One-pot synthesis of benzoxazines through Mannich condensations

Article abstract of DOI:10.14233/ajchem.2014.16479

Five benzoxazine were synthesized by Mannich condensation reaction between 2,4-ditert-butyl phenol, formaldehyde and different amines in one pot synthesis. The benzoxazines were characterized by elemental analysis, spectral and crystal structure determina

Full text of DOI:10.14233/ajchem.2014.16479

Asian Journal of Chemistry; Vol. 26, No. 19 (2014), 6519-6522
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.16479
One-Pot Synthesis of Benzoxazines Through Mannich Condensations
1
2
1,*
RAJIB KUMAR DEBNATH , APURBA KALITA , BIPLAB MONDAL2,* and JATINDRA NATH GANGULI
1Department of Chemistry, Guwahati University, Guwahati-781 014, India
2Department of Chemistry, Indian Institute of Technology Guwahati-781 039, India
*Corresponding authors: E-mail: rkdn1981@gmail.com
Received: 7 October 2013;
Accepted: 17 May 2014;
Published online: 16 September 2014;
AJC-15953
Five benzoxazine were synthesized by Mannich condensation reaction between 2,4-ditert-butyl phenol, formaldehyde and different
amines in one pot synthesis. The benzoxazines were characterized by elemental analysis, spectral and crystal structure determination. The
synthesis process requires considerable less time and three of the five benzoxazines are new and reported for the first time.
Keywords: Benzoxazines, 2,4-Ditert-butyl phenol, Formaldehyde, Different amines, Mannich reaction.
INTRODUCTION
Single crystals were grown by slow diffusion followed
by slow evaporation technique. The intensity data were
Benzoxazines are long been known for their biological
collected using a Bruker SMART APEX-II CCD diffracto-
activities including bacteriostatic, tuberculostatic, fungistatic
meter, equipped with a fine focus 1.75 kW sealed tube MoKα
activity1,2. Some benoxazines demonstrated an outstanding
radiation (λ = 0.71073 Å) at 273(3) K, with increasing ω (width
overall profile with in vivo activity in different animal models
of 0.3° per frame) at a scan speed of 3 s/frame. The SMART
of anxiety and depression and has been progressed as a clinical
software was used for data acquisition. Data integration and
candidate3-6. Benzoxazines are also best known for polymeri-
reduction were undertaken with SAINT and XPREP software.
zation hence called polybenzoxazines7,8. Mannich conden-
Multi-scan empirical absorption corrections were applied to the
sation reactions have been utilized since the time of its report
data using the program SADABS. Structures were solved by
to prepare various organic frame works comprising various
direct methods using SHELXS-97 and refined with full-matrix
hetero-atoms4. These frameworks have been used extensively
least squares on F2 using SHELXL-97.All non-hydrogen atoms
for the model studies in bioinorganic chemistry5,6,9-11. Benzo-
were refined anisotropically. The hydrogen atoms were located
xazines are known to be readily synthesized by the Mannich
from the difference Fourier maps and refined. Structural
condensation of a phenolic derivative, formaldehyde and a
illustrations have been drawn with ORTEP-3 for Windows.
primary amine12-14. However, it has been found in the literature
Synthesis of 1: To a solution of 2,4-ditert-butyl phenol (2.40
that these reactions take a long time starting from 3-5 days
g, 0.0115 mol ) in EtOH (12 mL) and water (3 mL) was added
depending on the nature of amine and phenolic derivative9,10
.
aqueous formaldehyde (37 %, 3.3 g, 0.041 mol), benzyl amine
(1.07 g, 0.010 mol) and triethylamine (V=0.500 mL, 0.004 mol)
for a catalyst. The resulting solution was kept in an oil bath (at
50 °C) for 12 h. The white precipitate formed was filtered, washed
with cold MeOH and dried under vacuo over P2O5.
Synthesis of 2: To a solution of 2,4-ditert-butyl phenol
(4.80 g, 0.023 mol) in EtOH (12 mL) and water (3 mL) was
added aqueous formaldehyde (37 %, 3.3 g, 0.041 mol),
ethylenediamine (0.60 g, 0.010 mol) and triethylamine (V =
0.500 mL, 0.004 mol) for a catalyst. The resulting solution
was kept in an oil bath (at 50 °C) for 5 h. The white precipitate
formed was filtered, washed with cold MeOH and dried under
vacuo over P2O5.
EXPERIMENTAL
All the reagents and solvents were purchased from commer-
cial sources and were of reagent grade.Acetonitrile was distilled
from calcium hydride. Deoxygenation of the solvent and solu-
tions were effected by repeated vacuum/purge cycles or bubb-
ling with nitrogen for 0.5 h. FT-IR spectra were taken on a
Perkin Elmer spectrophotometer with samples prepared as KBr
pellets. 1H NMR spectra were obtained with a 400 MHzVarian
FT spectrometer. Chemical shifts (ppm) were referenced either
with an internal standard (Me4Si) for organic compounds or
to the residual solvent peaks for copper complexes.

6520 Debnath et al.
Asian J. Chem.
Synthesis of 3: To a solution of 2,4-ditert-butyl phenol
(4.80 g, 0.023 mol) in EtOH (12 mL) and water (3 mL) was
added aqueous formaldehyde (37 %, 3.3 g, 0.041 mol), bis-
ethylenetriamine (1.03 g, 0.010 mol) and triethylamine (V =
0.500 mL, 0.004 mol) for a catalyst. The resulting solution
was kept in an oil bath (at 50 °C) for 24 h. The white precipitate
formed was filtered, washed with cold MeOH and dried under
vacuo over P2O5.
Synthesis of 4: To a solution of 2,4-ditert-butylphenol
(4.80 g, 0.023 mol) in EtOH (12 mL) and water (3 mL) was
added aqueous formaldehyde (37 %, 3.3 g, 0.041 mol), 1-(2-
aminoethyl)piperazine (1.29 g, 0.010 mol) and triethylamine
(V = 0.500 mL, 0.004 mol) for a catalyst. The resulting solution
was kept in an oil bath (at 50 °C) for 48 h. The white precipitate
formed was filtered, washed with cold MeOH and dried under
vacuo over P2O5.
for C36H57N3O2 is 564.4484 found 564.4456. Elemental
analyses: Calcd. for C36 H57N3O2: C, 76.68; H, 10.19; N, 7.45;
found (%): C, 77.04; H, 10.06; N, 7.34.
tris-[2-(6,8-Ditert-butyl-4H-benzo[e][1,3]oxazin-3-yl)-
ethyl]-amine (compound 4):Yield: 3.845 g (66.52 %). White
solid, m.p. 267-271 °C; IR (KBr, νmax, cm-1) 3434, 2966, 2864,
1642, 1480, 1225, 950; 1H NMR (400 MHz, CDCl3) δ 7.17 (s,
3H, Ph), 6.81 (s, 3H, Ph), 4.93 (s, 6H, OCH2N), 4.06 (s, 6H,
NCH2Ph), 2.78 (s, 12H, NCH2CH2N), 1.44-1.37 (s, 27H, tbp),
1.35-1.27 (s, 27H, tbp); 13C NMR (100 MHz, CDCl3) δ 150,
141.6, 135.9, 121.2, 118, 81.2, 54, 51.9, 49.7, 33.9, 33.1, 31,
29.1; (ESI) m/z [M + H]+ Calcd. for C54H84N4O3 is 837.6577;
found 837.6545. Elemental analyses: Calcd. for C54 H84N4O3:
C, 77.46; H, 10.11; N, 6.69; found (%): C, 77.19; H, 10.26;
N, 6.56.
2,4-Ditert-butyl-6-{4-[2-(6,8-ditert-butyl-4H-benzo
[e][1,3]oxazin-3-yl)-ethyl]-piperazin-1-ylmethyl}-phenol
(compound 5): Yield: 3.845 g (66.52 %). White solid, m.p.
254-259 °C IR; (KBr, νmax, cm-1) 3442, 2953, 2818, 1634, 1479,
13621, 1222, 1161, 945. 1H NMR (400 MHz, CDCl3) δ 7.17
(s, 2H, Ph), 6.81 (s, 2H, Ph), 4.93 (s, 2H, OCH2N), 3.96 &
3.60 (s, 4H, NCH2Ph), 2.83-2.42 (m, 8H, NCH2CH2N), 1.44-
1.27 (s, 18H, tbp), 1.26-1.17 (s, 18H, tbp); 13C NMR (100
MHz, CDCl3) δ 154.3, 150.7, 142.2, 140.7, 136.7, 135.6, 123.5,
123.4, 122, 120.5, 119.9, 82.1, 62.3, 57.5, 53.7, 53.5, 52.4,
51.7, 48.7, 35.9, 34.5, 34.3, 31.4, 31.2, 29.9, 29.7; (ESI) m/z
[M + H]+ Calcd. for C37H59N3O2 is 578.4641; found 578.4697.
Elemental analyses: Calcd. for C37H59N3O2: C, 76.90; H, 10.29;
N, 7.27; Found (%): C, 77.21; H, 10.06; N, 7.34.
Synthesis19 of 5: To a solution of 2,4-ditert-butyl phenol
(4.80 g, 0.023 mol) in EtOH (12 mL) and water (3 mL) was
added aqueous formaldehyde (37 %, 3.3 g, 0.041 mol), 1-(2-
aminoethyl)piperazine (1.29 g, 0.010 mol) and triethylamine
(V = 0.500 mL, 0.004 mol) for a catalyst. The resulting solution
was kept in an oil bath (at 50 °C) for 48 h. The white precipitate
formed was filtered, washed with cold MeOH and dried under
vacuo over P2O5.
3-Benzyl-6,8-ditert-butyl-3,4-dihydro-2H-benzo-
[e][1,3]-oxazine (compound 1): Yield: 2.233 g (71.35 %).
White solid, m.p. 163-168 °C; IR (KBr, νmax, cm-1) 3416, 2959,
1
2869, 1626, 1483, 1360, 1216, 1106, 1040, 872. H NMR
(400 MHz, CDCl3) δ 7.40-7.25 (m, 5H, Ph), 6.82 (s, 2H, ph),
4.83 (s, 2H, OCH2N), 4.06 (s, 2H NCH2Ph), 3.98 (s, 2H,
NCH2Ph), 1.49-1.43 (s, 9H, tbp), 1.37-1.28 (s, 9H, tbp), 13C
NMR (100 MHz, CDCl3) δ 150.7, 141.1, 138, 136.7, 129.3,
129.0, 127.4, 122.2, 119.4, 81.1, 55.8, 51.1, 36.1, 34.4, 31.9,
30.0; (ESI) m/z [M + H]+ Calcd. for C23H31NO is 238.2439;
found 338.2401. Elemental analyses: Calcd. for C23H31NO:
C, 81.85; H, 9.26; N, 4.15; found (%): C, 82.21; H, 9.06;
N, 4.34.
RESULTS AND DISCUSSION
In this report, we describe a facile one-pot Mannich con-
densation reaction in ethanol/water mixture for the synthesis
of the five benzoxazine derivatives with a high yield (Fig. 1).
All the products were precipitated out as white solid from the
reaction mixture. Hence only washing with cold water after
the completion of the reaction affords the desired products.
On the other hand, in the present cases, the reaction time
required is also much less compared to the earlier reported
ones15-18. For instances, compound 2 has been reported to form
by refluxing a mixture of corresponding phenol, amine and
formaldehyde in toluene for 3 days. However, in the present
case, we observed the completion of the reaction within 6 h.
2,4-Ditert-butyl phenol is used in combination with various
primary amines with a goal to prepare a series of sterically
crowded benzoxazines.
Here we report a single-pot synthetic methodology for
the synthesis of a series of benzoxazine derivatives (1-5) using
Mannich condensation reactions of various amines with 2,4-
ditert-butyl phenol and formaldehyde. The amines used for
the various benzoxazines are listed in Scheme-I; however, in
all cases other reactants i.e., 2,4-ditert-butyl phenol, form-
aldehyde, remain same (Scheme-I). The processes do not need
any inert atmospheric conditions.
bis-[2-(6,8-Ditert-butyl-4H-benzo[e][1,3]oxazin-3-yl)-
methyl]-amine (compound 2): Yield: 3.845 g (66.52 %).
White solid, m.p. 187-191 °C; IR (KBr, nmax, cm-1) 3441,
1
2960, 1483, 1360, 1216, 1099, 950. H NMR (400 MHz,
CDCl3) δ 7.16 (s, 2H, Ph), 6.81 (s, 2H, Ph), 4.94 (s, 4H,
OCH2N), 4.06 (s, 2H NCH2Ph), 3.02 (s, 4H, NCH2CH2N), 1.49-
1.43 (s, 18H, tbp), 1.37-1.28 (s, 18H, tbp); 13C NMR (100
MHz, CDCl3) δ 150.7, 142.1, 137.8, 122.1, 119.4, 82.0, 51.9,
49.7, 35.2, 34.8, 32.3, 30.0; (ESI) m/z [M + H]+ Calcd. for
C34H52N2O2 is 521.4062; found 521.7892. Elemental analyses:
Calcd. for C34 H52N2O2: C, 78.41; H, 10.06; N, 5.38; O, 6.14;
found (%): C, 78.21; H, 10.16; N, 5.23.
bis-[2-(6,8-Ditert-butyl-4H-benzo[e][1,3]oxazin-3-yl)-
ethyl]-amine (compound 3): Yield: 3.273 g (63.55 %). White
solid, m.p. 205-209 °C; IR (KBr, νmax, cm-1) 3424, 2945, 1611,
1561, 1296. 1H NMR (400 MHz, CDCl3) δ 7.18 (s, 2H, Ph),
6.80 (s, 2H, Ph), 4.92 (s, 4H, OCH2N), 4.07 (s, 4H, NCH2Ph),
2.82 (s, 4H, NCH2CH2N), 2.59 (s, 4H, NCH2CH2N), 1.49-
1.43 (s, 18H, tbp), 1.37-1.28 (s, 18H, tbp); 13C NMR (100
MHz, CDCl3) δ 150.3, 142.1, 137.8, 122.4, 119.0, 82.1, 54.1,
51.7, 49.7, 35.2, 34.9, 31.9, 30.1; (ESI) m/z [M + H]+ Calcd.
The formation of all the compounds were confirmed by
various spectroscopic techniques like FT-IR, 1H NMR, 13C
NMR, mass spectroscopy as well as by elemental analyses.
The compounds19 1 and 5 are also authenticated by the single

Vol. 26, No. 19 (2014)
One-Pot Synthesis of Benzoxazines Through Mannich Condensations 6521
O
R
H
N
O
R
R
N
R
R
N
N
N
N
R
R
O
O
O
R
R
R
1
2
3
R
R
N
O
R
R
OH
N
O
R
N
R
R
N
N
N
N
R
O
O
5
R
R
R= tBu
4
Fig. 1
NH2
1
NH2
2
OH
H2N
R
NH2
H2N
R
N
H
N
NH2
H2N
H2N
3
N
NH2
H
4
N
5
(R =tBu, excess HCHO, EtOH/H2O, reflux)
Scheme-I
Fig. 3. Ortep plot of 5 (50 % ellipsoid plot) hydrogens have been removed
for clarity
crystal X-ray structures determination. The X-ray quality crys-
tals were grown by the slow diffusion of chloroform solution
of compounds19 1 and 5 into hexane followed by its slow evapo-
ration. The ORTEP diagrams for these two benzoxazine de-
rivatives are shown in Figs. 2 and 3, respectively.
The crystallographic data20 are listed in Table-1, respec-
tively.
TABLE-1
CRYSTALLOGRAPHIC DATA FOR COMPOUND 1
m.f.
m.w.
C22H30NO
324.47
Triclinic
P-1
Crystal system
Space group
Temperature (K)
Wavelength (Å)
a (Å)
b (Å)
c (Å)
α (°)
β (°)
296(2)
0.71073
9.2714(8)
9.9886(8)
11.5113(10)
79.269(5)
85.574(6)
81.410(6)
1034.31(15)
2
γ (°)
V (Å3)
Z
Density (mg m-3)
Abs. coeff. (mm-1)
F(000)
1.042
0.063
354
Total no. of reflections
Reflections, I>2σ(I)
Max. 2θ (°)
Ranges (h, k, l)
4440
2716
28.330
-9 ≤ h ≤ 10, -13 ≤ k ≤ 13, -15 ≤ l ≤ 14
100
Complete to 2θ (%)
Refinement method
R2 (all data)
Full-matrix least-squares on F2
0.1719
1.012
Goof (F2)
0.0553
0.0993
R indices [I >2σ(I)]
R indices (all data)
Fig. 2. Ortep plot of 1 (50 % ellipsoid plot)

6522 Debnath et al.
Asian J. Chem.
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Conclusion
The benzoxazines may be prepared by one pot synthesis
in considerably less time by following our procedures. The
benzoxazines may be used in ligation with metals to mimic
Galactose oxidase. Further study for polymerization and use
as flame retardant paint with the new benoxazines may shed
new and interesting results.
ACKNOWLEDGEMENTS
The authors are pleased to acknowledge CSIR for financial
support to R K Debnath. Thanks are also due to DST-FIST for
single crystal X-ray, CIF, IIT Guwahati for NMR & Mass
spectrophotometry & Department of Chemistry for allowing
to do necessary work.
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