Three-component synthesis of 2-imino-1,4-benzoxazines

Article abstract of DOI:10.1016/j.tet.2009.04.080

A series of 2-imino-1,4-benzoxazines (8a-e) were prepared by the one-pot, three-component, condensation of salicylaldehyde (4), various ortho-aminophenols (5), and 2,6-dimethylphenylisonitrile (6). The structures of four of the crystalline benzoxazine der

Full text of DOI:10.1016/j.tet.2009.04.080

Tetrahedron 65 (2009) 5337–5342
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Three-component synthesis of 2-imino-1,4-benzoxazines
a
a
,
b
b
*
´
´
´
´
Ma. Carmen Garcıa-Gonzalez , Eduardo Gonzalez-Zamora , Rosa Santillan , Oscar Domınguez ,
c
c
´
´
´
Jose Manuel Mendez-Stivalet , Norberto Farfan
a
´
´
´
Departamento de Quımica, Universidad Autonoma Metropolitana-Iztapalapa, San Rafael Atlixco 186, Col. Vicentina Iztapalapa, Mexico D.F. 09340, Mexico
b Departamento de Qu´ımica, Centro de Investigacio´n y de Estudios Avanzados del IPN, Apdo. Postal 14-740, Me´xico D.F. 07000, Mexico
c
´
´
´
´
Facultad de Qu´ımica, Departamento de Qu´ımica Organica, Universidad Nacional Autonoma de Mexico, Mexico D.F. 04510, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 2-imino-1,4-benzoxazines (8a–e) were prepared by the one-pot, three-component, condensation
of salicylaldehyde (4), various ortho-aminophenols (5), and 2,6-dimethylphenylisonitrile (6). The structures
of four of the crystalline benzoxazine derivatives (8b–e) were unambiguously established by X-ray analysis.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 25 February 2009
Received in revised form 7 April 2009
Accepted 20 April 2009
Available online 3 May 2009
This paper is dedicated to the memory of
Bertha Maqueda
Keywords:
2-Imino-1,4-benzoxazines
Imine
Multicomponent reactions
1. Introduction
In 1964, Weidinger and Kranz reported the first and to date the
only synthesis of 2-imino-3-amino-1,4-benzoxazines (1) by the
condensation of various ortho-aminophenols with oxalyl bis-
methylimidate under acidic conditions (Scheme 1).1 In contrast,
several routes to the related 3-oxo-2H-1,4-benzoxazine 2a (Fig. 1),
which sometimes are used as precursors of biologically active
compounds, have been reported.2 For example, these compounds
and derivatives thereof can be prepared from ortho-aminophenols
and 1,2-dibromoethane3 or ethyl 2-bromopropionate.4,5
Figure 1.
isocyanide derivative is a component common to all three of these
coupling processes. Thus, these reactions have become known as
isocyanide-based multicomponent reactions (IMCR).6 Indeed,
Table 1
Selected 1H, 13C NMR (ppm), and IR (cmꢀ1) data for compounds 8a–e
Compounds 1H NMR 13C NMR 13C NMR IR (C]N)
Yielda (%) Yieldb (%)
two-steps one-pot
Scheme 1. Synthesis of imino-1,4-benzoxazines.
(ppm)
(H-6)
(ppm)
C-7
(ppm)
C-14
(cmꢀ1
)
Multicomponent reactions have become of considerable impor-
tance in synthetic organic chemistry.6 The Passerini three-compo-
nent reaction (P-3CR), and the Ugi three- and four-component
reactions (U-3CR, and U-4CR) are of particular importance, and an
8a
8b
8c
8d
8e
9.19
9.16
9.18
9.29
9.17
1156.9
154.7
153.5
151.9
152.2
134.0
129.9
129.0
135.7
140.4
1659, 1610 33
1670, 1590 45
1665, 1618 47
1666, 1611 43
1660, 1618 41
78
93
90
45
83
a
* Corresponding author. Tel.: þ52 55 58 04 49 13; fax: þ52 55 58 04 46 66.
Isolated yield.
Yields were determined by 1H NMR.
b
´
E-mail address: egz@xanum.uam.mx (E. Gonzalez-Zamora).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.080

´
5338
Ma.C. Garc´ıa-Gonzalez et al. / Tetrahedron 65 (2009) 5337–5342
Scheme 2. Preparation of 2-imino-1,4-benzoxazines.
a recent synthesis of 3,4-dihydro-3-oxo-2H-1,4-benzoxazine (2b) is
based on an U-4CR process,7 and a one-pot, multicomponent route
to 4-imino-4H-3,1-benzoxazines 3 has also been described.8
It occurred to us that 2-imino-1,4-benzoxazine derivatives
might be accessible via a multicomponent process involving an
arylisocyanide, an ortho-aminophenol, and a salicylaldehyde. This
article describes our initial results in this area.
ammonium chloride (1.2 equiv) was briefly (0.5 h) stirred at room
temperature and then an equivalent of 2,6-dimethylphenylisoni-
trile (6) was added. Heating at reflux temperature was required for
a reasonable reaction rate to be observed, and the yield of the
crystalline product 8a (Table 1) was significantly better in the
presence of ammonium chloride. In the same way, the imino-
benzoxazines 8b–e were produced, all except the sterically hin-
dered compound 8d being obtained in good yield. The benzoxazine
derivatives could also be obtained by first preparing the putative
Schiff base intermediates 7a–e ex situ,9 followed by addition of the
isonitrile 6, but the reactions had to be conducted under more
vigorous conditions (120 ꢁC, sealed tube), Scheme 2. In addition,
2. Results and discussion
An anhydrous toluene solution of an equimolar mixture of sal-
icylaldehyde (4) and the ortho-aminophenol (5a) containing
Figure 2. X-ray molecular structures of compounds 8b, 8c, 8d, and 8e. Ellipsoids are drawn at 35% probability level.

´
Ma.C. Garc´ıa-Gonzalez et al. / Tetrahedron 65 (2009) 5337–5342
5339
Table 2
Crystallographic data for compounds 8b–e
Compounds
8b
8c
8d
8e
Crystal data
Formula
Crystal size
FW (g molꢀ1
Space group
C22H17Cl N2O2
0.50ꢂ0.50ꢂ0.45
376.84
C22H18N2O2
0.55ꢂ0.30ꢂ0.30
342.38
C23H20N2O2
0.30ꢂ0.10ꢂ0.10
356.43
C23H20 N2O2
0.50ꢂ0.45ꢂ0.17
356.43
)
P21/a
P21/c
P21/n
P21/c
Cell parameters
a (Å)
b (Å)
14.8591(4)
7.4213(3)
16.9179(5)
90.00
101.759(2)
90.00
1826.45(10)
4
1.370
7.2055(2)
9.2170(3)
26.1763(8)
90.00
93.110(2)
90.00
1735.89(9)
4
1.310
13.4609(4)
7.4313(2)
18.9330(6)
90.00
101.1460
90.00
1858.18(9)
4
1.274
15.0887(13)
5.822(3)
22.020(3)
90.00
109.481(8)
90.00
1823.6(8)
4
1.298
c (Å)
a
b
g
(ꢁ)
(ꢁ)
(ꢁ)
V (Å3)
Z
dcalcd (Mg mꢀ3
)
Data collection
Limit of
q
2.46–54.92
7035
4103
6.44–54.90
8085
3381
3.42–55.30
18,568
4268
4.02–55.38
7598
4039
Total reflections
Unique reflections
Refinement
R/Rw (F)a
0.0499/0.1305
0.0827/0.1524
1.058
0.0710/0.1782
0.1293/0.2098
1.056
0.0608/0.1473
0.1539/0.1945
1.020
0.0459/0.1197
0.0680/0.1378
1.044
R/Rw (F2) (all data)
Goodness-of-fit
Number of variables
250
235
246
249
Drmin (e Åꢀ3
Drmax (e Åꢀ3
)
)
ꢀ0.305
ꢀ0.243
ꢀ0.291
ꢀ0.165
0.220
0.266
0.284
0.167
T¼293 K, lMoK ¼0.7173 radiation.
a
P
P
P
P
a
2
2 1=2
R ¼ ðjjFojꢀjFcjjÞ= jFoj; Row ¼ ½ wðjFojꢀjFcjÞ = wjFoj ꢃ
:
the product yields were considerably lower (See Table 1) than for
the three-component, ammonium chloride, presumably acid cata-
lyzed10 process.
benzoxazines. In contrast, these distances are very similar in the
benzoxazine 8b [1.304(2) Å] and the imine 7b [1.303(2) Å].13 The
oxazine rings defined by the N(1)–C(7)–C(14)–O(2)–C(9)–C(8)
fragment are nearly planar in all compounds, as evidenced
by observation of the N(1)–C(7)–C(14), C(14)–O(2)–C(9), and
C(7)–N(1)–C(8) bond angles, whose values are very close to 120ꢁ
(Table 3).
The 1H and 13C NMR spectra of the products provide strong
support for the benzoxazine structure (see Table 1 for selected NMR
spectroscopic data.). Thus, all of the compounds showed a low field
signal at
d 9.16–9.29 attributable to H-6, which is deshielded by the
isonitrile derived imine nitrogen atom. These signals are shifted
It is of considerable importance that the crystal structures of
benzoxazines 8b–e show two intramolecular interactions (D–H/
A), between O(1)–H(1)/N(1) and C(6)–H(6)/N(2), with distances
ranging from 1.79 to 1.87 Å (A/H) and 2.512 to 2.578 Å (D/A) for
O(1)–H(1)/N(1), while the C(6)–H(6)/N(2) distances are from
2.21 to 2.42 Å (A/H) and 2.857 to 2.936 Å (D/A). This proximity is
fully consistent with the strong deshielding of H-6 found in the 1H
NMR spectra of the benzoxazine derivatives.
downfield by ca. 1.7 d with respect to the corresponding signals for
the precursor Schiff bases.9a, 11a It should be noted that the 1H NMR
signals for the aromatic rings were assigned based on their COSY
spectra. The 13C spectra showed signals corresponding to the oxa-
zine carbons, at d 151.9–156.9 for C-7, and at d 129.0–140.4 for C-14.
The assignment of the quaternary carbon atoms was determined
from an analysis of long-range correlations using the HMBC tech-
nique. For example, C-7 in 8c shows a long-range correlation with
A possible reaction sequence that accounts for the formation of
the 2-imino-1,4-benzoxazines is depicted in Scheme 3. Initial
condensation of salicylaldehyde 4 with an aminophenol 5 gives the
H-6 and H-3 and, C-14, which resonates at
d 129.0 correlates with
H-10. In addition, C-9 exhibits a correlation with H-13 and H-12.
The HMBC spectra thus allowed assignment of all of the quaternary
carbons of the benzoxazines.
Table 3
Crystals suitable for X-ray diffraction were obtained for all of the
benzoxazines except 8a. These were produced by slow evaporation
of concentrated solutions thereof from various solvent systems [8b
(chloroform–hexane); 8c (hexane); 8d, 8e (acetone–hexane)]. The
crystal structures for these compounds are shown in Figure 2, and
the details of the crystal data and summary of the collection pa-
rameters are given in Table 2. The compounds crystallized in
monoclinic space groups, P21/a, P21/c, P21/n, and P21/c for 8b, 8c,
8d, and 8e, respectively.
The X-ray analysis unambiguously established the structure of
the benzoxazines 8b–e (Fig. 2). The data shows that the bond
distances for C(7)–N(1) and C(14)–N(2) range from 1.251(2) to
1.312(3) Å, in agreement with the values reported for a C–N
double bond.12 Moreover, the C(7)–N(1) distance in benzoxazines
8c and 8e [1.300(3) and 1.294(2) Å] are shorter than for the cor-
responding imine precursors 7c and 7e [1.317(6) and 1.323(6) Å],11
which is the evidence for a stronger C(7)–N(1) bond in these
Selected bond lengths (Å) and angles (ꢁ) for 8b–e
Compounds
8b
8c
8d
1.491(3)
8e
1.465(2)
Bond distances (Å)
C(1)–C(7)
C(7)–C(14)
C(7)–N(1)
C(8)–N(1)
C(9)–O(2)
C(14)–N(2)
C(14)–O(2)
Bond angles (ꢁ)
N(1)–C(7)–C(1)
N(1)–C(7)–C(14)
N(2)–C(14)–O(2)
N(2)–C(14)–C(7)
O(2)–C(14)–C(7)
C(14)–O(2)–C(9)
C(7)–N(1)–C(8)
1.474(2)
1.475(4)
1.506(4)
1.300(3)
1.391(3)
1.387(3)
1.258(3)
1.382(3)
1.500(2)
1.304(2)
1.391(2)
1.3779(19)
1.255(2)
1.376(2)
1.490(4)
1.312 (3)
1.396(4)
1.393(3)
1.257(3)
1.371(3)
1.490(2)
1.294(2)
1.385(2)
1.377(2)
1.251(2)
1.3694(19)
117.35(15)
119.96(15)
119.82(16)
123.15(16)
117.00(14)
121.19(13)
120.86(14)
117.4(2)
119.5(2)
119.9(2)
123.9(2)
116.2(2)
120.4(2)
121.6(2)
118.1(2)
120.0(2)
120.2(2)
123.2(3)
116.6(2)
120.2(2)
120.58(18)
118.51(14)
120.36(15)
120.58(14)
123.24(15)
116.12(14)
119.62(13)
120.25(13)

´
5340
Ma.C. Garc´ıa-Gonzalez et al. / Tetrahedron 65 (2009) 5337–5342
Scheme 3. Mechanism proposed for the formation of benzoxazines.
Scheme 4. Synthesis of 2-oxoacetamide.
Schiff base 7, which reacts with the isonitrile 6 to give the nitrilium
intermediate 9. Nucleophilic attack by the oxygen of the ortho-
aminophenol on the electrophilic isonitrile derived carbon atom
gives 2-imino-3,4-dihydrobenzoxazine 10, which on subsequent
oxidation14 provides the 2-imino-benzoxazine, 8 (path a). The
alternative cyclization, which would involve the salicylaldehyde
hydroxyl moiety and subsequent oxidation leading to formation of
the imino-1-benzofuran 12, was not observed (Scheme 3, path b). It
is possible that the putative NH precursor of 12 is in equilibrium
with 9, and that the formation of 10 and the final product 8 is
thermodynamic sink driving the reaction exclusively to the
observed benzoxazines.
To cast light on the importance of the hydroxyl group of the
ortho-aminophenols in the formation of the benzoxazines, the
Schiff base 13 was prepared and reacted with isonitrile 6 (Scheme
4). The only product isolated, after column chromatographic puri-
fication, was the 2-oxoacetamide derivative 14 (37% yield), the
formation of which is precedented.15 Thus the presence of the
hydroxyl group of the ortho-aminophenol is a requirement for
the generation of the benzoxazines 8a–e, and this is a limitation of
the synthesis described herein.
Additionally, the X-ray diffraction study of 14 allowed
its structural determination. The bond distances for C(7)–O(2),
C(8)–O(3), and C(8)–N(1) are 1.229(3), 1.243(3), and 1.324(3) Å,
respectively. Compound 14 crystallized in the monoclinic space
group P21/c with two molecules in the asymmetric unit (Fig. 3).
Figure 3. X-ray molecular structure of 2-oxoacetamide 14. Ellipsoids are drawn at 35%
probability level.

´
Ma.C. Garc´ıa-Gonzalez et al. / Tetrahedron 65 (2009) 5337–5342
5341
3. Conclusions
dimethylphenylisonitrile. The product 8a was obtained as an or-
ange solid, 78% yield, mp 215–217 ꢁC. IR vmax (KBr) 3433 (OH), 3103,
1659 (C]N), 1610, 1530, 1341, 1236, 770 cmꢀ1. 1H NMR (300 MHz,
In summary, a one-pot synthesis of five new 2-imino-1,4-ben-
zoxazines was achieved by a multicomponent process involving
salicylaldehyde, an ortho-aminophenol, and 2,6-dimethylphenyli-
sonitrile, in the presence of a stoichiometric amount of ammonium
chloride. The ortho hydroxyl group in the aminophenol is essential
for the formation of the benzoxazine ring system.
CDCl3)
d
: 13.38 (1H, br s, OH), 9.19 (1H, dd, J¼8.3, 1.5 Hz, H-6), 8.12
(1H, dd, J¼8.7, 2.3 Hz, H-12), 7.87 (1H, d, J¼2.3 Hz, H-10), 7.75 (1H,
d, J¼8.7 Hz, H-13), 7.51 (1H, ddd, J¼8.5, 7.0, 1.5 Hz, H-4), 7.17–7.05
(4H, m, H-3, H-17, H-18), 6.98 (1H, ddd, J¼8.3, 7.0, 1.0 Hz, H-5), 2.17
(6H, s, H-19). 13C NMR (75 MHz, CDCl3)
d: 163.3 (C-2), 156.9 (C-7),
147.8 (C-11), 145.8 (C-9), 143.0 (C-8), 138.9 (C-15), 135.7 (C-4), 134.0
(C-14), 133.4 (C-6), 128.5 (C-17), 127.9 (C-13), 126.9 (C-16), 124.9 (C-
18), 120.3 (C-12), 119.6 (C-5), 118.9 (C-3), 117.0 (C-1), 111.8 (C-10),
19.0 (C-19). MS (20 eV) m/z: 388 ([Mþ1]þ, 9), 387 ([M]þ, 35), 372
(65), 267 (100), 256 (95), 210 (19), 182 (40), 43 (11). HRMS:
C22H18N3O4, [MþþH]þ calcd 388.1292, found 388.1290, error
0.4707.
4. Experimental
4.1. General information
All reagents were purchased from Aldrich. Toluene was rou-
tinely dried (sodium/benzophenone).16 All reactions requiring an-
hydrous conditions were performed under a nitrogen atmosphere.
Melting points were recorded using an Electrothermal 9200 melt-
ing point apparatus. Infrared spectra were measured on a FTIR
Perkin–Elmer GX spectrophotometer using KBr pellets. Mass
spectra were obtained on a Hewlett–Packard 5989A spectrometer.
The high resolution mass spectra (HRMS) were taken on Agilent
Technologies, model 1100 coupled MSD-TOF spectrometer with
APCI as ionization source. 1H and 13C NMR spectra were recorded on
a Bruker avance DPX 300, Jeol GX 270, Jeol Eclipse þ400, and
4.3.4. 2-(2-(2,6-Dimethylphenylimino)-6-chloro-2H-
benzo[b][1,4]oxazin-3-yl)phenol (8b)
Compound 8b was obtained from 0.25 g (1.74 mmol) of 2-amino-
4-chlorophenol, 0.12 g (1.74 mmol) of salicylaldehyde, 0.11 g
(2.08 mmol) of ammonium chloride, and 0.27 g (2.08 mmol) of 2,6-
dimethylphenylisonitrile. The product was obtained as an orange
solid (0.54 g), 93% yield, mp 185–187 ꢁC. IR vmax (KBr) 3365 (OH),
2918, 1670 (C]N), 1590, 1443, 1235, 770 cmꢀ1. 1H NMR (400 MHz,
Bruker AMX 500 spectrometers. Chemical shifts (
d) are reported in
CDCl3)
d
: 13.30 (1H, br s, OH), 9.16 (1H, dd, J¼8.3, 1.5 Hz, H-6), 7.59
parts per million (ppm) relative to Si(CH3)4 for 1H and 13C. NMR
experiments were carried out in deuterochloroform (CDCl3). Cou-
pling constants (J) are reported in hertz (Hz), peak multiplicity is
indicated as follows: s: singlet, d: doublet, m: multiplet, br s: broad
singlet for proton spectra.
(1H, d, J¼2.4 Hz, H-13), 7.43 (1H, ddd, J¼8.3, 7.2, 1.5 Hz, H-4), 7.25
(1H, dd, 8.6, 2.4 Hz, H-11), 7.12 (2H, d, J¼7.7 Hz, H-17), 7.09–7.06 (2H,
m, H-3, H-18), 6.96–6.91 (2H, m, H-5, H-10), 2.16 (6H, s, H-19). 13C
NMR (100 MHz, CDCl3) d: 162.1 (C-2), 154.7 (C-7), 144.3 (C-9), 143.1
(C-8),139.8 (C-15),134.3 (C-4),132.8 (C-6),130.0 (C-11),129.9 (C-14),
129.8 (C-12), 128.0 (C-17), 126.9 (C-16), 126.8 (C-13), 124.2 (C-18),
118.9 (C-10), 118.5 (C-3), 117.1 (C-1), 116.7 (C-5), 18.7 (C-19). MS m/z:
378 ([Mþ2]þ, 9), 377 ([Mþ1]þ, 6), 376 ([M]þ, 23), 361 (65), 258 (25),
256 (63), 245 (100), 217 (29), 133 (12). HRMS: C22H18ClN2O2
[MþþH]þ, calcd 377.1051, found 377.1055, error 0.9754.
4.2. X-ray crystallography
Single crystal X-ray diffraction studies were realized on a KAPPACCD
diffractometer. Solution and refinement: direct methods SHELXS-8617
and SIR-200418 for structure solution and the SHELXL-9719 software
package for refinement and data output. For compounds 8b–e and 14
full crystallographic data were submitted as CIF files with the Cam-
bridge Crystallographic Data Center, CCDC Nos. 718286 for 8b, 718287
for 8c, 718285 for 8d, 718284 for 8e, and 718283 for 14.
4.3.5. 2-(2-(2,6-Dimethylphenylimino)-2H-benzo[b][1,4]oxazin-
3-yl)phenol (8c)
Compound 8c was obtained from 0.25 g (2.00 mmol) of 2-ami-
nophenol, 0.22 g (2.00 mmol) of salicylaldehyde, 0.13 g (2.40 mmol)
of ammonium chloride, and 0.32 g (2.40 mmol) of 2,6-dimethyl-
phenylisonitrile. The product was obtained as a yellow solid, 90%
yield, mp 124–125 ꢁC. IR vmax (KBr) 3361 (OH), 2971, 1665 (C]N),
4.3. General procedure for the preparation of benzoxazines
4.3.1. Method A
1618, 1464, 1228, 754 cmꢀ1. 1H NMR (500 MHz, CDCl3)
d: 13.58 (1H,
2,6-Dimethylphenylisonitrile 6 (2.00 mmol) and Schiff bases 7a–
e (1.00 mmol) in 2 ml of dry toluene were placed in a sealed ampule
and heated for 16–24 h at 120 ꢁC under a nitrogen atmosphere. The
solvent was removed under vacuum and the product was purified by
column chromatography on silica gel using hexane as the eluant.
br s, OH), 9.18 (1H, dd, J¼8.3, 1.7 Hz, H-6), 7.56 (1H, dd, J¼7.8, 1.7 Hz,
H-13), 7.39 (1H, ddd, J¼8.3, 7.1, 1.7 Hz, H-4), 7.26 (1H, ddd, J¼8.1, 7.4,
1.7 Hz, H-11), 7.19 (1H, ddd, J¼8.1, 7.4, 1.7 Hz, H-12), 7.10 (1H, d,
J¼7.7 Hz, H-17), 7.05 (1H, dd, J¼8.3, 1.3 Hz, H-3), 6.99 (1H, t,
J¼7.7 Hz, H-18), 6.94–6.89 (2H, m, H-5, H-10), 2.15 (6H, s, H-19). 13C
NMR (125 MHz, CDCl3) d: 161.8 (C-2), 153.4 (C-7), 145.5 (C-9), 143.2
4.3.2. Method B
(C-15),140.1 (C-8),133.6 (C-4),132.5 (C-6),130.1 (C-11),129.0 (C-14),
127.8 (C-17), 127.1 (C-13), 126.9 (C-16), 124.7 (C-12), 123.8 (C-18),
118.6 (C-5), 118.1 (C-3), 117.2 (C-1), 115.4 (C-10), 18.5 (C-19). MS m/z:
343 ([Mþ1]þ, 6), 342 ([M]þ, 24), 327 (32), 222 (83), 211 (100), 183
(27), 133 (16). HRMS: C22H19N2O2 [MþþH]þ, calcd 343.1441, found
343.1445, error 1.1526.
Salicylaldehyde 4 (1.00 mmol) was added to a solution of the
amines 5a–e (1.00 mmol) in 15 ml of dry toluene followed by am-
monium chloride (1.20 mmol) and the mixture was stirred for
30 min at room temperature. Finally, 2,6-dimethylphenylisonitrile
6 (1.20 mmol) was added, the mixture was refluxed for 72 h. The
reaction course was followed by TLC. The reaction mixture was
cooled to room temperature and evaporated to dryness. The crude
product was purified by column chromatography on silica gel using
hexane as the eluant.
4.3.6. 2-(2-(2,6-Dimethylphenylimino)-5-methyl-2H-
benzo[b][1,4]oxazin-3-yl)phenol (8d)
Compound 8d was obtained from 0.30 g (2.40 mmol) of 2-
amino-3-methylphenol, 0.29 g (2.40 mmol) of salicylaldehyde,
0.16 g (2.90 mmol) of ammonium chloride, and 0.32 g (2.40 mmol)
of 2,6-dimethylphenylisonitrile. The product was obtained as
a yellow solid (0.38 g), 45% yield, mp 153–154 ꢁC. IR vmax (KBr) 3435
(OH), 2950, 2918, 1666 (C]N), 1611, 1474, 1242, 745 cmꢀ1. 1H NMR
4.3.3. 2-(2-(2,6-Dimethylphenylimino)-7-nitro-2H-
benzo[b][1,4]oxazin-3-yl)phenol (8a)
Compound 8a was obtained from 0.25 g (2.00 mmol) of 2-
amino-5-nitrophenol, 0.32 g (2.00 mmol) of salicylaldehyde, 0.13 g
(2.40 mmol) of ammonium chloride, and 0.27 g (2.00 mmol) of 2,6-
(500 MHz, CDCl3)
d: 13.93 (1H, br s, OH), 9.29 (1H, dd, J¼8.3, 1.7 Hz,

´
Ma.C. Garc´ıa-Gonzalez et al. / Tetrahedron 65 (2009) 5337–5342
5342
H-6), 7.41 (1H, ddd, J¼8.3, 7.1, 1.7 Hz, H-4), 7.15 (1H, t, J¼7.8 Hz, H-
11), 7.10 (2H, d, J¼7.5 Hz, H-17), 7.08–7.05 (2H, m, H-3, H-10), 6.99
(1H, t, J¼7.5 Hz, H-18), 6.92 (1H, ddd, J¼8.3, 7.1, 1.3 Hz, H-5), 6.77
(1H, d, J¼8.2 Hz, H-12), 2.58 (3H, s, H-20), 2.15 (6H, s, H-19). 13C
(C-4), 135.5 (C-9), 134.2 (C-6), 132.4 (C-10), 128.9 (C-11), 128.5
(C-12), 120.1 (C-5), 119.0 (C-3), 118.0 (C-1), 18.9 (C–Me). HRMS:
C16H16NO3 [MþþH]þ, calcd 270.1124, found 270.1119, error 2.1101.
NMR (125 MHz, CDCl3) d: 162.1 (C-2), 151.9 (C-7), 145.8 (C-9), 143.4
Acknowledgements
(C-15), 140.1 (C-8), 135.7 (C-14), 133.6 (C-4), 132.5 (C-6), 129.6 (C-
11), 127.8 (C-17), 127.7 (C-13), 126.9 (C-16), 125.9 (C-10), 123.7 (C-
18), 118.6 (C-5), 118.0 (C-3), 117.2 (C-1), 113.2 (C-12), 18.6 (C-19), 17.4
(C-20). MS m/z: 357 ([Mþ1]þ, 6), 356 ([M]þ, 22), 341 (17), 236 (100),
225 (98), 197 (14). HRMS: C23H21N2O2 [MþþH]þ, calcd 357.1598,
found 357.1596, error 0.4327.
The authors thank CONACYT for financial support and the
scholarship to Ma. Carmen Garcı´a-Gonza´lez, V. Gonza´lez, and G.
Uribe for NMR spectra, G. Cuellar for MS spectra, and M.A. Leyva for
X-ray structures. We thank Professor Joseph M. Muchowski for
fruitful comments.
4.3.7. 2-(2-(2,6-Dimethylphenylimino)-7-methyl-2H-
Supplementary data
benzo[b][1,4]oxazin-3-yl)phenol (8e)
Compound 8e was obtained from 0.25 g (2.00 mmol) of 2-
amino-5-methylphenol, 0.25 g (2.00 mmol) of salicylaldehyde,
0.13 g (2.40 mmol) of ammonium chloride, and 0.32 g (2.40 mmol)
of 2,6-dimethylphenylisonitrile. The product was obtained as
a yellow solid, 83% yield, mp 154–156 ꢁC. IR vmax (KBr) 3353 (OH),
2917, 1660 (C]N), 1618, 1442, 1106, 754 cmꢀ1. 1H NMR (500 MHz,
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.04.080.
References and notes
CDCl3)
d
: 13.57 (1H, br s, OH), 9.17 (1H, dd, J¼8.3, 1.7 Hz, H-6), 7.44
1. Weidinger, H.; Kranz, J. Chem. Ber. 1964, 97, 1599–1608.
2. Taverne, T.; Diouf, O.; Depreux, P.; Poupaert, J.; Lesieur, D.; Guardiola-Lemaˆıtre,
B.; Renard, P.; Rettori, M. C.; Caignard, D. H.; Pfeiffer, B. J. Med. Chem. 1998, 41,
2010–2018.
3. Mizar, P.; Myrboh, P. Tetrahedron Lett. 2006, 47, 7823–7826.
4. Wei-Min, D.; Xuan, W.; Chen, M. Tetrahedron 2005, 61, 6879–6885.
5. Feng, G.; Wu, J.; Dai, W.-M. Tetrahedron 2006, 62, 4635–4642.
6. (a) Do¨mling, A. Chem. Rev. 2006, 106, 17–89; (b) Zhu, J. Eur. J. Org. Chem. 2003, 7,
1133–1144.
7. Xing, X.; Wu, J.; Feng, G.; Dai, W. Tetrahedron 2006, 62, 6774–6781.
8. Bonne, D.; Dekhane, M.; Zhu, J. Org. Lett. 2005, 7, 5285–5288.
9. (a) Barba, V.; Cuahutle, D.; Santillan, R.; Farfa´n, N. Can. J. Chem. 2001, 79, 1229–
1237; (b) Rodrı´guez, M.; Ochoa, Ma. E.; Santillan, R.; Farfa´n, N.; Barba, V.
J. Organomet. Chem. 2005, 690, 2975–2988.
10. (a) Janvier, P.; Sun, X.; Bienayme, H.; Zhu, J. J. Am. Chem. Soc. 2002, 124, 2560–
2567; (b) Bonne, D.; Dekhane, M.; Zhu, J. Org. Lett. 2004, 6, 4771–4774; (c) Pirali,
T.; Tron, C.; Masson, G.; Zhu, J. Org. Lett. 2007, 9, 5275–5278.
11. (a) Rodrı´guez, M.; Santillan, R.; Lo´pez, Y.; Farfa´n, N.; Barba, V.; Nakatani, K.;
Garcı´a Bae´z, E. V.; Padilla-Martı´nez, I. Supramol. Chem. 2007, 19, 641–653; (b)
Elerman, Y.; Elmali, A.; Atakol, O.; Svoboda, I. Acta Crystallogr., Sect. C: Cryst.
Struct. Commun. 1995, 51, 2344–2346.
12. Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen, A. G.; Taylor, R.
J. Chem. Soc., Perkin Trans. 2 1987, S1–S19.
13. Elmali, A.; Kabak, M.; Kavlakoglu, E.; Elerman, Y.; Durlu, T. N. J. Mol. Struct. 1999,
510, 207–214.
14. Fayol, A.; Zhu, J. Angew. Chem., Int. Ed. 2002, 41, 3633–3635.
15. Yavari, I.; Djahaniani, H. Tetrahedron Lett. 2006, 47, 1477–1481.
16. Armarego, W. L. F.; Li, C. Purification of Laboratory Chemicals; Butterworth-
Heinemann: USA, 2003.
17. Sheldrick, G. M. SHELXL-86, Program for Crystal Structure Solution; University of
Go¨ttigen: Germany, 1986.
(1H, d, J¼8.1 Hz, H-13), 7.38 (1H, ddd, J¼8.3, 7.1, 1.7 Hz, H-4), 7.10
(2H, d, J¼7.6 Hz, H-17), 7.04 (1H, dd, J¼8.3, 1.3 Hz, H-3), 7.01–6.98
(2H, m, H-10, H-18), 6.90 (1H, ddd, J¼8.3, 7.1, 1.3 Hz, H-5), 6.76–6.75
(1H, m, H-12), 2.31 (3H, s, H-20), 2.14 (6H, s, H-19). 13C NMR
(125 MHz, CDCl3) d: 161.6 (C-2), 152.3 (C-7), 145.3 (C-9), 143.4 (C-
15), 141.3 (C-11), 140.4 (C-8, C-14), 133.3 (C-4), 132.4 (C-6), 127.8 (C-
17),126.9 (C-16),126.7 (C-13), 125.6 (C-18),123.7 (C-10), 118.5 (C-5),
118.1 (C-3),117.4 (C-1),115.7 (C-12), 21.4 (C-20),18.5 (C-19). MS m/z:
357 ([Mþ1]þ, 5), 356 ([M]þ, 20), 341 (22), 270 (16), 259 (14), 236
(100), 225 (84), 197 (17). HRMS: C23H21N2O2 [MþþH]þ, calcd
357.1598, found 357.1597, error 0.1527.
4.3.8. N-(2,6-Dimethylphenyl)-2-(2-hydroxyphenyl)-2-
oxoacetamide (14)
Compound 14, obtained from 0.26 g (1.07 mmol) of Schiff base
13 and 0.28 g (2.14 mmol) of 2,6-dimethylphenylisonitrile, in dry
toluene, was placed in a sealed ampule and heated for 16 h at 120 ꢁC
under nitrogen atmosphere. The solvent was removed under vac-
uum. Purification by column chromatography and recrystallization
using hexane–ethyl acetate (98:2) afforded a yellow solid (0.107 g),
37% yield, mp 145–147 ꢁC. IR vmax (KBr) 3190 (OH), 1657 (C]O),
1629 (C]O) cmꢀ1. 1H NMR (300 MHz, CDCl3)
d: 11.84 (1H, s, OH),
8.66 (1H, dd, J¼8.2, 1.5 Hz, H-6), 8.47 (1H, br s, NH), 7.60 (1H, ddd,
J¼8.5, 7.0, 1.5 Hz, H-4), 7.23–7.14 (2H, m, H-11, H-12), 7.06 (1H, d,
J¼8.5 Hz, H-3), 6.98 (1H, t, J¼7.4 Hz, H-5), 2.31 (6H, s, H–Me). 13C
18. Burla, M. C.; Caliandro, R.; Camalli, M.; Carrozzini, B.; Cascarano, G. L.; De Caro,
L.; Giacovazzo, C.; Polidori, G.; Spagna, R. J. Appl. Crystallogr. 2005, 38, 381–388.
19. Sheldrick, G. M. SHELXL-97, Program for Crystal Structure Solution and re-
finement; University of Go¨ttigen: Germany, 1997.
NMR (75 MHz, CDCl3) d: 190.6 (C-7), 164.4 (C-8), 160.8 (C-2), 138.9