Synthesis of 4-alkoxy-4-methyl- and 4-alkoxy-4-fluoromethyl-1,3-benzoxazinones

Article abstract of DOI:10.1016/j.tet.2003.08.044

Cyclization of 2-hydroxyacetophenone hydrazones with triphosgene resulted in the formation of 4-methylene-1,3-benzoxazinones. These compounds were converted to 4-alkoxy-4-methyl-1,3-benzoxazinones and 4-fluoromethyl-4-methoxy-1,3-benzoxazinones upon treatment with alcohols under refluxing conditions and F-TEDA-BF₄ in acetonitrile and methanol, respectively.

Full text of DOI:10.1016/j.tet.2003.08.044

Tetrahedron 59 (2003) 8163–8170
Synthesis of 4-alkoxy-4-methyl- and
4-alkoxy-4-fluoromethyl-1,3-benzoxazinones
*
Hamad Z. Alkhathlan
Department of Chemistry, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
Received 2 May 2003; revised 25 July 2003; accepted 21 August 2003
Abstract—Cyclization of 2-hydroxyacetophenone hydrazones with triphosgene resulted in the formation of 4-methylene-1,3-
benzoxazinones. These compounds were converted to 4-alkoxy-4-methyl-1,3-benzoxazinones and 4-fluoromethyl-4-methoxy-1,3-
benzoxazinones upon treatment with alcohols under refluxing conditions and F-TEDA-BF4 in acetonitrile and methanol, respectively.
q 2003 Published by Elsevier Ltd.
1. Introduction
tives followed by their cyclization with triphosgene
(bis(trichloromethyl)carbonate) and then treatment of the
resulting 4-methylene-1,3-benzoxazinones with alcohols or
F-TEDA-BF4.
Bezoxazines are a very important class of heterocyclic
compounds and many derivatives of this heterocyclic
system exhibit biological activities. One of the most recent
and most important examples is the 3,1-benzoxazine
derivative Efavirenz, which has recently been approved as
an anti-HIV drug.1,2 It has also been reported that analogs of
Efavirenz where the alkynyl group has been replaced by an
alkoxy group show similar activities.3 Analogs of this ring
system such as the quinazoline derivative DPC 961 have
also been reported to be HIV-inhibitors.4
2. Results and discussion
A series of hydrazones 3 was prepared from the reaction of
substituted 2-hydroxyacetophenone 1 with aromatic hydra-
zines 2 in ethanol with a few drops of acetic acid (Scheme 1).
Scheme 1.
Compounds 3a–l (Table 1) show in their IR spectra
absorbances for the hydroxyl group at about 3350 cm21
1,3-Benzoxazines, on the other hand, have also been known
to exhibit a wide range of biological activities. They have
been used as antimycobacterial agents,5,6
1
and CvN at 1600 cm21, while in the H NMR spectra the
methyl group appears as a singlet at about d¼2.30 ppm and
the hydroxyl group as a broad singlet at d¼12.50 ppm. The
13C NMR and MS spectra of these compounds is in
agreement with the proposed structures.
CNS agents7 and Kþ channel openers.8 1,3-Benzoxazines
have been reported to convert to the 3,1-isomer.9
In this paper, we report the synthesis of a number of
4,4-disubstituted-1,3-benzoxazinones. Our approach for the
synthesis of these compounds is based upon three steps:
synthesis of hydrazones of 2-hydroxyacetophenone deriva-
Although 3 could exist as E or Z isomers, it was used in the
next step without investigating its stereochemistry. Previous
work on the cyclization of similar hydrazones to give the
benzotriazepine ring system did not investigate the stereo-
chemistry of the hydrazones.10,11 Nevertheless, in our case,
if the cyclization proceeds via the enamine form as shown in
Scheme 3, the CvN will be broken and its stereochemistry
will be lost.
Keywords: 2-hydroxyacetophenone; hydrazones; triphosgene; 1,3-
benzoxazinones.
*
Tel.: þ966-1-4675910; fax: þ966-1-4675992;
e-mail: khathlan@ksu.edu.sa
0040–4020/$ - see front matter q 2003 Published by Elsevier Ltd.
doi:10.1016/j.tet.2003.08.044

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H. Z. Alkhathlan / Tetrahedron 59 (2003) 8163–8170
Table 1. Hydrazone 3 derivatives
there has been one previous example in the literature were
only two similar compounds were prepared using phosgene
rather than the more advantageous and easy to handle
triphosgene.13
R1
R2
R3
Product
Yield (%)
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
H
Br
Cl
CH3
H
Br
Cl
CH3
H
Cl
CH3
Br
3a
3b
3c
3d
3e
3f
3g
3h
3i
71
78
75
68
82
63
78
79
75
81
80
89
Compounds of type 4 show in their IR spectra absorbance
for the carbonyl group at 1735 cm21 while the exocylic
double bond absorbs at 1600 cm21. The protons of the latter
group appear as two doublets at d¼4.95 and 5.15 ppm with
1
coupling constants of about 2.5–3.0 Hz in the H NMR
spectra. Furthermore, the 13C NMR spectra show a distinct
absorbance for the exocylic methylene group at about
d¼90 ppm, which is in agreement with previous studies on
related compounds.12
3j
3k
3l
Treatment of selected examples from the above hydrazones
with triphosgene in dichloromethane in the presence of
triethylamine resulted in the formation of the 4-methylene-
1,3-benzoxazinones 4a,b,e,i,j,l (Scheme 2, Table 2).
Finally, the structure of compounds of type 4 was confirmed
using X-ray crystallography. Figure 1 shows the crystal
structure of compound 4a as a representative example.
Benzoxazinones of type 4 were found to be susceptible to
additions across the exocyclic double bond. Reflux of these
compounds in ethanol resulted in the addition of ethanol
to the exocyclic double bond and the formation of the
4-ethoxy-4-methyl-1,3-benzoxazinones 5a,b,e,i,j (Scheme 4,
Table 3).
Scheme 2.
Table 2. 4-Methylene-1,3-benzoxazinone derivatives 4
R1
R2
R3
Product
Yield (%)
Br
Br
Cl
Cl
Cl
Cl
H
H
H
Cl
Cl
Cl
H
Br
H
H
Cl
Br
4a
4b
4e
4i
4j
4l
65
77
58
87
56
67
Scheme 4.
Table 3. 4,4-Disubstituted 1,3-benzoxazinone derivatives 5
R1
R2
R3
Product
Yield (%)
The cyclization of 3 to 4 did not proceed to form a seven
membered ring (benzoxadiazepine) in a similar manner to
that previously reported for the cyclization of hydrazones of
2-aminobenzophenone into benzotriazepines with phosgene
and paraformaldehyde.10,11 The methyl group in 3 is
involved in the cyclization step via the formation of the
enamine form of 3 which reacts with triphosgene to give the
six membered ring product (4) rather than the seven
membered ring benzoxadiazepine (Scheme 3). A similar
cyclization across the enol form of acetophenone has
previously been reported.12 To the best of our knowledge,
Br
Br
Cl
Cl
Cl
H
H
H
Cl
Cl
H
Br
H
H
Cl
5a
5b
5e
5i
48
68
53
72
50
5j
Compounds 5a,b,e,i,j show in their IR spectra no absor-
1
bance for the exocyclic methylene group, while their H
NMR spectra show absorbance for the newly created methyl
group at about d¼2.0 ppm.
Another assembly of compounds of type 5 was prepared in
one step from the hydrazone 3. In this case treatment of 3
with triphosgene followed by refluxing the resulting solid in
ethanol gave 5c,d,f,g,h,k (Scheme 5, Table 4).
This group of 4,4-disubstituted-1,3-benzoxazinones show
similar spectroscopic characteristics to the previous group
5a,b,e,i,j. The structure of compounds of type 5 was
confirmed using X-ray crystallography. Figure 2 shows the
crystal structure of compound 5j as a representative product.
In order to test the generality of this reaction process, a
series of alcohols with increasing hydrocarbon chain length
were used. Methanol, ethanol, propanol and butanol were all
Scheme 3.

H. Z. Alkhathlan / Tetrahedron 59 (2003) 8163–8170
8165
Figure 1. X-Ray crystal structure of 4a.
Table 5. 4,4-Disubstituted 1,3-benzoxazinones 5–8
R1
R2
R3
R4
Product
Yield (%)
Cl
Cl
Br
Br
Cl
Cl
H
Cl
Cl
Br
Br
CH3
CH2CH3
(CH2)2CH3
(CH2)3CH3
6j
5j
7b
8b
73
67
53
47
H
It turned out that in all cases the alcohol was added across
the exocyclic double bond following Markovnikov’s rule to
give 5j, 6j, 7b and 8b in very good yields. These compounds
show similar spectroscopic characteristics to those of the
previous two groups of type 5, except for the alkoxy side
chain at position 4.
Scheme 5.
Table 4. 4,4-Disubstituted 1,3-benzoxazinone derivatives 5
Next, the introduction of a fluorine substituent into the
C4-methyl group of compounds of type 5 was investigated.
Compounds 4b and 4e (as representative examples) were
treated with 1-chloromethyl-4-fluoro-1,4-diazabicyclo
[2.2.2]-octane bis(tetrafluoroborate) (F-TEDA-BF4) in
acetonitrile in the presence of methanol (Scheme 7, Table 6).
R1
R2
R3
Product
Yield (%)
Br
Br
Cl
Cl
Cl
Cl
H
H
H
H
H
Cl
Cl
CH3
Br
Cl
CH3
CH3
5c
5d
5f
5g
5h
5k
84
92
82
88
91
80
reacted with compounds 4j or 4b under acidic conditions
(Scheme 6, Table 5).
Scheme 7.
Table 6. 4-Fluoromethyl-4-methoxy-1,3-benzoxazinones 9
R1
R2
R3
Product
Yield (%)
Br
Cl
H
H
Br
H
9b
9e
49
42
Scheme 6.
Figure 2. X-Ray crystal structure of 5j.

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H. Z. Alkhathlan / Tetrahedron 59 (2003) 8163–8170
F-TEDA-BF4 is a known electrophilic fluorinating reagent
which has previously been used for the fluorination of
styrene and other similar alkenes.14,15 Reaction of 4b and 4e
with this reagent gave the addition products 9b and 9e,
respectively. The absorbance for the exocyclic double bond
of 4b and 4e is no longer present in the IR and NMR spectra
81), 382 (Mþ, 43), 369, 367, 288, 286, 224, 214, 199, 186,
171 (100), 155, 145, 133, 91, 75, 65, 63.
3.1.3. 5-Bromo-2-hydroxyacetophenone 4-chlorophenyl-
hydrazone 3c. This compound was prepared from 9 and
4-chlorophenylhydrazine 12. Yield¼4.6 g, 75%, pale yel-
low powder, mp 1728C. [Found: C, 49.73; H, 3.41.
C14H12BrClN2O requires: C, 49.51; H, 3.56]. IR: 3337
1
of 9b and 9e. The H NMR spectra of these compounds
show signals for the methoxy and CH2F groups at d¼3.04
and 4.80 ppm for 9b and d¼3.03 and 4.78 ppm for 9e. The
19F NMR spectra of 9b and 9e, on the other hand, show
signals at d¼2118.59 and d¼2117.43 ppm, respectively.
Finally, the MS spectra of these two compounds show
molecular ions at m/z¼458 for 9b and m/z¼336 for 9e
which is in agreement with the proposed structures.
1
(OH), 1592 (CvN); H NMR: 2.31 (s, 3H), 6.82 (d, 2H,
J¼8.1 Hz), 6.91 (d, 1H, J¼7.5 Hz), 7.18–7.31 (m, 3H),
7.49 (d, 1H, J¼2.0 Hz); 12.32 (bs, 1H); MS: m/z (%) 342
(Mþ4, 23), 340 (Mþ2, 83), 338 (Mþ, 68), 323, 174, 163,
161, 127 (100), 91, 65, 63.
3.1.4. 5-Bromo-2-hydroxyacetophenone 4-methylphenyl-
hydrazone 3d. This compound was prepared from 9 and
4-methylphenylhydrazine 13. Yield¼3.9 g, 68%, yellow
powder, mp 1568C. [Found: C, 56.19; H, 4.69. C15H15BrN2O
requires: C, 56.44; H, 4.73]. IR: 3345 (OH), 1604 (CvN);
1H NMR: 2.29 (s, 3H); 2.34 (s, 3H), 6.78 (d, 2H, J¼8.2 Hz),
7.01–7.34 (m, 4H), 7.48 (d, 1H, J¼2.1 Hz), 12.99 (bs, 1H);
MS: m/z (%) 320 (Mþ2, 71), 318 (Mþ, 78), 303, 301, 238,
222, 200, 183, 145, 107 (100), 91, 75, 63.
In conclusion, 4-methylene-1,3-benzoxazinones were
obtained from the reaction of hydrazones of 2-hydroxy-
acetophenone with triphosgene. Addition of alcohols
and F-TEDA-BF4 to the exocyclic double bond of these
1,3-benzoxazinones gave 4-alkoxy-4-methyl- and 4-alkoxy-
4-fluoromethyl-1,3-benzoxazinones, respectively.
3. Experimental
3.1.5. 5-Chloro-2-hydroxyacetophenonephenylhydrazone
3e. This compound was prepared from 5-chloro-2-hydroxy-
acetophenone 14 and 10. Yield¼3.9 g, 82%, yellow needles,
mp 1708C. [Found: C, 64.57; H, 4.98. C14H13ClN2O
requires: C, 64.49; H, 5.02]. IR: 3303 (OH), 1600 (CvN);
1H NMR: 2.29 (s, 3H), 6.86 (d, 2H, J¼8.7 Hz), 7.14–7.34
(m, 6H), 12.48 (bs, 1H); MS: m/z (%) 262 (Mþ2, 26),
260 (Mþ, 88), 245, 243, 208, 180, 155, 133, 93 (100), 91,
77, 65.
Melting points are uncorrected. IR spectra were recorded on
a Perkin–Elmer 883 spectrophotometer as KBr pellets and
expressed as n in cm21. NMR spectra were recorded on Jeol
FX-100 (100 MHz) and Jeol ECP 400 (400 MHz) in CDCl3
and expressed as d in ppm. Mass spectra were recorded on
Shimadzu QP-5050A GC/MS system. Microanalysis was
performed at KACST research laboratories.
3.1. General procedure 1: preparation of hydrazones
3a–l
3.1.6. 5-Chloro-2-hydroxyacetophenone 4-bromophenyl-
hydrazone 3f. This compound was prepared from 14 and
11. Yield¼3.9 g, 63%, yellow crystals, mp 1908C. [Found:
C, 49.37; H, 3.47. C14H12BrClN2O requires: C, 49.51; H,
3.56]. IR: 3372 (OH), 1590 (CvN); 1H NMR: 2.33 (s, 3H),
6.84–6.99 (m, 3H), 7.10–7.22 (m, 2H), 7.33–7.49 (m, 2H),
8.30 (bs, 1H), 12.55 (bs, 1H); MS: m/z (%) 342 (Mþ4, 23),
340 (Mþ2, 94), 338 (Mþ, 82), 325, 323, 259, 242, 207, 171
(100), 155, 127, 99, 91, 75, 63.
A solution of the appropriate 2-hydroxyacetophenone deriva-
tive (18 mmol), phenylhydrazine derivative (18 mmol),
1 mL of acetic acid in 50 mL of ethanol was refluxed for
two hours. The solvent was evaporated and the resulting
solid was filtered and washed several times with water.
Recrystallization from a mixture of ethanol and water (8:2)
afforded the required hydrazones.
3.1.7. 5-Chloro-2-hydroxyacetophenone 4-chlorophenyl-
hydrazone 3g. This compound was prepared from 14 and
12. Yield¼4.2 g, 78%, pale yellow powder, mp 1608C.
[Found: C, 57.11; H, 4.17. C14H12Cl2N2O requires: C,
3.1.1. 5-Bromo-2-hydroxyacetophenone phenylhydrazone
3a. This compound was prepared from 5-bromo-2-hydroxy-
acetophenone 9 and phenylhydrazine 10. Yield¼3.9 g, 71%,
yellow needles, mp 1648C. [Found: C, 55.16; H, 4.28.
C14H13BrN2O requires: C, 55.10; H, 4.29]. IR: 3307 (OH),
1600 (CvN); 1H NMR: 2.28 (s, 3H), 6.81 (d, 2H,
J¼8.6 Hz), 6.95 (t, 2H, J¼8.6 Hz), 7.24 (m, 3 H), 7.47 (d,
1H, J¼1.8 Hz), 12.51 (bs, 1H); MS: m/z (%) 306 (Mþ2, 63),
304 (Mþ, 60), 287, 256, 224, 200, 171, 153, 133, 106, 92
(100), 91, 77, 65.
1
56.96; H, 4.09]. IR: 3359 (OH), 1599 (CvN); H NMR:
2.35 (s, 3H), 6.85–7.05 (m, 3H), 7.20–7.38 (m, 4H), 8.32
(s, 1H), 12.58 (bs, 1H); MS: m/z (%) 298 (Mþ4, 7), 296
(Mþ2, 58), 294 (Mþ, 89), 281, 279, 259, 242, 169, 141, 127
(100), 111, 99, 91, 75, 65, 63.
3.1.8. 5-Chloro-2-hydroxyacetophenone 4-methylphenyl-
hydrazone 3h. This compound was prepared from 14 and 13.
Yield¼3.9 g, 79%, yellow powder, mp 1308C. [Found: C,
65.46; H, 5.39. C15H15ClN2O requires: C, 65.57; H, 5.50].
3.1.2. 5-Bromo-2-hydroxyacetophenone 4-bromophenyl-
hydrazone 3b. This compound was prepared from 9 and
4-bromophenylhydrazine 11. Yield¼5.3 g, 78%, yellow
crystals, mp 2018C. [Found: C, 43.53; H, 3.27. C14H12Br2N2O
requires: C, 43.78; H, 3.14]. IR: 3372 (OH), 1588 (CvN);
1H NMR: 2.35 (s, 3H), 6.79 (d, 2H, J¼9.0 Hz), 6.93 (d, 2H,
J¼9.0 Hz), 7.28–7.40 (m, 2H), 7.52 (d, 1H, J¼1.8 Hz),
12.07 (bs, 1H); MS: m/z (%) 386 (Mþ4, 40), 384 (Mþ2,
1
IR: 3324 (OH), 1593 (CvN); H NMR: 2.30 (s, 3H), 2.35
(s, 3H), 6.92 (d, 2H, J¼8.2 Hz), 7.06–7.25 (m, 4H), 7.34 (d,
1H, J¼2.2 Hz), 8.04 (s, 1H), 12.76 (bs, 1H); MS: m/z (%)
276 (Mþ2, 24), 274 (Mþ, 77), 257, 238, 222, 169, 154, 137,
120, 107 (100), 99, 91, 75, 65, 63.

H. Z. Alkhathlan / Tetrahedron 59 (2003) 8163–8170
8167
3.1.9. 3,5-Dichloro-2-hydroxyacetophenone phenyl-
hydrazone 3i. This compund was prepared from
3,5-dichloro-2-hydroxyacetophenone 15 and 10. Yield¼4.0
g, 75%, yellow needles, mp 1338C. [Found: C, 57.25; H,
4.11. C14H12Cl2N2O requires: C, 56.96; H, 4.09]. IR: 3338
(CH2), 114.0 (CH), 118.11 (C), 119.64 (CH), 121.64 (CH),
127.86 (CH), 129.98 (CH), 134.74 (CH), 138.49 (C), 147.01
(C), 148.30 (CvO); MS: m/z (%) 332 (Mþ2, 36), 330 (Mþ,
38), 287, 285, 251, 223, 198, 180, 168, 103, 92 (100), 77, 65,
63.
1
(OH), 1595 (CvN); H NMR: 2.29 (s, 3H), 6.98 (d, 2H,
J¼8.3 Hz), 7.18–7.28 (m, 5H), 13.26 (bs, 1H); MS: m/z (%)
296 (Mþ2, 28), 294 (Mþ, 52), 279, 277, 202, 166, 133, 106,
93 (100), 91, 77, 65, 63.
3.2.2. X-Ray crystallographic analysis of 6-bromo-4-
methylene-3-[N-phenylamino]-3,4-dihydro-2H-1,3-
benzoxazine-2-one 4a. Crystal data. Orthorhombic, Space
˚
group Pccn, a¼20.7767(2), b¼18.7789(4), c¼6.9452(1) A,
3
˚
3.1.10. 3,5-Dichloro-2-hydroxyacetophenone 4-chloro-
phenylhydrazone 3j. This compound was prepared from
15 and 12. Yield¼4.8 g, 81%, pale yellow powder, mp
2208C. [Found: C, 51.16; H, 3.29. C14H11Cl3N2O requires:
C, 51.00; H, 3.36]. IR: 3371 (OH), 1585 (CvN); 1H NMR:
2.33 (s, 3H), 6.92 (d, 2H, J¼8.5 Hz), 7.21–7.48 (m, 4H),
13.09 (bs, 1H); MS: m/z (%) 332 (Mþ4, 11), 330 (Mþ2,
39), 328 (Mþ, 43), 313, 311, 293, 276, 202, 188, 167, 133,
127 (100), 111, 99, 75, 63.
a¼90.00, b¼90.00, g¼90.008, V¼2709.76(7) A , Z¼8.
Data collection. A crystal (0.20£0.20£0.10 mm3) was used
to record 14828 reflections on a Siemens SMART dif-
fractometer (Mo–Ka, v 2 2u). Structure refinement. The
structure was refined anisotropically on F 2 (program
SHELXLT97, Sheldrick, G. M., University of Gottingen,
Germany) to wR2¼0.174, R1¼0.061 for 194 parameters
and 3521 unique reflections. Complete crystallographic data
(excluding structure factors) have been deposited at the
Cambridge Crystallographic Data Centre under the refer-
ence number CCDC 212482. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge, CB2 1EZ, UK [fax: þ44-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
3.1.11. 3,5-Dichloro-2-hydroxyacetophenone 4-methyl-
phenylhydrazone 3k. This compound was prepared from
15 and 13. Yield¼4.5 g, 80%, yellow powder, mp 1458C.
[Found: C, 58.42; H, 4.60. C15H14Cl2N2O requires: C,
1
58.26; H, 4.56]. IR: 3362 (OH), 1608 (CvN); H NMR:
2.30 (s, 3H), 2.32 (s, 3H), 6.83–7.24 (m, 5H), 7.29 (d, 1H,
J¼1.8 Hz), 12.76 (bs, 1H); MS: m/z (%) 310 (Mþ2, 51),
308 (Mþ, 78), 254, 230, 188, 147, 107 (100), 91, 65, 63.
3.2.3. 6-Bromo-4-methylene-3-[N-(4-bromophenyl)
amino]-3,4-dihydro-2H-1,3-benzoxazine-2-one 4b. This
compound was prepared from 3b. Yield¼0.94 g, 77%,
colorless crystals, mp 1668C. [Found: C, 43.75; H, 2.38.
C15H10Br2N2O2 requires: C, 43.93; H, 2.45]. IR: 3328 (NH),
1738 (CO), 1604 (vCH2); 1H NMR: 4.98 (d, 1H,
J¼2.7 Hz), 5.09 (d, 1H, J¼2.7 Hz), 6.43 (s, 1H), 6.67 (d,
2H, J¼8.3 Hz), 6.97 (d, 2H, J¼8.3 Hz), 7.31 (d, 1H,
J¼10.0 Hz), 7.46 (dd, 1H, J1¼10.0 Hz, J2¼2.1 Hz), 7.73 (d,
1H, J¼2.1 Hz); MS: m/z (%) 412 (Mþ4, 5), 410 (Mþ2, 12),
408 (Mþ, 6), 367, 314, 287, 243 (100), 217, 199, 170, 103,
91, 77, 63.
3.1.12. 3,5-Dichloro-2-hydroxyacetophenone 4-bromo-
phenylhydrazone 3l. This compound was prepared from
15 and 11. Yield¼6.0 g, 89%, yellow crystals, mp 2078C.
[Found: C, 44.79; H, 2.89. C14H11BrCl2N2O requires: C,
1
44.95; H, 2.96]. IR: 3355 (OH), 1604 (CvN); H NMR:
2.38 (s, 3H), 6.97 (d, 2H, J¼9.0 Hz), 7.32–7.47 (m, 4H),
9.20 (s, 1H), 12.59 (bs, 1H); MS: m/z (%) 376 (Mþ4, 38),
374 (Mþ2, 84), 372 (Mþ, 52), 359, 357, 295, 276, 222, 191,
173 (100), 157, 133, 106, 91, 63.
3.2.4. 6-Chloro-4-methylene-3-[N-phenylamino]-3,4-
dihydro-2H-1,3-benzoxazine-2-one 4e. This compound
was prepared from 3e. Yield¼0.5 g, 58%, colorless powder,
mp 1358C. [Found: C, 62.71; H, 3.81. C15H11ClN2O2
requires: C, 62.83; H, 3.87]. IR: 3323 (NH), 1728 (CO),
3.2. General procedure 2: preparation of 1,3-benzoxazi-
nones 4a,b,e,i,j,l
A solution of the appropriate hydrazone 3 (3 mmol) and
1 mL of triethylamine in 30 mL of dichloromethane was
stirred under nitrogen atmosphere. Triphosgene (1.5 mmol)
in 10 mL of dichloromethane was added dropwise over a
period of 20 min. The mixture was stirred at room
temperature for 1 h and then refluxed for 2 h. Water was
added, the organic layer was separated followed by
extraction of the aqueous layer with dichloromethane
(2£30 mL). The combined organic layers were dried over
magnesium sulfate and evaporated to dryness. The resulting
solid was crystallized from ethyl ether.
1
1600 (vCH2); H NMR: 4.98 (d, 1H, J¼2.6 Hz), 5.14 (d,
1H, J¼2.6 Hz), 6.45 (s, 1H), 6.78 (d, 2H, J¼8.1 Hz), 7.02–
7.28 (m, 5H), 7.60 (d, 1H, J¼2.0 Hz); MS: m/z (%) 288
(Mþ2, 16), 286 (Mþ, 51), 271, 243, 209, 180, 166, 125, 111,
92 (100), 77, 65.
3.2.5. 6,8-Dichloro-4-methylene-3-[N-phenylamino]-3,4-
dihydro-2H-1,3-benzoxazine-2-one 4i. This compound
was prepared from 3i. Yield¼0.84 g, 87%, colorless powder,
mp 1538C. [Found: C, 55.92; H, 3.11. C15H10Cl2N2O2
requires: C, 56.09; H, 3.13]. IR: 3328 (NH), 1732 (CO),
1
3.2.1. 6-Bromo-4-methylene-3-[N-phenylamino]-3,4-
dihydro-2H-1,3-benzoxazine-2-one 4a. This compound
was prepared from 3a. Yield¼0.64 g, 65%, colorless crystals,
mp 1558C. [Found: C, 54.51; H, 3.34. C15H11BrN2O2
requires: C, 54.40; H, 3.34]. IR: 3330 (NH), 1735 (CO),
1607 (vCH2); H NMR: 5.01 (d, 1H, J¼2.5 Hz), 5.19 (d,
1H, J¼2.5 Hz), 6.10 (s, 1H), 6.72–6.93 (m, 3H), 7.17–7.25
(m, 2H), 7.32 (d, 1H, J¼2.2 Hz), 7.51 (d, 1H, J¼2.2 Hz);
MS: m/z (%) 322 (Mþ2, 7), 320 (Mþ, 12), 277, 275, 233
(100), 207, 189, 123, 91, 77, 65, 63.
1
1602 (vCH2); H NMR: 4.97 (d, 1H, J¼3.0 Hz), 5.13 (d,
1H, J¼3.0 Hz), 6.46 (s, 1H, D2O exchangeable), 6.78–7.03
(m, 3H), 7.28–7.48 (m, 3H), 7.61 (dd, 1H, J1¼8.6 Hz,
J2¼2.3 Hz), 7.75 (d, 1H, J¼2.3 Hz); 13C NMR: 89.63
3.2.6. 6,8-Dichloro-4-methylene-3-[N-(4-chlorophenyl)-
amino]-3,4-dihydro-2H-1,3-benzoxazine-2-one 4j. This
compound was prepared from 3j. Yield¼0.6 g, 56%,

8168
H. Z. Alkhathlan / Tetrahedron 59 (2003) 8163–8170
colorless powder, mp 1428C. [Found: C, 50.50; H, 2.48.
C15H9Cl3N2O2 requires: C, 50.66; H, 2.55]. IR: 3318 (NH),
1726 (CO), 1601 (vCH2); 1H NMR: 5.01 (d, 1H,
J¼2.6 Hz), 5.15 (d, 1H, J¼2.6 Hz), 6.40 (s, 1H), 6.70 (d,
2H, J¼8.4 Hz), 7.16 (d, 2H, J¼8.4 Hz), 7.43 (d, 1H,
J¼1.7 Hz), 7.51 (d, 1H, J¼1.7 Hz); MS: m/z (%) 358 (Mþ4,
7), 356 (Mþ2, 21), 354 (Mþ, 22), 320, 311, 276, 256, 241,
186, 138, 126 (100), 111, 99, 75, 63.
7.10 (m, 2H), 7.19–7.35 (m, 3H), 7.54 (d, 1H, J¼2.0 Hz);
13C NMR: 15.01 (CH3), 23.47 (CH3), 59.11 (CH2), 89.98
(C), 113.27 (C), 118.15 (CH), 122.73 (CH), 126.83 (CH),
129.10 (CH), 130.19 (CH), 131.22 (CH), 132.11 (C), 146.67
(C), 147.25 (C), 150.33 (CvO); MS: m/z (%) 334 (Mþ2, 3),
332 (Mþ, 1), 288, 286 (100), 271, 209, 165, 103, 91, 77, 65.
3.3.4. 6,8-Dichloro-4-ethoxy-4-methyl-3-[N-phenyl-
amino]-3,4-dihydro-2H-1,3-benzoxazine-2-one 5i. This
compound was prepared from 4i. Yield¼0.79 g, 72%,
colorless crystals, mp 1678C. [Found: C, 55.47; H, 4.44.
C17H16Cl2N2O3 requires: C, 55.60; H, 4.39]. IR: 3333 (NH),
1735 (CO); 1H NMR: 1.12 (t, 3H, J¼7.2 Hz), 1.91 (s, 3H),
3.14 (q, 2H, J¼7.2 Hz), 6.65 (s, 1H), 6.83–6.97 (m, 3H),
7.16–7.28 (m, 2H), 7.33 (d, 1H, J¼1.9 Hz), 7.49 (d, 1H,
J¼1.9 Hz); 13C NMR: 14.81 (CH3), 18.37 (CH3), 57.49
CH2), 91.14 (C), 113.15 (C), 119.02 (CH), 122.46 (C),
124.89 (CH), 129.06 (CH), 129.21 (CH), 130.84 (CH),
136.47 (C), 143.31 (C), 145.16 (C), 149.87 CvO); MS: m/z
(%) 368 (Mþ2, 2), 366 (Mþ, 4), 322, 320 (100), 277, 275,
235, 207, 189, 123, 91, 77, 65, 63.
3.2.7. 6,8-Dichloro-4-methylene-3-[N-(bromophenyl)-
amino]-3,4-dihydro-2H-1,3-benzoxazine-2-one 4l. This
compound was prepared from 3 l. Yield¼0.8 g, 67%,
colorless powder, mp 1528C. [Found: C, 45.15; H, 2.19.
C15H9BrCl2N2O2 requires: C, 45.03; H, 2.26]. IR: 3325
1
(NH), 1736 (CO), 1598 (vCH2); H NMR: 5.01 (d, 1H,
J¼3.0 Hz), 5.14 (d, 1H, J¼3.0 Hz), 6.47 (s, 1H), 6.66 (d,
2H, J¼8.8 Hz), 7.31–7.40 (m, 3H), 7.46 (d, 1H, J¼2.1 Hz);
MS: m/z (%) 402 (Mþ4, 30), 400 (Mþ2, 70), 398 (Mþ, 43),
357, 319, 276, 233, 189, 170 (100), 155, 123, 91, 77, 63.
3.3. General procedure 3: preparation of
4,4-disubstituted 1,3-benzoxazinones 5a,b,e,i,j
3.3.5. 6,8-Dichloro-4-ethoxy-4-methyl-3-[N-(4-chloro-
phenyl)amino]-3,4-dihydro-2H-1,3-benzoxazine-2-one
5j. This compound was prepared from 4j. Yield¼0.6 g,
50%, colorless crystals, mp 1668C. [Found: C, 50.66; H,
3.69. C17H15Cl3N2O3 requires: C, 50.83; H, 3.76]. IR: 3325
(NH), 1730 (CO); 1H NMR: 1.14 (t, 3H, J¼6.9 Hz), 1.88 (s,
3H), 3.10 (q, 2H, J¼6.9 Hz), 6.04 (s, 1H), 6.70 (d, 2H,
J¼9.0 Hz), 7.16 (d, 2H, J¼9.0 Hz), 7.34 (d, 1H, J¼2.2 Hz),
7.50 (d, 1H, J¼2.2 Hz); 13C NMR: 14.86 (CH3), 18.53
(CH3), 58.97 (CH2), 90.74 (C), 115.28 (CH), 122.67 (C),
124.87 (CH), 126.57 (C), 129.27 (CH), 130.39 (C), 131.33
(CH), 136.37 (C), 143.41 (C), 145.07 (C), 149.42 (CvO);
MS: m/z (%) 402 (Mþ2, 3), 400 (Mþ, 3), 356, 354, 313,
276, 235, 233 (100), 205, 189, 126, 111, 99, 75, 63.
A solution of the appropriate 4-methylene-1,3-benzoxazine
(3 mmol) in 50 mL of ethanol was refluxed for 3 h. After
cooling the resulting solid was collected by suction and
dried.
3.3.1. 6-Bromo-4-ethoxy-4-methyl-3-[N-phenylamino]-
3,4-dihydro-2H-1,3-benzoxazine-2-one 5a. This com-
pound was prepared from 4a. Yield¼0.54 g, 48%, colorless
powder, mp 1258C. [Found: C, 54.52; H, 4.29. C17H17BrN2O3
requires: C, 54.12; H, 4.54]. IR: 3315 (NH), 1727 (CO); 1H
NMR: 0.90 (t, 3H, J¼7.2 Hz), 1.62 (s, 3H), 3.10 (q, 2H,
J¼7.2 Hz), 6.51–6.82 (m, 3H), 6.98–7.17 (m, 2H), 7.26–
7.35 (m, 2H), 7.47 (d, 1H, J¼2.0 Hz); 13C NMR: 14.79
(CH3), 25.68 (CH3), 58.14 (CH2), 90.34 (C), 112.78 (CH),
117.61 (C), 120.35 (CH), 126.29 (CH), 128.94 (C), 129.05
(CH), 130.01 (CH), 130.77 (CH), 146.83 (C), 147.16 (C),
149.87 (CvO); MS: m/z (%) 378 (Mþ2, 2), 376 (Mþ, 2),
330, 287, 223, 198, 168, 103, 92 (100), 77, 65.
3.3.6. X-Ray crystallographic analysis of 6,8-dichloro-4-
ethoxy-4-methyl-3-[N-(4-chlorophenyl)amino]-3,4-
dihydro-2H-1,3-benzoxazine-2-one 5j. Crystal data. Mono-
clinic, Space group P2(1)/c, a¼26.1426(11), b¼8.4051(6),
˚
c¼16.1619(11) A, a¼90.00, b¼94.971(4), g¼90.008,
3
˚
3.3.2. 6-Bromo-4-ethoxy-4-methyl-3-[N-(bromophenyl)-
amino]-3,4-dihydro-2H-1,3-benzoxazine-2-one 5b. This
compound was prepared from 4b. Yield¼0.9 g, 68%,
colorless crystals, mp 1708C. [Found: C, 44.52; H, 3.39.
C17H16Br2N2O3 requires: C, 44.76; H, 3.53]. IR: 3310 (NH),
1726 (CO); 1H NMR: 1.14 (t, 3H, J¼7.0 Hz), 1.88 (s, 3H),
3.29 (q, 2H, J¼7.0 Hz), 6.66 (d, 2H, J¼8.5 Hz), 7.04 (d, 1H,
J¼1.8 Hz), 7.26–7.51 (m, 4H); 13C NMR: 14.94 (CH3),
18.52 (CH3), 58.56 (CH2), 90.62 (C), 114.59 (C), 115.62
(CH), 118.24 (CH), 127.01 (CH), 129.46 CH), 132.21 (CH),
132.34 (C), 134.16 (C), 146.88 (C), 147.41 (C), 150.35
(CvO); MS: m/z (%) 456 (Mþ2, 2), 454 (Mþ, 1), 410, 367,
287, 243 (100), 217, 199, 170, 103, 91, 77, 63.
V¼3537.9(4) A , Z¼8. Data collection.
A
crystal
(0.35£0.32£0.30 mm3) was used to record 21338 reflec-
tions on a Siemens SMART diffractometer (Mo–Ka,
v 2 2u). Structure refinement. The structure was refined
anisotropically on F 2 (program SHELXLT97, Sheldrick,
G. M., University of Gottingen, Germany) to wR2¼0.1643,
R1¼0.0678 for 456 parameters and 5986 unique reflec-
tions. Complete crystallographic data (excluding structure
factors) have been deposited at the Cambridge Crystal-
lographic Data Centre under the reference number CCDC
212483. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: þ44-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
3.3.3. 6-Chloro-4-ethoxy-4-methyl-3-[N-phenylamino]-
3,4-dihydro-2H-1,3-benzoxazine-2-one 5e. This com-
pound was prepared from 4e. Yield¼0.52 g, 53%, colorless
powder, mp 1478C. [Found: C, 61.21; H, 5.07.
C17H17ClN2O3 requires: C, 61.35; H, 5.14]. IR: 3297
(NH), 1721 (CO); 1H NMR: 1.10 (t, 3H, J¼7.2 Hz), 1.51 (s,
3H), 3.16 (q, 2H, J¼7.2 Hz), 6.65 (d, 2H, J¼7.8 Hz), 6.91–
3.4. General procedure 4: preparation of
4,4-disubstituted 1,3-benzoxazinones 5c,d,f,g,h,k
These compounds were prepared from the corresponding
hydrazones and triphosgene using conditions similar to
those described in general procedure 2, except that the

H. Z. Alkhathlan / Tetrahedron 59 (2003) 8163–8170
8169
resulting solid was refluxed in ethanol for two hours and
then cooled to obtain the products.
amino]-3,4-dihydro-2H-1,3-benzoxazine-2-one 5h. This
compound was prepared from 3 h. Yield¼0.94 g, 91%,
colorless crystals, mp 1128C. [Found: C, 62.15; H, 5.64.
C18H19ClN2O3 requires: C, 62.33; H, 5.52]. IR: 3320 (NH),
1722 (CO); 1H NMR: 1.13 (t, 3H, J¼7.1 Hz), 1.92 (s, 3H),
2.26 (s, 3H), 3.17 (q, 2H, J¼7.1 Hz), 5.90 (s, 1H), 6.66 (d,
2H, J¼9.5 Hz), 7.01–7.11 (m, 3H), 7.27–7.43 (m, 2H); 13C
NMR: 14.85 (CH3), 20.56 (CH3), 20.68 (CH3), 58.73 (CH2),
85.10 (C), 112.96 (C), 117.59 (CH), 120.20 (CH), 127.25
(CH), 129.72 (C), 130.04 (CH), 131.50 (CH), 139.82 (C),
145.90 (C), 148.48 (C), 149.03 (CvO); MS: m/z (%) 348
(Mþ2, 14), 346 (Mþ, 43), 302, 300, 285, 257, 225, 201, 199
(100), 155, 106, 91, 77, 63.
3.4.1. 6-Bromo-4-ethoxy-4-methyl-3-[N-(4-chlorophenyl)-
amino]-3,4-dihydro-2H-1,3-benzoxazine-2-one 5c. This
compound was prepared from 3c. Yield¼1.0 g, 81%,
colorless crystals, mp 1538C. [Found: C, 49.63; H, 3.87.
C17H16BrClN2O3 requires: C, 49.59; H, 3.91]. IR: 3319
(NH), 1728 (CO); 1H NMR: 1.16 (t, 3H, J¼7.1 Hz), 1.88 (s,
3H), 3.18 (q, 2H, J¼7.1 Hz), 6.03 (s, 1H), 6.70 (d, 2H,
J¼9.0 Hz), 7.07–7.25 (m, 4H), 7.58 (d, 1H, J¼2.1 Hz); 13C
NMR: 14.94 (CH3), 18.52 (CH3), 58.55 (CH2), 90.62 (C),
115.22 (CH), 118.84 (CH), 127.01 (CH), 129.30 (CH),
129.43 (CH), 134.10 (C), 134.14 (C), 136.72 (C), 143.71
(C), 147.44 (C), 150.40 (CvO); MS: m/z (%) 414 (Mþ4, 2),
412 (Mþ2, 6), 410 (Mþ, 4), 366, 364, 331, 323, 285, 245,
243 (100), 217, 215, 201, 199, 168, 128, 111, 90, 75, 63.
3.4.6. 6,8-Dichloro-4-ethoxy-4-methyl-3-[N-(4-methyl-
phenyl)amino]-3,4-dihydro-2H-1,3-benzoxazine-2-one
5k. This compound was prepared from 3k. Yield¼0.91 g,
80%, colorless powder, mp 1488C. [Found: C, 56.51; H, 4.84.
C18H18Cl2N2O3 requires: C, 56.70; H, 4.75]. IR: 3333 (NH),
3.4.2. 6-Bromo-4-ethoxy-4-methyl-3-[N-(4-methylphenyl)-
amino]-3,4-dihydro-2H-1,3-benzoxazine-2-one 5d. This
compound was prepared from 3d. Yield¼1.1 g, 94%,
colorless powder, mp 1358C. [Found: C, 55.39; H, 4.74.
C18H19BrN2O3 requires: C, 55.25; H, 4.89]. IR: 3316 (NH),
1730 (CO); 1H NMR: 1.12 (t, 3H, J¼7.0 Hz), 1.92 (s, 3H),
2.26 (s, 3H), 3.09 (q, 2H, J¼7.0 Hz), 5.96 (s, 1H), 6.67 (d,
2H, J¼8.6 Hz), 7.01–7.23 (m, 3H), 7.38–7.56 (m, 2H); 13C
NMR: 14.97 (CH3), 18.52 (CH3), 20.70 (CH3), 58.54 (CH2),
89.77 (C), 114.05 (CH), 118.29 (CH), 118.82 (C), 126.98
(CH), 129.87 (CH), 129.96 (CH), 131.84 (C), 136.92 (C),
146.99 (C), 147.51 (C), 150.48 (CvO); MS: m/z (%) 392
(Mþ2, 16), 390 (Mþ, 17), 346, 344, 301, 303, 245, 243
(100), 216, 218, 201, 199, 164, 148, 105, 91, 77, 63.
1
1738 (CO); H NMR: 1.15 (t, 3H, J¼7.0 Hz), 1.91 (s, 3H),
2.30 (s, 3H), 3.30 (q, 2H, J¼7.0 Hz), 6.37 (s, 1H), 6.67 (d, 2H,
J¼8.8 Hz), 7.00 (d, 2H, J¼8.8 Hz), 7.32 (d, 1H, J¼2.1 Hz),
7.49 (d, 1H, J¼2.1 Hz); 13C NMR: 14.93 (CH3), 18.52 (CH3),
20.71(CH3), 58.56(CH2),91.13(C), 114.14(C), 119.01(CH),
122.45 (C), 129.87 (CH), 129.97 (CH), 130.49 (C), 131.17
(CH), 136.55 (C), 144.06 (C), 146.63 (C), 149.59 (CvO);MS:
m/z(%)382(Mþ2,29),380(Mþ, 48), 336, 334, 294, 292, 235,
233 (100), 189, 148, 120, 91, 77, 63.
3.5. General procedure 5: preparation of
4,4-disubtituted 1,3-benzoxazinones 5j, 6j, 7b and 8b
under acidic conditions
3.4.3. 6-Chloro-4-ethoxy-4-methyl-3-[N-(4-bromophenyl)-
amino]-3,4-dihydro-2H-1,3-benzoxazine-2-one 5f. This
compound was prepared from 3f. Yield¼1.0 g, 81%,
colorless crystal, mp 1528C. [Found: C, 49.41; H, 3.97.
C17H16BrClN2O3 requires: C, 49.59; H, 3.91]. IR: 3307
(NH), 1726 (CO); 1H NMR: 1.13 (t, 3H, J¼7.0 Hz,), 1.88 (s,
3H), 3.14 (q, 2H, J¼7.0 Hz,), 6.01 (s, 1H), 6.66 (d, 2H,
J¼8.7 Hz), 7.13–7.43 (m, 5H); 13C NMR: 14.88 (CH3),
25.90 (CH3), 58.56 (CH2), 90.57 (C), 113.0 (C), 114.94 (C),
117.82 (CH), 122.52 (CH), 126.52 (C), 130.45 (CH), 131.03
(CH), 131.97 (CH), 146.13 (C), 146.84 (C), 150.12 (CvO);
MS: m/z (%) 412 (Mþ2, 14), 410 (Mþ, 11), 366, 364, 351,
273, 271, 242, 199 (100), 183, 155, 125, 91, 77, 63.
A solution of 4b or 4j (3 mmol) in the appropriate alcohol
(20 mL) and drops of hydrochloric acid was refluxed for
2 hs. The excess of the alcohol was evaporated under
vacuum and ethyl ether was added to precipitate the product
which needed no further purification.
3.5.1. 6,8-Dichloro-4-ethoxy-4-methyl-3-[N-(4-chloro-
phenyl)amino]-3,4-dihydro-2H-1,3-benzoxazine-2-one
5j. Compound 5j obtained from this method (Yield¼0.8 g,
67%) was found to have similar physical and spectroscopic
characteristics to that obtained above using general
procedure 3.
3.5.2. 6,8-Dichloro-4-methoxy-4-methyl-3-[N-(4-chloro-
phenyl)amino]-3,4-dihydro-2H-1,3-benzoxazine-2-one
6j. This compound was prepared from 4j and methanol.
Yield¼0.85 g, 73%, colorless crystals, mp 1608C. [Found:
C, 49.79; H, 3.47. C16H13Cl3N2O3 requires: C, 49.57; H,
3.4.4. 6-Chloro-4-ethoxy-4-methyl-3-[N-(4-chlorophenyl)-
amino]-3,4-dihydro-2H-1,3-benzoxazine-2-one 5g. This
compound was prepared from 3g. Yield¼1.0 g, 88%,
colorless crystals, mp 1628C. [Found: C, 55.38; H, 4.29.
C17H16Cl2N2O3 requires: C, 55.60; H, 4.39]. IR: 3312 (NH),
1727 (CO); 1H NMR: 1.14 (t, 3H, J¼7.0 Hz), 1.89 (s, 3H),
3.31 (q, 2H, J¼7.0 Hz), 5.94 (s, 1H), 6.71 (d, 2H,
J¼9.1 Hz), 7.02–7.23 (m, 3H), 7.38–7.45 (m, 2H); 13C
NMR: 14.89 (CH3), 18.46 (CH3), 57.91 (CH2), 90.57 (C),
114.74 (C), 117.83 (CH), 123.95 (CH), 126.42 (CH), 129.09
(C), 129.22 (CH), 131.08 (CH), 136.88 (C), 144.10 (C),
147.25 (C), 150.14 (CvO); MS: m/z (%) 368 (Mþ2, 5), 366
(Mþ, 8), 322, 320, 303, 285, 243, 201, 201, 199 (100), 171,
155, 111, 99, 75, 63.
1
3.38]. IR: 3295 (NH), 1734 (CO); H NMR: 1.89 (s, 3H),
3.10 (s, 3H), 6.12 (s, 1H), 6.70 (d, 2H, J¼8.8 Hz), 7.16 (d,
2H, J¼8.8 Hz), 7.31 (d, 1H, J¼2.1 Hz), 7.51 (d, 1H,
J¼2.1 Hz); 13C NMR: 25.55 (CH3), 50.45 (CH3), 91.04 (C),
114.35 (CH), 122.17 (C), 123.28 (C), 124.87 (CH), 125.22
(C), 128.86 (CH), 130.09 (C), 131.09 (CH), 143.31 (C),
145.54 (C), 149.86 (CvO); MS: m/z (%) 388 (Mþ2, 3), 386
(Mþ, 2), 356, 354, 313, 311, 276, 221, 219 (100), 187, 159,
126, 111, 99, 77, 63.
3.5.3. 6-Bromo-4-methyl-4-propoxy-3-[N-(4-bromo-
phenyl)amino]-3,4-dihydro-2H-1,3-benzoxazine-2-one
3.4.5. 6-Chloro-4-ethoxy-4-methyl-3-[N-(4-methylphenyl)-

8170
H. Z. Alkhathlan / Tetrahedron 59 (2003) 8163–8170
7b. This compound was prepared from 4b and propanol.
Yield¼0.74 g, 53%, colorless powder, mp 1428C. [Found:
C, 45.72; H, 3.72. C18H18Br2N2O3 requires: C, 45.98; H,
3.6.2. 6-Chloro-4-fluoromethyl-4-methoxy-3-[N-phenyl-
amino]-3,4-dihydro-2H-1,3-benzoxazine-2-one 9e. This
compound was prepared from 4e. Yield¼0.07 g, 42%,
colorless powder, mp 1388C. [Found: C, 56.81; H, 4.05.
C16H14ClFN2O3 requires: C, 57.06; H, 4.19]. IR: 3305
(NH), 1708 (CO); 1H NMR: 3.03 (s, 3H), 4.78 (m, 2H), 6.17
(s, 1H), 6.93 (m, 3H), 7.11 (d, 1H, J¼8.8 Hz), 7.24–7.35
(m, 2H), 7.42–7.51 (m, 2H); 13C NMR: 50.87 (CH3), 81.72
(CH2), 91.78 (C), 113.78 (C), 118.26 (CH), 122.22 (CH),
126.43 (CH), 129.36 (CH), 130.81 (CH), 131.95 (CH),
146.08 (C), 148.55 (C), 150.32 (CvO); 19F NMR:
2117.43; MS: m/z (%) 338 (Mþ2, 3), 336 (Mþ, 8), 306,
304, 261, 205, 203 (100), 171, 143, 106, 92, 77, 65.
1
3.85]. IR: 3308 (NH), 1739 (CO); H NMR: 0.85 (t, 3H,
J¼7.0 Hz); 1.52 (m, 2H), 1.91 (s, 3H), 3.50 (t, 2H,
J¼6.5 Hz), 6.01 (s, 1H), 6.65 (d, 2H, J¼9.0 Hz), 6.98 (d,
2H, J¼9.0 Hz), 7.26–7.38 (m, 2H), 7.54 (d, 1H, J¼1.9 Hz);
13C NMR: 10.24 (CH3), 22.68 (CH3), 25.98 (CH2), 64.80
(CH2), 89.97 (C), 114.68 (C), 115.67 (CH), 118.87 (CH),
127.01 (CH), 129.31 (C), 132.23 (CH), 132.37 (CH), 134.17
(C), 144.20 (C), 146.89 (C), 147.38 (CvO); MS: m/z (%)
470 (Mþ2, 4), 468 (Mþ, 2), 410, 408, 369, 367, 331, 329,
259, 257, 217, 215 (100), 201, 199, 172, 170, 157, 155, 143,
91, 75, 63.
3.5.4. 6-Bromo-4-butoxy-4-methyl-3-[N-(4-bromophenyl)-
amino]-3,4-dihydro-2H-1,3-benzoxazine-2-one 8b. This
compound was prepared from 4b and butanol. Yield¼0.73
g, 47%, colorless powder, mp 1758C. [Found: C, 43.53; H,
3.86. C19H20Br2N2O3.HCl requires: C, 43.83; H, 4.06]. IR:
References
1. Pedersen, O. S.; Pedersen, E. B. Synthesis 2000, 479, and
references cited therein.
1
3317 (NH), 1729 (CO); H NMR: 0.82 (t, 3H, J¼6.9 Hz),
2. Young, S. D.; Britcher, S. F.; Tran, L. O.; Payne, L. S.;
Lumma, W. C.; Lyle, T. A.; Huff, J. R.; Anderson, P. S.; Olsen,
D. B.; Carroll, S. S.; Pettibone, D. J.; O’Brien, J. A.; Ball,
R. G.; Balani, S. K.; Lin, J. H.; Chen, I-W.; Schleif, W. A.;
Sardana, V. V.; Long, W. J.; Byrnes, V. W.; Emini, E. A.
Antimicrob. Agents Chemother. 1995, 39, 2602.
3. Cocuzza, A. J.; Chidester, D. R.; Cordova, B. C.; Jeffrey, S.;
Parsons, R. L.; Bacheler, L. T.; Erickson-Vitanen, S.; Trainor,
G. L.; Ko, S. S. Bioorg. Med. Chem. Lett. 2001, 11, 1177.
4. Magnus, N. A.; Confalone, P. N.; Storace, L. Tetrahedron Lett.
2000, 41, 3015.
1.31–1.51 (m, 4H); 1.95 (s, 3H), 3.42 (t, 2H, J¼6.8 Hz),
6.15 (s, 1H), 6.73 (d, 2H, J¼8.7 Hz), 7.02 (d, 2H,
J¼8.7 Hz), 7.30–7.45 (m, 2H), 7.51 (d, 1H, J¼2.1 Hz);
13C NMR: 11.14 (CH3), 18.98 (CH3), 22.31 (CH2), 26.42
(CH2), 61.78 (CH2), 89.38 (C), 113.88 (C), 116.21 (CH),
119.11 (CH), 126.89 (CH), 130.36 (C), 132.66 (CH), 133.68
(CH), 135.53 (C), 144.56 (C), 147.41 (C), 148.76 (CvO);
MS: m/z (%) 520 (M.HClþ2, 3), 518 (Mþ.HCl, 2), 446, 444,
410, 408, 365, 307, 305, 251 (100), 249, 214, 212, 172, 170,
145, 143, 91, 77, 63.
5. Waisser, K.; Gregor, J.; Kubicova, L.; Klimesova, V.; Kunes,
J.; Machacek, M.; Kaustova, J. Eur. J. Med. Chem. 2000, 35,
733.
3.6. General procedure 6: preparation of
4-fluoromethyl-4-methoxy-1,3-benzoxazinones 9b,e
6. Waisser, K.; Machacek, M.; Dostal, H.; Gregor, J.; Kubicova,
L.; Klimesova, V.; Kunes, J.; Palat, K.; Hladuvkova, J.;
Kaustova, J.; Moellmann, U. Collect. Czech. Chem. Commun.
1999, 64, 1902.
The appropriate 4-methylene-1,3-benzoxazinone (0.5 mmol)
was dissolved in a mixture of 20 mL of acetonitrile and
2 mL of methanol under nitrogen atmosphere. F-TEDA-BF4
(0.5 mmol) in 10 mL of acetonitrile was added and the
reaction mixture was stirred at room temperature for one
hour. After addition of dichloromethane (40 mL), the
mixture was washed once with 10% aqueous solution of
sodium bicarbonate and twice with water. The organic layer
was dried over anhydrous magnesium sulfate, filtered and
evaporated to dryness. The resulting solid was crystallized
from ethyl ether and further purified using TLC.
7. Mokrosz, M.; Kowalski, P.; Kowalska, T.; Majka, Z.;
Duszynska, B.; Bojarski, A. J.; Fruzinski, A.; Karolak-
Wojciechowska, J.; Wesolowska, A.; Klodzinska, A.; Tatarc-
zynska, E.; Chojnacka-Wojcik, E. Arch. Pharm. 1999, 332,
373.
8. Yamamoto, S.; Hashinguchi, S.; Miki, S.; Igata, Y.; Watanabe,
T.; Shiraishi, M. Chem. Pharm. Bull. 1996, 44, 734.
9. Tachikawa, R.; Wachi, K.; Terada, A. Chem. Pharm. Bull.
1982, 30, 559.
3.6.1. 6-Bromo-4-fluoromethyl-4-methoxy-3-[N-(4-
bromophenyl)amino]-3,4-dihydro-2H-1,3-benzoxazine-
2-one 9b. This compound was prepared from 4b.
Yield¼0.11 g, 48%, colorless powder, mp 1788C. [Found:
C, 41.47; H, 2.61. C16H13Br2FN2O3 requires: C, 41.76; H,
10. Ishiwaka, T.; Sano, M.; Isagawa, K.; Fushizaki, Y. Bull. Chem.
Soc. Jpn 1970, 43, 135.
11. Kohl, H.; Desai, P. D.; Dohadwalla, A. N; de Souza, N. J.
J. Pharm. Sci. 1974, 63, 838.
1
12. Molina, P.; Conesa, C.; Alias, A.; Arques, A.; Velasco, M.
Tetrahedron 1993, 49, 7599.
2.84]. IR: 3325 (NH), 1716 (CO); H NMR: 3.04 (s, 3H),
4.80 (m, 2H), 6.10 (s, 1H), 6.81 (d, 2H, J¼8.0 Hz), 7.05 (d,
1H, J¼8.8 Hz), 7.35 (d, 2H, J¼8.0 Hz), 7.54–7.60 (m, 2H);
13C NMR: 50.16 (CH3), 80.58 (CH2), 91.94 (C), 115.55 (C),
117.99 (C), 118.20 (CH), 118.60 (CH), 129.35 (CH), 132.21
(CH), 134.95 (CH), 145.27 (C), 148.98 (C), 150.11 (CvO);
19F NMR: 2118.59; MS: m/z (%) 460 (Mþ2, 10), 458 (Mþ,
5), 428, 426, 387, 385, 249, 247 (100), 215, 170, 136, 107,
81, 76, 63.
13. Barbieri, W.; Bernardi, L.; Bosisio, G.; Coda, S. Chim. Ind.
1969, 51, 1384. Chem. Abstr. 1970, 72, 111435b.
14. Stavber, S.; Sotler, T.; Zupan, M. Tetrahedron Lett. 1994, 35,
1105.
15. Sankar Lal, G. J. Org. Chem. 1993, 58, 2791.