A simple route for the synthesis of novel 1,4-benzoxazine derivatives by Baeyer–Villiger oxidation reaction

Article abstract of DOI:10.1016/j.tet.2016.05.086

Novel 1,4-benzoxazine derivatives were synthesized by an efficient and simple method in high yields. Readily available starting materials, operational simplicity, mild reaction conditions and novelty are the key advantages of this method. The syntheticall

Full text of DOI:10.1016/j.tet.2016.05.086

Accepted Manuscript
A simple route for the synthesis of novel 1,4-benzoxazine derivatives by Baeyer–
Villiger oxidation reaction
Mohammad Ghanbari, Khosrow Jadidi, Morteza Mehrdad, Nazanin Assempour
PII:
S0040-4020(16)30503-8
10.1016/j.tet.2016.05.086
TET 27813
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 March 2016
Revised Date: 14 May 2016
Accepted Date: 31 May 2016
Please cite this article as: Ghanbari M, Jadidi K, Mehrdad M, Assempour N, A simple route for the
synthesis of novel 1,4-benzoxazine derivatives by Baeyer–Villiger oxidation reaction, Tetrahedron
(2016), doi: 10.1016/j.tet.2016.05.086.
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Graphical Abstract
Leave this area blank for abstract info.
A simple route for the synthesis of novel 1,4-
benzoxazine derivatives by Baeyer-Villiger
oxidation reaction
Mohammad Ghanbari a,*, Khosrow Jadidi b,*, Morteza Mehrdad c, Nazanin Assempour b
a Department of Organic Chemistry, Faculty of Chemistry, University of Kashan, Kashan, 87317, Iran
b Department of Chemistry, Shahid Beheshti University, G.C. Tehran 1983963113, Iran
c Department of Chemistry, Faculty of Science, University of Guilan, P.O. Box: 41335-1914, Rasht, Iran

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A simple route for the synthesis of novel 1,4-benzoxazine derivatives by Baeyer-Villiger
oxidation reaction
Mohammad Ghanbari a, , Khosrow Jadidi b, *, Morteza Mehrdad c, Nazanin Assempour b
a Department of Organic Chemistry, Faculty of Chemistry, University of Kashan, Kashan, Iran
b Department of Chemistry, Shahid Beheshti University, G.C. Tehran 1983963113, Iran
c Department of Chemistry, Faculty of Science, University of Guilan, P.O. Box: 41335-1914, Rasht,
Iran
ABSTRACT
Novel 1,4-benzoxazine derivatives were synthesized by an efficient and simple method in high yields.
Readily available starting materials, operational simplicity, mild reaction conditions and novelty are
the key advantages of this method. The synthetically attractive feature of the procedure is reflected by
its applicability to a wide range of isatin and aniline derivatives. Besides their novel structures, these
compounds may have important biological activities and industrial applications. Furthermore, we
demonstrated that in Baeyer-Villiger oxidation reaction, the phenyl group migrate better than amidine
groups but not as good as amide group. The migratory ability for these groups in Baeye-Villiger
oxidation reaction is ranked amide > phenyl > amidine.
Keywords:
1,4-Benzoxazine
Baeyer-Villiger oxidation
N-oxide
Isatin
Heterocyclic
Corresponding author. Tel./fax: +98-31-5591-3044; e-mail: ghanbari-m@kashanu.ac.ir (M. Ghanbari),
k-jadidi@sbu.ac.ir (K. Jadidi)
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1. Introduction
Heterocyclic rings having heteroatoms at 1,4-positions and fused to a benzene ring are fundamental
components in medicinal chemistry due to their wide range of therapeutic and biological properties.
Among them, 1,4-benzoxazines have been an integral part of molecular skeletons for design of a
variety of biologically active compounds.1-9 According to their substituents, these compounds are
potential drugs for treating infections,10 diabetes,11 heart disease, inflammatory, neurodegenerative,
autoimmune and cardiovascular disorders.12,13 For example, 1,4-benzoxazines 1 and 2 has been shown
as inhibitors of nitric oxide synthase which are potential drugs for treating neurodegenerative,
autoimmune, inflammatory and cardiovascular disorders.12
Fig. 1. Structures of some bioactive compounds with a 1,4-benzoxazine core structure.
Due to the importance of 1,4-benzoxazines, their synthesis has attracted much attention in recent
years and many efforts have been made to develop methodologies for the synthesis of 1,4-
benzoxazines derivatives.14-22 1,4-benzoxazin derivatives are often achieved from 2-aminophenols or
2-nitrophenols derivatives. However, most of the these methods suffer from one or more drawbacks
such as lengthy sequences, higher reaction temperature, longer reaction time, toxic catalysts used, low
overall yields, and limited ability to vary substituents. Moreover, the starting materials were often not
readily available. Thus, the development of new and simple synthetic methods for the efficient
preparation of the heterocycles containing of 1,4-benzoxazines ring fragments will be a beneficial and
interesting challenge. As part of our ongoing research program on the development of efficient
methods for the preparation of heterocyclic compounds,23-30 herein we report a new procedure for the
synthesis of novel 1,4-benzoxazines derivatives with different substituents at 2 and 3 positions. The
notable advantages offered by this method are simple operation, readily available starting materials,
and good yields of the products.
2. Results and discussion
At the outset of our study, we prepared the N-phenyl-3-(phenylimino)-3H-indol-2-amine 3a from
commercially available isatin, PCl5 and aniline, using the modified procedure as previously reported
(Scheme 1).31
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Scheme 1. Synthesis of N-phenyl-3-(phenylimino)-3H-indol-2-amine 3a
To further test this approach, particularly with regard to construction of a library of compounds, this
methodology was evaluated by using different derivatives of isatin and aniline. The corresponding N-
aryl-3-(arylimino)-3H-indol-2-amine derivatives 3 were synthesized under solvent-free condition. The
results are summarized in Figure 2.
Fig. 2. Synthesis of N-aryl-3-(arylimino)-3H-indol-2-amine derivatives 3a-h. Yields are given for the
isolated products.
After the preparation of various derivatives of N-aryl-3-(arylimino)-3H-indol-2-amine 3, we turned
our focus on the evaluation of the Baeyer–Villiger oxidation reaction of these compounds. For this
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approach, we investigated the reaction of N-phenyl-3-(phenylimino)-3H-indol-2-amine 3a, as model
substrates, with m-chloroperbenzoic acid (m-CPBA) in dichloromethane as solvent at room
temperature. It was found that Baeyer-Villiger oxidation reaction proceeded with formation of N-
oxide product 5a. The products were easily purified by column chromatography, and pure products 4a
and 5a were characterized by spectroscopic analysis. At room temperature, the major product is N-
oxide (51%) (Scheme 2). To achieve suitable conditions for the selective synthesis of 1,4-benzoxazine
4a, we investigated the reaction conditions. It was found that the temperature played a key role in the
formation of 1,4-benzoxazines 4a. For example, only 31% of 1,4-benzoxazines 4a was detected when
the reaction was performed at room temperature, but the yield of the 1,4-benzoxazines product 4a
increased to 78% at −20 ˚C.
Scheme 2. Model reaction for the synthesis of 1,4-benzoxazines
Under the optimized conditions, the substrate scope of this reaction was investigated, and the results
are summarized in Figure 3. To the best of our knowledge, this new procedure provides the first
example of an efficient method for the synthesis of this 1,4-benzoxazines class. Given the large
number of commercially available aniline and isatin, the present method should be amenable for the
synthesis of libraries with high diversity. We expect this method to find extensive application in the
field of diversity oriented synthesis and drug discovery.
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Fig. 3. Synthesis of 1,4-benzoxazines derivatives 4a-h. Yields are given for the isolated products.
The structures of the products were characterized by spectroscopic analysis and further confirmed by
an X-ray diffraction study of 4b as a representative example (Fig. 4).32,33
Fig. 4. Solid-state molecular structure of 4b.
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As mentioned earlier, the reaction produces N-oxide 5a as major product at room temperature. To
evaluate the potential of this methodology for the synthesis of N-oxide derivatives, we investigated
the reaction with a series of N-aryl-3-(arylimino)-3H-indol-2-amine derivatives 3, and the
corresponding N-oxide derivatives 5 were obtained in good yields at room temperature (Fig. 5).
Fig. 5. Synthesis of N-oxide derivatives 5a-d. Yields are given for the isolated products.
The structures of the products were characterized by spectroscopic analysis and further confirmed by
an X-ray diffraction study of 5d as a representative example (Fig. 6).34,35
Fig. 6: Solid-state molecular structure of 5d
On the basis of previous chemistry and the results of our study, a plausible mechanism for the
syntheses of the products is shown in Scheme 3.36,37 In the first step, the peroxy acid attacks the
carbon of the imine group forming intermediate 6. In the next step of the reaction mechanism, through
a concerted mechanism, one of the substituents on the carbon of the imine migrates to the oxygen of
the peroxide group while a carboxylic acid leaves. In this step, there are two substituents attached to
the carbon of the imine group for migration, phenyl and amidine group. The regiospecificity of the
reaction depends on the relative migratory ability of the substituents. According to the product of
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reaction, it was found that the phenyl group migrate better than amidine group and deliver only 1,4-
benzoxazine 5 as product.
Scheme 3. Possible reaction mechanism.
In 2000, we reported Baeyer–Villiger oxidation of 1-alkyl-3-(arylimino)indolin-2-one 7 and we
showed that the amide group migrated better than phenyl group and 1-alkyl-4-(arylimino)-1H-
benzo[d][1,3]oxazin-2(4H)-one 8 formed in good yield (Scheme 4).38,39
Scheme 4. Synthesis of 1-alkyl-4-(arylimino)-1H-benzo[d][1,3]oxazin-2(4H)-one 8
Therefore, due to higher migratory aptitude of amid group and lower migratory aptitude of amidine
group relative to phenyl group, the migratory ability for these groups in Baeyer-Villiger oxidation
reaction is ranked amide > phenyl > amidine. Although the mechanism for the formation of N-oxide 5
has not been established experimentally, however, based on previous studies plausible mechanisms
are shown in the Scheme 5.40-43
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Scheme 5. Proposed mechanisms for the formation of the N-oxide 5
3. Conclusions
In conclusion, we have demonstrated an simple and efficient method for the preparation of 1,4-
benzoxazine derivatives by using readily available starting materials. Novelty, operational simplicity,
and good yields are the key advantages of this method. The methodology with substrate diversity
enables us to synthesize various derivatives of 1,4-benzoxazine. The reaction can be applied for the
synthesis of a variety of 1,4-benzoxazine with different functional groups by using other isatin and
aniline derivatives. With the results obtained in this paper and the previous our work, we
demonstrated that in Baeyer-Villiger oxidation reaction, the phenyl group migrate better than amidine
groups but not as good as amide group. Therefore, the migratory ability for these groups in Baeyer-
Villiger oxidation reaction is ranked amide > phenyl > amidine. Further reactivity studies and
synthetic applications of this methodology are in progress in our laboratory.
4. Experimental section
4.1.General
Solvents were distilled before use. CH2Cl2 was distilled under nitrogen from CaH2. All other
commercially available reagents were utilized as received without purification. PCl5, Isatin and aniline
derivatives were purchased from Alfa Aesar, Acros and Merck. Thin layer chromatography (TLC)
analysis was performed using Silicycle precoated TLC plates (silica gel 60 F254). The products were
purified by preparative column chromatography on silica gel (0.063-0.200 mm; Merck). IR Spectra:
1
Shimadzu FT-IR-4300 spectrometer; in cm-1. H and 13C-NMR Spectra: were recorded on Bruker
DRX-300-Advance instrument; in CDCl3 at 300.1, and 75.4 MHz, resp; δ in ppm, J in Hz. EI-MS (70
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eV): HP 5973 GC-MS instrument; in m/z. Melting points: Electrothermal 9200 apparatus. Elemental
analyses were performed with a Thermo Finnigan Flash-1112EA microanalyzer.
4.1.1 General procedure for the synthesis of N-aryl-3-(arylimino)-3H-indol-2-
amine derivatives 3:
A mixture of isatin (0.29 g, 2 mmol) and PCl5 (0.50 g, 2.4 mmol) was stirred at 90°C under nitrogen
for 10 min. Allowed to cold up to r.t. and then, the solution of aniline (6 mmol) in dry CH2Cl2 (5 mL)
was added and the reaction mixture was stirred under nitrogen for 24 h at r.t. After this time,
concentration of the solution by rotary evaporation under reduced pressure gave a residue that was
purified by column chromatography using 20% ethyl acetate/hexane as eluent.
4.1.1.1
N-Phenyl-3-(phenylimino)-3H-indol-2-amine (3a):
Red solid (77%), m.p. 212-214 ºC; [Found: C, 80.61; H, 4.95; N, 14.01. C20H15N3 requires C, 80.78;
H, 5.08; N, 14.13%]; νmax(KBr) 3336, 1574, 1546, 755 cm-1; δH (300 MHz, CDCl3) 6.69-6.71 (2H, m),
7.10 (2H, d, J 7.5 Hz), 7.16 (1H, t, J 7.5 Hz), 7.30-7.33 (3H, m), 7.42-7.51 (4H, m), 7.88 (2H, d, J 7.7
Hz); δC (75.46 MHz, CDCl3) 120.7, 120.7, 121.3, 122.3, 124.8, 125.7, 127.6, 131.3, 131.3, 131.4,
131.4, 136.6, 140.3, 150.7, 159.5, 161.7; m/z (CI) 297 (M+, 100), 220 (65), 77 (95), 51 (68%).
4.1.1.2. N-(4-Methoxyphenyl)-3-((4-methoxyphenyl)imino)-3H-indol-2-amine (3b):
Yellow solid (86%), m.p. 228-232 ºC; [Found: C, 73.78; H, 5.27; N, 11.57. C22H19N3O2 requires C,
73.93; H, 5.36; N, 11.76%]; νmax(KBr) 3343, 1572, 1533, 756 cm-1; δH (300 MHz, CDCl3) 3.85 (3H, s,
OCH3), 3.95 (3H, s, OCH3), 6.93-7.03 (2H, m), 7.11-7.26 (2H, m), 7.45-7.56 (4H, m), 7.87 (1H, d, J
8.5 Hz), 7.94 (1H, d, J 8.6 Hz), 8.03-8.09 (2H, m); δC (75.46 MHz, CDCl3) 55.5, 55.6, 114.0, 114.2,
115.0, 121.3, 124.5, 124.7, 125.9, 132.1, 132.2, 136.4, 138.4, 143.3, 144.7, 155.7, 157.5; m/z (CI) 357
(M+, 100), 235 (55), 122 (45), 77 (90%).
4.1.1.3. N-(p-Tolyl)-3-(p-tolylimino)-3H-indol-2-amine (3c):
Light yellow solid (84%), m.p. 214-218 ºC; [Found: C, 81.36; H, 5.98; N, 13.07. C22H19N3 requires C,
81.20; H, 5.89; N, 12.91%]; νmax(KBr) 3333, 1654, 1611, 1572 cm-1; δH (300 MHz, CDCl3) 2.38 (3H,
s, CH3), 2.42 (3H, s, CH3), 7.09-7.12 (2H, m), 7.16-7.28 (5H, m), 7.35 (2H, d, J 8.3 Hz), 7.48 (1H, d,
J 7.4 Hz), 7.82 (2H, d, J 8.4 Hz); δC (75.46 MHz, CDCl3) 20.9, 22.4, 116.7, 118.2, 119.9, 123.7,
127.1, 127.8, 129.5, 130.5, 131.4, 133.3, 135.6, 135.9, 139.4, 140.5, 143.5, 144.6; m/z (CI) 325 (M+,
70), 219 (55), 105 (100), 91 (90%).
4.1.1.4. 5-Bromo-N-(p-tolyl)-3-(p-tolylimino)-3H-indol-2-amine (3d):
Light brown solid (87%), m.p. 203-206 ºC; [Found: C, 65.22; H, 4.37; N, 10.25. C22H18BrN3 requires
C, 65.36; H, 4.49; N, 10.39%]; νmax(KBr) 3280, 1670, 1625, 1560 cm-1; δH (300 MHz, CDCl3) 2.37
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(3H, CH3), 2.46 (3H, CH3), 6.98-7.02 (3H, m), 7.08 (1H, d, J 8.2 Hz), 7.21 (2H, d, J 8.2 Hz), 7.29
(2H, d, J 8.0 Hz), 7.37 (1H, dd, J 2.0, 8.2 Hz), 7.73 (2H, d, J 8.2 Hz); δC (75.46 MHz, CDCl3) 18.5,
18.7, 112.2, 116.7, 116.8, 117.7, 118.6, 125.5, 127.3, 127.5, 130.9, 133.2, 133.6, 113.7, 134.2, 142.9,
155.2, 155.7; m/z (CI) 404 (M+, 60), 285 (80), 167 (30), 91 (100%).
4.1.1.5. 5-Nitro-N-(p-tolyl)-3-(p-tolylimino)-3H-indol-2-amine (3e):
Red solid (83%), m.p. 242-245 ºC; [Found: C, 71.45; H, 5.02; N, 15.24. C22H18N4O2 requires C,
71.34; H, 4.90; N, 15.13%]; νmax(KBr) 3314, 1636, 1597, 1565, 1318 cm-1; δH (300 MHz, CDCl3) 2.31
(3H, CH3), 2.44 (3H, CH3), 7.06-7.13 (2H, m), 7.20 (2H, d, J 8.2 Hz), 7.32-7.36 (3H, m), 7.54 (2H, d,
J 8.2 Hz), 8.08 (1H, d, J 2.0 Hz), 8.19-8.22 (1H, m); δC (75.46 MHz, CDCl3) 21.06, 21.34, 116.4,
117.5, 118.5, 120.0, 120.1, 122.2, 122.8, 130.2, 130.4, 131.8, 138.4, 139.2, 144.1, 151.5, 156.7, 157.7;
m/z (CI) 370 (M+, 30), 355 (100), 309 (25), 91 (75%).
4.1.1.6. N-(4-Chlorophenyl)-3-((4-chlorophenyl)imino)-3H-indol-2-amine (3f):
Light yellow solid (76%), m.p. 226-230 ºC; [Found: C, 65.43; H, 3.47; N, 11.33. C20H13Cl2N3 requires
C, 65.59; H, 3.58; N, 11.47%]; νmax(KBr) 3376, 1654, 1562, 1543, 777 cm-1; δH (300 MHz, CDCl3)
6.91-7.03 (4H, m), 7.17-7.22 (4H, m), 7.52 (2H, d, J 8.7 Hz), 7.84 (2H, d, J 7.5 Hz). δC (75.46 MHz,
CDCl3) 114.3, 114.9, 115.1, 121.5, 125.1, 125.5, 125.7, 126.4, 131.6, 137.8, 137.9, 138.4, 139.6,
143.0, 143.1, 144.0; m/z (CI) 366 (M+, 100), 254 (70), 239 (75), 126 (55), 111 (40%).
4.1.1.7. N-(4-Bromophenyl)-3-((4-bromophenyl)imino)-3H-indol-2-amine (3g):
Light red solid (79%), m.p. 222-225 ºC; [Found: C, 52.64; H, 2.75; N, 9.09. C20H13Br2N3 requires C,
52.78; H, 2.88; N, 9.23%]; νmax(KBr) 3445, 1713, 1562, 1442, 811 cm-1; δH (300 MHz, CDCl3) 6.77
(2H, d, J 7.6 Hz), 6.86 (2H, d, J 7.7 Hz), 7.22-7.33 (3H, m), 7.62 -7.70 (3H, m), 7.81 (2H, d, J 8.5
Hz); δC (75.46 MHz, CDCl3) 112.4, 116.1, 120.0, 120.7, 122.9, 123.5, 124.4, 126.1, 132.7, 133.3,
135.5, 146.2, 148.0, 149.0, 153.4, 155.6; m/z (CI) 454 (M+, 50), 374 (100), 294 (55), 219 (15), 155
(20%).
4.1.1.8. N-(4-Iodophenyl)-3-((4-iodophenyl)imino)-3H-indol-2-amine (3h):
Red solid (82%), m.p. 195-197 ºC; [Found: C, 43.88; H, 2.53; N, 7.81. C20H13I2N3 requires C, 43.74;
H, 2.39; N, 7.65%]; νmax(KBr) 3427, 1621, 1592, 1561, 808 cm-1; δH (300 MHz, CDCl3) 6.70-6.78
(2H, m), 6.85 (2H, d, J 8.5 Hz), 7.21 (1H, d, J 7.6 Hz), 7.28 -7.33 (1H, m), 7.62 (2H, d, J 8.4 Hz),
7.69 (2H, d, J 8.7 Hz), 7.78 (2H, d, J 8.4 Hz); δC (75.46 MHz, CDCl3) 86.9, 87.0, 119.0, 121.1, 121.1,
121.3, 123.2, 125.8, 135.1, 138.2, 138.2, 138.5, 138.5, 148.2, 157.1, 159.8; m/z (CI) 549 (M+, 40), 422
(100), 294 (35), 219 (20), 97 (30%).
4.1.2. General procedure for the synthesis of 1,4-benzoxazines derivatives (4):
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The solution of N-aryl-3-(arylimino)-3H-indol-2-amine 3 (0.30 g, 1.0 mmol) in 25 mL CH2Cl2 was
cooled to −20 ºC. Then, m-CPBA (0.26 g, 1.5 mmol) dissolved in 25 mL CH2Cl2 was added dropwise
to the stirred solution of 3. After stirring for 6 h at −20 °C, 1,4-benzoxazine 4 was formed (monitoring
by TLC). The crude product was poured into water and extracted with CH2Cl2 (3 × 15 mL). The
organic layer was dried over Na2SO4, and evaporation of the solvent afforded crude product 4. The
crude product 4 was purified on silica gel by column chromatography using 20% ethyl acetate/hexane
as eluent.
4.1.2.1. N-Phenyl-2-(phenylimino)-2H-benzo[b][1,4]oxazin-3-amine (4a):
Light yellow solid (78%), m.p. 118-120 ºC; [Found: C, 76.85; H, 4.98; N, 13.56. C20H15N3O requires
C, 76.66; H, 4.83; N, 13.41%]; νmax(KBr) 3426, 1650, 1592, 1444, 1025 cm-1; δH (300 MHz, CDCl3)
7.07-7.26 (5H, m), 7.41-7.52 (7H, m), 7.96 (2H, d, J 7.6 Hz), 8.74 (1H, NH); δC (75.46 MHz, CDCl3)
115.2, 119.7, 123.4, 123.6, 124.8, 125.1, 125.5, 126.3, 128.9, 129.0, 131.0, 138.8, 139.4, 143.6, 143.7,
144.5; m/z (CI) 313 (M+, 97), 210 (100), 181(30), 77 (68%).
4.1.2.2. N-(4-Methoxyphenyl)-2-((4-methoxyphenyl)imino)-2H-
benzo[b][1,4]oxazin-3-amine (4b):
Yellow solid (86%), m.p. 169-171 ºC; [Found: C, 70.92; H, 5.27; N, 11.41. C22H19N3O3 requires C,
70.76; H, 5.13; N, 11.25%]; νmax(KBr) 3441, 1651, 1538, 1243 cm-1; δH (300 MHz, CDCl3) 3.85 (3H,
s, OCH3), 3.88 (3H, s, OCH3), 6.95-7.00 (4H, m), 7.12 (2H, d, J 3.8 Hz), 7.16-7,21 (1H, m), 7.46 (1H,
d, J 7.6 Hz), 7.52 (2H, d, J 8.9 Hz), 7.85 (2H, d, J 8.9 Hz), 8.65 (1H, NH); δC (75.46 MHz, CDCl3)
55.5, 55.6, 114.1, 114.2, 115.0, 121.3, 121.4, 124.6, 124.7, 125.9, 132.1, 132.2, 136.4, 138.4, 143.3,
144.7, 155.8, 157.6; m/z (CI) 373 (M+, 60), 260 (50), 225 (100), 197 (20), 90 (30%).
4.1.2.3. N-(p-Tolyl)-2-(p-tolylimino)-2H-benzo[b][1,4]oxazin-3-amine (4c):
Light yellow solid (82%), m.p. 160-162 ºC; [Found: C, 77.22; H, 5.40; N, 12.14. C22H19N3O requires
C, 77.40; H, 5.61; N, 12.31%]; νmax(KBr) 3328, 1656, 1596, 1536, 1203 cm-1; δH (300 MHz, CDCl3)
2.38 (3H, s, CH3), 2.42 (3H, s, CH3), 7.10-7.17 (2H, m), 7.21-7.27 (5H, m), 7.35 (2H, d, J 7.6 Hz),
7.49 (1H, d, J 7.5 Hz), 7.82 (2H, d, J 7.2 Hz), 8.70 (1H, NH); δC (75.46 MHz, CDCl3) 20.9, 21.2,
115.1, 119.8, 123.8, 124.7, 124.8, 126.1, 129.5, 129.5, 132.1, 133.0, 135.3, 136.2, 139.1, 140.9, 143.3,
144.6; m/z (CI) 341 (M+, 100), 224 (95), 116 (20), 91 (55), 77 (20%).
4.1.2.4. 2-(p-Tolylimino)-7-bromo-N-p-tolyl-2H-benzo[b][1,4]oxazin-3-amine
(4d):
Light green (80%), m.p. 206-208 ºC; [Found: C, 63.05; H, 4.47; N, 10.17. C22H18BrN3O requires C,
62.87; H, 4.32; N, 10.00%]; νmax(KBr) 3447, 1655, 1602, 1563, 1472 cm-1; δH (300 MHz, CDCl3) 2.38
(3H, s, CH3), 2.42 (3H, s, CH3), 7.21-7.26 (5H, m), 7.31-7.37 (4H, m), 7.79 (2H, d, J 8.3 Hz), 8.74
(1H, br, NH); δC (75.46 MHz, CDCl3) 20.2, 20.4, 116.0, 117.5, 119.1, 123.1, 126.3, 127.1, 128.8,
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128.8, 130.6, 132.5, 135.0, 135.2, 137.4, 139.7, 142.7, 143.7; m/z (CI) 420 (M+, 60), 302 (100), 224
(20), 116 (25), 91 (90%).
4.1.2.5. 7-Nitro-N-(p-tolyl)-2-(p-tolylimino)-2H-benzo[b][1,4]oxazin-3-amine
(4e):
Yellow solid (83%), m.p. 224-227 ºC; [Found: C, 68.58; H, 4.86; N, 14.67. C22H18N4O3 requires C,
68.38; H, 4.70; N, 14.50%]; νmax(KBr) 3417, 1665, 1617, 1549, 1507, 1331, 818 cm-1; δH (300 MHz,
CDCl3) 2.40 (3H, s, CH3), 2.44 (3H, s, CH3), 7.24-7.26 (3H, m), 7.27-7.29 (1H, m), 7.37 (2H, d, J 8.2
Hz), 7.53 (1H, d, J 8.5 Hz), 7.81 (2H, d, J 7.6 Hz), 7.99 (1H, d, J 2.0 Hz), 8.08 (1H, d, J 8.2 Hz), 8.93
(1H, NH); δC (75.46 MHz, CDCl3) 21.1, 21.2, 111.2, 120.5, 120.6, 124.1, 125.9, 129.7, 129.7, 134.5,
135.2, 136.5, 137.4, 138.4, 139.9, 142.5, 143.5, 146.1; m/z (CI) 386 (M+,100), 370 (20), 269 (90), 239
(20), 195 (15), 118 (20), 91 (35%).
4.1.2.6. N-(4-Chlorophenyl)-2-((4-chlorophenyl)imino)-2H-benzo[b][1,4]oxazin-
3-amine (4f):
Light yellow solid (81%), m.p. 217-220 ºC; [Found: C, 62.66; H, 3.23; N, 10.81. C20H13Cl2N3O
requires C, 62.84; H, 3.43; N, 10.99%]; νmax(KBr) 3403, 1728, 1645, 1527, 1263, 1088 cm-1; δH (300
MHz, CDCl3) 7.07-7.25 (5H, m), 7.50 (1H, d, J 7.4 Hz), 7.71-7.76 (6H, m), 8.65 (1H, NH); δC (75.46
MHz, CDCl3) 116.5, 119.6, 121.8, 124.4, 126.6, 126.8, 127.3, 128.4, 129.4, 130.4, 130.8, 134.2,
136.5, 136.4, 141.3, 145.7; m/z (CI) 382 (M+, 30), 244 (70), 149 (100), 131 (30), 92 (20%).
4.1.2.7. N-(4-Bromophenyl)-2-((4-bromophenyl)imino)-2H-benzo[b][1,4]oxazin-
3-amine (4g):
Light yellow solid (79%), m.p. decomposed at 228 ºC; [Found: C, 50.77; H, 2.58; N, 8.71.
C20H13Br2N3O requires C, 50.99; H, 2.78; N, 8.92%]; νmax(KBr) 3437, 1649, 1611, 1535, 1073, 826
cm-1; δH (300 MHz, CDCl3) 7.10-7.27 (5H, m), 7.52-7.54 (5H, m), 7.84-7.86 (2H, m), 8.66 (1H, NH);
δC (75.46 MHz, CDCl3) 108.5, 112.3, 116.1, 116.7, 118.8, 119.9, 122.8, 125.8, 126.7, 126.8, 127.8,
128.9, 132.6, 134.2, 142.9, 144.6; m/z (CI) 471 (M+, 60), 290 (100), 209 (30), 155 (30), 102 (50), 75
(40%).
4.1.2.8. N-(4-Iodophenyl)-2-((4-iodophenyl)imino)-2H-benzo[b][1,4]oxazin-3-
amine (4h):
Yellow solid (85%), m.p. 206-210 ºC; [Found: C, 42.29; H, 2.11; N, 7.23. C20H13I2N3O requires C,
42.51; H, 2.32; N, 7.44%]; νmax(KBr) 3430, 1645, 1579, 1262, 806 cm-1; δH (300 MHz, CDCl3) 7.07-
7.24 (5H, m), 7.49 (1H, d, J 7.5 Hz), 7.68-7.76 (6H, m), 8.65 (1H, s, NH); δC (75.46 MHz, CDCl3)
86.4, 89.8, 115.2, 121.5, 125.2, 125.6, 125.7, 126.4, 131.6, 137.9, 138.0, 138.4, 139.6, 143.0, 143.2,
144.0; m/z (CI) 565 (M+, 65), 336 (70), 209 (50), 167 (40), 102 (60), 76 (100%).
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4.1.3. General procedure for the synthesis of N-oxides (5):
The solution of m-CPBA (0.26 g, 1.5 mmol) dissolved in 25 mL CH2Cl2 was added dropwise to the
stirred solution of N-aryl-3-(arylimino)-3H-indol-2-amine 3 (1.0 mmol) in 25 mL CH2Cl2 at room
temperature. After stirring for 6 h, N-oxide 5 was formed (monitoring by TLC). The crude product
was poured into water and extracted with ethyl acetate (3 × 15 mL). The organic layer was dried over
Na2SO4, and evaporation of the solvent afforded crude product 5. The crude product 5 was purified on
silica gel by column chromatography using 30% ethyl acetate/hexane as eluent.
4.1.3.1. (Z)-N-Phenyl-2-(phenylamino)-3H-indol-3-imine oxide (5a):
Violet solid (51%) yield, m.p. 183-184 ºC; [Found: C, 76.51; H, 4.66; N, 13.25. C20H15N3O requires
C, 76.66; H, 4.83; N, 13.41%]; νmax(KBr) 3421, 1617, 1565, 1442, 1195, 754 cm-1; δH (300 MHz,
CDCl3) 5.89 (1H, d, J 7.8 Hz), 6.63 (1H, t, J 7.5 Hz), 7.16 (1H, t, J 7.4 Hz), 7.22-7.33 (1H, m), 7.44
(3H, t, J 7.6 Hz), 7.55-7.58 (2H, m), 7.64-7.70 (3H, m), 7.99 (2H, d, J 8.0 Hz), 11.45 (1H, NH); δC
(75.46 MHz, CDCl3) 118.6, 119.3, 120.8, 121.6, 122.7, 123.3, 124.2, 129.1, 129.3, 130.4, 131.4,
132.4, 138.4, 142.6, 145.7, 155.5; m/z (CI) 313 (M+, 72), 296 (75), 221 (50), 119 (45), 77 (100%).
4.1.3.2. (Z)-N-(4-Methoxyphenyl)-2-((4-methoxyphenyl)amino)-3H-indol-3-imine
oxide (5b):
Red solid (47%), m.p. 188-192 ºC; [Found: C, 70.51; H, 4.90; N, 11.02. C22H19N3O3 requires C,
70.76; H, 5.13; N, 11.25%]; νmax(KBr) 3400, 1652, 1609, 1560 cm-1; δH (300 MHz, CDCl3) 3.85 (3H,
s, OCH3), 3.95 (3H, s, OCH3), 6.11 (1H, d, J 7.8 Hz), 6.67 (1H, t, J 7.5 Hz), 6.99 (2H, d, J 8.7 Hz),
7.11 (2H, d, J 8.6 Hz), 7.25-7.33 (2H, m), 7.51 (2H, d, J 8.6 Hz), 7.91 (2H, d, J 8.7 Hz), 11.58 (1H,
NH); δC (75.46 MHz, CDCl3) 55.5, 55.8, 114.6, 115.1, 118.2, 119.2, 121.4, 122.3, 122.7, 124.9,
124.9, 129.5, 131.4, 132.3, 138.9, 143.2, 156.5, 161.5; m/z (CI) 373 (M+, 50), 357 (55), 250 (40), 167
(20), 93 (30), 77 (100%).
4.1.3.3. (Z)-N-(p-Tolyl)-2-(p-tolylamino)-3H-indol-3-imine oxide (5c):
Violet solid (49%), m.p. 215-218 ºC; [Found: C, 77.61; H, 5.79; N, 12.50. C22H19N3O requires C,
77.40; H, 5.61; N, 12.31%]; νmax(KBr) 3410, 1715, 1619, 1565, 1439, 1101, 751 cm-1; δH (300 MHz,
CDCl3) 2.38 (3H, s, CH3), 2.54 (3H, s, CH3), 5.98 (1H, d, J 7.6 Hz), 6.61-6.67 (1H, m), 7.23-7.26
(4H, m), 7.42-7.46 (4H, m), 7.87 (2H, d, J 8.3 Hz), 11.45 (1H, NH); δC (75.46 MHz, CDCl3) 21.1,
21.5, 103.1, 118.4, 119.5, 120.7, 121.3, 122.7, 123.1, 129.8, 130.8, 132.2, 133.8, 135.9, 141.8, 142.5,
143.5, 155.6; m/z (CI) 341 (M+, 80), 324 (100), 235 (20), 91 (50%).
4.1.3.4. (Z)-5-Bromo-N-(p-tolyl)-2-(p-tolylamino)-3H-indol-3-imine oxide (5d):
Grey solid (55%), m.p. 218-222 ºC; [Found: C, 62.68; H, 4.17; N, 9.81. C22H18BrN3O requires C,
62.87; H, 4.32; N, 10.00%]; νmax(KBr) 3453, 1622, 1560, 1211, 817 cm-1; δH (300 MHz, CDCl3) 2.38
(3H, s, CH3), 2.55 (3H, s, CH3), 6.06 (1H, s), 7.14-7.26 (4H, m), 7.31-7.48 (5H, m), 7.84 (2H, d, J 8.2
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Hz), 11.38 (1H, NH); δC (75.46 MHz, CDCl3) 21.1, 21.6, 113.7, 119.6, 121.0, 123.0, 125.4, 127.7,
129.6, 129.9, 130.9, 131.2, 134.2, 134.6, 142.3, 143.2, 151.8, 155.4; m/z (CI) 420 (M+, 100), 404 (70),
388 (80), 314 (20), 107 (20), 91 (70), 81 (10%).
Supplementary data
Supplementary data associated with this article can be found in the online version, at
http://dx.doi.org/.
Acknowledgements
We gratefully acknowledge the financial support from the Research Council of Shahid Beheshti
University and University of Kashan.
References and notes
1.
2.
Sainsbury, M. Comprehensive Heterocyclic Chemistry, 3, 995-1038.
Touzeau, F.; Arrault, A.; Guillaumet, G.; Scalbert, E.; Pfeiffer, B.; Rettori, M.-C.; Renard, P.;
Mérour, J.-Y. Journal of medicinal chemistry 2003, 46, 1962-1979.
Hayakawa, I.; Atarashi, S.; Yokohama, S.; Imamura, M.; Sakano, K.; Furukawa, M.
Antimicrobial agents and chemotherapy 1986, 29, 163-164.
Kosemura, S.; Yamamura, S.; Anai, T.; Hasegawa, K. Tetrahedron Letters 1994, 35, 8221-
8224.
Patil, V. P.; Markad, V. L.; Kodam, K. M.; Waghmode, S. B. Bioorganic & medicinal
chemistry letters 2013, 23, 6259-6263.
Jubinsky, P. T.; Short, M. K.; Ghanem, M.; Das, B. C. Bioorganic & medicinal chemistry
letters 2011, 21, 3479-3482.
Sugimoto, Y.; Otani, T.; Oie, S.; Wierzba, K.; Yamada, Y. The Journal of antibiotics 1990,
43, 417-421.
Largeron, M.; Lockhart, B.; Pfeiffer, B.; Fleury, M.-B. Journal of medicinal chemistry 1999,
42, 5043-5052.
Koini, E. N.; Avlonitis, N.; Martins-Duarte, E. S.; de Souza, W.; Vommaro, R. C.;
Calogeropoulou, T. Tetrahedron 2012, 68, 10302-10309.
Miles, D.; Petrovna, K.; Naser, S.; Yurjevich, S.; Goun, E.; Michailovich, S. “Patent 2003,
US 6649, 610”; Chem. Abstr, 2003.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Bhuniya, D.; Das, S. K.; Madhavan, G. R.; Iqbal, J.; Chakrabarti, R.; Google Patents, 2008.
Ilaš, J.; Anderluh, P. Š.; Dolenc, M. S.; Kikelj, D. Tetrahedron 2005, 61, 7325-7348.
Achari, B.; Mandal, S. B.; Dutta, P. K.; Chowdhury, C. Synlett 2004, 2449-2467.
Tian, Y.; Wang, X.; Xiao, Q.; Sun, C.; Yin, D. The Journal of organic chemistry 2014, 79,
9678-9685.
15.
16.
Liu, B.; Yin, M.; Gao, H.; Wu, W.; Jiang, H. The Journal of organic chemistry 2013, 78,
3009-3020.
Sharifi, A.; Abaee, M. S.; Mokhtare, Z.; Mirzaei, M. Environmental chemistry letters 2014,
12, 365-370.
17.
18.
19.
Singh, S. K.; Bajpai, A. K.; Saini, R. Tetrahedron Letters 2013, 54, 7132-7135.
Brahma, K.; Das, B.; Chowdhury, C. Tetrahedron 2014, 70, 5863-5871.
Buon, C.; Chacun-Lefevre, L.; Rabot, R.; Bouyssou, P.; Coudert, G. Tetrahedron 2000, 56,
605-614.
20.
21.
Liu, Z.; Chen, Y. Tetrahedron Letters 2009, 50, 3790-3793.
Deshmukh, M. S.; Das, B.; Jain, N. RSC Advances 2013, 3, 22389-22396.
14

ACCEPTED MANUSCRIPT
22.
23.
24.
25.
Zhang, Y.-R.; Xie, J.-W.; Huang, X.-J.; Zhu, W.-D. Organic & biomolecular chemistry 2012,
10, 6554-6561.
Kianmehr, E.; Ghanbari, M.; Niri, M. N.; Faramarzi, R. Journal of combinatorial chemistry
2009, 12, 41-44.
Taghizadeh, M. J.; Arvinnezhad, H.; Samadi, S.; Jadidi, K.; Javidan, A.; Notash, B.
Tetrahedron Letters 2012, 53, 5148-5150.
Salahi, F.; Taghizadeh, M. J.; Arvinnezhad, H.; Moemeni, M.; Jadidi, K.; Notash, B.
Tetrahedron Letters 2014, 55, 1515-1518.
26.
27.
Samadi, S.; Jadidi, K.; Notash, B. Tetrahedron: Asymmetry 2013, 24, 269-277.
Kianmehr, E.; Ghanbari, M.; Faghih, N.; Rominger, F. Tetrahedron Letters 2012, 53, 1900-
1904.
28.
29.
30.
Kianmehr, E.; Ghanbari, M. European Journal of Organic Chemistry 2012, 2012, 256-259.
Kianmehr, E.; Zafarghandi, N. S.; Ghanbari, M. Molecular diversity 2013, 17, 383-388.
Ghanbari, M.; Kianmehr, E.; Behzad, S. K.; Ng, S. W. Journal of the Iranian Chemical
Society 2016, 13, 7-18.
31.
32.
GRIMSHAW, J.; BEGLEY, W. J. Synthesis 1974, 1974, 496-498.
Mehrdad, M.; Ghanbari, M.; Jadidi, K.; Salemi, A.; Khavasi, H. R. Acta Crystallographica
Section E: Structure Reports Online 2010, 67, o49-o49.
33.
CCDC-807666 (4b) contains the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
34.
35.
Asgri, D.; Ghanbari, M.; Mehrdad, M.; Jadidi, K.; Khavasi, H. R. Acta Crystallographica
Section E: Structure Reports Online 2011, 67, o350-o350.
CCDC-811521 (5d) contains the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
36.
Kurti, L.; Czakó, B. Strategic applications of named reactions in organic synthesis; Elsevier,
2005.
37.
38.
39.
Krow, G. R. Organic Reactions 1993.
Azizian, J.; Mehrdad, M.; Jadidi, K.; Sarrafi, Y. Tetrahedron Letters 2000, 41, 5265-5268.
Jadidi, K.; Ghahremanzadeh, R.; Mehrdad, M.; Ghanbari, M.; Arvin-Nezhad, H. Monatshefte
für Chemie-Chemical Monthly 2008, 139, 277-280.
40.
41.
42.
43.
Tennant, G. Sutherland Pergamon Press Oxford 1979, 2, 385.
Lee, T. D.; Keana, J. F. The Journal of Organic Chemistry 1976, 41, 3237-3241.
Christensen, D.; Joergensen, K. A. The Journal of Organic Chemistry 1989, 54, 126-131.
Bohé, L.; Lusinchi, M.; Lusinchi, X. Tetrahedron 1999, 55, 141-154.
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