Green and efficient synthesis of 1,2-bis(2H-benzo[e][1,3]oxazin-3(4H)-yl)ethanes and 1,2-bis(2H-benzo[e][1,3]thiazin-3(4H)-yl)ethanes

Article abstract of DOI:10.24820/ark.5550190.p010.854

An environmental friendly procedure for synthesis of 1,2-bis(2H-benzo[e][1,3]oxazin-3(4H)-yl)ethanes and 1,2-bis(2H-benzo[e][1,3]thizin-3(4H)-yl)ethanes is reported using water as solvent. A comparative study between a conventional and a microwave method

Full text of DOI:10.24820/ark.5550190.p010.854

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Green and efficient synthesis of 1,2-bis(2H-benzo[e][1,3]oxazin-3(4H)-yl)ethanes
and 1,2-bis(2H-benzo[e][1,3]thiazin-3(4H)-yl)ethanes
R.L. Nongkhlaw,a R. Nongrum,a S. Tumtin,b and I. T. Phuchob*
aDepartment of Chemistry
North Eastern Hill University, Shillong-793022, Meghalaya, India
bDepartment of Chemistry
Nagaland University, Lumami-798627, Nagaland, India
*Email: itphucho@gmail.com
Received 12-18-2018
Accepted 04-26-2019
Published on line 05-19-2019
Abstract
An environmental friendly procedure for synthesis of 1,2-bis(2H-benzo[e][1,3]oxazin-3(4H)-yl)ethanes and 1,2-
bis(2H-benzo[e][1,3]thizin-3(4H)-yl)ethanes is reported using water as solvent. A comparative study between
a conventional and a microwave method is also reported.
Keywords: Oxazines, benzoxazines, microwave, green chemistry
DOI: https://doi.org/10.24820/ark.5550190.p010.854
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Introduction
Heterocycles containing the oxazine nucleus possess a wide range of biological applications.1 Of the
many reported pathways, the Mannich reaction involving phenols, formalin and primary amines2 is
advantageous for developing a variety of heterocyclic compounds owing to its convenience and ease of
reagent availabilty. The interest for 1,3-oxazines has recently increased, mainly due to compounds containing
a dihydro-1,3-oxazine ring system leading to a wide spectrum of pharmacological activities such as anti-
tumor,3 anti-bacterial,4 anti-HIV5and anti-malarial agents6 and their versatility as synthetic intermediates.7 In
addition, naphthoxazine derivatives exhibit therapeutic potential for the treatment of Parkinson’s disease.8
Despite the fact that substituted 1,3-thiazines have been known for more than a century and
constitute the structural basis of several biologically active substances of both natural and synthetic origin,
methods for the synthesis of these heterocyclic systems have not been well developed. Various benzothiazine
derivatives are known to possess a versatile range of biological activities and have been synthesized
continuously since the very first synthesis by Abe et al.9 Among these, 1,2-benzothiazine-3-carboxamide-1,1-
dioxides such as piroxicam,10 ampiroxicam11 and meloxicam12 are familiar for their analgesic and anti-
inflammatory activities and are being used worldwide as non-steroidal anti-inflammatory drugs (NSAIDs).
A literature survey revealed that when one biodynamic heterocyclic system was coupled with another,
a molecule with enhanced biological activity13 was produced. The chemistry of these bi-heterocycles has
afforded a fascinating investigation in the field of medicinal chemistry as they have been found to exhibit an
enhanced biological profile.14 Synthesis and investigation of the activity of compounds in which an isoxazole
moiety is linked with a benzoxazine nucleus have been reported by Reddy et al.15 in a study on the anti-
microbial activity of 3-(3,5-dimethyl-isoxazol-4-yl)-3,4-dihydro-2H-benzo[e][1,3]-oxazines.
Synthesis of bisoxazines and bisthiazines
Our main focus in this paper is on bis-1,3-oxazines and bis-1,3-thiazines. Thorough literature survey revealed
that the compounds containing a dihydro-1,3-oxazine ring system exhibited a wide spectrum of
pharmacological activity and ever since the first isolation of 2, 4-dihydroxy-2H-1, 4-benzoxazin-3(4H)-one
(DIBOA) and 4-dihydroxy-7-methoxy-(2H)-1,4-benzoxazin-3(4H)-one (DIMBOA), benzoxazine derivatives have
attracted the attention of phytochemists.16
Our literature survey revealed that the synthesis of bis-heterocyclic compounds has become an
important field of research for finding new biologically active molecules.
Bisheterocyclic compounds possess important pesticidal properties,17 anti-bacterial properties18 and
anti-tumor activity.19 Following these reports, we envisaged that molecules with two
benzoxazine/benzothiazine rings linked through flexible aliphatic chains or through rigid aromatic chains could
have enhanced biological activities.
P. R. Carlier and co-workers20 worked on the synthesis and evaluation of alkylene-linked dimers of
tacarine (9-amino-1,2,3,4-tetrahydroacridine). The reaction of tacarine with dibromo alkanes gave the desired
bis-product,but in low yields (epecially when n = 2 to n = 6). To overcome this difficulty, Carlier and co-workers
explored the reaction of 9-chloro-1,2,3,4-tetrahydroacridine with diamines. This method was found to be
successful and the optimum conditions proved to be in refluxing 1-pentanol at atmospheric pressure for 40
hours.
To enhance the thermal characteristics, Ninan et al,21 synthesized a bis-benzoxazine monomer with
additional polymerizable allyl groups substituted on the active ortho sites of bisphenol-A. The composition,
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structure, cyclic ratio and polymer structure of a diallyl di-benzoxazine prepared by a suspension method were
studied.22
Information on bisbenzoxazines is scarce, but this interesting class of compounds acts as key
precursors that leads to nitrogen-containing heterocycles as well as skeletons of biologically related
molecules.
Bisbenzoxazines exhibit various biological activities including antibacterial, antitumor and plant growth
regulative properties. Bis-benzoxazine monomers containing phenylphosphine oxide have been synthesized
from phosphorous containing bisphenol compounds, primary amine and formaldehyde.23
The present paper describes a synthetic study of a series of bis-oxazine and bis-thiazine derivatives,
two oxazine/thiazine monomers connected by aliphatic alkyl linkers through an eco-friendly Mannich type
condensation–cyclization reaction of phenols or naphthol with formaldehyde and primary amines in water
under reflux or under microwave irradiation.
Synthetic approaches to 3,4-dihydro-2H-1,3-benzothiazines include (i) condensation of 4,5-dimethoxy-
2-mercaptobenzylammonium chloride with an aromatic aldehyde in the presence of potassium carbonate24
and (ii) cycloaddition of benzothiete with the corresponding substituted imines.25
The synthesis of oxazine and thiazine monomers has been reported extensively, but bis-oxazines have not
been well documented. The synthesis of two new bis-benzoxazines via Mannich reaction of β- and α-naphthol
with formaldehyde and ethylendiamine was also reported by Augusto Rivera and co-workers.26 R. Manikannan
and S. Muthusubramanian23 have successfully described the synthesis of symmetrical bis-benzoxazines using
microwave irradiation as well as the possibility of a multicomponent approach for the synthesis of the target
molecule.
Results and Discussion
Dihydro-1,3-oxazines have been reported to have a strong cytotoxic effect on tumor cells, especially inat low
concentrations. Reports on the synthesis of 3,4-dihydro-2H-1,3-benzoxazines describe (i) Mannich
condensation of phenol and a primary amine with formaldehyde,27(ii) condensation of o-hydroxybenzylamine
with an aldehyde,28 (iii) rearrangement reactions of 2-(allyloxy)benzylamine with H2/CO in the presence of
rhodium catalysts,29 (iv) condensation of a 4-substituted phenol with 1,3,5-trimethyl-hexahydro-triazine in the
presence of oxalyl chloride,30 (v) reaction of 1-(bromomethyl)-2 (chloromethoxy)benzene with primary
amines,31 (vi) dehydration of N-(2-hydroxybenzyl)-3-aminopropanoic acid in the presence of sulfuric acid32 and
(vii) by ortho lithiation.35
The synthesis of various 3,4-dihydro-2H-benzo[e]-2,3-dihydro-1H-naphtho[1,2-e]-, 3,4-dihydro-2H-
naphtho[2,1-e][1,3]oxazines and 1,2-bis[3,4-dihydrobenzo[e][1,3]oxazin-3(4H)-yl]ethanes involves a one-pot
condensation–cyclization reaction of phenols or naphthol with formaldehyde and primary amines. Various
methods have been reported34-45 for the synthesis of dihydro-1,3-oxazines including the reaction under neat
conditions.46 However, many of these processes have disadvantages such as the need for a prolonged reaction
time, high temperature, use of volatile and toxic organic solvents and the presence of side products.
In view of these liabilities, this paper presents a green synthesis of a new heterocyclic compounds with
a benzoxazine unit. With a vast number of suitable starting compounds available, multifunctional amine-based
bisbenzoxazines and bis-benzothiazines have tremendous untapped potential in the area of tailoring
molecular structure for specific applications. A solvent-less reaction is typically the synthetic procedure of
choice for the preparation of benzoxazine monomers, primarily due to simplicity and purity of the products.
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However, the high reactivity of the linear aliphatic diamines produced an elevated concentration of oligomeric
species during the solvent-less protocol. In an effort to minimize the generation of oligomers, the synthesis
was conducted with the reactants diluted in water (2ml/mmol). A variety of bisoxazines and bis-thiazines
having aliphatic linkages between the two monomers have been synthesized, under green chemistry
conditions. (Scheme-1 and Scheme-2).
The structures of the linear aliphatic diamine-based benzoxazines were confirmed by NMR, FTIR and
1
mass spectropmetry. Each H NMR spectrum showed two singlet peaks, centered at approximately 3.9 and 4.8
ppm, consistent with the formation of a benzoxazine ring. The -CH2- peak appears around 2.9 ppm as a singlet.
The Mannich bridge protons of the open oxazine rings are typically47 located at approximately 3.7 . The
absence of any peaks in this region indicates that the alcohol washes were successful in separating the
oligomeric species from the monomers. Integration shows the closed-ring content of each compound to be
higher than 98%. For polymerization kinetic studies, high purity of the synthesized compounds is of utmost
importance since the phenolic impurity acts as the cationic initiator for benzoxazine polymerization and thus
adversely affects the precision of the study.
As expected, the infrared spectra of the benzoxazine monomers are nearly identical for all of the
different diamine chain lengths. There are a number of infrared bands in the spectra, which can be used to
verify the formation of oxazine rings in each product. While not shown, the presence of the benzoxazine ring
aromatic ether is confirmed using absorbance peaks at 1043 and 1208 cm-1, due to the C-O-C symmetric and
the asymmetric stretching modes, respectively.48 Absorbance at 771 cm-1 shows the presence of the expected
ortho-substituted benzene rings, while the peaks at 857 and 930 cm-1 confirms the presence of benzene with
an attached oxazine ring. Also noteworthy is the complete lack of bands from free or hydrogen-bonded
hydroxyl groups. The absence of hydroxyl groups shows that the reaction optimization and purification has
successfully eliminated any unreacted phenol and oligomeric species.
Scheme 1
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Scheme 2
Table I. Reaction time and yield under different conditions for compounds 4a-j and 6)
Compound
Microwave
Irradiation
Conventional Heating
Products R1
R2
H
R3
H
X
O
O
O
O
O
O
O
S
Yield
(%)
78
Reaction Yield (%)
time (sec)
Reaction
time (hr)
2
4a
H
H
180
180
180
180
180
180
180
120
120
120
180
63
58
62
60
59
61
58
65
68
65
60
4b
4c
4d
4e
4f
4g
4h
4i
H
CH3
H
76
75
78
75
76
76
80
82
79
78
2
2
2
2
2
2
1
1
1
2
CH3
H
H
CH3
H
H
C6H5
H
H
C6H5
H
H
H
OCH3
H
H
H
OCH3
H
H
H
S
4j
OCH3
----
H
S
6
---
H
O
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Conclusions
Bisbenzoxazines and bis-benzothiazine exhibit high melting points compared to their monomers.26
Table 1 shows that reactions conventionally heating took longer to complete and produced a lower yield
compared to the reactions under microwave irradiation. The difference in total reaction time and increased
yields confirms the advantages of microwave asssited reactions compared to conventional heating.
Experimental Section
General. Microwave reactions were carried out in a CEM Discover Benchmate microwave digester. Melting
points are recorded in open capillary tubes and are uncorrected. Infrared spectra were recorded on a BOMEM
1
DA-8 FTIR instrument and the frequencies are expressed in cm-1. H and 13C NMR spectra were recorded on a
Bruker Avance II-400 spectrometer using CDCl3 as the solvent. Chemical shifts are reported in ppm downfield
from internal tetramethylsilane and are given on the δ scale. Mass spectral data were obtained with a JEOL D-
300 (EI) mass spectrometer. Elemental analyses were carried out on a Heraeus CHN-O-Rapid analyzer. All
compounds give satisfactory elemental analyses within ± 0.4% of the theoretical values. All reactions were
monitored by TLC using precoated aluminum sheets (silica gel 60 F254 0.2 mm thicknesses) and developed in an
iodine chamber or under UVGL-15 mineral light 254 lamp. Column chromatographic separations were carried
out using ACME silica gel (60–120 mesh).
Procedure for the preparation of the title compound (4a-j) by the conventional heating method. To a
solution of 1 or 5 (5 mmol) in water (10 ml), formaldehyde (37% by wt.) (20 mmol) was added. A thick milky
precipitate was formed. After 15 min., diamine (2) (10 mmol) was added and the reaction mixture was heated
under reflux for 1-2 hrs. After reaction was completed (as monitored by TLC), the crude compound was
extracted with ethyl acetate and purified by either by column chromatography using ethyl acetate/hexane as
an eluent or by repeated recrystallisation from hot ethanol.
Procedure for the preparation of the title compounds (4a-j and 6) by microwave irradiation. To a mixture of
1 or 5 (5 mmol), formaldehyde (37% by wt.) (20 mmol) and 2 (10 mmol) was added and the reaction mixtures
were irradiated at 5 bar, 100 W, 100oC for specific times (Table-1). After reaction was complete (as monitored
by TLC), the mixture was extracted with ethyl acetate and purified either by column chromatography using
ethyl acetate/hexane or by repeated recrystallisation from hot ethanol.
1,2-Bis(2H-benzo[e][1,3]oxazin-3(4H)-yl)ethane (4a). Mp 107-09˚C; IR (KBr): 2923, 2817, 1551, 1488 cm-1; 1H
NMR (CDCl3): δ 2.47 (s, 4H, -CH2-), 3.46 (s, 4H, CH2), 4.93 (s, 4H, N-CH2-O), 6.78-7.15 (m, 8H, ArH); 13C NMR
(CDCl3): δ 49.55, 50.38, 84.24, 115.45, 120.53, 126.93, 128.32, 128.65, 158.12; Mass: m/z 297 [M++1]; Anal.
Calcd for C18H20N2O2; C, 72.95; H, 6.80; N, 9.45; Found: C, 72.88; H, 6.67; N, 9.54%.
1,2-Bis(8-methyl-2H-benzo[e][1,3]oxazin-3(4H)-yl)ethane (4b). Mp: 108-110˚C; IR (KBr, cm-1): 2945, 2853,
1208, 1043, 930, 857, 771;1H NMR(CDCl3): δ 2.10 (s, 6H, CH3), 2.93 (s, 4H, -CH2-), 3.99 (s, 4H, CH2), 4.87 (s, 4H,
N-CH2-O), 6.68-7.18 (m, 6H, ArH); 13C NMR (CDCl3): δ 14.57, 48.33, 49.42, 81.56, 118.00, 118.96, 124.00,
124.58, 127.90, 151.07;Mass: m/z 325 [M++1]; Anal. Calcd for C20H24N2O2: C, 74.04; H, 7.46; N, 8.64; Found: C,
74.16; H, 7.37; N, 8.71%.
1,2-Bis(6-methyl-2H-benzo[e][1,3]oxazin-3(4H)-yl)ethane (4c). Mp: 109-111˚C; IR (KBr, cm-1): 2936, 2862,
1200, 1100, 990, 900, 791;1H NMR(CDCl3): δ 2.27 (s, 6H, CH3), 2.98 (s, 4H, -CH2-), 3.98 (s, 4H, CH2), 4.86 (s, 4H,
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N-CH2-O), 6.73-7.07 (m, 6H, ArH); 13C NMR (CDCl3): δ 17.85, 49.13, 50.85, 82.58, 115.70, 119.43, 126.32,
130.71, 131.42, 153.95;Mass: m/z 325 [M++1]; Anal. Calcd for C20H24N2O2: C, 74.04; H, 7.46; N, 8.64; Found: C,
%74.07; H, 7.52; N, 8.58%.
1,2-Bis(7-methyl-2H-benzo[e][1,3]oxazin-3(4H)-yl)ethane (4d). Mp: 107-109˚C; IR (KBr, cm-1): 2962, 2847,
1280, 1090, 989, 875, 790;1H NMR(CDCl3): δ 2.22 (s, 6H, CH3), 2.96 (s, 4H, -CH2-), 3.87 (s, 4H, CH2), 4.93 (s, 4H,
N-CH2-O), 6.73-6.97 (m, 6H, ArH); 13C NMR (CDCl3): δ 18.32, 49.03, 51.37, 82.11, 117.42, 121.61, 122.51,
128.92, 135.31, 156.23;Mass: m/z 324 [M+]; Anal. Calcd for C20H24N2O2; C, 74.04; H, 7.46; N, 8.64; Found: C,
74.11; H, 7.40; N, 8.54%.
1,2-Bis(6-phenyl-2H-benzo[e][1,3]oxazin-3(4H)-yl)ethane (4e). Mp: 102-103˚C; IR (KBr, cm-1): 3011, 2894,
1250, 1100, 950, 890, 810;1H NMR(CDCl3): δ 2.95 (s, 4H, -CH2-), 3.96 (s, 4H, CH2), 4.98 (s, 4H, N-CH2-O), 6.98-
7.46 (m, 16H, ArH); 13C NMR (CDCl3): δ 50.33, 52.71, 83.46, 120.17, 121.32, 126.73, 127.35, 128.65, 129.11,
129.96, 134.82, 137.49, 154.44;Mass: m/z 449 [M++1]; Anal. Calcd for C30H28N2O2: C, 80.33; H, 6.29; N, 6.25;
Found: C, 80.41; H, 6.37; N, 6.18%.
1,2-Bis(7-phenyl-2H-benzo[e][1,3]oxazin-3(4H)-yl)ethane (4f). Mp: 101-103˚C; IR (KBr, cm-1): 2996, 2888,
1230, 1117, 960, 861, 791;1H NMR(CDCl3): δ 2.95 (s, 4H, -CH2-), 3.96 (s, 4H, CH2), 4.86 (s, 4H, N-CH2-O), 6.97-
7.42 (m, 16H, ArH); 13C NMR (CDCl3): δ 51.23, 52.55, 83.74, 112.38, 118.32, 125.57, 127.61, 128.05, 129.21,
130.19, 139.94, 143.85, 156.28;Mass: m/z 448 [M+]; Anal. Calcd for C30H28N2O2: C, 80.33; H, 6.29; N, 6.25;
Found: C, 80.38; H, 6.21; N, 6.30%.
1,2-Bis(8-methoxy-2H-benzo[e][1,3]oxazin-3(4H)-yl)ethane (4g). Mp: 106-108˚C; IR (KBr, cm-1): 2948, 2822,
1209, 1025, 925, 870, 717;1H NMR(CDCl3): δ 2.91 (s, 4H, -CH2-), 3.96 (s, 4H, CH2), 3.87 (s, 6H, OCH3), 4.88 (s,
4H, N-CH2-O), 6.86-7.02 (m, 6H, ArH); 13C NMR (CDCl3): δ 50.23, 51.85, 56.07, 83.47, 104.23, 104.65, 107.48,
130.16, 156.28, 157.85; Mass: m/z 356 [M+]; Anal. Calcd for C20H24N2O2: C, 67.40; H, 6.79; N, 7.86; Found: C,
67.51; H, 6.84; N, 7.73%.
1,2-Bis(2H-benzo[e][1,3]thiazin-3(4H)-yl)ethane (4h). Mp: 98-99˚C; IR (KBr, cm-1): 2948, 2822, 1210, 1090,
980, 890, 810 ;1H NMR(CDCl3): δ 2.92 (s, 4H, -CH2-), 3.74 (s, 4H, CH2), 4.03 (s, 4H, N-CH2-S), 7.06-7.31 (m, 8H,
ArH); 13C NMR (CDCl3): δ 50.32, 58.47, 62.18, 126.31, 127.43, 128.04, 128.32, 130.86, 137.29; Mass: m/z 328
[M+]; Anal. Calcd for C18H20N2S2: C, 65.81; H, 6.14; N, 8.53; Found: C, 65.73; H, 6.28; N, 8.41%.
1,2-Bis(6-methoxy-2H-benzo[e][1,3]thiazin-3(4H)-yl)ethane (4i). Mp: 95-98˚C; IR (KBr, cm-1): 2985, 2864,
1220, 1101, 990, 815, 791 cm-1;1H NMR(CDCl3): δ 2.93 (s, 4H, -CH2-), 3.73 (s, 4H, CH2), 3.95 (s, 6H, OCH3), 4.98
(s, 4H, N-CH2-S), 6.98-7.22 (m, 6H, ArH); 13C NMR (CDCl3): δ 51.43, 54.15, 61.53, 63.11, 113.45, 114.09, 124.57,
127.42, 132.65, 156.83;Mass: m/z 388 [M+]; Anal. Calcd for C20H24N2 O2S2: C, 61.82; H, 6.23; N, 7.21; Found: C,
61.75; H, 6.14; N, 7.30%.
1,2-Bis(7-methoxy-2H-benzo[e][1,3]thiazin-3(4H)-yl)ethane (4j). Mp: 99-102˚C; IR (KBr, cm-1): 2977, 2859,
1205, 1041, 935, 860, 765;1H NMR(CDCl3): δ 2.92 (s, 4H, -CH2-), 3.78 (s, 4H, CH2), 3.91 (s, 6H, OCH3), 4.03 (s,
4H, N-CH2-S), 6.79-7.01 (m, 6H, ArH); 13C NMR (CDCl3): δ 51.38, 55.12, 61.58, 62.85, 109.96, 110.94, 125.09,
130.64, 132.75, 157.68;Mass: m/z 389 [M++1]; Anal. Calcd for C20H24N2O2S2: C, 61.82; H, 6.23; N, 7.21; Found:
C, 61.72; H, 6.34; N, 7.17%.
1,2-Bis(2H-naphtho[2,3-e][1,3]oxazin-3(4H)-yl)ethane (6). Mp: 108-110˚C; IR (KBr, cm-1): 2967, 2851, 1210,
1061, 993, 875, 792;1H NMR(CDCl3): δ 2.93 (s, 4H, -CH2-), 3.99 (s, 4H, CH2), 5.03 (s, 4H, N-CH2-O), 7.35-7.81 (m,
12H, ArH); 13C NMR (CDCl3): δ 50.92, , 52.33, 83.17, 107.48, 122.52, 125.74, 126.28, 127.54, 128.36, 128.96,
129.42, 132.66,157.43;Mass: m/z 396 [M+]; Anal. Calcd for C26H24N2O2: C, 78.76; H, 6.10; N, 7.07; Found: C,
78.83; H, 6.22; N, 7.15%.
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Acknowledgements
We gratefully acknowledge financial support from SERB-DST, New Delhi,India for Financial support and SAIF-
NEHU, Shillong, India for the spectral analysis.
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