Design and synthesis of novel 2-hydroxy-1,4-benzoxazine derivatives through three-component Petasis reaction catalysed by pyridinium toluene-sulphonate

Article abstract of DOI:10.3184/174751916X14656634976813

A variety of novel 2-hydroxy-1,4-benzoxazines were synthesised through the Petasis multicomponent reaction of 2-[(arylmethyl)amino] phenols with arylboronic acids and glyoxal catalysed by pyridinium toluene-p-sulphonate. A plausible reaction mechanism has

Full text of DOI:10.3184/174751916X14656634976813

JOURNAL OF CHEMICAL RESEARCH 2016
VOL. 40 AUGUST, 449–452
RESEARCH PAPER 449
Design and synthesis of novel 2-hydroxy-1,4-benzoxazine derivatives
through three-component Petasis reaction catalysed by pyridinium
toluene-sulphonate
Sara Mahdjouba, Chamseddine Derablia, Raouf Boulcinaa*, Gilbert Kirschb and
Abdelmadjid Debachea
aLaboratoire de Synthèse des Molécules d’intérêts Biologiques, Université de Constantine 1, 25000 Constantine, Algérie
bSRSMC Site Messin UMR 6575, Université de Lorraine, 57070 Metz, France
A variety of novel 2-hydroxy-1,4-benzoxazines were synthesised through the Petasis multicomponent reaction of 2-[(arylmethyl)amino]
phenols with arylboronic acids and glyoxal catalysed by pyridinium toluene-p-sulphonate. A plausible reaction mechanism has also
been proposed.
Keywords: multicomponent condensation, Petasis reaction, PPTS, boronic acids, secondary amines, 2-hydroxy-1,4-benzoxazines
The 1,4-benzoxazine nucleus is present in a large number of
pharmacologically active molecules, which are a common
heterocyclic scaffold in biologically active and medicinally
significant compounds. For example, various glycosides of the
2-hydroxy-2H-1,4-benzoxazine skeletons have been found to
occur in gramineous plants and have been suggested to act as
plant resistance factors against microbial diseases and insects.1
The 1,4-benzoxazine moiety is also found in various antibiotics2
and antirheumatic agents,3 calcium channel antagonists,4
central nervous system drugs,5 analgesics6 and others.7 Several
3,4-dihydro-2H-1,4-benzoxazine derivatives have been reported
to be potassium channel openers (PCOs) in vascular smooth
muscle.8 A variety of benzoxazines have been shown to have
interesting activity against Mycobacterium tuberculosis.9 Also,
a number of synthesised methotrexate derivatives incorporating
the benzoxazine moiety were found to be potent and safe
candidates as antirheumatic agents.10 Benzoxazine derivatives
have also been used as intermediates for the synthesis of other
heterocyclic structures of biological importance.11 Moreover,
the 2,3-disubstituted-1,4-benzoxazines constitute an interesting
group, which could find important application as key
intermediates in several synthetic pathways directed towards
the preparation of bioactive polycyclic heterocyclic systems.12
Several methods for the synthesis of 1,4-benzoxazine
derivatives have been reported.13 For example, O-alkylation,
nitro reduction and intramolecular N-substitution of
2-nitrophenols.14 In another approach, 2-aminophenols are
treated with 2-haloalkanoyl halides to form 2-amidophenols,
which then undergo intramolecular O-alkylation on heating
in the presence of a base.15 Recently, microwave-assisted one-
pot synthetic methods to construct 2H-1,4-benzoxazin-3(4H)-
ones have been developed,16 starting from 2-aminophenols
or N-alkyl-2-aminophenols. Also, one-pot cascade synthesis
of 2H-1,4-benzoxazin-3(4H)-ones through copper-catalysed
coupling of o-halophenols and 2-halo-amides.17
containing molecules by the condensation reaction of three
substrates: aldehyde; amine; and boronic acid.
Based on the Petasis reaction, we synthesised previously
numerous 2-hydroxy-1,4-benzoxazines from 2-aminophenols
and aldehydes in the presence of phenylboronic acid, at room
temperature. Indeed, we have reported that the reaction of
substituted aromatic aldehydes with secondary amines led
to 2-hydroxy-1,4-benzoxazines quantitatively. However, this
procedure required a long reaction time.19
Therefore development of new methodology should take into
consideration reduction in the reaction time, minimum metal
contamination of products, simple reaction conditions, and easy
isolation of products which are highly desirable for the Petasis
reaction.
Results and discussion
In this paper, we studied the extension of the multistep one-
pot Petasis synthesis of novel 2-hydroxy-1,4-benzoxazine
derivatives using pyridinium toluene-p-sulphonate (PPTS) as
catalyst, since this condensation should be useful to produce
libraries of molecules which constitute the molecular framework
of medicinally relevant compounds.
We first examined the reaction of a variety of commercially
available substituted 2-aminophenols 1 with aldehydes 2 as
shown in Scheme 1 and the results are summarised in Table 1.
We conducted the reaction in methanol at room temperature
for 18 h to allow a selective preparation of the imine
intermediates followed by the addition of an excess of sodium
cyanoborohydride under the same conditions for another 18 h
for completing reduction of these ones and the formation of the
corresponding secondary amines. Although we found later that
it was not necessary to carry out this reductive amination in
two different steps. As expected, in also one step, the previous
condensation in the presence of NaBH3CN gave rise to the
desired products in high yields.
Many groups have used the Petasis borono-Mannich
multicomponent reaction, known as the Petasis reaction.18 Such
reactions were widely studied for the construction of nitrogen-
Following our success of using new catalysts to effect
muticomponent synthesis of diverse heterocycles,20 we chose
herein PPTS as catalyst and 2-[(2-methoxynaphthalen-1-yl)
H
O
H
O
NaBH3CN
H
O
+
Ar1
MeOH, r.t.
18 h
Ar1
R
NH2
R
N
H
1
2
3
Scheme 1
* Correspondent. E-mail: boulcinaraouf@yahoo.fr

450 JOURNAL OF CHEMICAL RESEARCH 2016
Table 1 Synthesis of secondary amine derivativesa
Entry
R
Ar1
2-[(arylmethyl)amino]phenol
Yield/%b
89
91
90
86
M.p./°C
120–122
160–162
168–170
184–186
1
2
3
4
H
CH3
H
2-Methoxy-1-naphthyl
2-Methoxy-1-naphthyl
3-Pyridinyl
3a
3b
3c
3d
CH3
3-Pyridinyl
aReaction conditions: 2-aminophenols 1 (1.0 mmol), aldehydes 2 (1.0 mmol), NaBH3CN (1.5 mmol), in methanol (5 mL) at room temperature.
bIsolated yields.
H
O
B
O
H
N
OH
O
+
H
H
3CO
+
N
H
OC
3
H
OH
4b
5
3a
H
O
O
6b
Scheme 2 Optimisation of the conditions for the synthesis of 1,4-benzoxazine 6a.
Table 2 Synthesis of 1,4-benzoxazine derivatives under different
methylamino]phenol 3a, phenylboronic acid 4b, and glyoxal
5 as the model substrates to establish the reaction conditions
(Scheme 2, Table 2).
Our first attempt was made without any catalyst under room
temperature. The reaction in methanol proceeded smoothly but
long reaction time was required to produce the desired product
(Table 2, entry 1). On the other hand, repeating the reaction
under refluxing methanol was found to result in similar yield of
87% after 18 h, (entry 2).
Encouraged by this result, we tried to employ Lewis acids to
promote the reaction. In almost all cases, moderate yields were
attained. When the reaction was performed in the presence of
10 mol% of ZnCl2, a considerable decrease in product yield
(44%) was observed (entry 3). With 10 mol% of SnCl2, or
Ni(NO3)2.6H2O the reactions gave the desired product 6b in 47
and 52% yield respectively after 8 h (entries 4 and 5). When
K2CO3 was used (entry 6), no product was formed. Likewise,
lower product yields were obtained by introducing Et3N to
improve the reaction yield (entry 7).
conditionsa
Entry
Catalyst
–
–
Temperature
r.t.
Time/h Yield/%b
1
2
3
4
5
6
7
8
9
10
18
18
8
85
87
44
47
52
NR
38
65
92
88
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
r.t
ZnCl2
SnCl2
Ni(NO3)2.6H2O
K2CO3
Et3N
PTSA
PPTS
PPTS
8
5
18
8
4.5
3
8
aReactions were run with 1 mmol of 2-[(2-methoxynaphthalen-1-yl)methylamino]phenol
3a, 1 mmol of glyoxal 5, 1 mmol of phenylboronic acid 4, and 10 mol% of catalyst.
bYields were determined by 1H NMR spectroscopy.
In general, substituted 2-[(arylmethyl)amino]phenol
3
possessing alkyl or moderately electron-withdrawing groups
afforded the products 6 in good yields (Table 2, entries
1–4). Moreover, the steric effect of 2-methoxynaphtyl
substituent was not observed for the formation of the desired
2-hydroxybenzoxazines 6a–d. However, a significant reduction
in the yield was noted when pyridino-substituted secondary
amines 3c and 3d were used, presumably due to their diminished
reactivity. These substrates generally decreased the product
yields as compared to their analogues 3a–b (Table 2, entry 5–7).
Confirmation of the structures of 2-hydroxy-1,4-benzoxazines 6
was provided by their IR, HRMS, and NMR spectra.
To achieve better results, PTSA was used as Brønsted
acid. Notably, good yield of product 6b (65%) and a slightly
diminished reaction time was also obtained simultaneously
(entry 8). This study revealed that treating the previous
mixture with 10 mol% of PPTS (10 mol%) at refluxing MeOH
for 3 h gave the best result (entry 9). Under these conditions,
compound 6b was furnished in 92% yield. The structure of
1
the 1,4-benzoxazine ring product was determined by H NMR
spectroscopic measurements. A similar reaction using PPTS
was also performed at room temperature; however, product 6b
was obtained in slightly reduced yield after 8 h (entry 10).
We explored the scope of the one-pot synthesis of 2-hydroxy-
1,4-benzoxazines 6 by using PPTS as catalyst and a variety of
synthesised 2-[(arylmethyl)amino]phenols 3 with arylboronic
acids 4 and glyoxal 5. The results are summarised in Scheme
3 and Table 2.
Proton and 13C NMR spectra of these compounds did not show
any duplication of resonance signals, indicating that the isolated
product was not a mixture of diastereomers. The assignment of
a relative trans configuration for these products was secured by
X-ray crystallographic analysis as we have reported previously.21
H
H
O
B
O
H
O
O
N
Ar2
O
H
O
PPTS (10 mol%)
MeOH, reflux
Ar1
+
R
N
H
4
R
Ar2
Ar1
3
O
6
H
H
5
Scheme 3 Synthesis of 1,4-benzoxazine derivatives.

JOURNAL OF CHEMICAL RESEARCH 2016 451
Table 3 Synthesis of 1,4-benzoxazine derivativesa
Entry
2-[(Arylmethyl)amino]phenol
Ar2
1,4-Benzoxazine
Yield/%b
86
92
90
91
68
72
75
M.p./°C
174–176
104–106
156–158
166–168
110–112
148–150
142–144
1
2
3
4
5
6
7
3a
3a
3b
3b
3c
3c
3d
4-(CH3O)-C6H4
C6H5
4-(CH3O)-C6H4
C6H5
4-(CH3O)-C6H4
C6H5
4-(CH3O)-C6H4
6a
6b
6c
6d
6e
6f
6g
aReaction conditions: 2-[(arylmethyl)amino]phenol 3 (1.0 mmol), arylboronic acid 4 (1.0 mmol), and glyoxal 5 (1.0 mmol), PPTS (10 mol%) in methanol (5 mL) at reflux for 3 h.
bIsolated yields.
CH3
Using the same synthetic strategy, a series of 2-hydroxy-1,4-
benzoxazines 6 have been prepared in an efficient and economical
OH
N
O
manner by employing inexpensive, safe and commercially available
reagents under mild conditions. These results contribute to the
chemistry of 2-hydroxy-1,4-benzoxazines which have been much
less explored.
O
S
O
O
OH
CH3
R
OH
H
R
N
H
Ar1
Ar1
N
3
H
O
S
O
O
H
N
H
Experimental
O
O
5
OH
N
O
Melting points were determined on an Electrothermal capillary fine control
apparatus and are uncorrected. IR spectra were obtained on a Shimadzu
FTIR 8201 PC spectrophotometer, only significant absorption band
frequencies are cited. 1H and 13C NMR spectra were recorded on a Bruker
Avance 400 instrument at 400 and 100 MHz respectively, in CDCl3 or
DMSO-d6. Chemical shifts (δ) are given in part per million downfield from
TMS as an internal standard and J values in Hz. The chemicals used were
obtained commercially. High resolution mass spectra were recorded with a
MicroTof-Q 98.
H
N
CH3
R
OH
Ar1
O
S
O
O
O
O
H
O
S
O
R
N
OH
O
H
N
H2O
CH3
Ar1
7
Synthesis of 2-[(arylmethyl)amino]phenol 3; general procedure
A mixture of 2 aminophenol derivatives (1) (3 mmol) and aromatic
aldehydes (2) (3 mmol), in methanol (10 mL), was stirred at room
temperature for 24 h, hand monitored by TLC. After formation of imines
3, NaBH3CN (4.5 mmol) and HCl (few drops), were added and stirring
was continued for 24 h. After the end of the reaction the mixture was then
poured over ice water. The resulting precipitate was filtrated, washed with
water, and dried. The resulting amines were obtained after recrystallisation
from methanol in a very high purity with excellent yields. Spectroscopic
data of synthesised secondary amines are given below.
2-{[(2-Methoxynaphthalen-1-yl)methyl]amino}phenol (3a): IR (KBr) ν:
3476, 3418, 1601, 1258 cm–1. 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J =
8.6 Hz, 1H), 7.88 (d, J = 9.1 Hz, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.51 (t, J =
7.7 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.34 (d, J = 9.1 Hz, 1H), 7.04 (d, J = 7.9
Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 6.81–6.72 (m, 2H), 4.71 (s, 2H), 3.99 (s,
3H).13C NMR (101 MHz, CDCl3) δ 155.26, 145.11, 137.23, 133.28, 129.71,
129.20, 128.49, 127.04, 123.59, 123.11, 121.42, 119.48, 119.00, 114.45,
114.33, 113.32, 56.72, 39.49. HRMS for C18H17NO2Na [M + Na]+ calcd
302.1157; found: 302.1180.
2-{[(2-Methoxynaphthalen-1-yl)methyl]amino}-4-methylphenol (3b):
IR (KBr) ν: 3514, 3315, 1512, 1258 cm–1.1H NMR (400 MHz, CDCl3) δ 8.03
(d, J = 8.6 Hz, 1H), 7.87 (d, J = 9.1 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.51 (t,
J = 7.7 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.34 (d, J = 9.1 Hz, 1H), 6.86 (s, 1H),
6.68 (d, J = 7.1 Hz, 1H), 6.55 (d, J = 7.3 Hz, 1H), 4.71 (s, 2H), 3.99 (s, 3H),
2.34 (s, 3H).13C NMR (101 MHz, CDCl3) δ 155.30, 142.87, 136.24, 133.26,
130.82, 129.83, 129.17, 128.47, 127.05, 123.58, 123.07, 119.62, 118.97,
115.37, 114.58, 113.22, 56.62, 39.84, 21.14. HRMS for C19H19NO2Na [M +
Na]+ calcd 316.1313; found: 316.1345.
2-[(Pyridin-3-ylmethyl)amino]phenol (3c): IR (KBr) ν: 3433, 1520, 1261
cm–1. 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.53 (d, J = 4.8 Hz, 1H),
7.77 (d, J = 7.9 Hz, 1H), 7.35–7.31 (m, 1H), 6.79 (dd, J = 15.1, 7.5 Hz, 2H),
6.62 (dd, J = 15.2, 7.6 Hz, 2H), 4.43 (s, 2H).13C NMR (101 MHz, CDCl3) δ
148.68, 148.13, 143.81, 136.66, 135.63, 135.46, 123.72, 21.33, 117.99, 114.47,
111.89, 45.88. HRMS for C12H13N2O [M + H]+ calcd 201.1028; found:
201.1045.
OH
B
4
OH
O
O
O
N
O
Ar1
O
Ar2
OH
OH
B
Ar2
R
N
R
R
8
Ar1
9
O
OH
Ar2
O
N
OH
OH
B
H2O
R
N
Ar2
Ar1
- B(OH)3
6
Ar1
Scheme 4 A plausible mechanism for the synthesis of compounds 6.
A mechanistic rationalisation for the formation of compounds
6 in which the OH and aryl groups are in opposite sides is given in
Scheme 4. This involves an initial condensation of 2-[(arylmethyl)
amino]phenol 3 with glyoxal 5 facilitated by PPTS to give a cyclic
intermediate 7 which loses H2O molecule with assistance of the
catalyst and produce intermediate 8. Condensation of the latter
with arylboronic acid yields the tetracoordinate boron complex
9 that undergoes an irreversible transfer of the aryl group on
the opposite side of the hydroxyl group to generate the desired
2-hydroxy-1,4-benzoxazines 6. The observed diastereoselectivity
is consistent with addition of the aryl group to the intermediate
iminium ion 9, where approach of the aryl group of boronic acid
occurs from the face opposite of the N-benzyl substituent.22
Conclusion
In conclusion, the synthesis of some new 2-hydroxy-1,4-
benzoxazines 6 was accomplished via a PPTS-catalysed Petasis
multicomponent reaction. Compound 3 was obtained by reductive
amination of aldehydes with aminophenols.

452 JOURNAL OF CHEMICAL RESEARCH 2016
4-Methyl-2-[(pyridin-3-ylmethyl)amino]phenol (3d): IR (KBr) ν:
3398, 1524, 1215 cm–1. 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.56
(d, J = 5.0 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.38 (dd, J = 7.7, 5.1 Hz, 1H),
6.69 (d, J = 7.8 Hz, 1H), 6.45 (d, J = 7.9 Hz, 1H), 6.42 (s, 1H), 4.43 (s, 2H),
2.22 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 147.94, 147.35, 141.51, 136.40,
136.28, 130.84, 123.95, 118.18, 114.52, 112.84, 45.85, 21.17. HRMS for
C13H15N2O [M + H]+ calcd 215.1184; found: 215.1208.
4.63 (d, J = 17.1 Hz, 1H), 4.31 (s, 1H), 4.22 (d, J = 17.2 Hz, 1H), 3.69 (s,
3H).13C NMR (101 MHz, CDCl3) δ 159.54, 148.24, 146.61, 145.92, 135.59,
130.26, 128.30, 124.33, 122.34, 116.99, 114.37, 113.02, 111.36, 92.08, 63.91,
55.27, 49.60. HRMS for C21H20N2O3Na [M + Na]+ calcd 371.1372; found:
371.1359.
Trans-3-phenyl-4-(pyridin-3-ylmethyl)-3,4-dihydro-2H-1,4-
benzoxazin-2-ol (6f): IR (KBr) ν: 3159, 2912, 1597, 1504, 1261, 1038 cm–1.
1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.40 (d, J = 5.9 Hz, 1H), 7.72 (d,
J = 7.7 Hz, 1H), 7.32–7.25 (m, 1H), 7.18 (dd, J = 9.0, 2.8 Hz, 3H), 7.12–7.06
(m, 2H), 6.76 (t, J = 7.6 Hz, 2H), 6.62–6.44 (m, 2H), 5.47 (s, 1H), 4.61 (d,
J = 17.1 Hz, 1H), 4.38 (s, 1H), 4.19 (d, J = 17.2 Hz, 1H). 13C NMR (101 MHz,
CDCl3) δ 147.46, 147.27, 140.30, 138.64, 135.88, 134.42, 133.84, 128.90,
128.15, 127.46, 127.05, 124.04, 122.67, 110.76, 92.51, 64.64, 50.08. HRMS
for C20H19N2O2 [M + H]+ calcd 319.1447; found: 319.1445.
Trans-3-(4-methoxyphenyl)-6-methyl-4-(pyridin-3-ylmethyl)-3,4-
dihydro-2H-1,4-benzoxazin-2-ol (6g): IR (KBr) ν: 3117, 2901, 1605,
1512, 1254, 1030 cm–1. 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.41
(d, J = 4.3 Hz, 1H), 7.89–7.47 (m, 2H), 7.01 (d, J = 8.7 Hz, 2H), 6.74 (d,
J = 8.5 Hz, 2H), 6.68 (d, J = 7.9 Hz, 1H), 6.42 (d, J = 7.9 Hz, 1H), 6.34 (s,
1H), 5.40 (s, 1H), 4.60 (d, J = 16.9 Hz, 1H), 4.27 (s, 1H), 4.17 (d, J = 16.9 Hz,
1H), 3.68 (s, 3H), 2.12 (s, 3H).13C NMR (101 MHz, CDCl3) δ 154.85,
142.12, 137.61, 134.66, 134.42, 133.75, 131.73, 128.67, 127.87, 127.56,
124.33, 121.45, 119.19, 114.80, 99.74, 87.78, 65.99, 49.61, 29.73, 15.57.
HRMS for C22H22N2O3K [M + K]+ calcd 401.1267; found: 401.1304.
Synthesis of 1,4-benzoxazine derivatives 6; general procedure
A mixture of 2-[(arylmethyl)amino]phenols 3 (1 mmol), boronic acid 4
(1 mmol) and glyoxal 5 (1 mmol) in methanol (5 mL) was stirred at room
temperature for 18 h. The solvent was removed in vacuo to give crude
products 6, which were purified by flash chromatography (silica gel,
dichloromethane). Further purification was performed by recrystallisation
from diethyl ether. Spectroscopic data of synthesised compounds are given
below.
Trans-4-[(2-methoxynaphthalen-1-yl)methyl]-3-(4-methoxyphenyl)-
3,4-dihydro-2H-1,4-benzoxazin-2-ol (6a): IR (KBr) ν: 3391, 2936,
1
1608, 1504, 1254, 1092 cm–1. H NMR (400 MHz, DMSO-d6) δ 7.97
(d, J = 8.6 Hz, 1H), 7.91 (d, J = 9.1 Hz, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.41
(t, J = 7.6 Hz, 1H), 7.33 (d, J = 6.9 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 6.93
(t, J = 6.9 Hz, 1H), 6.82 (d, J = 8.7 Hz, 2H), 6.75 (d, J = 8.7 Hz, 2H), 6.69
(dd, J = 7.6, 1.6 Hz, 2H), 6.60 (t, J = 7.6 Hz, 1H), 5.19 (s, 1H), 5.00 (d,
J = 13.0 Hz, 1H), 4.75 (d, J = 13.0 Hz, 1H), 3.96 (s, 1H), 3.68 (s, 3H), 3.52
(s, 3H).13C NMR (101 MHz, DMSO-d6) δ 158.13, 155.87, 140.81, 135.39,
133.47, 131.92, 129.89, 128.40, 128.03, 127.41, 126.49, 123.79, 123.33,
121.84, 116.22, 116.01, 113.40, 110.58, 91.84, 58.90, 55.84, 54.97, 41.79.
HRMS for C27H25NO4Na [M + Na]+ calcd 450.1681; found: 450.1680.
Trans-4-[(2-methoxynaphthalen-1-yl)methyl]-3-phenyl-3,4-dihydro-
2H-1,4-benzoxazin-2-ol (6b): IR (KBr) ν: 3445, 2939, 1609, 1504, 1250,
1042 cm–1. 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 9.0 Hz, 1H), 7.74 (t,
J = 8.9 Hz, 2H), 7.32 (t, J = 8.3 Hz, 1H), 7.27 (t, J = 7.3 Hz, 1H), 7.18–7.11
(m, 5H), 7.00 (t, J = 7.7 Hz, 1H), 6.88 (dd, J = 6.3, 2.9 Hz, 2H), 6.82 (d,
J = 7.9 Hz, 1H), 6.74 (t, J = 8.2 Hz, 1H), 5.24 (s, 1H), 5.09 (d, J = 12.7 Hz,
1H), 4.80 (d, J = 12.6 Hz, 1H), 3.90 (s, 1H), 3.53 (s, 3H).13C NMR (101
MHz, CDCl3) δ 156.35, 140.93, 138.22, 134.28, 133.47, 130.50, 129.08,
128.90, 128.46, 127.45, 126.57, 123.83, 122.43, 122.12, 118.59, 117.29,
115.71, 112.66, 111.09, 91.98, 58.75, 55.71, 41.21. HRMS for C26H23NO3Na
[M + Na]+ calcd 420.1576; found: 420.1570.
Received 18 April 2016; accepted 29 April 2016
Paper 1604054 doi: 10.3184/174751916X14656634976813
Published online: 22 July 2016
References
1
2
3
4
H. Hartenstein, J. Klein and D. Sicker, Indian J. Heterocycl. Chem., 1993, 2,
151.
N. Matzanke, W. Lowe, S. Perachon, P. Sokoloff, J.-C. Schwartz and H. Stark,
Eur. J. Med. Chem., 1999, 34, 791.
T. Fukuda, M. Setoguchi, K. Inaba, H. Shoji and T. Tahara, Eur. J. Pharmacol.,
1991, 196, 299.
A.S. Bourlot, I. Sánchez, G. Dureng, G. Guillaumet, R. Massingham, A.
Monteil, E. Winslow, M.D. Pujol and J.Y. Mérour, J. Med. Chem., 1998, 41,
3142.
Trans-4-[(2-methoxynaphthalen-1-yl)methyl]-3-(4-methoxyphenyl)-
6-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ol (6c): IR (KBr) ν: 3387,
2932, 1605, 1508, 1254, 1018 cm–1. 1H NMR (400 MHz, CDCl3) δ 7.79 (d,
J = 9.1 Hz, 1H), 7.74 (dd, J = 8.4, 4.7 Hz, 2H), 7.32 (t, J = 7.6 Hz, 1H), 7.27
(t, J = 7.4 Hz, 1H), 7.17 (d, J = 9.1 Hz, 1H), 6.93 (s, 1H), 6.80 (d, J = 8.6 Hz,
2H), 6.71 (d, J = 7.9 Hz, 1H), 6.67 (d, J = 8.8 Hz, 2H), 6.54 (d, J = 8.0 Hz,
1H), 5.16 (s, 1H), 5.04 (d, J = 12.7 Hz, 1H), 4.74 (d, J = 12.6 Hz, 1H),
3.80 (s, 1H), 3.67 (s, 3H), 3.58 (s, 3H), 2.30 (s, 3H).13C NMR (101 MHz,
CDCl3) δ 158.91, 156.29, 138.69, 133.90, 133.54, 131.71, 130.43, 130.03,
129.06, 128.87, 127.87, 127.43, 123.81, 122.25, 119.00, 116.93, 115.91,
113.85, 112.67, 111.98, 91.98, 58.33, 55.94, 55.16, 41.23, 21.33. HRMS for
C28H27NO4Na [M + Na)]+ calcd 464.1838; found: 464.1841.
5
6
E. Blattes, B. Lockhart, P. Lestage, L. Schwendimann, P. Gressens, M.-B.
Fleury and M. Largeron, J. Med. Chem., 2005, 48, 1282.
G. Thuillier, J. Laforest, P. Bessim, J. Bonnet and J. Thuillier, Eur. J. Med.
Chem., 1975, 10, 37.
A. Basudeb, M. Sukhendu, P.K. Dutta and C. Chowdhury, Synlett, 2004, 2449.
J.R. Empfield and K. Russell, Ann. Rep. Med. Chem., 1995, 30, 81.
T. Hirata, H. Saito, H. Tomioka, K. Sato, J. Jidoi, K. Hosoe and T. Hidaka,
Antimicrob. Agents Chemother., 1995, 39, 2295.
7
8
9
10 H. Matsuoka, N. Ohi, M. Mihara, H. Suzuki, K. Miyamoto, N. Maruyama, K.
Tsuji, N. Kato, T. Akimoto, Y. Takeda, K. Yano and T. Kuroki, J. Med. Chem.,
1997, 40, 105.
11 S. Atarashi, H. Tsurumi, T. Fujiwara and I. Hayakawa, J. Heterocycl. Chem.,
1991, 28, 329.
Trans-4-[(2-methoxynaphthalen-1-yl)methyl]-6-methyl-3-phenyl-3,4-
dihydro-2H-1,4-benzoxazin-2-ol (6d): IR (KBr) ν: 3387, 2939, 1605, 1508,
1258, 1042 cm–1. 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 9.1 Hz, 1H),
7.76–7.70 (m, 2H), 7.32 (ddd, J = 8.5, 6.8, 1.5 Hz, 1H), 7.26 (ddd, J = 7.9,
6.8, 1.2 Hz, 1H), 7.13 (dd, J = 9.9, 6.1 Hz, 4H), 6.96 (s, 1H), 6.87 (dd, J = 6.6,
2.9 Hz, 2H), 6.70 (d, J = 8.0 Hz, 1H), 6.54 (d, J = 8.0 Hz, 1H), 5.22 (s, 1H),
5.06 (d, J = 12.7 Hz, 1H), 4.78 (d, J = 12.6 Hz, 1H), 3.85 (s, 1H), 3.51 (s, 3H),
2.31 (s, 3H).13C NMR (101 MHz, CDCl3) δ 156.32, 138.65, 138.33, 133.98,
133.52, 131.77, 130.47, 129.06, 128.87, 128.43, 127.42, 127.36, 126.57,
123.81, 122.19, 119.02, 116.99, 116.01, 115.72, 112.64, 111.88, 91.88, 58.77,
55.63, 41.45, 21.59. HRMS for C27H25NO3Na [M + Na]+ calcd 434.1732;
found: 434.1765.
Trans-3-(4-methoxyphenyl)-4-(pyridin-3-ylmethyl)-3,4-dihydro-
2H-1,4-benzoxazin-2-ol (6e): IR (KBr) ν: 3209, 2924, 1608, 1508, 1250,
1034 cm–1. 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.49 (s, 1H), 7.89
(d, J = 8.2 Hz, 1H), 7.30–7.22 (m, 1H), 7.01 (d, J = 8.6 Hz, 2H), 6.86–6.80
(m, 2H), 6.75 (d, J = 8.7 Hz, 2H), 6.71–6.60 (m, 2H), 5.45 (s, 1H),
12 A. Basudef, B.M. Sukhendu, P.K. Dutta and C. Chowdhury, Synlett, 2004,
2449.
13 K. Iakovou, M. Kazanis, A. Vavayannis, G. Bruni, M.R. Romeo, P. Massarelli,
S. Teramoto, H. Fujiki and T. Mori, Eur. J. Med. Chem., 1999, 34, 903.
14 P.J. Rybczynski, R.E. Zeck, J.Jr. Dudash, D.W. Combs, T.P. Burris, M. Yang,
M.C. Osborne, X. Chen and K.T. Demarest, J. Med. Chem., 2004, 47, 196.
15 G. Caliendo, E. Perissutti, V. Santagada, F. Fiorino, B. Severino, D. Cirillo, R.
d’Emmanuele di Villa Bianca, L. Lippolis, A. Pinto and R. Sorrentino, Eur. J.
Med. Chem., 2004, 39, 815.
16 G.F. Feng, J.L. Wu and W.-M. Dai, Tetrahedron, 2006, 62, 4635.
17 D. Chen, G. Shenand and W. Bao, Org. Biomol. Chem., 2009, 7, 4067.
18 W.-Y. Han, Z.-J. Wu, X.-M. Zhang and W.-C. Yuan, Org. Lett., 2012, 14, 976.
19 L. Chouguiat, R. Boulcina, B. Carboni, A. Demonceau and A. Debache,
Tetrahedron Lett., 2014, 55, 5124.
20 C. Derabli, R. Boulcina, A. Debache, G. Kirsch and B. Carboni, Tetrahedron
Lett., 2014, 55, 200.
21 L. Chouguiat, R. Boulcina, S. Bouacida, H. Merazig and A. Debache, Acta
Crystallogr. Sect. E, 2014, 70, 863.
22 22 N. Schlienger, M.R. Bryce and T.K. Hansen, Tetrahedron, 2000, 56, 10023.