (3c). The product was
1
obtained as red powder; mp 179–180ꢀC; IR: 1730, 1630 cmꢂ1
;
(0.7 Torr); H NMR: d 0.90 (6H, s, 2 ꢁ CH3), 3.08 (2H, t, J
¼ 1.1 Hz, NCH2), 3.47 (2H, s, ArACH2), 3.67 (2H, t, J ¼ 1.1
Hz, OCH2), 7.20–7.24 (1H, m, ArAH), 7.29–7.30 (4H, m,
ArAH).
1H NMR: d 2.22 (1H, t, J ¼ 6.3 Hz, CHAHB), 2.23 (1H, t, J
¼ 6.3 Hz, CHAHB), 2.32 (3H, s, ArAH), 3.77 (3H, s, OCH3),
4.03 (2H, t, J ¼ 6.3 Hz, OCH2), 4.56 (1H, d, J ¼ 5.4 Hz,
NCHAHB), 4.57 (1H, d, J ¼ 5.4 Hz, NCHAHB), 6.18 (1H, s,
CH), 7.13 (2H, d, J ¼ 8.0 Hz, ArAH), 7.72 (2H, d, J ¼ 8.0
Hz, ArAH); 13C NMR: d 21.2, 21.9, 43.3, 52.0, 67.5, 93.7,
99.5, 125.9, 127.7, 128.9, 134.8, 142.8, 166.0, 171.9, 180.4;
MALDI-TOF MS: 299.1 (Mþ); Anal. Calcd. for C17H17NO4 :
C, 68.21; H, 5.72; N, 4.68. Found: C, 68.45; H, 5.75; N, 4.76.
2-(4-Methylbenzyl)-5,6-dihydro-4H-1,3-oxazine
(1c). The
product was collected as colorless oil; 63% yield; bp 106–
108ꢀC (0.5 Torr); 1H NMR: d 1.81 (2H, quin, J ¼ 5.7 Hz,
CH2), 2.31 (3H, s, ArACH3), 3.36 (2H, t, J ¼ 5.8 Hz, NCH2),
3.39 (2H, s, ArACH2), 4.09 (2H, t, J ¼ 5.5 Hz, OCH2), 7.11
(2H, d, J ¼ 8.0 Hz, ArAH), 7.17 (2H, d, J ¼ 8.0 Hz, ArAH).
2-(4-Methylbenzyl)-5,5-dimethyl-5,6-dihydro-4H-1,3-oxazine
(1d). The product was collected as colorless oil; 89% yield; bp
105–115ꢀC (0.7 Torr); 1H NMR: d 0.90 (6H, s, 2 ꢁ CH3),
2.31 (3H, s, ArACH3), 3.07 (2H, s, NCH2), 3.43 (2H, s,
ArACH2), 3.66 (2H, s, OCH2), 7.10 (2H, d, J ¼ 8.0 Hz,
ArAH), 7.18 (2H, d, J ¼ 8.0 Hz, ArAH).
Methyl
dihydro-2H-pyrrolo[2,1-b]-1,3-oxazin-7-ylideneacetate (3d). The
(E)-(3,3-dimethyl-[6-oxo-8-(4-methylphenyl)-3,4-
product was obtained as red powder; mp 188–190ꢀC; IR:
1720, 1639cmꢂ1
;
1H NMR: d 1.14 (6H, s, 2 ꢁ CH3), 2.32
(3H, s, ArACH3), 3.72 (2H, s, OCH2), 3.78 (3H, s, OCH3),
4.17 (2H, s, NCH2), 6.17 (1H, s, CH), 7.14 (2H, d, J ¼ 7.9
Hz, ArAH), 7.74 (2H, d, J ¼ 7.9 Hz, ArAH); 13C NMR: d
21.2, 23.0, 29.5, 52.0, 54.9, 76.4, 93.4, 99.2, 125.9, 127.7,
128.9, 134.8, 143.0, 165.9, 170.9, 180.5; MALDI-TOF MS:
327.1 (Mþ); Anal. Calcd. for C19H21NO4 : C, 69.71; H, 6.47;
N, 4.28. Found: C, 69.91; H, 6.49; N, 4.41.
2-(4-Methoxybenzyl)-5,6-dihydro-4H-1,3-oxazine (1e). The
product was collected as pale yellow oil; 82% yield; bp 120–
124ꢀC (0.3 Torr); 1H NMR: d 1.83 (2H, quin, J ¼ 5.7 Hz,
CH2), 3.36–3.38 (4H, m, overlap of NCH2 and ArACH2), 4.12
(2H, t, J ¼ 5.6 Hz, OCH2), 6.84 (2H, d, J ¼ 8.7 Hz, ArAH),
7.21 (2H, d, J ¼ 8.7 Hz, ArAH).
Methyl (E)-[8-(4-methoxyphenyl)-6-oxo-3,4-dihydro-2H-pyrrolo
[2,1-b]-1,3-oxazin-7-ylidene]acetate (3e). The product was
obtained as dark red powder; mp 162–164ꢀC; IR: 1728, 1645
2-(4-Methoxybenzyl)-5,5-dimethyl-5,6-dihydro-4H-1,3-oxa-
zine (1f). The product was collected as pale yellow oil; 74%
1
yield; bp 117–120ꢀC (0.2 Torr); H NMR: d 0.90 (6H, s, 2 ꢁ
1
cmꢂ1; H NMR: d 2.19 (1H, t, J ¼ 6.3 Hz, CHAHB), 2.21(1H, t,
CH3), 3.07 (2H, t, J ¼ 1.1 Hz, NCH2), 3.41 (2H, s, ArACH2),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

580
S. Ihara, T. Soma, D. Yano, S. Aikawa, and Y. Yoshida
Vol 48
1
J ¼ 6.3 Hz, CHAHB), 3.76 (3H, s, OCH3), 3.79 (3H, s, OCH3),
3.99 (2H, t, J ¼ 6.3 Hz, OCH2), 4.52 (1H, d, J ¼ 5.2 Hz,
NCHAHB), 4.53 (1H, d, J ¼ 5.2 Hz, NCHAHB), 6.15 (1H, s,
CH), 6.87 (2H, d, J ¼ 8.9 Hz, ArAH), 7.77 (2H, d, J ¼ 8.9 Hz,
ArAH); 13C NMR: d 21.7, 43.2, 52.0, 55.3, 67.6, 93.4, 99.4,
113.6, 123.3, 127.2, 142.8, 157.2, 165.9, 171.7, 180.4; MALDI-
TOF MS: 315.1 (Mþ); Anal. Calcd. for C17H17NO5: C, 64.75; H,
5.43; N, 4.44. Found: C, 64.84; H, 5.47; N, 4.52.
1645 cmꢂ1; H NMR: d 2.02–2.14 (2H, m, CH2), 2.33 (3H, s,
ArACH3), 3.50 (1H, dt, J ¼ 13.2, 6.6 Hz, NCHAHB), 3.65
(3H, s, OCH3), 3.75 (3H, s, OCH3), 3.91 (1H, d, J ¼ 2.2 Hz,
malonate CH), 3.99 (1H, dt, J ¼ 11.0, 5.5 Hz, OCHAHB), 4.06
(1H, d, J ¼ 2.2 Hz, COCH), 4.11 (1H, ddd, J ¼ 11.0, 7.5, 5.5
Hz, OCHAHB), 4.21 (1H, dt, J ¼ 13.2, 6.6 Hz, NCHAHB),
7.14 (2H, d, J ¼ 8.1 Hz, ArAH), 7.29 (2H, d, J ¼ 8.1 Hz,
ArAH); 13C NMR: d 21.2, 22.7, 38.2, 43.8, 50.6, 52.7, 53.2,
65.5, 93.4, 128.4, 129.0, 133.2, 136.1, 144.4, 164.7, 168.4,
171.7; MALDI-TOF MS: 359.1 (Mþ); Anal. Calcd. for
C19H21NO6: C, 63.50; H, 5.89; N, 3.90. Found: C, 63.54; H,
5.99; N, 3.83.
Methyl (E)-[8-(4-methoxyphenyl)-3,3-dimethyl-6-oxo-3,4-
dihydro-2H-pyrrolo[2,1-b]-1,3-oxazin-7-ylidene]acetate (3f). The
product was obtained as dark red powder; mp 157–159ꢀC; IR:
1718, 1637 cmꢂ1
;
1H NMR: d 1.15 (6H, s, 2 ꢁ CH3), 3.72
(2H, s, OCH2), 3.78 (3H, s, OCH3), 3.80 (3H, s, OCH3), 4.18
(2H, s, NCH2), 6.17 (1H, s, CH), 6.89 (2H, d, J ¼ 8.0 Hz,
ArAH), 7.78 (2H, d, J ¼ 8.0 Hz, ArAH); 13C NMR: d 23.0,
29.6, 52.0, 54.9, 55.3, 76.4, 93.2, 99.2, 113.7, 123.3, 127.2,
143.0, 157.2, 166.0, 170.7, 180.5; MALDI-TOF MS: 343.1
(Mþ); Anal. Calcd. for C19H21NO5: C, 66.46; H, 6.16; N,
4.08. Found: C, 66.68; H, 6.08; N, 4.26.
Dimethyl 2-[3,3-dimethyl-6-oxo-8-(4-methylphenyl)-3,4,6,7-
tetrahydro-2H-pyrrolo-[2,1-b]-1,3-oxazin-7-yl]malonate (5d). The
mixture of 1d (30 mmol) and 4 (30 mmol) were stirred for 5 h
to afford 5d as white powder; mp 179–181ꢀC; IR: 1730, 1689,
1
1649 cmꢂ1; H NMR: d 1.07 (3H, s, CH3), 1.08 (3H, s, CH3),
2.33 (3H, s, ArACH3), 3.10 (1H, d, J ¼ 12.9 Hz, NCHAHB),
3.64 (3H, s, OCH3), 3.64 (1H, d, J ¼ 10.3 Hz, OCHAHB),
3.74 (3H, s, OCH3), 3.74 (1H, d, J ¼ 10.3 Hz, OCHAHB),
3.92 (1H, d, J ¼ 2.2 Hz, malonate CH), 4.00 (1H, d, J ¼ 12.9
Hz, NCHAHB), 4.07 (1H, d, J ¼ 2.2 Hz, COCH), 7.14 (2H, d,
J ¼ 8.0 Hz, ArAH), 7.29 (2H, d, J ¼ 8.0 Hz, Ar-H); 13C
NMR: d 21.2, 23.3, 23.9, 30.7, 43.8, 49.6, 50.7, 52.6, 53.1,
75.9, 93.3, 128.4, 129.0, 133.2, 136.1, 143.5, 164.8, 168.5,
171.6; MALDI-TOF MS: 387.1 (Mþ); Anal. Calcd. for
C21H25NO5: C, 65.10; H, 6.50; N, 3.62. Found: C, 65.29; H,
6.65; N, 3.57.
Dimethyl [8-(4-methoxyphenyl)-6-oxo-3,4,6,7-tetrahydro-2H-
pyrrolo[2,1-b]-1,3-oxazin-7-yl]malonate (5e). The mixture of 1e
(30 mmol) and 4 (30 mmol) were stirred for 4 h to afford 5e
as pale yellow powder; mp 136–139ꢀC; IR: 1732, 1689, 1651
cmꢂ1; H NMR: d 2.02–2.14 (2H, m, CH2), 3.50 (1H, dt, J ¼
General procedure for the synthesis of methyl 2-(6-oxo-
3,4,6,7-tetrahydro-2H-pyrrolo-[2,1-b]-1,3-oxazin-7-yl)malonates
5. To a stirred solution of trimethyl ethylenetricarboxylate 4
(20 or 30 mmol) in DMF (15 mL) was added dropwise a solu-
tion of 2-benzyl-5,6-dihydro-4H-1,3-oxazines 1 (20 or 30
mmol) in DMF (15 mL) over 30 min at room temperature. The
reaction mixture was refluxed at 100ꢀC (oil bath) for 4–6 h with
stirring. After removal of the solvent and low boiling temperature
materials under reduced pressure, the precipitated materials were
collected by filtration and then washed with ethyl acetate. Sam-
ples for analysis were recrystallized from ethyl acetate.
Dimethyl 2-(6-oxo-8-phenyl-3,4,6,7-tetrahydro-2H-pyrrolo[2,1-
b]-1,3-oxazin-7-yl)-malonate (5a). The mixture of 1a (20
mmol) and 4 (20 mmol) were stirred for 4 h. The product was
1
1
obtained as nondistilled crude oil; H NMR: d 2.02–2.13 (2H,
13.2, 6.6 Hz, NCHAHB), 3.65 (3H, s, OCH3), 3.76 (3H, s,
OCH3), 3.80 (3H, s, OCH3), 3.91 (1H, d, J ¼ 2.3 Hz, malonate
CH), 4.00 (1H, ddd, J ¼ 11.0, 7.5, 4.9 Hz, OCHAHB), 4.04 (1H,
d, J ¼ 2.3 Hz, COCH), 4.11 (1H, dt, J ¼ 11.0, 5.5 Hz,
OCHAHB), 4.21 (1H, dt, J ¼ 13.2, 6.6 Hz, NCHAHB), 6.87 (2H,
d, J ¼ 9.0 Hz, Ar-H), 7.33 (2H, d, J ¼ 9.0 Hz, ArAH); 13C
NMR: d 22.7, 38.2, 43.9, 50.6, 52.6, 53.2, 55.3, 65.5, 93.2,
113.7, 128.5, 129.7, 144.0, 158.1, 164.6, 168.4, 171.7; MALDI-
TOF MS: 375.1 (Mþ); Anal. Calcd. for C19H21NO7: C, 60.50; H,
5.64; N, 3.73. Found: C, 60.50; H, 5.70; N, 3.73.
m, CH2), 3.52 (1H, dt, J ¼ 13.2, 6.6 Hz, NCHAHB), 3.65 (3H,
s, OCH3), 3.76 (3H, s, OCH3), 3.93 (1H, d, J ¼ 2.3 Hz, malo-
nate CH), 4.01 (1H, ddd, J ¼ 11.0, 7.5, 4.9 Hz, OCHAHB),
4.08 (1H, d, J ¼ 2.3 Hz, COCH), 4.13 (1H, dt, J ¼ 11.0, 6.0
Hz, OCHAHB), 4.21 (1H, dt, J ¼ 13.2, 6.6 Hz, NCHAHB),
7.20 (1H, t, J ¼ 7.4 Hz, ArAH), 7.33 (2H, t, J ¼ 4 7. Hz,
ArAH), 7.40 (2H, d, J ¼ 8.3 Hz, ArAH).
Dimethyl
2-(3,3-dimethyl-6-oxo-8-phenyl-3,4,6,7-tetrahy-
(5b). The
dro-2H-pyrrolo[2,1-b]-1,3-oxazin-7-yl)-malonate
mixture of 1b (20 mmol) and 4 (20 mmol) were stirred for 4 h
to afford 5b as white powder; mp 157–159ꢀC; IR: 1730, 1686,
Dimethyl 2-[8-(4-methoxyphenyl)-3,3-dimethyl-6-oxo-3,4,6,7-
tetrahydro-2H-pyrrolo-[2,1-b]-1,3-oxazin-7-yl]malonate (5f). The
mixture of 1f (20 mmol) and 4 (20 mmol) were stirred for 6 h
to afford 5f as pale yellow powder; mp 138–141ꢀC; IR: 1732,
1
1645 cmꢂ1; H NMR: d 1.08 (3H, s, CH3), 1.09 (3H, s, CH3),
3.12 (1H, d, J ¼ 12.6 Hz, NCHAHB), 3.65 (3H, s, OCH3),
3.66 (1H, OCHAHB overlapped with OCH3), 3.75 (3H, s,
OCH3), 3.76 (1H, OCHAHB overlapped with OCH3), 3.93
(1H, d, J ¼ 2.1 Hz, malonate CH), 4.01 (1H, d, J ¼ 12.6 Hz,
NCHAHB), 4.09 (1H, d, J ¼ 2.1 Hz, COCH), 7.20 (1H, t, J ¼
7.5 Hz, ArAH), 7.33 (2H, t, J ¼ 8.0 Hz, ArAH), 7.40 (2H, d,
J ¼ 8.3 Hz, ArAH); 13C NMR: d 23.3, 23.9, 30.7, 43.8, 49.6,
50.6, 52.7, 53.1, 75.9, 93.2, 126.4, 128.2, 128.5, 136.2, 143.8,
164.8, 168.4, 171.6; MALDI-TOF MS: 373.1 (Mþ); Anal.
Calcd. for C20H23NO6: C, 64.33; H, 6.21; N, 3.75. Found: C,
64.59; H, 6.28; N, 3.77.
1
1689, 1651 cmꢂ1; H NMR: d 1.07 (3H, s, CH3), 1.08 (3H, s,
CH3), 3.09 (1H, d, J ¼ 12.9 Hz, NCHAHB), 3.64 (3H, s,
OCH3), 3.64 (1H, d, J ¼ 10.6 Hz, OCHAHB), 3.74 (1H, d, J ¼
10.6 Hz, OCHAHB), 3.75 (3H, s, OCH3), 3.80 (3H, s, OCH3),
3.92 (1H, d, J ¼ 2.2 Hz, malonate CH), 4.01 (1H, d, J ¼ 12.9
Hz, NCHAHB), 4.05 (1H, d, J ¼ 2.2 Hz, COCH), 6.88 (2H, d, J
¼ 8.9 Hz, ArAH), 7.33 (2H, d, J ¼ 8.9 Hz, ArAH); 13C NMR:
d 23.3, 23.9, 30.7, 43.9, 49.6, 50.7, 52.6, 53.1, 55.3, 76.0, 93.1,
113.7, 128.5, 129.7, 143.1, 158.1, 164.8, 168.5, 171.6; MALDI-
TOF MS: 403.1 (Mþ); Anal. Calcd. for C16H15NO4: C, 62.52;
H, 6.25; N, 3.47. Found: C, 62.68; H, 6.31; N, 3.44.
Dimethyl 2-[6-oxo-8-(4-methylphenyl)-3,4,6,7-tetrahydro-
2H-pyrrolo[2,1-b]-1,3-oxazin-7-yl]malonate (5c). The mixture
of 1c (20 mmol) and 4 (20 mmol) were stirred for 4 h to
afford 5c as white powder; mp 109–111ꢀC; IR: 1736, 1697,
General procedure for the synthesis of methyl 3,4-dihy-
dro-2H,6H-pyrido[2,1-b]-1,3-oxazine-7-carboxylates 7. To a
stirred solution of dimethyl 2-(methoxymethylene)malonate 6
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2011
Reaction of Cyclic Imidates with a,b-Unsaturated Esters: Synthesis of
New Pyrrolo[2,1-b]-1,3-oxazine and Pyrido[2,1-b]-1,3-oxazine Derivatives
581
(33–40 mmol) in diglyme (15 mL) was added dropwise a solu-
tion of 2-benzyl-5,6-dihydro-4H-1,3-oxazines 1 (30 mmol) in
diglyme (15 mL) at room temperature. The reaction mixture
was stirred at 180ꢀC (oil bath) for 8–20 h. After removal of
the solvent and low boiling temperature materials under
reduced pressure, the precipitated materials were collected by
filtration and then washed with ethyl acetate. Samples for anal-
ysis were recrystallized from ethyl acetate.
Anal. Calcd. for, C19H21NO4: C, 69.71; H, 6.47; N, 4.28.
Found: C, 69.98; H, 6.56; N, 4.38.
Methyl 9-(4-methoxyphenyl)-6-oxo-3,4-dihydro-2H,6H-pyr-
ido[2,1-b]-1,3-oxazine-7-carboxylate (7e). The mixture of 1e
(30 mmol) and 6 (40 mmol) were stirred for 8 h to affordꢂ71e
as pale pink powder; mp 180–182ꢀC; IR: 1724, 1655 cm
;
1H NMR: d 2.29 (2H, quin, J ¼ 6.0 Hz, CH2), 3.83 (3H, s,
OCH3), 3.89 (3H, s, OCH3), 4.13 (2H, t, J ¼ 6.0 Hz, OCH2),
4.39 (2H, t, J ¼ 5.6 Hz, NCH2), 6.93 (2H, d, J ¼ 8.9 Hz,
ArAH), 7.32 (2H, d, J ¼ 8.9 Hz, ArAH), 8.30 (1H, s, CH);
13C NMR: d 21.2, 40.2, 52.0, 55.4, 66.0, 105.3, 108.0, 113.9,
127.2, 130.3, 147.7, 156.0, 158.7, 158.8, 166.4; MALDI-TOF
MS: 315.1 (Mþ); Anal. Calcd. for C17H17NO5: C, 64.75; H,
5.43; N, 4.44. Found: C, 64.80; H, 5.46; N, 4.53.
Methyl
6-oxo-9-phenyl-3,4-dihydro-2H,6H-pyrido[2,1-b]-
1,3-oxazine-7-carboxylate (7a). The mixture of 1a (30 mmol)
and 6 (40 mmol) were stirred for 8 h to afford 7a as pale yel-
low powder; mp 155–156ꢀC; IR: 1728, 1645 cmꢂ1 1H NMR
;
(DMSO-d6): d 2.30 (2H, quin, J ¼ 6.0 Hz, CH2), 3.89 (3H, s,
OCH3), 4.13 (2H, t, J ¼ 6.3 Hz, OCH2), 4.40 (2H, t, J ¼ 5.4
Hz, NCH2), 7.30 (1H, t, J ¼ 6.6 Hz, Ar-H), 7.38–7.43 (4H, m,
ArAH), 8.09 (1H, s, CH); 13C NMR: d 21.1, 40.2, 52.0, 66.0,
105.5, 108.2, 127.2, 128.4, 129.1, 134.9, 147.8, 156.1, 158.7,
166.3; MALDI-TOF MS: 285.1 (Mþ); Anal. Calcd. for
C16H15NO4: C, 67.36; H, 5.30; N, 4.91. Found: C, 67.56; H,
5.30; N, 4.89.
Methyl 9-(4-methoxyphenyl)-3,3-dimethyl-6-oxo-3,4-dihy-
dro-2H,6H-pyrido[2,1-b]-1,3-oxazine-7-carboxylate (7f). The
mixture of 1f (30 mmol) and 6 (40 mmol) were stirred for 8 h
to afford 7f as pale pink powder; mp 169–172ꢀC; IR: 1730,
1693, 1664 cmꢂ1
;
1H NMR: d 1.15 (6H, s, 2 ꢁ CH3), 3.83
(2H, s, OCH2), 3.84 (3H, s, OCH3), 3.89 (3H, s, OCH3), 3.99
(2H, s, NCH2), 6.93 (2H, d, J ¼ 8.9 Hz, ArAH), 7.32 (2H, d,
J ¼ 8.9 Hz, ArAH), 8.32 (1H, s, CH); 13C NMR: d 23.0, 28.3,
51.4, 52.0, 55.4, 75.1, 104.9, 108.3, 113.9, 127.2, 130.2, 147.7,
154.9, 158.7, 158.8, 166.4; MALDI-TOF MS: 343.1 (Mþ);
Anal. Calcd. for C19H21NO5: C, 66.46; H, 6.16; N, 4.08.
Found: C, 66.71; H, 6.06; N, 4.02.
Methyl
3,3-dimethyl-6-oxo-9-phenyl-3,4-dihydro-2H,6H-
pyrido[2,1-b]-1,3-oxazine-7-carboxylate (7b). The mixture of
1b (30 mmol) and 6 (33 mmol) were stirred for 8 h to afford
7b as pale yellow powder; mp 177–180ꢀC; IR: 1730, 1687,
1662, cmꢂ1
;
1H NMR (DMSO-d6): d 1.15 (6H, s, 2 ꢁ CH3),
3.84 (2H, s, OCH2), 3.89 (3H, s, OCH3), 4.00 (2H, s, NCH2),
7.28 (1H, t, J ¼ 6.9 Hz, ArAH), 7.37–7.42 (4H, m, ArAH),
8.36 (1H, s, CH); 13C NMR: d 23.0, 28.3, 51.4, 52.1, 75.1,
105.1, 108.4, 127.2, 128.4, 129.1, 135.0, 147.8, 155.0, 158.8,
166.3; MALDI-TOF MS: 313.1 (Mþ); Anal. Calcd. for
C18H19NO4: C, 68.99; H, 6.11; N, 4.47. Found: C, 69.23; H,
6.31; N, 4.44.
REFERENCES AND NOTES
[1] Toke, L.; Blasko, G.; Szabo, L.; Szantay, Cs. Tetrahedron
Lett 1972, 24, 2459.
Methyl 6-oxo-9-(4-methylphenyl)-3,4-dihydro-2H,6H-pyr-
ido[2,1-b]-1,3-oxazine-7-carboxylate (7c). The mixture of 1c
(30 mmol) and 6 (33 mmol) were stirred for 6 h to affordꢂ71c
[2] (a) Pfau, M.; Chiriacescu, M.; Revial, G. Tetrahedron Lett
1993, 34, 327; (b) Pfau, M.; Felk, A.; Revial, G. Tetrahedron Lett
1994, 35, 1549.
as pale yellow powder; mp 188–190ꢀC; IR: 1724, 1655 cm
;
[3] Trost, B. M.; Kunz, R. A. J Org Chem 1974, 39, 2475.
[4] Erden, I.; Ozer, G.; Hoarau, C.; Cao, W. J Heterocyclic
Chem 2006, 43, 395.
1H NMR: d 2.29 (2H, quin, J ¼ 6.0 Hz, CH2), 2.38 (3H, s,
ArACH3), 3.89 (3H, s, OCH3), 4.13 (2H, t, J ¼ 6.0 Hz,
OCH2), 4.39 (2H, t, J ¼ 5.5 Hz, NCH2), 7.20 (2H, d, J ¼ 8.3
Hz, ArAH), 7.28 (2H, d, J ¼ 8.3 Hz, ArAH), 8.32 (1H, s,
CH); 13C NMR: d 21.1, 21.2, 40.2, 52.0, 66.0, 105.5, 108.1,
129.0, 129.1, 131.9, 137.0, 147.8, 156.1, 158.7, 166.4;
MALDI-TOF MS: 299.1 (Mþ); Anal. Calcd. for C17H17NO4:
C, 68.21; H, 5.72; N, 4.68. Found: C, 68.48; H, 5.74; N, 4.73.
Methyl 3,3-dimethyl-6-oxo-9-(4-methylphenyl)-3,4-dihydro-
2H,6H-pyrido[2,1-b]-1,3-oxazine-7-carboxylate (7d). The mix-
ture of 1d (30 mmol) and 6 (40 mmol) were stirred for 8 h to
afford 7d as pale yellow powder; mp 195–196ꢀC; IR: 1728,
[5] b-Methyl-trans-cinnamylidenemalononitrile (BMCM) as
matrix for MALDI-TOF-MS analysis was synthesized by Knoevenagel
reaction with a-methyl-trans-cinnamaldehyde and malononitrile at
65ꢀC for 1 h in ion exchanged water under argon atmosphere. Reac-
tion mixture was cooled to 10ꢀC, and then collected by filtration
affording yellow powder. 1H NMR: d 2.41 (2H, d, J ¼ 1.2 Hz), 7.14
(1H, br s), 7.46 (1H, d, J ¼ 0.9 Hz), 7.39–7.49 (5H, m); 13C NMR: d
14.9, 81.0, 112.8, 114.4, 128.8, 130.1, 130.3, 133.4, 134.5, 149.6,
164.4; Anal. Calcd. For C13H10N2: C, 80.39; H, 5.19; N, 14.42. Found:
C, 80.67; H, 5.21; N, 14.56.
[6] Butt, M. I.; Neilson, D. G.; Watson, K. M.; Zakir-Ullah.
J Chem Soc, Perkin Trans 1, 1977, 2328.
1637 cmꢂ1
;
1H NMR: d 1.15 (6H, s, 2 ꢁ CH3), 2.38 (3H, s,
ArACH3), 3.83 (2H, s, OCH2), 3.89 (3H, s, OCH3), 3.99 (2H,
s, NCH2), 7.21 (2H, d, J ¼ 8.3 Hz, ArAH), 7.29 (2H, d, J ¼
8.3 Hz, ArAH), 8.34 (1H, s, CH); 13C NMR: d 21.2, 23.0,
28.3, 51.4, 52.0, 75.0, 105.1, 108.3, 129.0, 129.2, 132.0, 137.0,
147.7, 155.0, 158.8, 166.4; MALDI-TOF MS: 327.1 (Mþ);
[7] Melvin, S. M.; Stevens, C. L. J Am Chem Soc 1946, 68,
1917.
[8] Badiang, J. G.; Aube, J. J Org Chem 1996, 61, 2484. 1H NMR
(300 MHz, CDCl3): d 1.84 (2H, pentet, J ¼ 5.7 Hz), 3.39 (2H, t, J ¼ 5.9
Hz), 3.45 (2H, s), 4.13 (2H, t, J ¼ 5.6 Hz), 7.22–7.36 (5H, m).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet