Simple grinding-induced reactions of 2-aminobenzyl alcohol and benzaldehyde derivatives, a rapid synthetic route to 3,1-benzoxazines

Article abstract of DOI:10.4314/bcse.v28i2.14

The grinding-induced reactions of 2-aminobenzyl alcohol and benzaldehyde derivatives in the presence of 30 mol% of acetic acid to give 3,1-benzoxazines are described. The reactions were performed at room temperature affording 3,1-benzoxazines in yields above 95% and high purity when benzaldehyde and its chloro and nitro derivatives were used.

Full text of DOI:10.4314/bcse.v28i2.14

Bull. Chem. Soc. Ethiop. 2014, 28(2), 301-304.
Printed in Ethiopia
DOI: http://dx.doi.org/10.4314/bcse.v28i2.14
ISSN 1011-3924
 2014 Chemical Society of Ethiopia
SHORT COMMUNICATION
SIMPLE GRINDING-INDUCED REACTIONS OF 2-AMINOBENZYL ALCOHOL AND
BENZALDEHYDE DERIVATIVES, A RAPID SYNTHETIC ROUTE TO
3,1-BENZOXAZINES
Ishmael B. Masesane*, Eva Muriithi and Tebogo H. Tabane
Department of Chemistry, University of Botswana, P/Bag 00704, Gaborone, Botswana
(Received July 24, 2013; revised May 3, 2014)
ABSTRACT. The grinding-induced reactions of 2-aminobenzyl alcohol and benzaldehyde
derivatives in the presence of 30 mol% of acetic acid to give 3,1-benzoxazines are described. The
reactions were performed at room temperature affording 3,1-benzoxazines in yields above 95%
and high purity when benzaldehyde and its chloro and nitro derivatives were used.
KEY WORDS: 2-Aminobenzyl alcohol, Benzaldehyde, Acetic acid, 3,1-Benzoxazines
INTRODUCTION
The development of environmentally benign methods for the synthesis of organic compounds
has attracted the attention of synthetic chemists due to the increase in ecological concerns. One
of the most important goals of these methods developments is the elimination or reduction of
volatile organic solvents [1-4]. Solvent-free and liquid-assisted organic reactions have captured
great interest not only because of their ecological importance, but also because they offer many
synthetic advantages in terms of high efficiency, yield, selectivity, simplicity of the reaction
procedure, mild conditions, reduction of waste, as well as their safety, and low cost [5-9].
As part of our broad interest in the chemistry of heterocyclic compounds [10, 11], the quick,
environmental safe and clean synthesis of 2-phenyl-3,4-dihydro-3,1-benzoxazine derivatives
from 2-aminobenzyl alcohol and benzaldehyde derivatives in the presence of minimal amount
of acetic acid under grinding conditions utilizing a mortar and a pestle is described. The 3,1-
benzoxazine moiety features in the natural product terresoxazine isolated from Tribulus
terrestris [12] and many other bioactive molecules [13-15]. Although several methods for the
preparation of 1,3-oxazine derivatives have previously been reported [16-21] few have been
focused on the solid-solid or solid-liquid grinding method.
RESULTS AND DISCUSSION
The acetic acid-catalysed reaction of 2-aminobenzyl alcohol 1 and benzaldehyde 2 was
considered as the model reaction. Thus, grinding of equivalent molar amounts of aminoalcohol
1 and benzaldehyde 2 with a mortar and pestle in the presence of catalytic amount of acetic acid
and monitoring the progress of the reaction by TLC (mobile phase = petroleum ether:ethyl
acetate (7:3); Rf value = 0.52) gave benzoxazine 6 as a white solid in 98% yield, Scheme 1. No
product was detected when aminoalcohol 1 and benzaldehyde 2 were ground without the
organic acid. No significant difference was observed in the reaction when the amount of the
acid was increased up to molar equivalent. Reducing the acid below the 30% molar equivalent
threshold made grinding difficult because the reaction mixture dried relatively faster.
__________
*Corresponding author. E-mail: masesane@mopipi.ub.bw

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Ishmael B. Masesane et al.
To further access the scope of this procedure, the solvent-free reactions of aminoalcohol 1
with several benzaldehyde derivatives bearing electron-withdrawing groups were examined.
Thus, grinding a mixture of aminoalcohol 1 and o-chlorobenzaldehyde 3 in the presence of
acetic acid gave benzoxazine 7 as a yellow gum in 96% yield. m-Nitrobenzaldehyde 4 also
reacted with 1 under the conditions described above to give benzoxazine 8 as a yellow solid in
quantitative yield. Lastly, benzoxazine 9 was prepared in 99% yield by grinding p-
nitrobenzaldehyde 5 and 1. No observable difference in reactivity exerted by -NO2 group at the
m- or p-position of the benzaldehyde was noticed. The yields and reaction times were almost
same.
The first step of the mechanism for the formation of the 3,1-benzoxazines is the nucleophilic
attack of the amino group of 2-aminoalcohol 1 on the electrophilic carbonyl carbon of
benzaldehyde derivatives to form an imine intermediate [22]. The imine intermediate then
tautomerise to give the benzoxazines [23].
Benzoxazines 6-9 were obtained in pure forms that allow spectral characterization without
1
need for any purification. The H NMR spectra of benzoxazines 6-9 showed typical singlet
peaks in the region 5.65-6.61 ppm assigned to the proton on C-2. In addition, two doublet peaks
with a germinal coupling (14.6-14.8 Hz) in the region 4.98-6.32 and 5.15-6.39 ppm which are
due to the protons on carbon-4 were observed.
Scheme 1. Reactions of aminoalcohol 1 with benzaldehyde and its derivatives 3, 4 and 5.
Scheme 2. Reactions of aminoalcohol 1 with hydroxyl- and methoxybenzaldehyde derivatives.
Next, to further delineate the scope of this procedure, the reactions of aminoalcohol 1 and
benzaldehyde derivatives bearing electron-donating hydroxyl or methoxy groups under the
grinding conditions were studied. In the event, o-hydroxybenzaldehyde 10 reacted with
aminoalcohol 1 in 30 minutes of grinding to give imine 13 as the only detectable product in
98% yield. Attempts to cyclise imine 13 to benzoxazine 14 by grinding for 1 hour and adding
more acetic acid were futile. Interestingly and somewhat surprisingly, grinding of aminoalcohol
1 with m-hydroxybenzaldehyde 11 gave a yellow gum in 88% yield (Scheme 2). The 1H NMR
spectrum of the product revealed that it was a 4:1 tautomeric mixture of benzoxazine 16 and
imine 15 respectable. The proportion of the tautomers was determined by integration of the well
separated H-2 of the benzoxazine 16 and the –N=CH- proton of imine 15. Likewise, p-
methoxybenzaldehyde 12 reacted under the same conditions to yield a 3:1 mixture of
benzoxazine 18 and imine 17 in 97% yield. Attempts to separate these mixtures by column
chromatography were futile suggesting that the benzoxazines and their imine tautomers existed
in equilibrium [23].
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Short Communication
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CONCLUSION
In conclusion, benzaldehyde, o-chloro-, m-nitro- and p-nitro-substituted derivatives of
benzaldehyde reacted with 2-aminobenzyl alcohol in the presence of catalytic amount of acetic
acid under grinding conditions at room temperature to give the corresponding 1,3-benzoxazines
in short reaction times with high yields and purity. In contrast, o-hydroxybenzaldehyde reacted
with 2-aminobenzyl alcohol to give the corresponding imine while m-hydroxy- and p-methoxy-
substituted derivatives of benzaldehyde reacted under the conditions described above to give an
equilibrium mixture of the corresponding benzoxazines and imines.
EXPERIMENTAL
General experimental conditions. All reagents were purchased from Merck and Aldrich and
used without further purification. Thin layer chromatography experiments were performed on
TLC silica gel 60 aluminium plates and a mixture of petroleum ether and ethyl acetate (7:3) was
used as the mobile phase. Melting points were recorded using a Stuart scientific melting point
apparatus and are uncorrected. The NMR spectra were acquired on a Bruker DPX 300
spectrometer using TMS as the internal standard. The mass spectra were obtained on a GCT
Premier instrument.
General procedure for the synthesis of 3,1-benzoxazines. A mixture of 2-aminobenzyl alcohol
(1 mmol), benzaldehyde derivative (1 mmol) and acetic acid (0.3 mmol) was mixed thoroughly
in a mortar followed by grinding with a pestle till the completion of the reaction as indicated by
TLC (5-30 min). The product was then allowed to stand in a fumehood over night to allow the
acetic acid to evaporate and the product was then characterized.
2-Phenyl-1,2-dihydro-4H-3,1-benzoxazine (6). White solid, m.p. 94-96 oC. 1H NMR (300 MHz,
CDCl3): 4.72 (1H, s, NH), 4.99 (1H, d, J = 14.7 Hz, H-4), 5.17 (1H, d, J = 14.7 Hz, H-4), 5.65
(1H, s, H-2), 6.76 (1H, d, J = 7.5 Hz, H-8), 6.91 (1H, dd, J = 7.5 and 7.8 Hz, H-6), 7.03 (1H, d,
J = 7.5 Hz, H-5), 7.14 (1H, dd, J = 7.5 and 7.8 Hz, H-7), 7.44 (3H, m, H-3’, 4’ and 5’), 7.60
(2H, m, H-2’ and 6’); 13C (75 MHz, CDCl3): 67.7 (C-4), 82.8 (C-2), 115.7(C-8), 122.3 (C-6),
125.9 (C-5), 126.4 (C-4’), 126.8 (C-2’ and 6’), 128.5 (C-3’ and 5’),128.8 (C-7), 134.7 (C-4a),
140.5 (C-1’), 145.1 (C-8a). HRMS (EI): m/z calcd for C14H13NO (M+) 211.2590; found:
211.2593.
2-(2’-Chlorophenyl)-1,2-dihydro-4H-3,1-benzoxazine (7). Yellow gum. 1H NMR (300 MHz,
CDCl3): 4.18 (1H, br, NH), 5.02 (1H, d, J = 14.6 Hz, H-4), 5.23 (1H, d, J = 14.6 Hz, H-4), 6.04
(1H, s, H-2), 6.76 (1H, d, J = 7.8 Hz, H-8), 6.93 (1H, t, J =7.44 and 7.56 Hz, H-6) 7.04 (1H, d,
J = 7.44 Hz, H-5) 7.17 (1H, dd, J = 7.56 and 7.8 Hz, H-7), 7.43 (3H, m, H-4’, 5’ and 6’), 7.84
(1H, dd, J = 7.5 and 2.6 Hz, H-3); 13C NMR (75 MHz, CDCl3): 68.0 (C-4), 81.8 (C-2), 116.7
(C-8), 121.7 (C-6), 124.2 (C-5), 127.4 (C-5’), 127.6 (C-6’), 128.1 (C-7), 129.2 (C-3’), 130.5 (C-
2’), 132.7 (C-4a), 136.7 (C-1’), 142.1 (C-8a). HRMS (EI): m/z calcd for C14H12NOCl (M+)
245.0668; found: 245.0632.
o
1
2-(3’-Nitrophenyl)-1,2-dihydro-4H-3,1-benzoxazine (8). Yellow solid, m.p. 80-82 C. H NMR
(300 MHz, CDCl3): 5.99 (1H, br, NH), 6.32 (1H, d, J = 14.8 Hz, H-4), 6.39 (1H, d, J = 14.8 Hz,
H-4), 6.61 (1H, s, H-2), 7.04 (1H, d, J = 7.9 Hz, H-8), 7.08 (1H, dd, J = 7.3 and 7.0 Hz, H-6),
7.12 (1H, d, J = 7.0 Hz , H-5), 7.17 (1H, dd, J = 7.3 and 7.9 Hz , H-7), 7.35 (1H, dd, J = 8.2 and
7.6 Hz, H-5’), 7.49 (1H, d, J = 8.2 Hz, H-6’), 7.60 (1H, d, J = 7.6 Hz, H-4’), 7.69 (1H, s, H-2’);
13C NMR (75 MHz, CDCl3): 67.3 (C-4), 83.8 (C-2), 117.9 (C-8), 120.7 (C-6), 122.0 ( C-4’)
122.4 (C-2’), 123.9 (C-5), 124.9 (C-5’), 127.7 (C-6’), 129.7 (C-4a), 132.9 (C-7), 141.9 (C-1’),
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141.3 (C-8a), 148.4 (C-3’). HRMS (EI): m/z calcd for C14H12N2O3 (M+) 256.25668; found:
256.25664.
2-(4’-nitrophenyl)-1,2-dihydro-4H-3,1-benzoxazine (9). Yellow solid, m.p. 102-104 oC. 1H
NMR (300 MHz, CDCl3): 4.21 (1H, br, NH), 4.98 (1H, d, J = 14.7 Hz, H-4), 5.15 (1H, d, J =
14.7 Hz, H-4), 5.74 (1H, s, H-2), 6.83 (1H, d, J = 8.0 Hz, H-8), 6.98 (1H, dd, J = 7.2 and 6.9
Hz, H-6), 7.03 (1H, d, J = 6.9 Hz, H-5), 7.19 (1H, dd, J = 7.2 and 8.0 Hz, H-7), 7.82 (2H, d, J =
8.6 Hz, H-2’ and 6’), 8.31 (2H, d, J = 8.6 Hz, H-3’ and 5’); 13C NMR (75 MHz, CDCl3): 67.2
(C-4), 83.9 (C-2), 118.0 (C-8), 120.8 (C-6), 122.5 (C-5), 123.9 (C-2’ and 6’), 125.1 (C-7),
127.7 (C-3’and 5’), 140.8 (C-4a), 145.9 (C-1’ and 8a), 148.3 (C-4’); HRMS (EI): m/z calcd for
C14H12N2O3 (M+) 256.2568; found 256.2572.
ACKNOWLEDGEMENTS
The authors gratefully acknowledge the Royal Society of Chemistry, DAAD-NAPRECA (EM’s
study grant) and the University of Botswana (THT study grant) for financial support, Dr
Sichilingo for MS data and Dr Mazimba for NMR spectra.
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Bull. Chem. Soc. Ethiop. 2014, 28(2)

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