One-pot three-component synthesis of dihydrobenzo- and naphtho[e]-1,3- oxazines in water

Article abstract of DOI:10.1002/jhet.147

(Chemical Equation Presented) A simple, green and efficient method has been developed for the synthesis of biologically and materially important dihydrobenzo/naphtho[e]-1,3-oxazines in good to excellent yields through a Mannich-type condensation cyclizati

Full text of DOI:10.1002/jhet.147

September 2009
One-Pot Three-Component Synthesis of Dihydrobenzo- and
Naphtho[e]-1,3-oxazines in Water
1003
Bijoy P. Mathew and Mahendra Nath*
Department of Chemistry, University of Delhi, Delhi-110 007, India
*E-mail: mnath@chemistry.du.ac.in
Received May 15, 2008
DOI 10.1002/jhet.147
Published online 2 September 2009 in Wiley InterScience (www.interscience.wiley.com).
A simple, green and efficient method has been developed for the synthesis of biologically and materi-
ally important dihydrobenzo/naphtho[e]-1,3-oxazines in good to excellent yields through a Mannich-
type condensation cyclization reaction of aromatic alcohols with HCHO and primary amines in aqueous
media at ambient temperature.
J. Heterocyclic Chem., 46, 1003 (2009).
INTRODUCTION
diverse applications of this class of heterocyclic systems
inspired chemists to develop new and efficient synthetic
strategies for the preparation of these bioactive and
materially important molecules.
Recently, great attention has been focused to develop
nonhazardous and environment friendly synthetic strat-
egies for organic reactions by replacing volatile organic
solvents with nontoxic and noninflammable media such
as water, ionic liquids, supercritical fluids, and even
under neat conditions [1]. Among these, water has
emerged as a versatile solvent for several organic trans-
formations [2]. Water is not only a desirable solvent for
chemical processes because of cost, safety, and environ-
mental concerns but also provides completely new reac-
tivity. The wide range of organic reactions is known in
water including Diels-Alder cycloadditions, Knoevena-
gal condensations, Aldol-condensations, epoxidation,
and oxidation–reduction reactions [3–7]. In addition to
these, water has also been used as a solvent in reactions
involving carbanions, carbocations, radicals, carbenes,
and most recently transition metal catalyzed reactions
[8]. In many organic reactions, the use of water as a sol-
vent not only accelerates the rate and the yield but also
enhances enantioselectivity in chiral synthesis [9].
The syntheses of dihydro-1,3-oxazines have been pre-
viously reported by several investigators via Mannich-
type condensation of a phenol or naphthol with formal-
dehyde and primary amine using highly inflammable or-
ganic solvents [16] and alkaline media [17]. Further,
researchers have also been successful in developing
mild and solvent free protocol for the construction of
these molecules [18]. However, many of these processes
are associated with several shortcomings such as long
duration of reaction, high temperature, use of volatile
and hazardous organic solvents, and occurrence of side
products. As a part of our research program to develop
a simple methodology for the preparation of target com-
pounds of pharmaceutical interests, we wish to report
herein a simple one-pot three-component synthesis of
3,4-dihydro-2H-benzo[e]-1,3-oxazines (Scheme 1) and
dihydronaphtho[e]-1,3-oxazines (Scheme 2) in neat
water at ambient temperature.
Dihydrobenzo/naphtho[e]-1,3-oxazines are known to
exhibit a wide range of valuable pharmacological prop-
erties as antitumor [10], antibacterial [11], anti-HIV
[12], and antimicrobial agents [13]. In addition, 6-aryl-
benzoxazines have also been examined as progesterone
receptor modulators and reported as potent nonsteroidal
progesterone receptor agonists [14]. On the other hand,
these molecules are materially very useful for making
phenol type polymers such as polybenzoxazines, offers
lucrative mechanical, and electrical properties [15]. The
RESULTS AND DISCUSSION
Our initial efforts are focused on the search of a green
solvent to carry out the synthesis of dihydrobenzo/naph-
tho[e]-1,3-oxazines at ambient temperature. In this con-
nection, water was chosen for the condensation reaction
of phenol, HCHO, and butylamine at room temperature.
The completion of the reaction was monitored by TLC
C
V
2009 HeteroCorporation

1004
B. P. Mathew and M. Nath
Vol 46
Scheme 1
Table 1
Synthesis of 3,4-dihydro-2H-benzo[e]-1,3-oxazines and 1,2-bis(2H-
benzo[e]-1,3-oxazin-3(4H)-yl)ethanes in water.
Entry
Compound
R1
R2
R
Yield (%)
1
2a
2b
2c
2d
2e
2f
2g
3a
3b
3c
3d
H
H
H
H
H
H
C4H9
C6H5
C6H11
4–CH3C6H4
2–ClC6H4
2–ClC6H4
2–ClC6H4
64
77
80
90
82
84
74
87
75
77
70
2
3
4
5
Cl
H
H
CH3
Cl
H
6
7
H
Cl
H
8
H
–
–
–
–
9
10
11
H
Cl
Cl
Cl
H
Cl
oxazines were prepared in a short time (30 min to 1 h)
at 25ꢀC in water, whereas in other organic solvents the
reaction takes several hours to days for complete con-
sumption of starting materials. All the synthesized dihy-
dro-1,3-oxazine derivatives have been characterized by
1H, 13C NMR, IR, mass, and elemental analyses. The
physical data of all the known compounds (2a-c, 3a, b,
d, 5a-c, 6a-e) are in agreement with those of reported
data [11,16,20,21]. The spectral and analytical data of
new compounds (2d-g, 3c, 5d, 6f-g) are presented in the
experimental section.
and the product was extracted with ethyl acetate, and
purified by column chromatography on silica gel using
ethyl acetate/heptane as eluent to afford 3-butyl-6-
chloro-3,4-dihydro-2H-benzo[e]-1,3-oxazine (2a) in 64%
yield. To demonstrate the versatility of this methodol-
ogy, synthesis of a variety of 3,4-dihydro-2H-benzo[e]-
1,3-oxazines (2b-g) and 1,2-bis(3,4-dihydro-2H-benzo
[e]-1,3-oxazin-3-yl)ethanes (3a-d) has been carried out
in good to excellent yields (Table 1).
Under these optimized reaction conditions, the scope
of the reaction was then further explored by reacting 1-
naphthol (4a) and 2-naphthol (4b) with aqueous HCHO
and primary amines in water at ambient temperature
separately to obtain 3,4-dihydro-2H-naphtho[e]-1,3-oxa-
zines (5a-d) and 2,3-dihydro-1H-naphtho[e]-1,3-oxazines
(6a-g), respectively in good yields (Table 2).
Our synthetic strategy does not require hazardous and
toxic organic solvents, and the products were isolated
by extraction with ethyl acetate, a preferred and safer
solvent [19]. In fact, the dihydrobenzo/naphtho[e]-1,3-
Furthermore, the polymerization behavior of novel
benzoxazine analogues (2f; 4.79 mg & 3c; 6.30 mg)
was examined by Differential Scanning Calorimetry
(DSC) with a heating rate of 10ꢀC per min. The endo-
thermic peaks at 67.5ꢀC and 167ꢀC are attributed to the
melting of both 2f and 3c. For 6-chloro-3-(2-chloro-
phenyl)-3,4-dihydro-2H-benzo[e]-1,3-oxazine (2f), an
exotherm was observed due to the ring opening poly-
merization [16j] with onset at 267ꢀC and maximum at
270ꢀC. The amount of heat of polymerization is 218 J/g.
The DSC trace of 1,2-bis(8-chloro-2H-benzo[e]-1,3-oxa-
zin-3(4H)-yl)ethane (3c) showed an exotherm with onset
Scheme 2
Table 2
Synthesis of 3,4-dihydro-2H-naphtho[e]-1,3-oxazines and 2,3-dihydro-
1H-naphtho[e]-1,3-oxazines in water.
Entry
Compound
R
Yield (%)
1
5a
5b
5c
5d
6a
6b
6c
6d
6e
6f
C6H5
CH2C6H5
C6H11
C4H9
C6H5
CH2C6H5
C6H11
C4H9
90
60
62
85
79
75
87
80
73
65
63
2
3
4
5
6
7
8
9
4-BrC6H4
2,5-Cl2C6H3
2,4,6-Cl3C6H2
10
11
6g
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2009
One-Pot Three-Component Synthesis of Dihydrobenzo- and
Naphtho[e]-1,3-oxazines in Water
1005
1
at 195ꢀC and maximum at 200ꢀC. The amount of heat
of polymerization for 3c is 289 J/g. The shift of the cure
exotherm to a lower temperature in case of 3c than that
of 2f is possibly due to the flexibilizing effect of the
ethylene bridge, which accelerated the ring opening
polymerization.
916, 814; H nmr (CDCl3): d 2.24 (s, 3H, CH3), 4.52 (s, 2H,
NCH2), 5.25 (s, 2H, OCH2N), 6.72–7.38 (m, 7H, ArH); 13C
nmr (CDCl3): d 152.2, 146.9, 130.9, 130.7, 128.9, 128.1,
127.4, 125.3, 123.3, 120.8, 117.1, 80.8, 51.3, 21.0. HRMS:
exact mass calculated for C15H14ClNO (Mþ): 259.0764; found:
259.0696.
6-Chloro-3-(2-chlorophenyl)-3,4-dihydro-2H-benzo[e]-1,3-
oxazine (2f). Pale yellow solid; mp 67.5 ꢀC; mmax (film,
cmꢁ1): 2921, 2851, 1588, 1481, 1439, 1413, 1248, 1228, 1160,
In conclusion, we have developed a rapid, energy effi-
cient, and environmentally conducive one-pot process
for the preparation of dihydrobenzo- and naphtho[e]-1,3-
oxazines in good yields at ambient temperature. In com-
parison with reported methods for making these mole-
cules, the procedure presented herein avoids the use of
hazardous organic media and the reactions are run in
pure water, which is the cheapest and most harmless
solvent available. Finally, these green advantages make
the process more attractive for the synthesis of various
biologically important dihydro-1,3-oxazine molecules.
1
1040, 942, 878, 815; H nmr (CDCl3): d 4.52 (s, 2H, NCH2),
5.26 (s, 2H, OCH2N), 6.77–7.39 (m, 7H, ArH); 13C nmr
(CDCl3): d 153.0, 146.4, 131.0, 128.9, 128.4, 128.1, 126.8,
126.1, 125.6, 123.2, 122.5, 118.7, 81.0,þ51.0; HRMS: exact
mass calculated for C14H12Cl2NO (MH ): 280.0296; found:
280.0770; Anal. Calcd. for C14H11Cl2NO: C, 60.02; H, 3.96;
N, 5.00. Found: C, 60.07; H, 4.03; N, 5.04.
8-Chloro-3-(2-chlorophenyl)-3,4-dihydro-2H-benzo[e]-1,3-
oxazine (2g). Viscous liquid; H nmr (CDCl3): d 4.58 (s, 2H,
1
NCH2), 5.41 (s, 2H, OCH2N), 6.81–6.92 (m, 2H, ArH), 7.03
(t, J ¼ 7.6 Hz, 1H, ArH), 7.15 (t, J ¼ 8 Hz, 1H, ArH), 7.24
(d, J ¼ 8.1 Hz, 1H, ArH), 7.33–7.40 (m, 2H, ArH); HRMS:
exact mass calculated for C14H12Cl2NO (MHþ): 280.0296;
found: 280.0972.
3-Butyl-3,4-dihydro-2H-naphtho[2,1-e]-1,3-oxazine (5d). Dark
viscous liquid; mmax (film, cmꢁ1): 2924, 2853, 1578, 1465,
EXPERIMENTAL
All the chemicals were used as received without any further
purification. The products were purified by column chromatog-
raphy using silica gel (60–120 mesh size). 1H and 13C NMR
were recorded on Brucker 300 MHz spectrometer in CDCl3
and referenced to the proton or carbon resonances resulting
from incomplete deuteration of deuterated solvent. IR spectra
were recorded on Perkin Elmer IR spectrometer and mass
spectra were recorded on ESI-MS (micromass LCT, Water)
mass spectrometer. DSC traces were recorded by using 4–
6 mg samples in aluminium pan on Perkin Elmer DSC with a
heating rate of 10ꢀC minꢁ1 in nitrogen atmosphere. Elemental
Analyses were obtained from CHNSO Lab, University Science
Instrumentation Centre, University of Delhi, Delhi.
1
1404, 1070, 913, 801; H nmr (CDCl3): d 0.90 (t, J ¼ 7.3 Hz,
3H, CH3), 1.32–1.39 (m, 2H, CH2), 1.56–1.61 (m, 2H, CH2),
2.79 (t, J ¼ 7.4 Hz, 2H, CH2), 4.09 (s, 2H, NCH2), 5.04 (s,
2H, OCH2N), 7.05 (d, J ¼ 8.3 Hz, 1H, ArH), 7.35 (d, J ¼ 8.4
Hz, 1H, ArH), 7.41–7.47 (m, 2H, ArH), 7.73–7.76 (m, 1H,
ArH), 8.11–8.14 (m, 1H, ArH); HRMS: exact mass calculated
for C16H19NO (Mþ): 241.1467; found: 241.5292.
2-(2,5-Dichloro-phenyl)-2,3-dihydro-1H-naphtho[1,2-
e]-1,3-oxazine (6f). Pale yellow solid; mp 139ꢀC; mmax
(film, cmꢁ1): 2890, 1625, 1600, 1582, 1559, 1516, 1474, 1435,
1403, 1383, 1267, 1230, 1191, 1159, 1131, 1102, 1059, 1047,
1
1008, 981, 950, 917, 857, 810; H nmr (CDCl3): 4.88 (s, 2H,
NCH2), 5.32 (s, 2H, OCH2N), 6.97 (dd, J ¼ 2.4 Hz, 1H,
ArH), 7.10 (d, J ¼ 8.9 Hz, 1H, ArH), 7.29 (d, J ¼ 8.5 Hz,
1H, ArH), 7.35–7.40 (m, 2H, ArH), 7.47–7.52 (m, 1H, ArH),
7.61–7.69 (m, 2H, ArH), 7.78 (d, J ¼ 8.0 Hz, 1H, ArH); Anal.
Calcd. for C18H13Cl2NO: C, 65.47; H, 3.97, N, 4.24. Found:
C, 65.19, H, 4.27, N, 4.16.
General procedure for the one-pot synthesis of dihydro-
benzo/naphtho[e]-1,3-oxazines (2a-g, 5a-d, 6a-g). To a mix-
ture of aromatic alcohol (10 mmol) and primary amine (10
mmol) in water (20 ml), formalin (37%, w/v, 20 mmol) was
added. The reaction mixture was stirred at 25ꢀC for 30 min to
1 h. After completion of the reaction, the product was
extracted with ethyl acetate (20 ml, two times). The organic
layers were combined and washed with 10% aqueous NaOH
solution (30 ml, two times) followed by water (50 ml). The or-
ganic layer was dried over sodium sulfate and evaporated
under reduced pressure. The crude product was purified by col-
umn chromatography on silica gel using ethyl acetate/heptane
as eluent to afford the desired product.
2-(2,4,6-Trichloro-phenyl)-2,3-dihydro-1H-naphtho[1,2-e]-
1,3-oxazine (6g). Pale yellow solid; mp 122ꢀC; mmax (film,
cmꢁ1): 2891, 1626, 1599, 1516, 1469, 1382, 1334, 1229, 1157,
1
1138, 1068, 1009, 953, 921, 880, 811; H nmr (CDCl3): d 4.85
(s, 2H, NCH2), 5.24 (s, 2H, OCH2N), 7.09 (d, J ¼ 8.9 Hz, 1H,
ArH), 7.38 (t, J ¼ 7.1 Hz, 1H, ArH), 7.46–7.52 (m, 3H, ArH),
7.61 (d, J ¼ 8.3 Hz, 1H, ArH), 7.68 (d, J ¼ 8.9 Hz, 1H, ArH),
7.78 (d, J ¼ 8.0 Hz, 1H, ArH); Anal. Calcd. for C18H12Cl3NO:
C, 59.29, H, 3.32, N, 3.84. Found: C, 59.22, H, 3.57, N, 3.79.
General procedure for the one-pot synthesis of 1,2-
8-Chloro-3-(4-methylphenyl)-3,4-dihydro-2H-benzo[e]-
1,3-oxazine (2d). Brown colored viscous liquid; mmax (film,
cmꢁ1): 2922, 2851, 1615, 1574, 1515, 1461, 1378, 1240, 927,
818; 1H nmr (CDCl3): d 2.26 (s, 3H, CH3), 4.59 (s, 2H,
NCH2), 5.44 (s, 2H, OCH2N), 6.79 (dd, J ¼ 7.8, 7.6 Hz, 1H,
ArH), 6.91 (d, J ¼ 7.6 Hz, 1H, ArH), 7.02 (d, J ¼ 8.3 Hz,
2H, ArH), 7.07 (d, J ¼ 8.3 Hz, 2H, ArH), 7.19 (d, J ¼ 7.5
Hz, 1H, ArH), HRMS: exact mass calculated for C15H13ClNO
(MþꢁH): 258.0686; found: 258.0246.
bis(2H-benzo[e]-1,3-oxazin-3(4H)-yl)ethanes (3a-d). To
a
mixture of aromatic alcohol (20 mmol) and ethylene diamine
(10 mmol) in water (20 ml), formalin (37%, w/v, 40 mmol)
was added. The reaction mixture was stirred at 25ꢀC for
30 min. After completion of the reaction, the product was
extracted with ethyl acetate (20 ml, two times). The organic
layers were combined and washed with 10% aqueous NaOH
solution (30 ml, two times) followed by water (50 ml). The or-
ganic layer was dried over sodium sulfate and evaporated
3-(2-Chlorophenyl)-6-methyl-3,4-dihydro-2H-benzo-[e]-
1,3-oxazine (2e). Viscous liquid; mmax (film, cmꢁ1): 2924,
2856, 1618, 1589, 1502, 1483, 1441, 1226, 1041, 971, 949,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1006
B. P. Mathew and M. Nath
Vol 46
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under reduced pressure. The crude solid was washed with etha-
nol to obtained sufficiently pure product.
1,2-Bis(8-chloro-3,4-dihydro-2H-benzo[e]-1,3-oxazin-
3(4H)-yl)ethane (3c). White solid; mp 167ꢀC; mmax (film,
cmꢁ1) 2918, 2854, 1572, 1456, 1353, 1321, 1231, 1120, 1071,
1031, 981, 894, 762; 1H nmr (CDCl3): d 2.98 (s, 4H,
NCH2CH2N), 4.04 (s, 4H, 2NCH2), 5.02 (s, 4H, 2OCH2N),
6.77–6.87 (m, 4H, ArH), 7.21 (d, J ¼ 6.8 Hz, 2H, ArH). Anal.
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C, 59.39, H, 5.22, N, 7.91.
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Acknowledgments. We thank the University of Delhi for finan-
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet