A convenient synthesis of 1H-2,3-benzoxazines by an acid-catalyzed intramolecular Mitsunobu reaction

Article abstract of DOI:10.1016/S0040-4039(01)01406-X

A convenient, efficient method for the preparation of benzoxazines is described. 2-(Hydroxyiminomethyl)benzyl alcohols were cyclodehydrated to construct 1H-2,3-benzoxazines by acid-catalyzed intramolecular Mitsunobu reaction. This reaction depended on the

Full text of DOI:10.1016/S0040-4039(01)01406-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6895–6897
A convenient synthesis of 1H-2,3-benzoxazines by an
acid-catalyzed intramolecular Mitsunobu reaction
Hiroyuki Kai* and Toru Nakai
Aburahi Laboratories, Shionogi & Co., Ltd., Koka-cho, Koka-gun, Shiga 520-3423, Japan
Received 18 June 2001; revised 23 July 2001; accepted 27 July 2001
Abstract—A convenient, efficient method for the preparation of benzoxazines is described. 2-(Hydroxyiminomethyl)benzyl
alcohols were cyclodehydrated to construct 1H-2,3-benzoxazines by acid-catalyzed intramolecular Mitsunobu reaction. This
reaction depended on the geometry of the hydroxyimino moiety in the reaction precursor. © 2001 Elsevier Science Ltd. All rights
reserved.
In our previous papers,1 we reported the structure–
activity relationship of fungicidal or acaricidal benzo-
hydroximoyl derivatives (1a) designed by replacing the
carbamoyl moiety in the known fungicidal methoxyimi-
noacetamide derivatives (1b)2 with heterocycles (Het.)
or a benzene ring. In our continuing study, we next
designed 1H-2,3-benzoxazines (2) which have the essen-
tial elements for activity, that is, a methoxyimino moi-
ety and ortho substitution (Scheme 1). A few synthetic
methods of 1H-2,3-benzoxazines were reported. How-
ever, these were complicated and unsatisfactory.3 So,
we examined here a new and convenient method of
constructing benzoxazines from 2-(hydroxyimono-
methyl)benzyl alcohols (3), which are obtainable by
oximation from ketone 4, a key synthetic intermediate
of 1a.
Several attempts at ring closure by dehydration with
thionyl chloride or p-toluene sulfonic acid led either to
minimal or no reaction. However, using Mitsunobu
conditions,4 although the reaction was sluggish and did
not continue to completion, 21% yield of the desired
product (2b) was obtained (entry 1, Table 1).
We considered this cyclization on the basis of an ordi-
nary Mitsunobu reaction illustrated in Scheme 2. Phos-
phonium salt (8) and oxime anion (9) are produced by
the protonation of betaine 7 from oxime 3. Then, the
hydroxy moiety of 9 attacks 8 to produce alkoxyphos-
phonium salt (10). Finally, the desired product 2 is
produced by intramolecular cyclization. We considered
that the low yield of this reaction is due to the slow
protonation of 7 from 3. Therefore, it was expected that
7 is smoothly transformed to 8 by the addition of acid
13. The intramolecular cyclization to produce 2 is faster
than the attack of anion 14, and anion 14 is simulta-
neously retransformed to 13 to work as a catalyst.
First, for the investigation of cyclodehydration, 2-[4-
chlorophenyl(hydroxyimino)methyl]benzyl alcohol (3b)
was selected for optimization of the reaction conditions.
OH
MeO
R'
O
O
HO
THP O
N
N
O
N
R
R
R
R
4
2
3
1a R=Het., Ph
1b R=CONHMe
Scheme 1.
Keywords: benzoxazines; Mitsunobu reactions; catalysts; geometry.
* Corresponding author. Tel.: +81-748-88-3281; fax: +81-748-88-2783; e-mail: hiroyuki.kai@shionogi.co.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01406-X

6896
H. Kai, T. Nakai / Tetrahedron Letters 42 (2001) 6895–6897
Table 1. Mitsunobu reaction with various acid catalysts
13
OH
DEAD (2eq)
Ph3P (1.5eq)
O
HO
N
N
THF, rt, 1h
Cl
Cl
3ba
2b
Entry
13
pKa
Equiv.
Recovery
2b (%)b
3b (%)b
1
2
3
4
5
6
7
8
None
CH3CO2H
C6H5CO2H
C6H5OH
4-NO2C6H4OH
4-NO2C6H4OH
4-NO2C6H4OH
2,4-(NO2)2C6H3OH
–
4.8
4.2
10.0
7.2
–
21
62
70
66
53
82
82
70
38
19
0
15
12
0
0.2
0.2
0.2
0.05
0.2
1.2
0.2
0
10
4.0
a E/Z mixture (approximately 5:95 from 1H NMR spectra).
b Isolated yields.
O
HO
O
HO
N
HO
Ph3P O
N
N
R
R
R
10
3
9
General Mitsunobu condition
Slow
O
Ph3P
N
Ph3P
Ph3P
6
EtO2C N N CO2Et
H H
EtO2C N N CO2Et
R
O PPh3
EtO2C N N CO2Et
EtO2C N N CO2Et
H
2
12
8
5
7
11
Fast
H
Presence of catalytic acid
13
.
O
.
14
Z
O
Z
OH
Ph3P
O
3
N
14
13
R
15
Catalytic cycle
Scheme 2.
According to the above consideration, cyclodehydra-
tion of 3b to form 2b under Mitsunobu conditions by
adding some acids was examined, and the results are
listed in Table 1. The addition of a catalytic amount of
acetic acid significantly increased the yield of 2b (entry
2). Then, various acids were employed, and the influ-
ence of the acidity was examined. Among these acids,
4-nitrophenol gave the best result (entry 6).5 And the
optimal pKa was approximately seven, although defini-
tive reasons for this result have not been clarified.
Decreasing the amount of 4-nitrophenol to 0.05 equiv.
reduced the yield to 53% (entry 5), but the reaction of
3b with 1.2 equiv. of the catalyst gave the same yield
(entry 7). From this result, we confirmed that the acid
works as a catalyst.
Next, we attempted to apply the optimal conditions
obtained above (entry 6, Table 1) to the synthesis of
various benzoxazines 2 from oximes 3, which were
afforded by oximation and subsequent in situ deprotec-
tion of ketones 4 with hydroxylamine hydrochloride
and pyridine in methanol (Table 2). The electronic or
steric effects of the substituents (R) did not affect
cyclodehydration. However, when the geometry of the
hydroxyimino moiety in the reaction precursor was E,
no product was obtained (entries 8 and 9), and the

H. Kai, T. Nakai / Tetrahedron Letters 42 (2001) 6895–6897
Table 2. Synthesis of 4-substituted 1H-2,3-benzoxazines 2
6897
DEAD (2eq)
Ph3P (1.5eq)
4-NO2C6H4OH (0.2eq)
Z
E
OH
N
HONH2·HCl (2eq)
pyridine (2.2eq)
O
HO
THP
O
N
O
R
R
R
MeOH, reflux, 4-12h
THF, rt, 1h
4
3
2
Entry
R
Oxime
Yield (%)b
E/Za
Benzoxazine
Yield (%)b
Mp (°C)
1
2
3
4
5
6
7
8
9
C6H5
3a
3b
3c
3d
3e
3f
3g
3h
3i
97
98
92
76
53
67
69
61
23
54
7/93
2a
2b
2c
2d
2e
2f
2g
2h
2i
85
82
25
90
92
71
71
0
74–75d
135.5–136.5
68–70
111.5–112.5
154–155
148–150
105–106
–
4-ClC6H4
2-CH3C6H4
4-CH3C6H4
3-HOC6H4
3-NO2C6H4
5/95
70/30
7/93
0/100
7/93
0/100
100/0
0/100c
100/0c
3,4-(CH3O)2C6H4
CH3
54
0
66–67
–
2i
Cl
S
10
3j
93
0/100c
2j
54
67–68
CH3
N
O
a 1H NMR spectra.
b Isolated yields.
c The name of the geometrical isomer is disregarded IUPAC nomenclature.
d Lit.3 mp 76.5–77°C.
reaction of the E/Z mixture containing predominantly
the E isomer resulted in a low yield (entry 3). Appar-
ently, this reaction was dependent on the geometry of
the hydroxyimino moiety in the reaction precursor.
3. (a) Barnish, I. T.; Hauser, C. R. J. Org. Chem. 1968, 33,
1372 H374; (b) Pifferi, G.; Consonni, P.; Testa, E. Tetra-
hedron 1968, 24, 4923–4932; (c) Pifferi, G.; Monguzzi, R.
J. Heterocycl. Chem. 1972, 9, 1445–1447.
4. Mitsunobu, O. Synthesis 1981, 1–28.
In conclusion, we have developed a convenient and
efficient method for the synthesis of benzoxazines 2
from 2-(hydroxyiminomethyl)benzyl alcohols 3 by an
acid-catalyzed intramolecular Mitsunobu reaction. The
biological assay showed that several compounds of
synthesized 2 have herbicidal activity. The structure–
activity relationships of 2 will be reported elsewhere.
5. Typical procedure: 3b“2b: diethyl azodicarboxylate
(DEAD, 0.31 ml, 2.0 mmol) was added to a mixture of 3b
(0.26 g, 1.0 mmol), 4-nitrophenol (0.02 g, 0.2 mmol),
triphenylphosphine (0.39 g, 1.5 mmol) and tetra-
hydrofuran (3 ml) in an ice bath, and the mixture was
stirred at room temperature for 1 h. The reaction mixture
was poured into toluene (100 ml) and washed with 0.1N
sodium hydroxide (80 ml). The organic layer was washed
with brine (80 ml), dried over anhydrous magnesium sul-
fate and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (ethyl
acetate/hexane: 1/9 v/v) to give 0.20 g (82%) of 4-(4-
chlorophenyl)-1H-2,3-benzoxazine (2b) as a white solid.
The product was recrystallized from hexane and ethyl
acetate to give colorless prisms, mp 135.5–136.5°C. 1H
NMR (270 MHz, CDCl3) l ppm: 5.04 (s, 2H), 7.20 (d,
J=7.1 Hz, 1H), 7.27 (d, J=7.1 Hz, 1H), 7.35–7.63 (m,
6H). 13C NMR (100 MHz, CDCl3) l ppm: 67.2, 122.4,
124.5, 125.7, 128.4, 128.9, 130.3, 131.6, 132.2, 132.7, 136.0,
160.0. IR (KBr) cm−1: 2836, 1592, 1486, 1397, 1335, 1090,
975, 860. Anal. calcd for C14H10ClNO: C, 69.00; H, 4.14;
Cl, 14.55; N, 5.75. Found: C, 68.93; H, 3.99; Cl, 14.63; N,
5.73.
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J. Pesticide Sci. 1999, 24, 130–137; (b) Kai, H.; Ichiba, T.;
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