Synthesis and complete NMR characterization of 4-alkyl-2-(6-substituted-1,3-benzoxazol-2-yl)benzenols

Article abstract of DOI:10.1002/mrc.1169

This paper describes the complete assignment of all carbons and hydrogens of several newly synthesized 6-substituted 2-(2-hydroxyaryl)benzoxazoles from 2,2′-dihydroxydiaryl Schiff bases by the use of two-dimensional NMR techniques. Copyright

Full text of DOI:10.1002/mrc.1169

MAGNETIC RESONANCE IN CHEMISTRY
Magn. Reson. Chem. 2003; 41: 291–295
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/mrc.1169
Spectral Assignments and Reference Data
R1
Synthesis and complete NMR
R2
characterization of 4-alkyl-2-(6-substituted-
1,3-benzoxazol-2-yl)benzenols
O
N
OH
LTA
AcOH
V. Sridharan, S. Muthusubramanian∗ and
S. Sivasubramanian
R1
N
HO
OH
Department of Organic Chemistry, Madurai Kamaraj University, Madurai-
625 021, India
R2
I
II
Received 26 September 2002; revised 11 December 2002; accepted 14
December 2002
R1
R2
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH(CH3)2
C(CH3)3
This paper describes the complete assignment of
all carbons and hydrogens of several newly synthe-
sized 6-substituted 2-(2-hydroxyaryl)benzoxazoles from
2,2ꢀ-dihydroxydiaryl Schiff bases by the use of two-
dimensional NMR techniques. Copyright  2003 John
Wiley & Sons, Ltd.
CH(CH3)2
C(CH3)2CH2CH3
CH2CH3
C(CH3)2Ph
Ph
Cl
KEYWORDS: NMR; 1H NMR; 13C NMR; 2D techniques;
6-substituted 2-(2-hydroxyaryl)benzoxazoles
Br
OCH3
C(CH3)3
CH(CH3)2
C(CH3)2CH2CH3
C(CH3)2Ph
Ph
INTRODUCTION
Benzoxazole derivatives are used as dye lasers,1 and zoxazolamine,
a derivative of benzoxazole, is an effective sedative and muscle
relaxant.2 Some of these compounds have been tested for their anti
tumor activities.3 2-(2-Hydroxyaryl)benzoxazoles assume impor-
tance because of their fluorescence and light-yield characteristics.4
Although there are several methods of preparing benzoxazoles,
oxidative ring closure of hydroxyimines is a popular method.
During our investigations of the new precursors for side chain mod-
ified calixarenes, we synthesized several 4-alkyl-2[(5-substituted-
2-hydroxyphenyl)iminomethyl]benzenols.5 In this work, these 2-
hydroxylimines were subjected to oxidative cyclization to obtain the
corresponding benzoxazoles, which were fully characterized by a
combined use of 1D and 2D NMR techniques.
Cl
Br
OCH3
Scheme 1
Table 1. Yields and melting-points of II
Melting-point
Yield
(%)
°
Compound
( C)
RESULTS AND DISCUSSION
The imines 4-alkyl-2-[(5-substituted-2-hydroxyphenyl) iminome-
thyl]benzenols (I) were prepared by the treatment of equimolar
quantities of the corresponding aldehydes and amines.5 The N-(2-
hydroxyaryl)aldimines can be easily converted into benzoxazoles by
oxidation with copper (II) acetate, lead tetraacetate6 or silver oxide.7
Among these reagents, lead tetraacetate is a common oxidizing agent
and it was employed in this work.
Accordingly, a new series of benzoxazoles (II) were obtained
in good yield by the treatment of the corresponding Schiff bases in
acetic acid with one molar equivalent of lead tetraacetate (Scheme 1).
The physical constants and the yields are given in Table 1. It should
be noted that although there are two hydroxyl groups, both in the
ortho positions of the C-aryl and N-aryl ring, it is the hydroxyl group
in the N-aryl ring that is involved in cyclization, and that in C-aryl
ring is not disturbed.
The synthesized compounds were fully characterized by NMR
spectroscopy. The assignments of all the hydrogens and carbons were
achieved by a systematic approach involving several 2D techniques
such as H–H COSY, C–H COSY, DEPT, HMBC, NOESY, etc. The
NMR data are given in Tables 2 (1H) and 3 (13C). The complete
assignment for a representative benzoxazole, IIa, is presented here.
The 300 MHz 1H NMR spectrum of IIa (Fig. 1) shows two
doublets (J D 8.7 Hz) at 7.05 and 7.49 ppm. These must be due to
H-30and H-7. The highly shielded doublet at 7.05 ppm was assigned
to H-30, as it is ortho to the hydroxyl group. This is confirmed
IIa
IIb
IIc
IId
IIe
IIf
162–163
116–117
120–121
109–110
134–135
120–121
135–136
145–146
89–90
81
77
75
73
79
78
80
77
63
78
75
75
82
79
76
75
60
IIg
IIh
IIi
IIj
119–120
99–100
84–85
IIk
IIl
IIm
IIn
IIo
IIp
IIq
90–91
119–120
112–113
116–117
68–69
by the HMBC correlation of this peak with that at 156.96 ppm,
which is easily assigned to C-20 (see below). Consequently, the
signal at 7.49 ppm is assigned to H-7. The two doublets of doublets
at 7.46 ppm (J D 8.7, 2.4 Hz) and 7.40 ppm (J D 8.7, 1.8 Hz) are
assigned between H-40 and H-6 and the two doublets at 7.99 ppm
ŁCorrespondence to: S. Muthusubramanian, Department of Organic
Chemistry, Madurai Kamaraj University, Madurai- 625 021, India.
E-mail: muthumanian2001@yahoo.com
Copyright  2003 John Wiley & Sons, Ltd.

292
Spectral Assignments and Reference Data
Table 2. 1H NMR data for IIa
H-4
d
H-6
dd
H-7
d
H-30
d
H-40
dd
H-60
d
Compound
R1
R2
OH
IIa
7.72
7.40
7.49
7.05
7.46
7.99
1.39
1.37
11.39
(1.8 Hz)
(8.7, 1.8 Hz)
(8.7 Hz)
(8.7 Hz)
(8.7, 2.4 Hz)
(2.4 Hz)
singlet
singlet
IIb
IIc
7.71
7.40
7.48
7.04
7.28
7.84
1.39
1.29(6H)
doublet
2.90(1H)
septet
11.36
11.39
(1.8 Hz)
(8.7, 1.8 Hz)
(8.7 Hz)
(8.4 Hz)
(8.4, 2.1 Hz)
(2.1 Hz)
singlet
7.73
7.43
7.52
7.06
7.40
7.94
1.40
0.72(3H)
triplet
(1.8 Hz)
(8.7, 1.8 Hz)
(8.7 Hz)
(8.7 Hz)
(8.7, 2.4 Hz)
(2.4 Hz)
singlet
1.34(6H)
singlet
1.68(2H)
quartet
IId
IIe
7.72
7.41
7.48
7.03
7.24
7.81
1.39
1.27(3H)
triplet
11.35
11.46
(1.8 Hz)
(8.4, 1.8 Hz)
(8.4 Hz)
(8.7 Hz)
(8.7, 2.4 Hz)
(2.4 Hz)
singlet
2.65(2H)
quartet
7.73
7.42
7.50
7.00
7.22
7.97
1.40
1.74(6H)
singlet
(1.8 Hz)
(8.7, 1.8 Hz)
(8.7 Hz)
(8.7 Hz)
(8.7, 2.4 Hz)
(2.4 Hz)
singlet
7.24–7.29
(5H)m
IIf
7.73
7.41
7.49
7.16
7.63
8.21
1.39
7.32(1H)
para
11.57
(1.5 Hz)
(8.7, 1.5 Hz)
(8.7 Hz)
(8.4 Hz)
(8.4, 2.4 Hz)
(2.4 Hz)
singlet
7.44(2H)
ortho
7.61(2H)
meta
IIg
IIh
IIi
7.73
7.40
7.50
7.04
7.33
7.95
1.40
—
11.50
11.49
11.15
11.39
(1.8 Hz)
(8.7, 1.8 Hz)
(8.7 Hz)
(9.0 Hz)
(9.0, 2.7 Hz)
(2.7 Hz)
singlet
7.72
7.45
7.48
6.96
7.43
8.07
1.39
—
(2.1 Hz)
(8.4, 2.1 Hz)
(8.4 Hz)
(8.7 Hz)
(8.7, 2.7 Hz)
(2.7 Hz)
singlet
7.75
7.44
7.52
7.05
—
7.05
—
7.48
—
1.41
3.87
(1.5 Hz)
(8.7, 1.5 Hz)
(8.7 Hz)
singlet
singlet
IIj
7.55
7.22
7.49
7.05
7.47
7.99
1.31(6H)
doublet
3.04(1H)
septet
1.37
(1.5 Hz)
(8.4, 1.5 Hz)
(8.4 Hz)
(8.7 Hz)
(8.7, 2.4 Hz)
(2.4 Hz)
singlet
IIk
IIl
7.54
7.20
7.46
7.03
7.28
7.83
1.30(6H)
doublet
3.02(1H)
septet
1.28(6H)
doublet
2.92(1H)
septet
11.37
11.39
(1.8 Hz)
(8.4, 1.8 Hz)
(8.4 Hz)
(8.4 Hz)
(8.4, 2.1 Hz)
(2.1 Hz)
7.57
7.24
7.51
7.06
7.41
7.93
1.32(6H)
doublet
3.05(1H)
septet
0.72(3H)
triplet
(1.5 Hz)
(8.4, 1.5 Hz)
(8.4 Hz)
(8.7 Hz)
(8.7, 2.4 Hz)
(2.4 Hz)
1.33(6H)
singlet
1.68(2H)
quartet
Copyright  2003 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2003; 41: 291–295

293
Spectral Assignments and Reference Data
Table 2. (Continued)
H-4
H-6
dd
H-7
d
H-30
d
H-40
dd
H-60
d
Compound
d
R1
R2
OH
IIm
7.55
7.21
7.46
7.00
7.21
7.96
1.30(6H)
doublet
3.03(1H)
septet
1.73(6H)
singlet
11.46
(1.5 Hz)
(8.4, 1.5 Hz)
(8.4 Hz)
(8.7 Hz)
(8.7, 2.4 Hz)
(2.4 Hz)
7.24–7.28
(5H) m
IIn
7.55
7.21
7.46
7.14
7.61
8.18
1.36(6H)
doublet
3.02(1H)
septet
7.31(1H)
para
11.55
(1.8 Hz)
(8.4, 1.8 Hz)
(8.4 Hz)
(8.4 Hz)
(8.4, 2.4 Hz)
(2.4 Hz)
7.41(2H)
ortho
7.59(2H)
meta
IIo
IIp
IIq
7.48
7.12
7.39
6.94
7.24
7.83
1.29(6H)
doublet
2.99(1H)
septet
—
11.40
11.45
11.14
(1.8 Hz)
(8.4, 1.8 Hz)
(8.4 Hz)
(9.0 Hz)
(9.0, 2.4 Hz)
(2.4 Hz)
7.51
7.21
7.42
6.92
7.40
8.02
1.30(6H)
doublet
3.01(1H)
septet
—
(1.5 Hz)
(8.4, 1.5 Hz)
(8.4 Hz)
(8.7 Hz)
(8.7, 2.4 Hz)
(2.4 Hz)
7.57
7.25
7.51
7.03
—
7.03
—
7.46
—
1.32(6H)
doublet
3.05(1H)
septet
3.86
(1.5 Hz)
(8.4, 1.5 Hz)
(8.4 Hz)
singlet
a Chemical shifts in ppm and coupling constants (Hz) in parentheses.
The deshielded carbon at 163.76 ppm can be assigned to C-2 as it is
directly attached to both oxygen and nitrogen atoms, this assignment
being corroborated by the fact that it has a cross peak with H-60 in
the HMBC spectrum. The carbons at 147.53 and 140.47 ppm can
be fixed as C-7a and C-3a, respectively, as the former has HMBC
correlations with H-6 and H-4 and the latter with H-7 and H-4. The
signal at 148.92 ppm is due to C-5, since it couples with H-7 strongly
in the HMBC spectrum. This carbon also exhibits an HMBC cross
peak with the hydrogens at 1.39 ppm, proving that these are the R1
methyl protons. The C–H COSY experiment makes the assignment
complete as these methyl hydrogens have a correlation at 32.20 ppm.
The NOESY experiment helps to determine the orientation of
the hydroxyl group in II. The position of the hydroxyl hydrogen
suggests that strong intramolecular hydrogen bonding exists in the
system. This hydrogen has NOESY contours only with H-30 and H-4
and not with H-7, indicating that the hydroxyl group is closer to
nitrogen than oxygen. Hence the structure shown in Fig. 1 represents
the correct orientation of the hydroxyl group with the preferred
hydrogen bonding to nitrogen. This also accounts for the abnormal
deshielding of H-60, which has to experience the anisotropy effect of
the benzoxazole ring in a rotation-restricted planar arrangement.
It should be noted that in IIi and IIq, protons H-30and H-40
overlap to give a single signal at 7.05 ppm. Here the assignment of
the respective carbons was made not from the C–H COSY spectrum,
but by the fact that C-30 has an HMBC correlation with the hydroxyl
hydrogen. In the case of IIf and IIn, protons 40 and 60 are more
deshielded (0.4 and 0.2 ppm, respectively, compared with other
systems), which can be ascribed to the ring current anisotropy
effect of the 50-substituted phenyl ring. It is surprising that the
1H-decoupled 13C NMR spectrum of IIj has only three signals in
the aliphatic region. The fact that the CH carbon of the isopropyl
group and the quaternary carbon of the tert-butyl group have the
same chemical shift value of 34.66 ppm, a rare observation, was
established by an HMBC experiment.
R2
7
1
O
6′
5′
7a
3a
6
5
2
4′
1′
3N
R1
3′
2′
4
H
O
Figure 1. Orientation of hydroxyl group in II.
(J D 2.4 Hz) and 7.72 ppm (J D 1.8 Hz) to H-60 and H-4. In the
H–H COSY experiment the signal at 7.05 ppm exhibits a cross peak
with the signal at 7.46 ppm, which in turn couples with the signal
at 7.99 ppm. Similarly, the signal at 7.49 ppm couples with that
at 7.40 ppm, which also couples with the signal at 7.72 ppm. This
clearly shows that H-40, H-60, H-6 and H-4 appear at 7.46, 7.99, 7.40
and 7.72 ppm, respectively. The abnormal deshielding of H-60 can be
explained as a consequence of hydrogen bonding (see below).
As all the aromatic hydrogens have been unambiguously
assigned, a C–H COSY experiment helps to assign all the CH
carbons (Table 2). The signals at 35.41 and 34.66 ppm were assigned
to the quaternary carbons of R1 and R2, respectively, as the former
signal shows HMBC cross peaks with H-6 and H-4 and the latter with
H-40 and H-60. Since the signal at 156.90 ppm couples with the OH
proton at 11.39 ppm, H-30, H-40 and H-60 in the HMBC spectrum, it is
assigned to C-20. Similarly, the signal at 142.65 ppm couples with the
H-30 proton, so it is C-50. This carbon has HMBC connections with the
methyl hydrogens at 1.37 ppm, and hence these are the R2 methyls.
The C–H COSY experiment indicates a connection between these
hydrogens and the carbon at 31.88 ppm. The carbon at 110.35 ppm,
which has HMBC correlations with OH and H-30, must be C-10.
Copyright  2003 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2003; 41: 291–295

294
Spectral Assignments and Reference Data
13
Table 3.
C NMR data for II (in ppm)
Compound
C-2
C-3a
C-4
C-5
C-6
C-7
C-7a
C-10
C-20
C-30
C-40
C-50
C-60
IIa
IIb
IIc
IId
IIe
IIf
163.76
163.63
163.79
163.56
163.62
163.32
162.14
161.99
163.25
163.75
163.63
163.78
163.66
163.32
162.03
161.95
163.24
140.47
140.46
140.49
140.45
140.41
140.35
140.10
140.07
140.44
140.66
140.65
140.68
140.65
140.45
140.24
140.24
140.63
116.15
116.16
116.13
116.16
116.14
116.25
116.33
116.32
116.24
116.86
116.86
116.85
116.88
116.96
116.99
117.01
116.94
148.92
148.90
148.92
148.95
148.96
149.11
149.32
149.29
149.08
146.58
146.59
146.58
146.63
146.76
146.84
146.88
146.72
123.38
123.39
123.34
123.39
123.42
123.66
124.02
124.02
123.56
124.49
124.51
124.46
124.56
124.76
125.05
125.09
124.66
110.15
110.12
110.13
110.11
110.16
110.23
110.31
110.30
109.97
110.48
110.45
110.46
110.53
110.56
110.57
110.60
109.96
147.53
147.53
147.52
147.52
147.50
147.58
147.53
147.51
147.52
147.87
147.86
147.86
147.87
147.91
147.78
147.80
147.86
110.35
110.68
110.36
110.73
110.27
111.33
112.10
112.67
110.66
110.32
110.66
110.34
110.29
111.31
111.95
112.60
110.63
156.96
157.24
156.86
157.15
157.11
158.52
157.51
157.95
153.52
156.94
157.24
156.84
157.18
158.53
157.49
157.95
153.46
117.41
117.63
117.33
117.62
117.52
118.23
119.26
119.64
118.77
117.39
117.63
117.32
117.58
118.23
119.18
119.61
118.76
131.35
132.29
131.85
133.64
133.29
132.51
133.53
136.31
121.66
131.36
132.31
131.88
133.33
132.51
133.44
136.28
121.66
142.65
140.29
140.96
135.61
142.22
133.17
124.75
111.64
152.89
142.66
140.29
140.95
142.25
133.15
124.68
111.62
152.88
123.63
124.68
124.41
126.10
124.62
125.69
126.67
129.60
110.15
123.63
124.68
124.41
124.67
125.67
126.57
129.56
110.48
IIg
IIh
IIi
IIj
IIk
IIl
IIm
IIn
IIo
IIp
IIq
For IIa
For IIb
For IIc
R1: C(CH3)3 35.41, C(CH3)3 32.20,
R1: C(CH3)3 35.41, C(CH3)3 32.19,
R1: C(CH3)3 35.40, C(CH3)3 32.18,
R2: C(CH3)3 34.66, C(CH3)3 31.88
R2: CH(CH3)2 33.77, CH(CH3)2ꢀ 24.54
R2: C(CH3)2CH2CH3 37.85, C(CH3)2CH2CH3 28.95,
C(CH3)2CH2CH3 37.25, C(CH3)2CH2CH3 9.56
R2: CH2CH3 28.41, CH2CH3 16.18
For IId
For IIe
R1: C(CH3)3 35.40, C(CH3)3 32.18,
R1: C(CH3)3 35.41, C(CH3)3 32.18,
R2: C(CH3)2Ph-42.86, C(CH3)2Ph-31.26, C(CH3)2Ph-ipso-150.81,
Others-126.18, 127.12, 128.52
For IIf
For IIg
For IIh
For IIi
For IIj
For IIk
For IIl
R1: C(CH3)3 35.44, C(CH3)3 32.19,
R1: C(CH3)3 35.43, C(CH3)3 32.14,
R1: C(CH3)3 35.43, C(CH3)3 32.15,
R1: C(CH3)3 35.41, C(CH3)3 32.16,
R1: CH(CH3)2 34.66, CH(CH3)2 24.84
R1: CH(CH3)2 34.66, CH(CH3)2 24.84
R1: CH(CH3)2 34.65, CH(CH3)2 24.83
R2: Ph-ipso 140.47, ortho 129.28, meta 127.11, para 127.47
R2: -
R2: -
R2: OCH3 56.35
R2: C(CH3)3 34.66, C(CH3)3 31.87
R2: CH(CH3)2 33.77, CH(CH3)2 —24.54
R2: C(CH3)2CH2CH3 37.85, C(CH3)2CH2CH3 28.95,
C(CH3)2CH2CH3 37.25,C(CH3)2CH2CH3 9.55
R2: C(CH3)2Ph 42.89, C(CH3)2Ph 31.29, C(CH3)2Ph-ipso 150.84,
Others 126.21, 127.16, 128.57
For IIm
R1: CH(CH3)2 34.67, CH(CH3)2 24.86
For IIn
For IIo
For IIp
For IIq
R1: CH(CH3)2 34.68, CH(CH3)2 24.86
R1: CH(CH3)2 34.62, CH(CH3)2 24.79
R1: CH(CH3)2 34.63, CH(CH3)2 24.81
R1: CH(CH3)2 34.65, CH(CH3)2 24.82
R2: Ph- ipso 140.55, ortho 129.28, meta 127.10, para 127.47
R2: -
R2: -
R2: OCH3 56.33
°
The mass spectral fragmentation of IIa shows a prominent
M ꢀ 15 peak as the base peak, characteristic for systems with tert-
butyl or isopropyl substituents. It is interesting that this fragment
ion loses oxygen and CO units to give M ꢀ 31 and M ꢀ 43 peaks,
respectively. It should be noted that IIh does not have the M ꢀ 31
peak, although it has the other two prominent peaks shown by IIa.
spectra, a pulse angle of 37.5 (5 µs), an acquisition time of 0.75 s and
a repetition time of 3.72 s were used. The mass spectra were recorded
on a Finnigan GC–MS instrument.
Preparation of 4-alkyl-2[(5-substituted-2-
hydroxyphenyl)iminomethyl]benzenol
A mixture of 0.01 mol of aldehyde and 0.01 mol of amine was
refluxed in 100 ml of alcohol for 1 h. The pure Schiff base I became
solidified on cooling after concentrating the solvent.
EXPERIMENTAL
The melting-points are uncorrected. The 1H, 13C and related 2D
NMR spectra were recorded on a Bruker 300 MHz (UltraShield)
NMR spectrometer at room temperature. The 1H NMR spectra were
measured for an ¾0.03 M solution in CDCl3 and 13C NMR spectra
for an ¾0.05 M solution in CDCl3 with TMS as internal reference
for both 1H and 13C. The one- and two-dimensional NMR spectra
were recorded using the Bruker icon NMR software. For 13C NMR
Preparation of
4-alkyl-2-(6-substituted-1,3-benzoxazol-2-yl)benzenol
A 0.01 mol amount of the Schiff base (I) was stirred in acetic
acid (50 ml) with 0.01 mol of lead tetraacetate. The reaction was
completed within 10 min. The pure benzoxazole II was isolated
after dilution, extracted with chloroform followed by silica column
chromatography, and crystallized from ethanol.
Copyright  2003 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2003; 41: 291–295

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Spectral Assignments and Reference Data
2. Boyd GV. In Comprehensive Heterocyclic Chemistry, Katrizky AR,
Acknowledgments
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thanks CSIR, New Delhi, for a Junior Research Fellowship. The
authors thank DST for assistance under the IRHPA program for the
NMR facility.
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Copyright  2003 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2003; 41: 291–295