Synthesis of 2-substituted 4H-3,1-benzoxazin-4-ones by thermally induced cyclization of N-(2-benzyloxycarbonyl)phenyl ketenimines; oxygen-to-carbon migration of a benzyl group

Article abstract of DOI:10.1055/s-2005-870015

N-(2-Benzyloxycarbonyl)phenyl ketenimines undergo a thermally induced cyclization to give 2-substituted 4H-3,1-benzoxazin-4-ones. These processes involve the formation of a new carbon-oxygen bond and the migration of the benzyl group from the oxygen atom of the benzyloxy unit at the ester function to the terminal carbon atom of the ketenimine fragment. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-870015

2426
PAPER
Synthesis of 2-Substituted 4H-3,1-Benzoxazin-4-ones by Thermally Induced
Cyclization of N-(2-Benzyloxycarbonyl)phenyl Ketenimines; Oxygen-to-
Carbon Migration of a Benzyl Group
Oxygen to
C
arbon Mig
a
r
ation of
a
t
Benzyl
e
G
roup o Alajarín,*a Ángel Vidal,*a María-Mar Ortín,a Delia Bautistab
a
Departamento de Química Orgánica, Facultad de Química, Universidad de Murcia, Campus de Espinardo, 30100 Murcia, Spain
b
Servicio Universitario de Instrumentación Científica, Universidad de Murcia, Campus de Espinardo, 30100 Murcia, Spain
Fax +34(968)364149; E-mail: alajarin@um.es
Received 18 March 2005; revised 12 April 2005
anilines with unsaturated halides or triflates16 or with acid
chlorides,17 the oxidation from 3-oxoindolines and in-
doles,18 [4+2] cycloaddition reactions of the imino-ketene
resulting from the thermolysis of benzotriazinone,19 the
Abstract: N-(2-Benzyloxycarbonyl)phenyl ketenimines undergo a
thermally induced cyclization to give 2-substituted 4H-3,1-benzox-
azin-4-ones. These processes involve the formation of a new car-
bon–oxygen bond and the migration of the benzyl group from the
oxygen atom of the benzyloxy unit at the ester function to the termi- condensation of 2-azidobenzoic acid with aldehydes,20 or
nal carbon atom of the ketenimine fragment.
the electrochemical cyclization of N-acyl-2-trichloro-
acetylanilines.21
Key words: azides, ketenimines, cyclizations, rearrangements,
benzoxazinones
Ketenimines have been frequently used as precursors of
nitrogen-containing heterocycles.22 As a matter of fact we
have successfully employed these heterocumulenes in the
4H-3,1-Benzoxazin-4-ones (also known by the common
name ‘acylanthranils’), particularly those with a carbon
substituent at the 2-position, are important fused heterocy-
cles. Compounds possessing this heterocyclic ring system
are found in nature, as the phytoalexins avenalumin I1 and
dianthalexin,2 and some hydroxylated derivatives of this
last compound.3 The 3,1-benzoxazin-4-one core is a key
structural fragment in a range of biologically active com-
pounds. Some derivatives of this family act as competitive
inhibitors4 or potent inactivators5 of chymotrypsin and
other serine proteases, or are inhibitors of human leuko-
cyte elastase (HLE),6 herpes simplex virus type 1 (HSV-
1) protease,7 and C1r serine protease.8 Moreover, some 2-
substituted 4H-3,1-benzoxazin-4-ones have the ability to
lower the levels of cholesterol and triglycerides in plasma,
and to raise the proportion of total cholesterol carried by
high-density lipoproteins.9 The importance of these benz-
oxazinones also reside in that these compounds are useful
precursors for the preparation of other pharmaceutically
active heterocyclic compounds, mainly quinazoline and
quinoline derivatives.10
synthesis of a variety of nitrogenated heterocycles. For in-
stance, we have prepared isoquinolines by electrocyclic
ring closure of ketenimines,23 azeto[2,1-b]quinazolines
via intramolecular imino-ketenimine [2+2] cycloaddi-
tion,24 benz[b]acridines,25 benzimidazo[1,2-b]isoquino-
lines,26 or pyrido[1,2-a]benzimidazoles27 through [4+2]
cycloaddition reactions, and indoles or 1,4-benzoxazines
by intramolecular addition of carbon centered radicals
onto ketenimines.28
Here we report a new synthesis of 2-substituted 4H-3,1-
benzoxazin-4-ones based on the thermally induced cy-
clization of N-(2-benzyloxycarbonyl)phenyl ketenimines.
These processes involve the thermal rearrangement of an
O-benzyl group to a carbon atom.
The reaction of 2-azidobenzoyl chloride (1a) and 2-azido-
5-chlorobenzoyl chloride (1b) with benzylic alcohols 2, in
CH2Cl2 solution, in the presence of a slight excess of 4-
dimethylaminopyridine, provided benzyl 2-azidoben-
zoates 3 in good to excellent yields (Table 1). CH2Cl2 so-
lutions of 3 were treated, at room temperature, with
triphenylphosphane to give triphenylphosphazenes 4. The
transformation 3 → 4 was complete in about 16 hours, as
followed by IR (disappearance of the azide vibration near
2100 cm–1, and observation of the new bands at 1438
cm–1 and 1121 cm–1 corresponding to the phosphazene
groups). Treatment of the resulting solutions containing
compounds 4 with a stoichiometric amount of diphe-
nylketene or methylphenylketene afforded N-(2-benzyl-
oxycarbonyl)phenyl ketenimines 5. The formation of
ketenimines 5 was established by IR spectroscopy: the IR
spectra of the reaction mixtures showed very strong ab-
sorptions around 2000 cm–1 attributable to the N=C=C
group. After removal of the solvent, the mixtures contain-
ing the N-(2-benzyloxycarbonyl)phenyl ketenimines 5
and triphenylphosphane oxide were heated at 200 °C, in a
Different general protocols have been reported for the
preparation of 4H-3,1-benzoxazin-4-ones bearing a car-
bon substituent at C2,11 such as the condensation of an-
thranilic acids with acid anhydrides, orthoesters or acid
chlorides,12 the cyclodehydration of N-acylanthranilic ac-
ids,13 or those that use the closely related 2H-3,1-benzox-
azine-2,4(1H)dione system (isatoic anhydride) as starting
material.14 Other synthetic methods involve the thallation
and subsequent Pd-catalyzed carbonylation of acetanil-
ide,15 the Pd-catalyzed cyclocarbonylation of ortho-iodo-
SYNTHESIS 2005, No. 14, pp 2426–2432
x
x.
x
x
.
2
0
0
5
Advanced online publication: 13.07.2005
DOI: 10.1055/s-2005-870015; Art ID: Z06305SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Oxygen-to-Carbon Migration of a Benzyl Group
2427
Table 1 Benzyl 2-Azidobenzoates 3
Table 2 2-Substituted 4H-3,1-Benzoxazin-4-ones 6
Compound R1
R2
Ph
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ar
Yield (%)a,b
Compound
R1
H
Ar
Yield (%)
3a
3b
3c
3d
3e
3f
4-MeC6H4
82
75
91
70
80
60
78
6a
6b
6c
6d
6e
6f
H
4-MeC6H4
45
43
41
42
50
40
43
40
H
4-MeOC6H4
3,4-(MeO)2C6H3
4-MeC6H4
H
4-MeC6H4
H
H
4-MeOC6H4
3,4-(MeO)2C6H3
4-MeC6H4
Cl
Cl
Cl
Cl
H
4-MeOC6H4
3,4-(MeO)2C6H3
3,5-(MeO)2C6H3
Cl
Cl
Cl
Cl
4-MeOC6H4
3,4-(MeO)2C6H3
3,5-(MeO)2C6H3
3g
6g
6h
a Global yield for the conversion 3 → 6.
sealed tube, for one hour.29 The crude materials resulting
from this thermal treatment were chromatographed, thus
resulting in the isolation of pure 2-substituted 4H-3,1-
benzoxazin-4-ones 6 (Scheme 1).30 Compounds 6 were
obtained in acceptable global yields (40–50%) for the
conversion 3 → 6, three reaction steps in a one-pot pro-
cess (Table 2).
b Isolated yield after silica gel column chromatography.
bond range between 1628 cm–1 and 1640 cm–1. In the 1H
NMR spectra of compounds 6a,c–h the two protons at the
methylene carbon of the side chain resonate as a singlet at
d = 3.90–3.93 ppm. However, in the 1H NMR spectrum of
6b [R1 = H; R2 = Me; Ar = 4-MeC6H4] these two protons
turned out to be diastereotopic, appearing at d = 3.38 ppm
and d = 3.65 ppm with a geminal coupling constant J =
13.4 Hz, due to its stereogenic carbon atom. The proxim-
ity of the carbonyl group to the aromatic proton at C5 ac-
counts for its chemical shift, d = 8.08–8.15 ppm. The 13C
NMR spectra of the 2-substituted benzoxazinones 6 show
the signal of the aliphatic quaternary carbon atom linked
The structural elucidation of the 4H-3,1-benzoxazin-4-
ones 6 was achieved following their analytical and spec-
tral data, and confirmed by the X-ray structure determina-
tion of a monocrystal of 6g [R1 = Cl; R2 = Ph; Ar = 3,4-
(MeO)2C6H3].31 The IR spectra of the 4H-3,1-benzoxazin-
4-ones 6 exhibit strong absorptions in the region 1757–
1772 cm–1 due to the vibration of the lactone carbonyl
group, whereas the bands associated to the C=N double
Ar
1)
, DMAP
HO
O
O
2) PPh3
2
R1
R1
CH2Cl2, r.t., 16 h
CH2Cl2, r.t., 5 h
O
Ar
Cl
N3
N3
1a (R1 = H)
1b (R1 = Cl)
3
O
O
N
3) Ph(R2)C=C=O
CH2Cl2, r.t., 10 min
R1
R1
O
Ar
Ph
O
Ar
O
PPh3
+
N
C
C
PPh3
R2
5
4
4) 200 °C
neat, sealed tube, 1 h
O
N
R1
O
Ar
R2
Ph
6
Scheme 1 Preparation of 2-Substituted 4H-3,1-Benzoxazin-4-ones 6
Synthesis 2005, No. 14, 2426–2432 © Thieme Stuttgart · New York

2428
M. Alajarín et al.
PAPER
to C2 at d = 49.7–60.8 ppm, and the signal of the methyl- quence to that involved in the conversion 5 → 6, could
ene carbon at d = 43.5–44.8 ppm. In these spectra the car- transform into quinazolin-4-ones 8 (Scheme 2). Unfortu-
bonyl carbon C4 appear at d = 158.5–159.7 ppm, and nately, when compounds 7 were heated at 200 °C for one
carbon C2 fall in the range of d = 163.5–165.7 ppm.
hour in a sealed tube only very complex reaction mixtures
were obtained.29
In the crystal structure of 6g the 3,1-benzoxazin-4-one
ring is planar, with a mean deviation of only 0.01 Å
(Figure 1). The dihedral angles between the mean planes
defined by the benzoxazinone nucleus and the phenyl
rings are 99.4° (C11–C16), 89.4° (C21–C26), and 27.2°
(C31–C36).
O
N
Ar
O
N
R1
R1
O
O
Ar
Ph
Ph
R2
R2
O
N
R1
CH2-Ar
Ph
O
R2
Figure 2 Putative intermediates in the transformation 5 → 6
O
N
O
N
R
N
∆
N
R
C
Ar
Ar
Ph
Ph
Ph
C
Ph
7a R = Me, Ar = 3-MeOC6H4
7b R = PhCH2, Ar = Ph
8
Scheme 2 Attempted synthesis of quinazolin-4-ones 8
Figure 1 Molecular structure of 6g with 50% probability ellipsoids,
and the labeling scheme. Selected bond lengths (Å) and angles (°):
C(1)–C(3) 1.509 (5), C(1)–C(21) 1.542 (5), C(1)–C(11) 1.548 (5),
C(1)–C(2) 1.574 (4), O(1)–C(4) 1.385 (4), O(1)–C(3) 1.386 (4),
N(1)–C(3) 1.268 (4), N(1)–C(10) 1.400 (4), C(3)–N(1)–C(10) 117.5
(3), C(4)–O(1)–C(3) 121.8 (3), C(3)–C(1)–C(21) 113.5 (3), C(3)–
C(1)–C(11) 105.6 (3), C(21)–C(1)–C(11) 110.9 (3), C(3)–C(1)–C(2)
108.0 (3), C(21)–C(1)–C(2) 108.9 (3), C(11)–C(1)–C(2) 109.9 (3),
N(1)–C(3)–O(1) 124.9 (3), C(31)–C(2)–C(1) 116.2 (3), N(1)–C(3)–
C(1) 126.1 (3), O(1)–C(3)–C(1) 109.0 (3)
In summary, the thermally induced intramolecular cy-
clization of the N-(2-benzyloxycarbonyl)phenyl keten-
imines 5 provides new 2-substituted derivatives of the 4H-
3,1-benzoxazin-4-one system, an heterocyclic nucleus of
particular interest. Moreover, this process constitutes a
new type of reaction in ketenimine chemistry, which in-
volves the intramolecular migration of a benzyl group
over its terminal carbon atom.
All melting points were determined on a Kofler hot-plate mp appa-
ratus and are uncorrected. IR spectra were obtained as films or Nu-
jol emulsions on a Nicolet Impact 400 spectrophotometer. NMR
spectra were recorded on a Bruker Avance 300 (300 MHz and 75
The conversion of ketenimines 5 into the 4H-3,1-benzox-
azin-4-ones 6 involves the formation of a new carbon–ox-
ygen bond, and the migration of the benzyl group from the
oxygen atom of the ester function to the terminal carbon
atom of the ketenimine fragment. Most probably, this mi-
gration occurs through one of the dipolar or radical-cage
intermediates represented in Figure 2, although a precise
mechanistic investigation of this process is out of the
scope of the present work. The shift of benzyl groups from
an oxygen atom to a carbon atom is quite rare, and, to our
knowledge, only a few examples have been reported.32
1
MHz for H and 13C, respectively) or a Bruker Avance 400 spec-
trometer (400 MHz and 100 MHz for 1H and 13C, respectively), in
CDCl3 as solvent, and the chemical shifts are expressed in ppm rel-
1
ative to TMS at d = 0.00 for H and to CDCl3 at d = 77.1 for 13C.
Mass spectra were recorded on a Hewlett-Packard 5993C spectrom-
eter or on a VG-Autospec spectrometer. Microanalyses were per-
formed on a Carlo Erba EA-1108 instrument.
2-Azidobenzoyl chloride (1a),33 2-azido-5-chlorobenzoyl chloride
(1b),33 diphenylketene34 and methylphenylketene35 were prepared
according to literature procedures.
Starting from 2-azidobenzoyl chloride (1a) and N-substi-
tuted benzyl amines we prepared ketenimines 7, in which
The crystal and molecular structure of 6g has been determined by
the amide function bears at least one benzyl group at the X-ray diffraction studies. Crystal was mounted on glass fibre and
transferred to the cold gas stream of the diffractometer Bruker
Smart APEX. Data were recorded with Mo–Ka radiation (l =
nitrogen atom. We reasoned that by thermal treatment
these ketenimines, following a similar mechanistic se-
Synthesis 2005, No. 14, 2426–2432 © Thieme Stuttgart · New York

PAPER
Oxygen-to-Carbon Migration of a Benzyl Group
2429
0.71073Å) in w-scan mode. The structure was solved by the direct
method and refined anisotropically on F2 (program SHELXL-97,
G.M. Sheldrick, University of Göttingen, Germany). Methyl groups
were refined using rigid groups and other hydrogens were refined
using a riding method.
Yield: 1.05 g (70%); colorless prisms; mp 71–73 °C (Et2O–n-hex-
ane).
IR (Nujol): 2130, 1722, 1480, 1310, 1294, 1241, 1227, 1135, 1119,
1073, 1055, 830, 806, 783, 720, 623 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.35 (s, 3 H), 5.29 (s, 2 H), 7.13
(d, J = 8.6 Hz, 1 H), 7.19 (d, J = 8.0 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2
H), 7.44 (dd, J = 8.6, 2.5 Hz, 1 H), 7.82 (d, J = 2.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.2, 67.4, 121.3, 123.8 (s), 128.6,
129.4, 129.9 (s), 131.7, 132.4 (s), 133.1, 138.4 (s), 138.9 (s), 163.8
(s).
Benzyl 2-Azidobenzoates 3; General Procedure
To a solution of 2-azidobenzoyl chloride (1a; 0.91 g, 5 mmol) or 2-
azido-5-chlorobenzoyl chloride (1b; 1.08 g, 5 mmol) in anhyd
CH2Cl2 (50 mL) were added DMAP (0.79 g, 6.5 mmol) and the cor-
responding benzyl alcohol 2 (5 mmol). The reaction mixture was
stirred at r.t. for 5 h. Then n-hexane (50 mL) was added and the stir-
ring was continued for 30 min. The precipitated solid was separated
by filtration, and washed with n-hexane (3 × 15 mL). From the fil-
trate the solvent was removed under reduced pressure and the re-
sulting material was purified by column chromatography.
MS (EI, 70 eV): m/z (%) = 105 (100), 301 (4) [M+], 303 (2) [M+ +
2].
Anal. Calcd for C15H12ClN3O2: C, 59.71; H, 4.01; N, 13.93. Found:
C, 59.65; H, 4.17; N, 13.90.
4-Methoxybenzyl 2-Azido-5-chlorobenzoate (3e)
Silica gel; hexane–Et2O, 7:3. Yield: 1.27 g (80%); colorless prisms;
mp 60–62 °C (Et2O–n-hexane).
4-Methylbenzyl 2-Azidobenzoate (3a)
Silica gel; hexane–Et2O, 4:1. Yield: 1.1 g (82%); yellow oil.
IR (neat): 2124, 1724, 1597, 1580, 1520, 1489, 1452, 1373, 1301,
1253, 1129, 1074, 810, 755, 690 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.34 (s, 3 H), 5.30 (s, 2 H), 7.10–
7.24 (m, 4 H), 7.34 (d, J = 8.0 Hz, 2 H), 7.46–7.52 (m, 1 H), 7.86
(dd, J = 7.8, 1.6 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.2, 67.0, 119.9, 122.6 (s), 124.4,
128.5, 129.3, 131.9, 132.8 (s), 133.2, 138.1 (s), 140.2 (s), 165.0 (s).
IR (Nujol): 2133, 1726, 1616, 1481, 1309, 1257, 1227, 1175, 1134,
1115, 1073, 1036, 829, 782, 715, 624 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.81 (s, 3 H), 5.27 (s, 2 H), 6.89–
6.93 (m, 2 H), 7.14 (d, J = 8.6 Hz, 1 H), 7.37–7.40 (m, 2 H), 7.45
(dd, J = 8.6, 2.5 Hz, 1 H), 7.81 (d, J = 2.5 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 55.3, 67.3, 114.1, 121.3, 123.8
(s), 127.5 (s), 129.9 (s), 130.4, 131.6, 133.1, 138.8 (s), 159.9 (s),
163.9 (s).
MS (EI, 70 eV): m/z (%) = 105 (100), 267 (2) [M+].
Anal. Calcd for C15H13N3O2: C, 67.40; H, 4.90; N, 15.72. Found: C,
67.21; H, 4.77; N, 15.90.
MS (EI, 70 eV): m/z (%) = 121 (100), 317 (4) [M+], 319 (2) [M+ +
2].
Anal. Calcd for C15H12ClN3O3: C, 56.70; H, 3.81; N, 13.23. Found:
C, 56.61; H, 3.77; N, 13.04.
4-Methoxybenzyl 2-Azidobenzoate (3b)
Silica gel; hexane–Et2O, 7:3. Yield: 1.06 g (75%); yellow oil.
IR (neat): 2126, 1725, 1616, 1597, 1518, 1490, 1450, 1302, 1243,
1179, 1124, 1073, 1037, 829, 752 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.79 (s, 3 H), 5.26 (s, 2 H), 6.88
(m, 2 H), 7.13 (t, J = 7.8 Hz, 1 H), 7.20 (d, J = 7.8 Hz, 1 H), 7.37–
7.40 (m, 2 H), 7.46–7.50 (m, 1 H), 7.84 (dd, J = 7.8, 1.5 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 55.3, 66.8, 114.0, 119.8, 122.6
(s), 124.4, 127.9 (s), 130.2, 131.8, 133.2, 140.1 (s), 159.7 (s), 165.0
(s).
3,4-Dimethoxybenzyl 2-Azido-5-chlorobenzoate (3f)
Silica gel; hexane–Et2O, 1:1. Yield: 1.04 g (60%); colorless prisms;
mp 81–83 °C (Et2O–n-hexane).
IR (Nujol): 2134, 2101, 1717, 1524, 1311, 1271, 1219, 1169, 1142,
1113, 1023, 943, 859, 833, 805, 786 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.81 (s, 3 H), 3.82 (s, 3 H), 5.20
(s, 2 H), 6.79 (d, J = 8.0 Hz, 1 H), 6.91–6.96 (m, 2 H), 7.07 (d, J =
8.6 Hz, 1 H), 7.38 (dd, J = 8.6, 2.5 Hz, 1 H), 7.74 (d, J = 2.5 Hz, 1
H).
MS (EI, 70 eV): m/z (%) = 121 (100), 283 (4) [M+].
13C NMR (75 MHz, CDCl3): d = 55.9, 67.5, 111.1, 112.0, 121.3,
121.6, 123.8 (s), 127.9 (s), 129.9 (s), 131.6, 133.1, 138.8 (s), 149.1
(s), 149.3 (s), 163.9 (s).
MS (EI, 70 eV): m/z (%) = 151 (100), 347 (9) [M+], 349 (3) [M+ +
2].
Anal. Calcd for C15H13N3O3: C, 63.60; H, 4.63; N, 14.83. Found: C,
63.41; H, 4.57; N, 14.90.
3,4-Dimethoxybenzyl 2-Azidobenzoate (3c)
Silica gel; hexane–Et2O, 2:3. Yield: 1.42 g (91%); yellow oil.
IR (neat): 2126, 1729, 1598, 1515, 1484, 1449, 1378, 1250, 1161,
1125, 1074, 1029, 946, 859, 809, 760 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.88 (s, 3 H), 3.90 (s, 3 H), 5.29
(s, 2 H), 6.85–6.88 (m, 1 H), 7.00–7.04 (m, 2 H), 7.16 (td, J = 8.1,
1.1 Hz, 1 H), 7.23 (dd, J = 8.1, 0.8 Hz, 1 H), 7.51 (ddd, J = 8.1, 7.5,
1.6 Hz, 1 H), 7.85 (dd, J = 7.5, 1.5 Hz, 1 H).
Anal. Calcd for C16H14ClN3O4: C, 55.26; H, 4.06; N, 12.08. Found:
C, 55.02; H, 3.97; N, 11.94.
3,5-Dimethoxybenzyl 2-Azido-5-chlorobenzoate (3g)
Silica gel; hexane–Et2O, 7:3. Yield: 1.36 g (78%); colorless prisms;
mp 71–73 °C (Et2O–n-hexane).
13C NMR (75 MHz, CDCl3): d = 55.9, 56.0, 67.2, 111.1, 111.9,
119.9, 121.4, 122.7 (s), 124.5, 128.3 (s), 131.9, 133.3, 140.1 (s),
149.0 (s), 149.2 (s), 165.1 (s).
IR (Nujol): 2135, 2102, 1698, 1614, 1559, 1430, 1405, 1305, 1249,
1210, 1175, 1155, 1065, 1010, 835 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.79 (s, 6 H), 5.28 (s, 2 H), 6.44
(t, J = 2.3 Hz, 1 H), 6.59 (d, J = 2.3 Hz, 2 H), 7.17 (d, J = 8.6 Hz, 1
H), 7.47 (dd, J = 8.6, 2.5 Hz, 1 H), 7.85 (d, J = 2.5 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 55.4, 67.3, 100.4, 106.2, 121.3,
123.6 (s), 130.0 (s), 131.8, 133.3, 137.6 (s), 138.9 (s), 161.0 (s),
163.8 (s).
MS (EI, 70 eV): m/z (%) = 151 (100), 313 (29) [M+].
Anal. Calcd for C16H15N3O4: C, 61.34; H, 4.83; N, 13.41. Found: C,
61.09; H, 4.67; N, 13.23.
4-Methylbenzyl 2-Azido-5-chlorobenzoate (3d)
Silica gel; hexane–Et2O, 4:1.
Synthesis 2005, No. 14, 2426–2432 © Thieme Stuttgart · New York

2430
M. Alajarín et al.
PAPER
MS (EI, 70 eV): m/z (%) = 151 (100), 347 (9) [M+], 349 (3) [M+ +
2].
1H NMR (300 MHz, CDCl3): d = 3.63 (s, 3 H), 3.92 (s, 2 H), 6.52
(d, J = 8.6 Hz, 2 H), 6.65 (d, J = 8.6 Hz, 2 H), 7.17–7.33 (m, 10 H),
7.40 (t, J = 7.8 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 7.73 (t, J = 8.1
Hz, 1 H), 8.08 (d, J = 7.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 43.5, 55.0, 60.7 (s), 112.7, 116.7
(s), 127.0, 127.1, 127.7, 128.7, 129.0, 129.7, 132.2, 136.4, 138.5 (s),
142.5 (s), 146.0 (s), 158.0 (s), 159.4 (s), 163.5 (s).
Anal. Calcd for C16H14ClN3O4: C, 55.26; H, 4.06; N, 12.08. Found:
C, 55.09; H, 3.98; N, 11.89.
4H-3,1-Benzoxazin-4-ones 6; General Procedure
A solution of the corresponding benzyl 2-azidobenzoate 3 (2.5
mmol) in anhyd CH2Cl2 (10 mL) was introduced in a glass tube, and
a solution of triphenylphosphane (0.65 g, 2.5 mmol) in the same sol-
vent (6 mL) was added dropwise. The reaction mixture was stirred
at r.t. under N2 for 16 h. Then, methylphenylketene or diphe-
nylketene (2.5 mmol) in CH2Cl2 (4 mL) was added. After stirring at
r.t. for 10 min the solvent was removed to dryness under reduced
pressure. The glass tube was sealed and the mixture containing the
corresponding ketenimine 5 and triphenylphosphane oxide was
heated at 200 °C for 1 h. After cooling at r.t. the crude mixture was
dissolved in CH2Cl2 (20 mL) and transferred to a round bottom
flask. Finally, the solvent was removed under reduced pressure and
the resulting material was chromatographed. After removing the
chromatography solvents under reduced pressure the 4H-3,1-
benzoxazin-4-ones 6 were obtained as solids, that were triturated
and dried under high vacuum a 50 °C for 24 h, and used as such for
characterization.
2-[2-(3,4-Dimethoxyphenyl)-1,1-diphenylethyl]-4H-3,1-benzox-
azin-4-one (6d)
Silica gel; hexane–Et2O, 2:3. Yield: 0.49 g (42%).
IR (Nujol): 1759, 1636, 1608, 1516, 1496, 1445, 1421, 1283, 1263,
1159, 1140, 1029, 1005, 777, 701 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.46 (s, 3 H), 3.76 (s, 3 H), 3.92
(s, 2 H), 6.06 (s, 1 H), 6.51–6.56 (m, 2 H), 7.25–7.32 (m, 10 H), 7.49
(t, J = 7.7 Hz, 1 H), 7.76 (d, J = 8.0 Hz, 1 H), 7.79 (td, J = 8.0, 1.3
Hz, 1 H), 8.14 (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 43.9, 55.3, 55.7, 60.7 (s), 110.2,
114.5, 116.8 (s), 123.4, 127.1, 127.9, 128.4, 128.6, 129.5 (s), 129.8,
136.5, 142.6 (s), 146.2 (s), 147.4 (s), 147.6 (s), 159.6 (s), 163.5 (s).
MS (EI, 70 eV): m/z (%) = 151 (100), 463 (3) [M+].
Anal. Calcd for C30H25NO4: C, 77.73; H, 5.44; N, 3.02. Found: C,
77.55; H, 5.29; N, 3.24.
As compounds 6c and 6f were isolated along with the correspond-
ing 2-diphenylmethyl-4H-3,1-benzoxazin-4-one 9 (see ref.30) only
their 1H and 13C NMR data are given.
6-Chloro-2-[2-(4-methylphenyl)-1,1-diphenylethyl]-4H-3,1-
benzoxazin-4-one (6e)
Silica gel; hexane–Et2O, 9:1. Yield: 0.56 g (50%).
2-[2-(4-Methylphenyl)-1,1-diphenylethyl]-4H-3,1-benzoxazin-
4-one (6a)
IR (Nujol): 1772, 1628, 1603, 1514, 1495, 1472, 1312, 1249, 1156,
1047, 1033, 875, 838, 771, 716, 702 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.19 (s, 3 H), 3.91 (s, 2 H), 6.59
(d, J = 8.0 Hz, 2 H), 6.79 (d, J = 8.0 Hz, 2 H), 7.22–7.28 (m, 10 H),
7.60 (d, J = 8.6 Hz, 1 H), 7.71 (dd, J = 8.6, 2.4 Hz, 1 H), 8.08 (d,
J = 2.4 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.0, 44.0, 60.7 (s), 117.9 (s),
127.2, 127.8, 127.9, 128.2, 128.8, 129.7, 131.2, 133.8 (s), 134.2 (s),
135.9 (s), 136.7, 142.3 (s), 144.6 (s), 158.5 (s), 163.9 (s).
Silica gel; hexane–Et2O, 9:1. Yield: 0.47 g (45%).
IR (Nujol): 1760, 1631, 1607, 1515, 1495, 1263, 1172, 1046, 1002,
776, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.18 (s, 3 H), 3.93 (s, 2 H), 6.62
(d, J = 7.9 Hz, 2 H), 6.79 (d, J = 7.9 Hz, 2 H), 7.21–7.34 (m, 10 H),
7.45 (td, J = 7.8, 1.1 Hz, 1 H), 7.65 (d, J = 8.1 Hz, 1 H), 7.75 (td,
J = 8.1, 1.4 Hz, 1 H), 8.12 (dd, J = 7.8, 1.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.0, 44.0, 60.6 (s), 116.8 (s),
127.1, 127.2, 127.8, 128.1, 128.4, 128.5, 129.8, 131.2, 134.0 (s),
135.7 (s), 136.4, 142.5 (s), 146.2 (s), 159.6 (s), 163.5 (s).
MS (EI, 70 eV): m/z (%) = 105 (100), 451 (13) [M+], 453 (4) [M+ +
2].
MS (EI, 70 eV): m/z (%) = 105 (100), 417 (27) [M+].
Anal. Calcd for C29H22ClNO2: C, 77.07; H, 4.91; N, 3.10. Found: C,
76.94; H, 4.78; N, 3.04.
Anal. Calcd for C29H23NO2: C, 83.43; H, 5.55; N, 3.35. Found: C,
83.21; H, 5.39; N, 3.14.
6-Chloro-2-[2-(4-methoxyphenyl)-1,1-diphenylethyl]-4H-3,1-
benzoxazin-4-one (6f)
Silica gel; hexane–Et2O, 9:1. Yield: 0.47 g (40%).
2-[1-Methyl-2-(4-methylphenyl)-1-phenylethyl]-4H-3,1-benz-
oxazin-4-one (6b)
Silica gel; hexane–Et2O, 4:1. Yield: 0.38 g (43%).
1H NMR (300 MHz, CDCl3): d = 3.70 (s, 3 H), 3.93 (s, 2 H), 6.54–
6.58 (m, 2 H), 6.63–6.67 (m, 2 H), 7.26–7.33 (m, 10 H), 7.64 (d,
J = 8.6 Hz, 1 H), 7.74 (dd, J = 8.6, 2.4 Hz, 1 H), 8.11 (d, J = 2.4 Hz,
1 H).
13C NMR (75 MHz, CDCl3): d = 43.5, 55.1, 60.8 (s), 112.8, 117.9
(s), 127.2, 127.9, 128.8, 129.0, 129.7, 132.2, 134.3 (s), 136.7, 138.3
(s), 142.3 (s), 144.6 (s), 158.1 (s), 158.5 (s), 163.9 (s).
IR (Nujol): 1757, 1633, 1608, 1475, 1447, 1323, 1262, 1165, 1111,
1067, 1039, 1007, 815, 778, 739, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.67 (s, 3 H), 2.22 (s, 3 H), 3.38
(d, J = 13.4 Hz, 1 H), 3.65 (d, J = 13.4 Hz, 1 H), 6.78 (d, J = 7.9 Hz,
2 H), 6.92 (d, J = 7.9 Hz, 2 H), 7.18–7.35 (m, 5 H), 7.46 (td, J = 8.0,
1.1 Hz, 1 H), 7.62 (d, J = 7.9 Hz, 1 H), 7.75 (td, J = 7.9, 1.5 Hz, 1
H), 8.15 (dd, J = 8.0, 1.5 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.0, 22.7, 44.8, 49.7 (s), 116.8
(s), 126.6, 127.0, 127.2, 128.3, 128.4, 128.6, 128.7, 130.5, 133.9 (s),
135.9 (s), 136.4, 143.3 (s), 146.1 (s), 159.7 (s), 165.7 (s).
6-Chloro-2-[2-(3,4-dimethoxyphenyl)-1,1-diphenylethyl]-4H-
3,1-benzoxazin-4-one (6g)
Silica gel; hexane–Et2O, 9:1. Yield: 0.53 g (43%).
MS (EI, 70 eV): m/z (%) = 105 (100), 355 (14) [M+].
IR (Nujol): 1765, 1640, 1608, 1520, 1424, 1314, 1264, 1238, 1143,
1027, 1019, 877, 857, 812, 768, 708 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.45 (s, 3 H), 3.76 (s, 3 H), 3.90
(s, 2 H), 6.00 (d, J = 1.7 Hz, 1 H), 6.51 (dd, J = 8.3, 1.7 Hz, 1 H),
6.55 (d, J = 8.3 Hz, 1 H), 7.23–7.32 (m, 10 H), 7.60 (d, J = 8.6 Hz,
1 H), 7.72 (dd, J = 8.6, 2.4 Hz, 1 H), 8.09 (d, J = 2.4 Hz, 1 H).
Anal. Calcd for C24H21NO2: C, 81.10; H, 5.90; N, 3.94. Found: C,
81.29; H, 5.79; N, 3.84.
2-[2-(4-Methoxyphenyl)-1,1-diphenylethyl]-4H-3,1-benzox-
azin-4-one (6c)
Silica gel; hexane–Et2O, 7:3. Yield: 0.44 g (41%).
Synthesis 2005, No. 14, 2426–2432 © Thieme Stuttgart · New York

PAPER
Oxygen-to-Carbon Migration of a Benzyl Group
2431
13C NMR (75 MHz, CDCl3): d = 43.8, 55.3, 55.7, 60.7 (s), 110.2,
114.5, 117.9 (s), 123.3, 127.2, 127.8, 127.9, 128.6, 129.3 (s), 129.8,
134.3 (s), 136.7, 142.3 (s), 144.6 (s), 147.5 (s), 147.6 (s), 158.5 (s),
163.9 (s).
MS (EI, 70 eV): m/z (%) = 151 (100), 497 (4) [M+], 499 (2) [M+ +
2].
(8) Gilmore, J. L.; Hays, S. J.; Caprathe, B. W.; Lee, C.;
Emmerling, M. R.; Michael, W.; Jaén, J. C. Bioorg. Med.
Chem. Lett. 1996, 6, 679.
(9) Fenton, G.; Newton, C. G.; Wyman, B. M.; Bagge, P.; Dron,
D. I.; Riddell, D.; Jones, G. D. J. Med. Chem. 1989, 32, 265.
(10) (a) Clémence, F.; Martret, O. L.; Collard, J. J. Heterocycl.
Chem. 1984, 21, 1345. (b) Ibrahim, S. S.; Abdel-Halim, A.
M.; Gabr, Y.; El-Edfawy, S.; Abdel-Rahman, R. M. J. Chem.
Res., Synop. 1997, 154.
Anal. Calcd for C30H24ClNO4: C, 72.36; H, 4.86; N, 2.81. Found: C,
73.21; H, 4.69; N, 2.77.
(11) (a) For a review on the synthesis and reactivity of 4H-3,1-
benzoxazin-4-ones bearing a carbon substituent at the 2
position see: Coppola, G. M. J. Heterocycl. Chem. 1999, 36,
563. (b) For a review on the synthesis and reactivity of 4H-
3,1-benzoxazin-4-ones bearing oxy, mercapto or amino
functionalities at the 2-position see: Coppola, G. M. J.
Heterocycl. Chem. 2000, 37, 1369.
(12) For examples of preparations of 2-substituted 4H-3,1-
benzoxazin-4-ones from anthranilic acids, see: (a) Bain, D.
I.; Smalley, R. K. J. Chem. Soc. C 1968, 1593.
Crystal Data for 6g
C30H24ClNO4, M = 497.95, Monoclinic, space group P2(1)/c, a =
9.1353 (6), b = 17.3153 (11), c = 15.5769 (11) Å, b = 98.496 (2),
V = 2436.9 (3) Å3, Z = 4, l(Mo – Ka) = 0.71073 Å, T = 100 K, m =
0.19 mm–1, 26253 reflections measured, 4995 unique (Rint = 0.0738)
used in all calculations. The final R1 was 0086 [I > 2a (I)] and wR2
was 0.144 (all data).
6-Chloro-2-[2-(3,5-dimethoxyphenyl)-1,1-diphenylethyl]-4H-
3,1-benzoxazin-4-one (6h)
Silica gel; hexane–Et2O, 7:3. Yield: 0.5 g (40%).
(b) Bergman, J.; Bergman, S. J. Org. Chem. 1985, 50, 1246.
(c) Hauteville, M.; Ponchet, M.; Ricci, P.; Favre-Bonvin, J.
J. Heterocycl. Chem 1988, 25, 715. (d) Parkanyi, C.; Yuan,
H. L.; Stromberg, B. H. E.; Evenzahav, A. J. Heterocycl.
Chem. 1992, 29, 749. (e) Atkinson, R. S.; Coogan, M. P.;
Cornell, C. L. J. Chem. Soc., Perkin Trans. 1 1995, 157.
(f) Khajavi, M. S.; Montazari, N.; Hosseini, S. S. S. J. Chem.
Res., Synop. 1997, 286.
IR (Nujol): 1764, 1628, 1599, 1471, 1380, 1314, 1206, 1153, 1068,
838, 776, 705 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.48 (s, 6 H), 3.90 (s, 2 H), 5.91
(d, J = 2.3 Hz, 2 H), 6.18 (t, J = 2.3 Hz, 1 H), 7.24–7.34 (m, 10 H),
7.62 (d, J = 8.6 Hz, 1 H), 7.73 (dd, J = 8.6, 2.4 Hz, 1 H), 8.09 (d,
J = 2.4 Hz, 1 H).
(13) For examples of preparations of 2-substituted 4H-3,1-
benzoxazin-4-ones from N-acylanthranilic acids see:
(a) Zentmyer, D. T.; Wagner, E. C. J. Org. Chem. 1948, 13,
967. (b) Rabilloud, G.; Sillion, B. J. Heterocycl. Chem.
1980, 17, 1065. (c) Conley, R. A.; Barton, D. L.; Stefanick,
S. M.; Lam, M. M.; Lindabery, G. C.; Kasulanis, C. F.;
Cesco-Cancian, S.; Currey, S.; Fabian, A. C.; Levine, S. D.
J. Heterocycl. Chem. 1995, 32, 761. (d) Marsham, P. R.;
Jackman, A. L.; Barker, A. J.; Boyle, F. T.; Pegg, S. J.;
Wardleworth, J. M.; Kimbell, R.; O’Connor, B. M.; Calvert,
A. H.; Hughes, L. R. J. Med. Chem. 1995, 38, 994.
(e) Mohapatra, D. K.; Datta, A. Synlett 1996, 1129.
(14) For examples of preparations of 2-substituted 4H-3,1-
benzoxazin-4-ones from isatoic anhydride see: (a) Minami,
T.; Ogata, M.; Hirao, I.; Tanaka, M.; Agawa, T. Synthesis
1982, 231. (b) Tsubota, M.; Hamashima, M. Heterocycles
1984, 21, 706.
13C NMR (100 MHz, CDCl3): d = 44.5, 55.0, 60.7 (s), 99.3, 109.1,
117.9 (s), 127.3, 127.8, 127.9, 128.7, 129.7, 134.3 (s), 136.8, 139.1
(s), 142.3 (s), 144.6 (s), 158.5 (s), 159.7 (s), 163.8 (s).
MS (EI, 70 eV): m/z (%) = 151 (100), 497 (13) [M+], 499 (4) [M+ +
2].
Anal. Calcd for C30H24ClNO4: C, 72.36; H, 4.86; N, 2.81. Found: C,
72.09; H, 4.71; N, 2.68.
Acknowledgment
This work was supported by the DGES and FEDER (Project
BQU2001-0010) and Fundación Séneca-CARM (Project 00458/PI/
04). One of us (M.-M. O.) thanks Fundación Cajamurcia for a fel-
lowship.
(15) Larock, R. C.; Fellows, C. A. J. Org. Chem. 1980, 45, 363.
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Synthesis 2005, No. 14, 2426–2432 © Thieme Stuttgart · New York

2432
M. Alajarín et al.
PAPER
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ketenimines 5 to yield the corresponding amides, followed
by intramolecular nucleophilic displacement of the
benzyloxy group from the ester group by the carbonyl
oxygen of the amide function. We tried very hard to exclude
water from the reaction mixtures, but probably we did not
succeed as the results were invariable, and small amounts of
benzoxazinones 9 were always formed.
Compounds 9a (R1 = H) and 9b (R1 = Cl) could not be
separated from the 4H-3,1-benzoxazin-4-ones 6c [R1 = H;
R2 = Ph; Ar = 4-MeOC6H4] and 6f [R1 = Cl; R2 = Ph; Ar = 4-
MeOC6H3], respectively.
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(31) CCDC 264507 contains the supplementary crystallographic
data for 6g. The data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; e-
mail:deposit@ccdc.cam.ac.uk).
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M.; Vidal, A.; Ortín, M.-M.; Bautista, D. Synlett 2004, 991.
(29) Ketenimines 5 and 7 remained unaltered when heated in
boiling toluene or boiling ortho-xylene.
(30) In the thermal treatment of the N-(2-benzyloxycarbo-
nyl)phenyl ketenimines 5 small amounts of the corres-
ponding 4H-3,1-benzoxazin-4-ones 9 (Figure 3) were
always formed (8–13%).
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2265. (b) Arnold, R. T.; Kulenovic, S. T. J. Org. Chem.
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J. Org. Chem. USSR (Engl. Transl.) 1988, 24, 1007.
(e) Burger, K.; Gaa, K.; Geith, K.; Schierlinger, C. Synthesis
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(33) 2-Azidobenzoyl chloride (1a) and 2-azido-5-chlorobenzoyl
chloride (1b) were both prepared following the experimental
procedure described for 1a: Porter, T. C.; Smalley, R. K.;
Teguiche, M.; Purwono, B. Synthesis 1997, 773.
O
9a R1 = H; R2 = Ph
R1
O
9b R1 = Cl; R2 = Ph
H
N
9c
R
1 = H; R2 = Me
R2
Ph
Figure 3
(34) Taylor, E. C.; McKillop, A.; Hawks, G. H. Org. Synth. 1973,
52, 36.
(35) Pracejus, H.; Wallura, G. J. Prakt. Chem. 1962, 19, 33.
Probably, compounds 9 resulted from the hydrolysis of the
ketenimine function in the N-(2-benzyloxycarbonyl)phenyl
Synthesis 2005, No. 14, 2426–2432 © Thieme Stuttgart · New York