One-pot three-component synthesis of oxazine derivatives in water

Article abstract of DOI:10.1002/jhet.1112

A one-pot synthesis of oxazine derivatives via reaction between activated acetylenic compounds, benzoyl cyanide, and N-nucleophiles in water as the solvent is describeda€.

Full text of DOI:10.1002/jhet.1112

E174
One-Pot Three-Component Synthesis of Oxazine Derivatives in Water
Vol 50
a
b
b
*
Faramarz Rostami-Charati, Zinatossadat Hossaini, Ebrahim Gharaee,
and Mohammad A. Khalilzadehb
aDepartment of Chemistry, Faculty of Science, Gonbad Kavous University, P.O. Box 163, Gonbad, Iran
bDepartment of Chemistry, Qaemshahr Branch, Islamic Azad University, Qaemshahr, Iran
*
E-mail: f_rostami_ch@yahoo.com
Received July 3, 2011
DOI 10.1002/jhet.1112
Published online 18 April 2013 in Wiley Online Library (wileyonlinelibrary.com).
COR
O
H2O, r.t.
N
COR
COR
+
+
Ph
CN
10 h
N
O
CN
Ph
COR
4
3
2
1
A one-pot synthesis of oxazine derivatives via reaction between activated acetylenic compounds, benzoyl
cyanide, and N-nucleophiles in water as the solvent is described.
J. Heterocyclic Chem., 50, E174 (2013).
INTRODUCTION
moiety. The 13C NMR spectrum of 4a exhibited 21 sig-
nals in agreement with the proposed structure.
Water is an ideal solvent and reagent for biochemical
transformations. In the past, water was not used as a
solvent for synthetic organic chemistry owing to the poor
solubility and, in some cases, the instability of organic
reagents in aqueous solutions. Now, it has been recognized
that chemical reactions in mixed aqueous solutions or
two-phase systems often give better results than in organic
solvents, and often the insolubility of the final products
facilitates their isolation [1–4].
Bridgehead nitrogen heterocycles are of interest because
they constitute an important class of natural and non-natural
products, many of which exhibit useful biological activity
[5]. As part of our current studies on the development of
new routes in heterocyclic synthesis, we report an efficient
procedure for direct synthesis of oxazine derivatives 4 from
the reaction of benzoyl cyanide 1 and activated acetylenic
compounds 2 in the presence of N-nucleophiles such as
isoquinoline, quinolin, or N-methylimidazole 3 in water
at room temperature (Scheme 1).
Although the mechanistic details of the reaction are not
known, a plausible rationalization may be advanced to
explain the product formation. Presumably, the reaction
involves the initial formation of a 1:1 zwitterionic intermedi-
ate [6] 5 between isoquinoline and the activated acetylene,
which undergoes reaction with 1 to produce 6. Intermediate
6 can undergo cyclization under the reaction conditions
employed to produce 4 (Scheme 2).
Under similar conditions, the reaction of quinoline,
pyridine, or N-methylimidazole with dialkyl acetylenedicar-
boxylates in the presence of 1 led to fused [1,3]oxazines 7–9
in good yields (Scheme 3).
In conclusion, we report a novel transformation involving
activated acetylenes and isoquinoline, quinoline, or pyridine
in the presence of benzoyl cyanide, which affords bridgehead
nitrogen-containing heterocycles. The present procedure has
the advantage that not only is the reaction performed in water
but also the reactants can be mixed without any prior activa-
tion or modification. The simplicity of the present procedure
makes it an interesting alternative to other approaches.
RESULT AND DISCUSSION
The structures of compounds 4a–4d were apparent
EXPERIMENTAL
1
from their H NMR and 13C NMR spectroscopic data,
All chemicals were obtained from commercial sources. Melting
points were measured on a Kofler hot stage apparatus and are
uncorrected. 1H NMR and 13C NMR spectra were obtained with a
Bruker FT-500 spectrometer (Bruker, Germany) in chloroform-d1,
and tetramethylsilane was used as an internal standard. Mass
spectra were recorded with a Finnigan Mat TSQ-70 spectrometer
as well as infrared (IR) spectra, in agreement with the
proposed structures. The 1H NMR spectrum of 4a in
CDCl3 exhibited two singlets for the methoxy protons
(d 3.59 and 4.03 ppm) and one singlet for the methin
(d 6.57 ppm) proton along with multiplets for the aromatic
© 2013 HeteroCorporation

February 2013
Synthesis of Oxazine Derivatives in Water
E175
Scheme 1. Three-component reactions of benzoyl cyanide, activated acetylenes, and isoquinoline.
COR
O
H2O, r.t.
N
COR
COR
+
+
Ph
CN
10 h
N
O
CN
Ph
COR
4
3
2
1
R
Yield (%) of 4
2, 4
a
b
c
MeO
EtO
tBuO
Ph
90
72
75
82
d
Scheme 2. Proposed mechanism for the one-pot synthesis of [1, 3]oxazines.
2 + 3
N
R
N
R
1
4
+
O
COR'
COR'
Ph CN
5
6
Scheme 3. Three-component reactions of benzoyl cyanide, activated acetylenes and quinoline, pyridine, and N-methylimidazole.
Me
N
H
H
H
N
O
N
O
N
O
Ph
Ph
Ph
RO2C
MeO2C
MeO2C
CN
CO2R
CN
CO2Me
CN
CO2Me
Yield/ %
7
R
8 (76%)
9 (82%)
a
b
Me
Et
75
72
(Vernon Hills, IL). IR spectra were acquired on a Nicolet Magna
550-FT spectrometer (Oshawa, Ontario, Canada). Elemental
analyses were carried out with a PerkinElmer model 240-C
apparatus (England). The results of elemental analyses (C, H,
and N) were within Æ0.4% of the calculated values.
by filtration and recrystallized from EtOH to afford the pure
title compounds.
Dimethyl 2-cyano-2-phenyl-2,11b-dihydro-[1,3]oxazino
[2,3-a]isoquinoline-3,4-dicarboxylate (4a). Yellow powder, mp
68–70ꢀC, 0.36g, yield 90%. IR (KBr) (nmax/cmÀ1): 1737 (C═O),
1699 (C═O), 1582, 1556, 1420, 1277, 1232. MS (EI, 70eV):
m/z (%)= 401 (2), 149 (64), 129 (44), 105 (90), 77 (100), 59
(86). Anal. Calcd for C23H18N2O5 (402.40): C, 68.65 H, 4.51 N,
6.96%. Found: C, 68.71 H, 4.60 N, 7.07%. 1H NMR: d 3.59
General procedure for preparation of compounds 4a–4d
and 7–9. Magnetically stirred solution of benzoyl cyanide
(2mmol) and dialkyl acetylenedicarboxylate (2 mmol) in H2O
(10 mL) was added isoquinoline, quinoline, pyridine, or N-
methylimidazole (2mmol), and the reaction was mixed for 10h at
room temperature. The completion of reaction was confirmed by
TLC (EtOAc–hexane 6:1). The resulting precipitate was separated
3
(s, 3 H, OCH3), 4.03 (s, 3 H, OCH3), 5.88 (d, J = 7.8, 1H, CH),
6.40 (d, 3J = 7.8, 1H, CH), 6.57 (s, 1H, CH), 7.13 (d, 3J = 7.5,
3
3
1H, CH), 7.29 (t, J = 7.1, 1H, CH), 7.34 (d, J = 7.4, 1H, CH),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E176
F. Rostami-Charati, Z. Hossaini, E. Gharaee, and M. A. Khalilzadeh
Vol 50
3
7.38–7.40 (m, 3 H, 3 CH), 7.48 (d, J = 7.7, 1H, CH), 7.65–7.67
(m, 2 H, 2 CH). 13C NMR: d 51.9 (OCH3), 53.7 (OCH3), 78.1
(C), 82.1 (CH), 106.1 (CH), 118.1 (CN), 122.8 (CH), 125.1 (C),
125.5 (CH), 126.6 (2 CH), 127.7 (CH), 128.1 (CH), 128.7
(2 CH), 128.9 (C), 129.4 (C), 129.6 (CH), 130.1 (CH), 136.0
(C), 145.3 (C), 163.0 (C═O), 163.1 (C═O).
1775, 1752, 1748, 1538, 1345, and 1300 cmÀ1
.
1H NMR
(500.1 MHz, CDCl3): d = 3.80 (3 H, s, MeO), 3.92 (3 H, s,
3
MeO), 5.82 (1 H, d, JHH = 6.8 Hz, CH), 7.50 (2 H, d,
3
3JHH = 7.5 Hz, 2 CH), 7.56 (2 H, t, JHH = 7.2 Hz, 2 CH), 7.60
3
3
(2 H, t, JHH = 7.2 Hz, 2 CH), 7.79 (2 H, d, JHH = 7.7 Hz, 2
3
CH), 8.15 (2 H, d, JHH = 7.2 Hz, 2 CH), 8.21 (1 H, d,
Diethyl 2-cyano-2-phenyl-2,11b-dihydro-[1,3]oxazino[2,3-
a]isoquinoline-3,4-dicarboxylate (4b). White powder, mp
148–150ꢀC, 0.31 g, yield 72%. IR (KBr) (nmax/cmÀ1): 1730
(C═O), 1695 (C═O), 1583, 1557, 1273, 1222, 764. MS (EI,
70 eV): m/z (%) = 258 (16), 105 (80), 77 (100). Anal. Calcd
for C25H22N2O5 (430.46): C, 69.76 H, 5.15 N, 6.51%.
Found: C, 69.74 H, 5.10 N, 6.60%. 1H NMR: d 1.03 (t,
3J = 7.1, 3 H, CH3), 1.46 (t, 3J = 7.1, 3 H, CH3), 4.05
(q, 3J = 7.1, 2 H, CH2), 4.45–4.56 (m, 2 H, CH2), 5.88 (d,
3JHH = 7.7 Hz, CH) ppm. 13C NMR (125.7 MHz, CDCl3):
d = 51.9 (OCH3), 52.8 (OCH3), 75.7 (C), 83.4 (CH), 117.0
(C), 117.6 (2 CH), 118.5 (CN), 119.7 (2 CH), 124.2 (C),
125.4 (2 CH), 126.3 (C), 128.8 (2 CH), 129.2 (2 CH), 129.8
(CH), 132.4 (C), 132.8 (C), 165.1 (C═O), 175.2 (C═O) ppm.
Anal. Calcd for C23H18N2O5 (402.40): C, 68.65 H, 4.51 N,
6.96%. Found: C, 68.58, H, 4.42, N, 6.85%.
Diethyl 3-cyano-3-phenyl-3H,4aH-[1,3]oxazino[3,2-a]
quinoline-1,2-dicarboxylate (7b). Yellow powder, mp
150–152ꢀC, yield: 0.62 g (72%). IR (KBr) (nmax/cmÀ1):
3J = 7.8, 1H, CH), 6.43 (d, J = 7.8, 1H, CH), 6.58 (s, 1H, CH),
3
7.13 (d, 3J = 7.5, 1H, CH), 7.29 (t, 3J = 7.5, 1H, CH), 7.34
(t, 3J = 7.4, 1H, CH), 7.38–7.40 (m, 3 H, 3 CH), 7.48 (d,
3J = 7.6, 1H, CH), 7.68 (d, 3J = 7.6, 2 H, 2 CH). 13C NMR: d 13.6
(CH3), 13.9 (CH3), 61.0 (OCH2), 63.2 (OCH2), 76.6 (C), 82.1
(CH), 105.8 (CH), 105.9 (C), 118.2 (CN), 122.8 (CH), 125.1 (C),
125.5 (CH), 126.7 (2 CH), 127.7 (CH), 128.1 (CH), 128.6 (2
CH), 129.5 (C), 129.6 (CH), 130.1 (CH), 136.3 (C), 145.4 (C),
162.4 (C═O) 162.5 (C═O).
1738, 1725, 1715, 1658, 1458, 1325, and 1245 cmÀ1
.
1H
3
NMR (500.1 MHz, CDCl3): d = 1.25 (3 H, t, J = 7.3 Hz, Me),
3
3
1.32 (3 H, t, J = 7.3 Hz, Me), 4.20 (2 H, q, J = 7.3 Hz, CH2O),
4.40 (2 H, q, 3J = 7.3Hz, OCH2), 5.83 (1 H, d, JHH = 7.2 Hz,
3
3
CH), 7.52 (2 H, d, JHH = 7.4 Hz, 2 CH), 7.62 (2 H, t,
3JHH = 7.2 Hz, 2 CH), 7.64 (2 H, t, JHH = 7.3 Hz, 2 CH), 7.75
3
(2 H, d, 3JHH = 7.5 Hz, 2 CH), 8.22 (2 H, d, 3JHH = 7.2 Hz, 2 CH),
8.25 (1 H, d, 3JHH = 7.7 Hz, CH) ppm. 13C NMR (125.7 MHz,
CDCl3): d = 14.1 (CH3), 14.2 (CH3), 62.5 (OCH2), 62.7
(OCH2), 76.2 (C), 83.5 (CH), 117.2 (C), 118.0 (2 CH),
118.6 (CN), 120.1 (2 CH), 124.5 (C), 125.6 (2 CH), 126.7
(C), 129.2 (2 CH), 129.5 (2 CH), 130.4 (CH), 132.5 (C),
133.4 (C), 164.8 (C═O), 172.7 (C═O) ppm. Anal. Calcd for
C25H22N2O5 (430.46): C, 69.76 H, 5.15 N, 6.51%. Found:
C, 69.68, H, 5.07, N, 6.47%.
Di(tert-butyl) 2-cyano-2-phenyl-2,11b-dihydro-[1,3]oxazino
[2,3-a]isoquinoline-3,4-dicarboxylate (4c). Yellow powder, mp
69–71ꢀC, 0.26 g, yield 55%. IR (KBr) (nmax/cmÀ1): 1726 and
1696 (2 C═O), 1280, 1230, 1138, 763. Anal. Calcd for
C29H30N2O5 (486.56): C, 71.59 H, 6.21 N, 5.76%. Found: C,
1
71.68 H, 6.24 N, 5.80%. H NMR: d 1.29 (s, 9H, CMe3), 1.67
(s, 9H, CMe3), 5.78 (d, 3J = 7.4, 1H, CH), 5.80 (s, 1H, CH),
3
3
6.43 (d, J = 7.0, 1H, CH), 6.82 (d, J = 6.7, 1H, CH), 7.05 (d,
3J = 6.7, 1H, CH), 7.12 (t, 3J = 6.7, 1H, CH), 7.25–7.26 (m,
1H, CH), 7.35–7.36 (m, 1H, CH), 7.48–7.50 (m, 3 H, 3 CH),
7.71–7.72 (m, 1H, CH). 13C NMR: d 27.7 (CMe3), 27.8
(CMe3), 75.1 (C), 78.0 (CH), 82.5 (CMe3), 84.9 (CMe3), 103.3
(C), 105.0 (CH), 119.0 (CN), 122.8 (CH), 125.1 (C), 125.2
(CH), 126.6 (C), 127.1 (CH), 127.4 (CH), 128.2 (2 CH), 128.7
(2 CH), 129.6 (CH), 129.7 (CH), 139.4 (C), 146.2 (C), 161.5
(C═O), 162.2 (C═O).
Dimethyl 2-cyano-2-phenyl-2H,9aH-pyrido[2,1-b][1,3]oxazin-
3,4-dicarboxylate (8). Pale yellow powder, mp 127–129ꢀC,
yield: 0.54 g (76%). IR (KBr) (nmax/cmÀ1): 1785, 1770, 1725,
1652, 1447, and 1254 cmÀ1 1H NMR (500.1 MHz, CDCl3):
.
d = 3.63 (s, 3 H, MeO), 3.85 (s, 3 H, MeO), 5.83 (1 H, d,
3JHH = 7.1 Hz, CH), 7.14 (2 H, t, 3JHH = 7.2 Hz, 2 CH), 7.47 (2 H,
3
3
t, JHH = 7.2 Hz, 2 CH), 7.52 (1 H, d, JHH = 7.4 Hz, CH), 7.62
(1 H, t, 3JHH = 7.2 Hz, CH), 7.64 (1 H, t, 3JHH = 7.3 Hz, CH), 8.47
3
3
(1 H, d, JHH = 7.3 Hz, CH), 9.51 (1 H, d, JHH = 7.2 Hz, CH)
ppm. 13C NMR (125.7 MHz, CDCl3): d = 52.2 (OCH3), 52.7
(OCH3), 78.6 (CH), 80.2 (C), 104.3 (CH), 113.8 (C), 111.4
(CH), 116.9 (CH), 119.0 (CN), 120.1 (C), 120.4 (CH), 124.7
(CH), 124.8 (CH), 128.3 (CH), 129.4 (C), 130.2 (CH), 134.3
(CH), 163.3 (C═O), 164.6 (C═O) ppm. Anal. Calcd for
C19H16N2O5 (352.34): C, 64.77; H, 4.58; N, 7.95. Found: C,
64.68; H, 4.47; N, 7.86%.
3,4-Dibenzoyl-2-phenyl-2H,11bH-[1,3]oxazino[2,3-a]
isoquinoline-2-yl-cyanide (4d). Yellow powder, yield: 0.81 g
(82%), mp 100–102ꢀC. IR (KBr): n = 1700, 1695, 1656, and
1584 cmÀ1
.
1H NMR (500 MHz, CDCl3): d = 5.74 (1 H, s,
3
CH), 7.31 (1 H, d, JHH = 7.6 Hz, CH), 7.33 (4 H, m, 4 CH of
C6H5), 7.35–7.36 (1H, m, CH), 7.48–7.50 (3 H, m, 3 CH),
3
7.52 (1 H, d, JHH = 7.2 Hz, CH of C6H5), 7.58 (1 H, t,
3
3JHH = 7.2 Hz, CH), 7.60 (1 H, t, JHH = 7.2 Hz, CH), 7.64 (4
Dimethyl 7-cyano-1-methyl-7-phenyl-1,8a-dihydro-7H-
imidazo[2,1-b] [1,3]oxazine-5,6-dicarboxylate (9). Yellow
3
H, m, 4 CH of C6H5), 7.67 (1 H, d, JHH = 7.2 Hz, CH of
C6H5), 7.71–7.72 (m, 1H, CH), 8.02 (1 H, t, JHH = 7.9 Hz,
CH), 8.06 (1 H, d, JHH = 7.9 Hz, CH), 9.58 (1 H, d,
3
powder, mp 145–147ꢀC, yield: 0.58 g (82%). IR (KBr) (nmax
/
cmÀ1): 1765, 1758, 1735, 1654, 1429, and 1254 cmÀ1 1H
.
3
3JHH = 7.6 Hz, CH) ppm. 13C NMR (125.7 MHz, CDCl3):
d = 75.6 (C), 82.5 (CH), 117.8 (2 CH), 118.3 (CN), 120.2 (C),
120.7 (C), 124.5 (C), 125.5 (2 CH), 126.3 (2 CH), 128.1
(2 CH), 129.1 (2 CH), 129.2 (2 CH), 129.4 (2 CH), 130.4
(2 CH), 130.5 (C), 130.7 (2 CH), 131.4 (CH), 134.2 (CH), 134.3
(C), 134.5 (CH), 138.9 (C), 139.3 (C), 192.2 (C═O), 193.8
(C═O) ppm. Anal. Calcd for C33H22N2O3 (499.55): C, 80.15; H,
4.48; N, 5.66. Found: C, 80.02; H, 4.39; N, 5.58%.
NMR (500.1 MHz, CDCl3): d = 2.47 (s, 3 H, NMe), 3.58 (s,
3 H, OMe), 3.74 (s, 3 H, OMe), 6.54 (1 H, s, CH), 6.76 (d,
1 H, 3J = 8.5 Hz, CH), 6.86 (d, 1 H, 3J = 9.8 Hz, CH), 7.03
(t, 1 H, 3J = 7.4 Hz, CH), 7.12 (d, 1 H, 3J = 5.4 Hz, CH),
7.24 (m, 2 H, 2 CH), 7.42 (d, 1 H, 3J = 5.4 Hz, CH) ppm.
13C NMR (125.7 MHz, CDCl3): d = 36.5 (NMe), 51.5
(MeO), 52.8 (MeO), 75.4 (C), 100.3 (2 CH), 105.8 (2 CH),
112.4 (2 C), 118.5 (CN), 121.8 (CH), 129.0 (CH), 132.4 (2
CH), 140.1 (C), 163.4 (C═O), 165.8 (C═O) ppm. Anal.
Calcd for C18H17N3O5 (355.35): C, 60.84; H, 4.82; N,
11.83. Found: C, 60.89; H, 4.87; N, 11.90%.
Dimethyl 3-cyano-3-phenyl-3H,4aH-[1,3]oxazino[3,2-a]
quinoline-1,2-dicarboxylate (7a). Yellow powder, mp
138–140ꢀC, yield: 0.60 g (75%). IR (KBr) (nmax/cmÀ1):
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

February 2013
Synthesis of Oxazine Derivatives in Water
E177
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[5] Swinbourne, J. F.; Hunt, H. J.; Klinkert, G. Adv Heterocycl
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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