M. Imran et al. / Tetrahedron Letters 54 (2013) 4966–4969
4967
OH
Li
R
OH
OH
OH
OH
O
CHO
H
sec-BuLi
Li
N
+
EtOH,
reflux
R
NH2
NaBH4
R'
N
EtOH
ZnBr2
Bt
Bt
OH
OH
O
N
O
CH2O
N
H
R'
N
O
RNH2
1,4-dioxane
reflux
N
R
(HPAMP)
Bt: benzotriazol-1-yl
R
Scheme 5. Synthesis of unsymmetric bisbenzoxazines.
Scheme 3. Synthesis of 1,3-benzoxazines via
a dilithiation approach using
benzotriazoles.
OH
OH
CHO
H+
R'
R'
N
+
NH2
R'
R
R
R
NaBH4
R'
N
O
OH
CH2O
N
H
R
Scheme 4. Synthesis of 1,3-benzoxazines via a three-step approach.
Figure 1. 1H NMR spectrum of u-hexyl-benz.
Although the classical benzoxazine synthesis methodology is
most commonly applied, step-wise procedures have received con-
siderable interest. For example, ortho–metalation methodology
used for the construction of heterocyclic compounds has been
adapted successfully to benzoxazine synthesis. Accordingly,
dilithiation of phenols and subsequent use of benzotriazoles with
ZnBr2 as the catalyst gave various benzoxazines (Scheme 3). How-
ever, low yields and difficulties in the isolation of the products,
particularly when aliphatic amines were used have limited their
wider application.34
Another stepwise strategy involves the use of 2-hydroxybenzal-
dehyde or similar structurally related compounds as starting
reagents. Imine formation is accomplished between the aldehyde
and amino compound, followed by reduction to form 2-aminom-
ethylphenols, and finally ring closure takes place using formalde-
hyde (Scheme 4). This methodology is especially useful when the
starting reagents possess groups that do not tolerate the Mannich
reaction. For example, phenolic hydroxy functionalized benzoxa-
zines, which cannot be synthesized by the classical method due
to the high reactivity of the free phenolic groups at the ortho
position toward the Mannich base, essentially yielding gels and
side products, are readily obtained.
Due to its tolerance of various functional groups, this step-wise
method was utilized for the synthesis of different benzoxazine or
benzoxazine-based polymeric precursors.35–40 The one-pot synthe-
sis of benzoxazines using this strategy has also been reported.41
We now report analogous investigations on the combination of this
three-step approach with the one step classical method. As shown
below, unsymmetric bisbenzoxazines can be synthesized via two
tandem reactions.
The crucial component for the combined method is the prepara-
tion of 4-hydroxyphenylaminomethyl phenol (HPAMP), since the
synthesis of the unsymmetric benzoxazine proceeds in preference
to the ring-closure between the aminomethyl moiety and its
neighboring phenolic OH, and at the same time the 4-hydroxy-
phenyl moiety undergoes the classical benzoxazine formation
reaction. In order to synthesize HPAMP, a two-step reaction was
performed. In the first step, 2-hydroxybenzaldehyde was reacted
with 4-hydroxyaniline catalyzed by H2SO4 to yield a Schiff base.
Next, reduction was carried out using sodium borohydride without
any further purification to produce the starting material for the
subsequent step in a good yield. Finally, the unsymmetric benzox-
azines were obtained by the reaction of HPAMP with three equiv-
alents of paraformaldehyde and one equivalent of a primary amine,
namely n-hexyl or n-butylamines in chloroform for 24 h
(Scheme 5).
The resulting unsymmetric benzoxazines were isolated simply
by washing the chloroform solution with 0.2 M NaOH solution to
remove the unreacted phenolics. After neutralization of the chloro-
form phase by several washings with distilled water, a second
extraction with benzonitrile-hexane mixture was performed. Fol-
lowing evaporation of the benzonitrile phase, relatively pure com-
pounds were obtained. The ‘u-hexyl-benz’ and ‘u-butyl-benz’
abbreviations are used for unsymmetric bisbenzoxazines from
n-hexylamine and n-butylamine, respectively. The characterization
of the unsymmetric bisbenzoxazines was achieved by spectral
methods. The 1H NMR spectra of the unsymmetric bisbenzoxazines
exhibited two different types of 1,3-oxazine rings. In Figure 1, the
protons of the u-hexyl-benz oxazine rings emerge at 5.25
(O–CH2–N–Ph), 4.78 (O–CH2–N–hexyl), 4.52 (Ph–CH2–N–Ph), and
3.91 ppm (Ph–CH2–N–hexyl), respectively. Aromatic and aliphatic
protons were also detectable. Similarly, in Figure 2, the protons of
the u-butyl-benz oxazine rings appeared at 5.32 (O–CH2–N–Ph),
4.70 (O–CH2–N–butyl), 4.54 (Ph–CH2–N–Ph), and 3.86 ppm
(Ph–CH2–N–butyl), respectively.
The structures of the unsymmetric bisbenzoxazines were also
confirmed by IR analysis ( Fig. 3). The IR spectra of both
u-hexyl-benz and u-butyl-benz revealed asymmetric stretching
Imran, Muhammad
