Novel synthesis of benzoxazoles from o-nitrophenols and amines

Article abstract of DOI:10.3987/COM-04-S(P)11

o-Nitrophenols and o-nitroaniline were reacted with amines at 210-215°C to produce the corresponding benzoxazoles and benzimidazoles, respectively, in moderate yields. The reactions between o-nitrophenols containing a CO₂Me or OMe group on their benzene rings and N,N-diethylaniline were examined to investigate the effects of the position and electronic character of these substituents on the formation of the oxazole ring.

Full text of DOI:10.3987/COM-04-S(P)11

HETEROCYCLES, Vol. 64, 2004
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HETEROCYCLES, Vol. 64, 2004, pp. 193 - 198
Received, 26th May, 2004, Accepted, 29th June, 2004, Published online, 29th June, 2004
NOVEL SYNTHESIS OF BENZOXAZOLES FROM O-NITROPHENOLS
AND AMINES
Hiromi Nishioka*, Yukiko Ohmori, Yumiko Iba, Eri Tsuda, and Takashi
Harayama*
Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka,
Okayama 700-8530, Japan
e-mail : koi@pharm.okayama-u.ac.jp
Abstract – o-Nitrophenols and o-nitroaniline were reacted with amines at
210-215°C to produce the corresponding benzoxazoles and benzimidazoles,
respectively, in moderate yields. The reactions between o-nitrophenols containing
a CO2Me or OMe group on their benzene rings and N,N-diethylaniline were
examined to investigate the effects of the position and electronic character of
these substituents on the formation of the oxazole ring.
INTRODUCTION
In studying the synthesis of simple 3,4-unsaturated coumarin using the Wittig reaction with
salicylaldehyde in N,N-diethylaniline (Et2NPh) under reflux, we found that 3-nitrosalicylaldehyde
afforded 2-methylbenzoxazole and 8-aminocoumarin along with the expected 8-nitrocoumarin, in
moderate yields.1 We clarified that formation of the benzoxazole ring required the o-nitrophenol moiety
and that the carbon unit introduced in the benzoxazole ring originated from the alkyl group of the solvent
(amine). Moreover, the reaction temperature (210-215°C) was crucial.1 Subsequently, we investigated the
generality of benzoxazole synthesis from o-nitrophenol with amines, the effects of other substituent
groups in o-nitrophenols on benzoxazole formation, and the reaction mechanism. We present those results
here.
RESULTS AND DISCUSSION
This paper is dedicated to Dr. Pierre Potier on the occation of his 70th birthday.

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HETEROCYCLES, Vol. 64, 2004
First, we examined oxazole ring formation from o-nitrophenol (1a) and amines other than diethylaniline
at high temperature. The results are summarized in Table 1. The reaction of o-nitroaniline (3) with amines
under similar conditions afforded the corresponding benzimidazoles (4) in moderate yields, as shown in
Scheme 1. As the reactions of o-nitrophenol (1a) and o-nitroaniline (3) with alkylamines yielded
benzoxazoles (2) and benzimidazoles (4), respectively, the aromatic ring interaction between the amine
and o-nitrophenol (1a) is nonessential, and the benzyl group transfers more easily than the ethyl group.
Table 1. Reactions of oxazole ring formation from o-nitrophenol (1a) and a few amines.
OH
O
N
RCH2NR'2
R
NO2
1a
2
Time (h)
Run
Temp.(ºC)
Yield (%)
Amine
1
2
3
4
5
EtNHPh
Bu3N
Me2NPh
Bu2NPh
PhCH2NEt2
210-215
210-215
190
210-215
210-215
10
8
3
6
10
27 (R=Me: 2a)
24 (R=Pr: 2b)
many spots
22 (R=Pr: 2b)
13 (R=Ph: 2c)
Scheme 1
H
N
Bu2NPh
CH2CH2CH3
4a
210–215ºC, 8 h (57%)
N
NH2
NO2
Bu3N
210–215ºC, 6 h (37%)
H
N
PhCH2NEt2
3
210–215ºC, 8 h (4%)
N
4b
In order to examine the effects of the position and electronic character of the o-nitrophenol substituent on
the formation of the oxazole ring, we investigated the reactions of o-nitrophenols with electron-
withdrawing (CO2Me) (1d-g) or electron-donating (OMe) (1h-k) groups with Et2NPh under reflux (at
210-215°C). The results are summarized in Table 2. In general, an electron-donating group (OMe)
facilitated the formation of the oxazole ring regardless of the position of the substituents on the benzene
ring. A C3-substituent group accelerated ring formation and a C6-substituent group retarded it regardless
of its electronic character. These results seem to reflect a steric factor in ring formation. Interestingly, the
reaction of 6-carbomethoxy-2-nitrophenol (1g) with Et2NPh under reflux for 3 h afforded 6-carbethoxy-2-
nitrophenol (1l) and the corresponding amine (5l), while the same reaction for 6 h produced
7-carbethoxy-2-methylbenzoxazole (2l) along with 5l (Scheme 2). This ester-exchange is characteristic of

HETEROCYCLES, Vol. 64, 2004
195
the salicylate moiety, as the Wittig reaction of 3-methoxycarbonylsalicylaldehyde in Et2NPh produced 5-
carbethoxycoumarin, while salicylaldehydes with a methoxycarbonyl group at a position other than C3
produced no ester-exchanged products.2
Table 2. The results of reaction of o-nitrophenol (1) with Et2NPh under reflux.
6
OH
OH
O
N
5
4
Et2NPh
+
Me
R
R
R
210–215ºC
NO2
NH2
3
1d-l
2d-l
5d-l
Yield (%)a)
Run
Time
R
2
5
1
2
3
4
5
6
7
8
3-CO2Me (1d)
4-CO2Me (1e)
5-CO2Me (1f)
6-CO2Et (1l)
3-OMe (1h)
4-OMe (1i)
1.0 h
3.0 h
3.0 h
7.0 h
20 min
1.5 h
27 (2d)
75 (2e)
59 (2f)
21 (2l)
75 (2h)
50 (2i)
51 (2j)
42 (2k)
48 (5d)
7.4 (5e)
17 (5f)
41 (5l)
traceb) (5h)
> 6b) (5i)
>17b) (5j)
>12b) (5k)
5-OMe (1j)
6-OMe (1k)
1.5 h
2.0 h
a) Isolated yield. b) Yields were not reliable because of instability of amines (5).
Scheme 2
CO2Et
CO2Et
OH
OH
Et2NPh
+
+
210–215ºC, 3 h
CO2Me
OH
NH2
NO2
1l (11%)
5l
CO2Et
OH
NO2
CO2Et
O
1g
Et2NPh
Me
210–215ºC, 6 h
N
NH2
2l (24%)
5l
The generation of amino-phenol (5) suggests that the alkyl group(s) of the amine used as the solvent is
oxidized by the nitro group or air to produce an oxygenated amine, which takes part in the formation of
the oxazole ring. More detailed studies of the mechanism of this reaction are underway.
EXPERIMENTAL
Melting points were measured on a micro-melting point hot-stage apparatus (Yanagimoto) and are
1
13
uncorrected. IR spectra were recorded on a JASCO A-102 spectrometer. H and C-NMR spectra were
taken with a Hitachi R-1500 (60 MHz) or Varian VXR-200 (200 MHz) instrument with chemical shifts

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HETEROCYCLES, Vol. 64, 2004
reported as δ ppm and coupling constants given in Hertz. FAB-MS was obtained with a VG-70SE mass
spectrometer. Elemental analyses were carried out on a Yanaco MT-5 CHN analyzer. Column
chromatography was performed on silica gel (Merck, Silica gel 60, No. 9385).
Materials
Compounds (1a, 1i and 3) are commercially available. Compounds (1d3, 1e4, 1f5, 1g6 and 1l7) were
prepared by esterification of the corresponding carboxylic acid. Compounds (1h8, 1j9 and 1k10) were
prepared according to the literature.
General procedure for the reaction of o-nitrophenols or o-nitroaniline with amines
The reactions of o-nitrophenols or o-nitroaniline (500 mg) with an amine (10 mL) at 210-215°C were
carried out for the times indicated in Tables 1 and 2, Schemes 1 and 2. The reaction mixtures were
chromatographed on silica gel. Alkylaniline was eluted with hexane.
Methyl 2-methylbenzoxazole-4-carboxylate (2d) and methyl 2-amino-3-hydroxybenzoate (5d)
Elution with hexane-AcOEt (4:1) gave 5d, mp 97–99˚C (lit.,11a mp 97-98˚C) (colorless needles from
Et2O-hexane). Further elution with the same solvent afforded 2d, mp 74–75˚C (lit.,11b mp 77–79˚C)
(colorless needles from hexane).
Methyl 2-methylbenzoxazole-5-carboxylate (2e) and methyl 3-amino-4-hydroxybenzoate (5e)
Elution with hexane-AcOEt (4:1) gave 2e, mp 63–64˚C (lit.,12 mp 66˚C) (colorless needles from hexane).
Further elution with hexane-AcOEt (1:1) afforded 5e, mp 110–111˚C (lit.,13 mp 110–111˚C) (pale yellow
sands from AcOEt-CH2Cl2).
Methyl 2-methylbenzoxazole-6-carboxylate (2f) and methyl 4-amino-3-hydroxybenzoate (5f)
Elution with hexane-AcOEt (3:1) gave 2f, mp 103.5–104.5˚C (lit.,12 mp 103–104˚C) (colorless needles
from hexane). Further elution with the same solvent afforded 5f, mp 120˚C (lit.,13 mp 120–121˚C) (pale
yellow plates from CH2Cl2).
Ethyl 2-methylbenzoxazole-7-carboxylate (2l) and ethyl 3-amino-2-hydroxybenzoate (5l)
Elution with hexane-AcOEt (6:1) gave 5l, mp 41˚C (lit.,13 mp 47˚C) (colorless needles from hexane).
Further elution with the same solvent afforded 2l. IR (CHCl3) cm-1: 1720. 1H-NMR (200 MHz, CDCl3)
δ: 1.45 (3H, t, J=7.2 Hz, CH3), 2.72 (3H, s, 2-CH3), 4.47, (2H, q, J=7.2 Hz, CH2), 7.36 (1H, dd, J=7.8, 7.8
Hz, 5-H), 7.84 (1H, dd, J=1.4, 7.8 Hz, 6-H), 7.94 (1H, dd, J=1.4, 7.8 Hz, 4-H). FAB-MS m/z: 206
(M++1).
4-Methoxy-2-methylbenzoxazole (2h) and 2-amino-3-methoxyphenol (5h)
Elution with hexane-AcOEt (4:1) gave 2h, mp 57.5–59˚C (pale yellow needles from Et2O). IR (CHCl3)
cm-1: 1630, 1590, 1100. 1H-NMR (60 MHz, CDCl3) δ: 2.60 (3H, s, CH3), 4.00 (3H, s, OCH3), 6.74 (1H,
dd, J=2.3, 7.0 Hz, 5-H), 7.00–7.23 (2H, m, 6, 7-H). FAB-MS m/z: 164 (M++1). Anal. Calcd for C9H9NO2:

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C, 66.25; H, 5.56; N, 8.58. Found: C, 66.46; H, 5.82; N, 8.50. 5h was recognized on TLC, but not
isolated.
5-Methoxy-2-methylbenzoxazole (2i) and 2-amino-4-methoxyphenol (5i)
Elution with hexane-AcOEt (4:1) gave 2i, mp 32–34˚C (lit.,14 low mp.) (colorless needles from Et2O-
hexane). Further elution with hexane-AcOEt (1:1) afforded 5i, mp 131–135˚C (lit.,15 mp 129–132˚C)
(yellow prisms from AcOEt-Et2O).
6-Methoxy-2-methylbenzoxazole (2j) and 2-amino-5-methoxyphenol (5j)
Elution with hexane-AcOEt (6:1) gave 2j, mp 51.5–53˚C (lit.,16 mp 57˚C) (pale yellow needles from petr.
ether). Further elution with hexane-AcOEt (1:1) afforded 5j, mp 128–131˚C (lit.,17 mp 128–131˚C) (pale
pink prisms from Et2O).
7- Methoxy-2-methylbenzoxazole (2k) and 6-aminoguaiacol (5k)
1
Elution with hexane-AcOEt (6:1) gave 2k. IR (CHCl3) cm-1: 1640, 1580, 1100. H-NMR (60 MHz,
CDCl3) δ: 2.64 (3H, s, CH3), 4.01 (3H, s, OCH3), 6.82 (1H, dd, J=2.2, 7.2 Hz, 6-H), 7.17–7.28 (2H, m, 4,
5-H). FAB-MS m/z: 164 (M++1). Further elution with the same solvent afforded 5k, mp 83–84˚C (lit.,18
mp 83.5˚C) (pale yellow plates from Et2O-hexane).
Ethyl 2-hydroxy-3-nitrobenzoate (1l) and ethyl 3-amino-2-hydroxybenzoate (5l)
Elution with hexane-AcOEt (6:1) gave a mixture of 1l and 5l. The mixture in Et2O was chromatographed
on silica gel. Elution with CHCl3-hexane (20:1) gave 1l. Further elution with the same solvent afforded
5l.
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