A simple indirect route for the synthesis of N-alkyl-4-imino-1,4-dihydro- 2H-3,1-benzoxazin-2-ones

Article abstract of DOI:10.1007/s00706-007-0761-8

Novel N-alkyl-4-imino-1,4-dihydro-2H-3,1-benzoxazin-2-ones were synthesized in a single step by Baeyer-Villiger oxidation of N-alkyl-3-imino-2-indolinone derivatives in high yields. The structures of the products were determined by spectral data and by X-ray diffraction. Besides their novel structures, these compounds may have important biological activities and industrial applications.

Full text of DOI:10.1007/s00706-007-0761-8

Monatsh Chem 139, 277–280 (2008)
DOI 10.1007/s00706-007-0761-8
Printed in The Netherlands
A Simple Indirect Route for the Synthesis of N-Alkyl-4-imino-
1,4-dihydro-2H-3,1-benzoxazin-2-ones
Khosrow Jadidi1;ꢀ, Ramin Ghahremanzadeh1, Morteza Mehrdad2,
Mohammad Ghanbari1, and Hamid Arvin-Nezhad1
1
Department of Chemistry, Shahid Beheshti University, Tehran, Iran
2
Department of Environmental Pollutants, Environmental Sciences Research Institute,
Shahid Beheshti University, Tehran, Iran
Received June 13, 2007; accepted July 1, 2007; published online January 28, 2008
# Springer-Verlag 2008
Summary. Novel N-alkyl-4-imino-1,4-dihydro-2H-3,1-ben-
zoxazin-2-ones were synthesized in a single step by
Baeyer–Villiger oxidation of N-alkyl-3-imino-2-indolinone de-
rivatives in high yields. The structures of the products were
determined by spectral data and by X-ray diffraction. Besides
their novel structures, these compounds may have important
biological activities and industrial applications.
complex molecules used in the synthesis of pharma-
ceutical products [3].
As a continuation of our previous work and as part
of our ongoing research program on the synthesis of
various heterocyclic compounds [4], we wish to re-
port the synthesis of novel derivatives 5 that may
produce desired activity against Mycobacterium
avium and may posses other antibacterial and antivi-
ral activities [2b]. A new two-step method, which
used the key Baeyer–Villiger oxidation reaction in
the second step, was developed for the synthesis of
novel compounds 5 since direct reaction of isatoic
anhydride 4 with amines 2 did not afford them
(Scheme 1).
Keywords. 3,1-Benzoxazin-2-ones; Baeyer–Villiger oxida-
tion; 3-Imino-2-indolinone.
Introduction
A literature survey reveals that 3,1-benzoxazin-
2-ones and their homologue compounds have wide
ranges of valuable pharmacological properties as
well as industrial applications [1]. It is well known
that similar compounds, such as 3-aryl-2,4-quina-
zolinediones are of current interest from both phar-
macological and chemical aspects. These compounds
have been tested against Mycobacterium avium, the
most common systematic bacterial infection compli-
cating AIDS [2]. On the other hand, Baeyer–Villiger
oxidation is now a frequently used synthesis method
for the conversion of cycloalkanones to lactones.
The reaction can also be used in the synthesis of a
wide variety of other chemicals, ranging from simple
monomers used in the polyester industry to the more
Results and Discussion
Direct reaction of amines with isatoic anhydrides
4 produces anthranilic acid derivatives instead of
N-alkyl-1,4-dihydro-4-imino-2H-3,1-benzoxazin-2-
ones 5 (Scheme 1). Direct nucleophilic attack by
amines on the oxazine ring of isatoic anhydrides
results in loss of carbon dioxide and produces anthra-
nilic acid derivatives [5]. To synthesize novel N-alkyl-
4-imines 5 of the isatoic anhydrides 4 and to prevent
the rearrangement of the oxazine ring, N-alkyl-3-imi-
no-2-indolinones 3 were first synthesized from the
reaction of anilines 2 with N-alkylisatin 1. Then,
ꢀ
Corresponding author. E-mail: k-jadidi@cc.sbu.ac.ir

278
K. Jadidi et al.
Scheme 1
Table 1. The preparation of 3,1-benzoxazin-2-ones 5a–5i
Producta
R1
R2
R3
Yield=%
5a
5b
5c
5d
5e
5f
5g
5h
5i
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
H
H
NO2
H
H
H
H
H
H
H
Me
H
OMe
Br
OMe
Me
Br
80
85
82
83
83
86
80
85
80
H
Fig. 1. X-Ray crystal structure of 5g
a
All compounds were recrystallized from methanol
the corresponding N-alkyl-3-imino-2-indolinones
3 were oxidized with m-chloroperbenzoic acid
(m-CPBA) at 0ꢁC in dichloromethane or methanol
(Scheme 1). The Baeyer–Villiger oxidation products
were easily purified by dry flash chromatography or
by recrystallization in the appropriate solvent, and
pure products 5a–5i were obtained in high yields
(Table 1).
The structural assignments of the products, which
could not be concluded from NMR spectra and mass
spectroscopy alone, were achieved by X-ray crystal-
lographic analysis of 5g (Fig. 1). For crystallization
of 5g n-hexane:ethanol (1:4) was used. Light-yellow
crystals of 5g were obtained by slow evaporation of
the solvent.
According to geometrical parameters of 5g, the
backbone of this molecule is nearly flat. This can
be also explained by existence of maximum tricyclic
ꢀ–ꢀ overlap. As a result of torsional angles of C16–
N2–C7–O1 and C21–C16–N2–C7 which are nearly
0ꢁ, and existence of possible hydrogen bonding
between O1 and H21, the imine moiety is forced
to adopt the (Z)-configuration. Moreover, the only
group nearly orthogonal with respect to the rest of
the molecule is the N-benzyl substituent ring (N1–
C9–C10–C15 ¼ 122.7ꢁ).
In conclusion, a total of nine novel N-alkyl-4-
imino substituted isatoic anhydrides 5 were syn-
thesized from indirect Baeyer–Villiger oxidation of
1
N-alkyl-3-imino-2-indolinones 3. H and 13C NMR

N-Alkyl-4-imino-1,4-dihydro-2H-3,1-benzoxazin-2-ones
279
(Z)-1-Methyl-4-(4-tolylimino)-1,4-dihydro-2H-3,1-
spectra of the oxidation products could not confirm
the exact structural assignment of these compounds.
Therefore, X-ray diffraction was used to obtain
the exact structural assignment of the compounds.
Besides their novel structures, as mentioned earlier,
these compounds may possess some important bio-
logical activities.
benzoxazin-2-one (5b, C17H16N2O)
Yellow crystals, mp 114–116ꢁC; 1H NMR (300MHz, CDCl3):
ꢁ ¼ 2.27 (s, 3H), 3.42 (s, 3H), 6.96–8.22 (8H) ppm; 13C NMR
(75 MHz, CDCl3): ꢁ ¼ 29.58, 31.15, 111.34–145.50 (12 signal
arom), 142.10 (CN), 145.49 (CO) ppm; IR (KBr): ꢂꢀ¼ 1652
(CN), 1734 (CO), 2859, 2894, 2957, 3046 cmꢃ1; MS: m=z
(%) ¼ 266 (Mþ, 80), 221 (M–CO2, 100).
(Z)-1-Methyl-4-(3-nitrophenylimino)-1,4-dihydro-2H-3,1-
benzoxazin-2-one (5c, C16H13N3O3)
Experimental
1
Light-brown crystals, mp 201–203ꢁC; H NMR (300MHz,
Melting points were measured on a Mettler FP5. Mass spec-
tra were recorded on a Shimadzu QP 1100 Ex mass spectrom-
eter operating at an ionization potential of 70 eV. IR spectra
were obtained with a Shimadzu IR-470 spectrometer (KBr).
1H and 13C NMR spectra were measured with a Bruker 500
DRX AVANCE instrument at 500 and 125 MHz. Isatin, ani-
lines, and solvents used in the reactions were commercially
available, and they were used after additional purification by
distillation or crystallization. Educts 3a–3i were prepared
according to Ref. [4d].
CDCl3): ꢁ ¼ 3.56 (s, 3H), 7.09–8.31 (m, 8H, arom) ppm;
13C NMR (75 MHz, CDCl3): ꢁ ¼ 31.77, 113.64–139.82 (12
signals arom), 146.82 (CN), 148.76 (CO) ppm; IR (KBr):
ꢂꢀ¼ 1658 (CN), 1739 (CO), 2330, 2357, 2848, 2949cmꢃ1
;
MS: m=z (%) ¼ 297 (Mþ, 70), 253 (M–CO2, 100).
(Z)-1-Methyl-4-(4-methoxyphenylimino)-1,4-dihydro-2H-
3,1-benzoxazin-2-one (5d, C17H16N2O2)
Light-gray crystals, mp 206–210ꢁC; 1H NMR (300 MHz,
DMSO-d6): ꢁ ¼ 3.40 (s, 3H), 3.75 (s, 3H), 6.92–8.11 (8H)
ppm; 13C NMR (75 MHz, DMSO-d6): ꢁ ¼ 31.56, 55.46,
113.34–143.27 (12 signal arom), 147.69 (CN), 157.23
(CO) ppm; IR (KBr): ꢂꢀ¼ 1654 (CN), 1706 (CO), 2859,
2894, 2957, 3046 cmꢃ1; MS: m=z ¼ 282 (Mþ, 100), 237 (M–
CO2, 50).
X-Ray Crystallography
The room temperature diffraction measurements were carried
out with a colorless 0.14ꢂ0.14ꢂ0.06mm3 plate of crystal of
5g on a Bruker AXS area-detector diffractometer. The struc-
ture was solved by using SHELXS 97. The structure refine-
ment and data reduction were carried out with SAINT (Bruker
1998). Non-hydrogen atoms were refined anisotropically. All
hydrogen atoms were located by subsequent difference Fourier
maps and were refined to a final R value of 0.045. Crystallo-
graphic data were deposited at the Cambridge Crystallo-
graphic Data Centre with the No. 673–953 and can be
obtained, on request, from the Director, Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
U.K. (fax: þ44-1223-336033, e-mail: deposit@ccdc.cam.
ac.uk, or http:==www.ccdc.cam.ac.uk).
(Z)-1-Methyl-4-(4-bromophenylimino)-1,4-dihydro-2H-3,1-
benzoxazin-2-one (5e, C16H13BrN2O)
Light-orange crystals, mp 180–182ꢁC; 1H NMR (300 MHz,
CDCl3): ꢁ ¼ 3.39 (s, 3H), 6.94–8.13 (m, 8H, arom) ppm;
13C NMR (75 MHz, CDCl3): ꢁ ¼ 31.69, 113.56–143.33
(12 signals arom), 145.21 (CN), 147.23 (CO) ppm; IR
(KBr): ꢂꢀ¼ 1606 (CN), 1734 (CO), 2964, 3042 cmꢃ1; MS:
m=z (%) ¼ 330 (Mþ, 90), 332 (Mþ þ 2, 90), 286 (M–CO2,
100).
(Z)-1-Benzyl-4-(4-methoxyphenylimino)-1,4-dihydro-2H-3,1-
benzoxazin-2-one (5f, C23H20N2O)
Typical Procedure for the Preparation of (Z)-1-methyl-4-
(phenylimino)-1,4-dihydro-2H-3,1-benzoxazin-2-one as
Exemplified with 5a
Light-gray crystals, mp 148–150ꢁC; 1H NMR (300 MHz,
CDCl3): ꢁ ¼ 3.88 (s, 3H), 5.42 (s, 2H), 7.05–8.30 (m,
13H, arom) ppm; 13C NMR (75 MHz, CDCl3): ꢁ ¼ 47.56,
55.51, 111.56–151.79 (18 signal arom), 159.59 (CN),
162.09 (CO) ppm; IR (KBr): ꢂꢀ¼ 1659 (CN), 1708 (CO),
2859, 2894, 2957, 3046 cmꢃ1; MS: m=z (%) ¼ 358 (Mþ,
100), 314 (M–CO2, 20).
A solution of 0.472 g 3a (2.0mmol) [4d] in 25 cm3 CH2Cl2
was cooled to 0ꢁC in an ice-bath. mCPBA (0.516g, 3 mmol),
which was dissolved in 25 cm3 CH2Cl2, was added drop-
wise to the stirred solution of imine 3a. After stirring
45min at 0ꢁC, product 5a was formed (TLC). The crude prod-
uct was poured into water and extracted with dichloromethane
(3ꢂ20 cm3). The organic layer was dried (Na2SO4) and evap-
oration of the solvent afforded the crude product 5a. The latter
was purified on silica gel by dry-flash chromatography using
n-hexane=ethyl acetate or by recrystallization in methanol.
Yield 80%; light-yellow crystals, mp 118–122ꢁC; 1H NMR
(300 MHz, CDCl3): ꢁ ¼ 3.53 (s, 3H), 7.08–8.35 (m, 9H, arom)
ppm; 13C NMR (75 MHz, CDCl3): ꢁ ¼ 31.65, 113.44–144.25
(12 signals arom), 144.50 (CN), 147.49 (CO) ppm; IR (KBr):
ꢂꢀ¼ 1675 (CN), 1740 (CO), 2964, 3042 cmꢃ1; MS: m=z
(%) ¼ 252 (Mþ, 50), 208 (M–CO2, 100).
(Z)-1-Benzyl-4-(4-tolylimino)-1,4-dihydro-2H-3,1-
benzoxazin-2-one (5g, C22H17BrN2O)
Light-yellow crystals, mp 156–158ꢁC; 1H NMR (300 MHz,
CDCl3): ꢁ ¼ 2.32 (s, 3H), 5.22 (s, 2H), 6.93–8.30 (m, 13H,
arom) ppm; 13C NMR (75 MHz, CDCl3): ꢁ ¼ 21.48, 48.41,
114.44–140.45 (18 signal arom), 145.39 (CN), 147.68 (CO)
ppm; IR (KBr): ꢂꢀ¼ 1660 (CN), 1731 (CO), 2859, 2894,
2957, 3046 cmꢃ1; MS: m=z (%) ¼ 342 (Mþ, 100), 298 (M–
CO2, 40).

280
K. Jadidi et al.: N-Alkyl-4-imino-1,4-dihydro-2H-3,1-benzoxazin-2-ones
(Z)-1-Benzyl-4-(4-bromophenylimino)-1,4-dihydro-2H-3,1-
benzoxazin-2-one (5h, C22H17BrN2O)
References
[1] a) Coppola GM (1980) Chem Rev 78: 505; b) Tran TP,
Ellsworth EL, Watson BM, Sanchez JP, Showalter DH
(1982) J Heterocyclic Chem 19: 123
[2] a) Waisser K, Machacek M, Dostal H, Gregor J,
Kubicova L, Klimesova V, Kunes J, Palat K Jr,
Hladuvkova J, Kaustova J, Mollmann U (1999) Collect
Czech Chem Commun 64: 1902; b) Waisser K, Dostal H,
Kubicova L, Kaustova J (1998) Folia Pharm Univ Carol
23: 139
Brown crystals, mp 144–145ꢁC; 1H NMR (300 MHz,
CDCl3): ꢁ ¼ 5.23 (s, 2H), 6.97–8.26 (13H) ppm; 13C NMR
(75 MHz, CDCl3): ꢁ ¼ 48.24, 114.41–143.20 (18 signal arom),
145.00 (CN), 147.68 (CO) ppm; IR (KBr): ꢂꢀ¼ 1658 (CN),
1747 (CO), 2859, 2894, 2957, 3046cmꢃ1; MS: m=z (%) ¼ 407
(Mþ, 100), 410 (Mþ+2, 30), 363 (M–CO2, 40).
(Z)-1-Benzyl-4-(phenylimino)-1,4-dihydro-2H-3,1-
[3] Krow GC (1993) Org React 43: 251
benzoxazin-2-one (5i, C22H18N2O)
Light-green crystals, mp 116–118ꢁC; 1H NMR (300MHz,
CDCl3): ꢁ ¼ 5.23 (s, 2H), 6.97–8.26 (m, 13H, arom) ppm;
13C NMR (75 MHz, CDCl3): ꢁ ¼ 48.24, 114.41–143.20 (18
signal arom), 145.00 (CN), 147.68 (CO) ppm; IR (KBr): ꢂꢀ¼
1650 (CN), 1732 (CO), 2859, 2894, 2957, 3046 cmꢃ1; MS: m=z
(%) ¼ 327 (Mþ, 100), 329 (Mþ+2, 30), 283 (M–CO2, 40).
[4] a) Jadidi K, Gharemanzadeh R, Mehrdad M, Darabi HR,
Khavasi HR, Asgari D (2007) Ultrasonics Sonochemistry
(in press); b) Jadidi K, Mirhosseini Moghaddam M,
Aghapoor K, Gharemanzadeh R (2007) J Chem Res
(S): 79; c) Azizian J, Morady AV, Jadidi K, Mehrdad
M, Sarrafi Y (2000) Synth Commun 30: 537; d) Azizian J,
Jadidi K, Mehrdad M, Sarrafi Y (2000) Synth Commun
30: 2309; e) Azizian J, Asadi A, Jadidi K (2001) Synth
Commun 31: 2727; f) Azizian J, Mehrdad M, Jadidi K,
Sarrafi Y (2000) Tetrahedron Lett 41: 5265
Acknowledgements
The authors thank Professor A. Yanovsky and Dr. Z. Starikov of
the X-ray structural center (XRSC) at the Russian Academy of
Sciences for the crystallographic measurement.
[5] a) Sunder S, Peet NP, Trepanies DL (1967) J Org
Chem 41: 2712; b) Sheibley FE (1952) J Org Chem
17: 221