Pd-catalysed one-pot synthesis of 2H-1,4-benzoxazin-3-(4H)-ones from o-halophenols and 2-chloroacetamides

Article abstract of DOI:10.3184/174751912X13263685422317

A Pd-catalysed cascade protocol, consisting of intermolecular O-alkylation and spontaneous intramolecular amidation, has been established for efficient synthesis of 2H-1,4-benzoxazin-3-(4H)-ones from o-halophenols and 2-chloroacetamides. A varity of substrates afford the desired products in good to excellent yields. It is particularly attractive for synthesis of a library of 2H-1,4-benzoxazin-3-(4H)-ones.

Full text of DOI:10.3184/174751912X13263685422317

JOURNAL OF CHEMICAL RESEARCH 2012
RESEARCH PAPER 41
JANUARY, 41–44
Pd-catalysed one-pot synthesis of 2H-1,4-benzoxazin-3-(4H)-ones from
o-halophenols and 2-chloroacetamides
Fangling Yina, Gaofeng Fengb, Qingbao Songa* and Chenze Qib
aCollege of Chemical Engineering and Material Science, Zhejiang University ofTechnology, Hangzhou, 310027, P. R. China
bThe Institute of Applied Chemistry, Shaoxing University, Shaoxing, 312050, P. R. China
A Pd-catalysed cascade protocol, consisting of intermolecular O-alkylation and spontaneous intramolecular
amidation, has been established for efficient synthesis of 2H-1,4-benzoxazin-3-(4H)-ones from o-halophenols and
2-chloroacetamides. A varity of substrates afford the desired products in good to excellent yields. It is particularly
attractive for synthesis of a library of 2H-1,4-benzoxazin-3-(4H)-ones.
Keywords: Pd catalysis, cascade reaction, 2H-1,4-benzoxazin-3-(4H)-ones, O-alkylation, amidation
2H-1,4-Benzoxazin-3-(4H)-one1 (1, Fig. 1) is one of the
privileged heterocyclic N derivatives skeleta in drug design.
Naturally occurring and synthetic N derivatives of this hetero-
cycle exhibit potent biological and medicinal activities
(Fig. 1). For instance, the enediyne antitumour antibiotic,
C-1027 2,2 possesses a 2-methylene-2H-1,4-benzoxazin-3-
(4H)-one subunit.
alternative and improved procedure towards this heterocycle is
still in demand. Herein, we report an Pd-catalysed cascade
process for efficient synthesis of 2H-1,4-benzoxazin-3-(4H)-
ones from readily available 2-halophenols and 2-chloroacet-
amides.
Results and discussion
Because of their novel biological activities, a great deal of
effort has been devoted to their synthesis by synthetic chem-
ists.3,4 Several novel strategies exist for constructing 2H-1,
4-benzoxazin-3-(4H)-ones starting from different building
blocks. Commonly, substituted 2-nitrophenols5–7 and 2-amino-
phenols8–10 have been employed as the starting material for
accessingtheheterocyclethroughstepwisesyntheticsequences.
Recently, Ugi-4CRs and subsequent cyclisation (through
intramolecular O-alkylaton or Mitsunobu reaction) strategies
were developed.11–12 Alternatively, Zuo’s group13 developed
one-pot efficient synthesis of 2H-1,4-benzoxazin-3-(4H)-ones
from 2-chlorophenols, 2-chloroacetyl chlorides and primary
amines via a Smile rearrangement. Although encouraging, this
method is limited by the substrate scope. Improvements were
achieved by Liu14 and Bao’s15 groups on the basis of intermol-
ecular O-alkylation and spontaneous Cu-catalysed amidation
sequence from o-halophenols and 2-chloroacetamides. How-
ever, 2-iodophenols were necessary for achieving good yields.
When 2-bromophenols were employed, only moderate yields
could be obtained. Very recently, a simple Pd-catalysed
intramolecular O-arylation reaction as the key annulation step
for making 2H-1,4-benzoxazin-3-(4H)-ones was revealed by
Kundig’s group.16 However, a three-steps sequence, consisting
of condensation of N-alkyl-2-bromoaniline with 2-oxo-2-aryl-
acetic acid, NaBH4 reduction and Pd-catalysed intramolecular
O-arylation, was adopted. Therefore, the development of an
2-Bromophenol 3 and 2-chloro-N-phenylacetamide 4 were
selected as the model substrates for optimising the reaction
conditions in terms of catalyst, ligand, base, and molar ratio of
substrates. Toluene was used as the solvent, as it is less toxic
and commonly used in Pd-catalysed amidation reactions. The
reaction temperature and time were set at 110 °C and 24 h,
respectively. The results are summarised in Table 1. Initially,
the combination of Pd(OAc)2 (10 mol%), Xphos (10 mol%),
and Cs2CO3 (2 equiv.) were selected for study, and the desired
4-phenyl-2H-1,4-benzoxazin-3-(4H)-one 1a was isolated in
19% yield when the molar ratio of 3 and 4 is 1.2/1 (entry 1).
Dppf showed no improvement (entry 2), while racemic BINAP
exhibited good activity, furnishing 1a in 64% yield (entry 3).
Gratifyingly, the yield of the desired product 1a was improved
to 84% when the molar ratios of the starting material was
inversed (3/4 = 1/1.2). Further improvement of the yield (99%)
was achieved by simply increasing the amount of the 2-chloro-
N-phenylacetamide (3/4 = 1/1.5). The above results indicated
that the molar ratio of the building blocks was crucial for the
present transformation. Other ligands, such as Xantphos and
PPh3, were then examined. Both were not as efficient as BINAP
(entries 6 and 7). Further investigation showed that K2CO3
and t-BuONa were also not effective affording the product in
low yields (entries 8 and 9). Other Pd(II) sources were then
examined, and it was found that PdCl2 and Pd2(dba)3 proved as
Fig. 1 Structures of 2H-1,4-benzoxazin-3-(4H)-one 1 and some biologically active derivatives.
* Correspondent. E-mail: qbsong@zjut.edu.cn; qichenze@usx.edu.cn

42 JOURNAL OF CHEMICAL RESEARCH 2012
Table
1
Optimisation for synthesis of 4-phenyl-2H-1,4-
Table 2 Synthesis of 2H-1,4-benzoxazin-3-(4H)-ones via Pd-
benzoxazin-3-onesa
catalysed cascade processa
Entry Catalyst
Ligand
Base
Ratio
3/4
Yieldb
/%
Products and yield
1
2
Pd(OAc)2 Xphos
Pd(OAc)2 dppf
Pd(OAc)2 BINAP
Pd(OAc)2 BINAP
Pd(OAc)2 BINAP
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
1.2:1
1.2:1
1.2:1
1:1.2
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
19
18
3
64
4
84
5
99
6
Pd(OAc)2 Xantphos Cs2CO3
63
7
Pd(OAc)2 PPh3
Pd(OAc)2 BINAP
Pd(OAc)2 BINAP
Cs2CO3
K2CO3
Trace
Trace
32
8
9
t-BuONa
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
10
11
12c
13d
14e
PdCl2
BINAP
93
Pd2(dba)3 BINAP
Pd(OAc)2 BINAP
Pd(OAc)2 BINAP
Pd(OAc)2 BINAP
84
98
97
38
a Reaction conditions: catalyst (10 mol%), ligand (10 mol%),
base (2.0 equiv.), toluene (0.1 M), 110 °C, 24 h.
b Isolated yield.
c The loadings of catalyst and ligand were 5 mol% and 5 mol%,
respectively.
d The loadings of catalyst and ligand were 2.5 mol% and
2.5 mol%, respectively.
e The loadings of catalyst and ligand were 1 mol% and 1 mol%,
respectively.
Xantphos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
Xphos: 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl
effective, although the yields were slightly lower than that of
Pd(OAc)2 (entry 10 and 11). Finally, an effort to reduce the
catalyst loading was carried out. Gratifyingly, the yield of the
desired product was not decreased (98% and 97%) when the
loadings of catalyst and ligand were reduced to 5 mol% and
5 mol%, even to 2.5 mol% and 2.5 mol%, respectively (entries
12 and 13). However, when 1 mol% of catalyst and 1 mol% of
ligand were employed, the yield was decreased dramatically
(entry 14). On the basis of these investigations, the optimum
conditions are: 2-chloroacetamide (1.5 equiv.) and 2-bromo-
phenol (1.0 equiv.) with Pd(OAc)2 (2.5 mol%), ( )BINAP
(10 mol%), and Cs2CO3 (2.0 equiv.) in toluene at 110 °C for
24 h.
With the optimised conditions in hand, the generality of the
process was then examined. As shown in Table 2, the process
was compatible with various 2-chloroacetamides, providing
a verity of N-substituted-2H-1,4-benzoxazin-3-(4H)-one in
good to excellent yields. Acetamides possessing methyl group
at para and meta positions of phenyl ring provided the
corresponding products (1b and 1c) in excellent yields with
2.5 mol% loadings of catalyst and ligand. A small steric effect
on the amidation step was observed as ortho methyl substituted
2-chloroacetamide afforded the corresponding product in
moderate yield (60%).
Highly bulky N-(2,6-dimethylphenyl) acetamide was also
compatible, although the corresponding product 1e was
isolated in only 25% yield under the same condition. The yield
could be improved to 51% by increasing the catalyst loading
to 10 mol%. Moreover, the process was compatible with
2-chloroacetamides containing both electron-donating and
electron-withdrawing substituents. It was observed that N-
(4-methoxyphenyl) and N-(3-methoxyphenyl) acetamides
provided the corresponding products 1f and 1g in excellent
a Reaction conditions: catalyst (2.5 mol%), ligand (2.5 mol%),
base (2.0 equiv.), toluene (0.1 M), 110 °C, 24 h.
b The loadings of catalyst and ligand were 10 mol% each.
c Melting point measured.
d Melting point from ref.15.
yields (90% and 91%, respectively). While N-(4-chlorophenyl)
and N-(4-ethoxycarbony)phenyl acetamdie, which are sensitive
to bases or acids, exhibited a little lower reactivity, providing

JOURNAL OF CHEMICAL RESEARCH 2012 43
HRMS (+EI) were carried out on ThermoFinnigan EA-1112 and
Bruker Daltonics FT-ICR APEX III 7.0, respectively, in Zhejiang
University. Mass spectra (MS) were carried out on Thermo LCQ
Fleet and measured by ESI. The reaction mixture was monitored
by thin-layer chromatography on silica gel plates (60 F-254) using
UV light, or 7% ethanolic phosphomolybdic acid and heating as the
visualising methods. Flash column chromatography on silica gel was
used for purification. Reagents were obtained commercially and used
as received.
the corresponding products in 80% and 70% yield, respectively,
although 10 mol% loading of catalyst was necessary. In
addition, the reaction of 2-bromophenol and N-(1-naphthyl)
acetamide proceeded smoothly, furnishing product 1j in 72%
yield using 10 mol% loading of catalyst. However, it was found
that Me group at alpha position of 2-chloroacetamide was
deleterious for achieving good yield, as 1k, 1l, and 1m were
isolated in only 60%, 57% and 53% yields, respectively, even
when using an increased 10 mol% loading of catalyst. The
lower yields were due to the incomplete amidation process, as
the O-alkylated intermediates were observed in 20% yields
or so as a mixture with the desired product. The observation
of O-alkylated intermediate supported the idea that the
present cascade protocol proceeded through a sequence of
intermolecular O-alkylation and intramolecular amidation
reactions. The problem could be solved by using more reactive
2-iodophenol, resulting in 92% yield. However, the significant
influence of alpha substitution on the amidation process is
puzzling and will require further investigation. Notably,
reactions involving the N-alkyl groups such as n-butyl and
benzyl also proceeded smoothly to provide the desired products
1n and 1o in moderate to good yield using 2.5 mol% loading
of catalyst.
Synthesis of (2H)-1,4-benzoxazin-3-(4H)-ones (1a–o); general
procedure
To a 10-mL pressurised process vial were added magnetic stir bar,
Pd(OAc)2 (1.7 mg, 7.5 × 10−3 mmol, 2.5 mol%), ( )BINAP (4.7 mg,
7.5 × 10−3 mmol, 2.5 mol%), N-phenyl-2-chloroacetamides (0.45 mmol),
and Cs2CO3 (195 mg, 0.6 mmol). The loaded vial was then sealed with
a rubber cap. The vial was evacuated and backfilled with nitrogen
through the cap (this procedure was repeated several times). The dry
and degassed toluene (3 mL) and o-bromophenol (0.30 mmol) were
added by syringe through the cap. The resultant mixture was heated at
110 °C for 24 h in an oil bath, and then filtered through celite which
was washed with EtOAc. The combined filtrate was concentrated
under reduced pressure. The residue was purified by column chroma-
tography on silica gel eluted with EtOAc and petroleum ether (60–
90 °C) to afford 1a–o. The structures and yields of the products are
given in Table 2.
The scope of the process was further investigated by
employing 2-chlorophenol as the building block, as aryl
chloride is a challenging substrate in Pd-catalysed amidation
reactions. As illustrated in Scheme 1, when N-phenyl, N-
(4-methylphenyl), and N-(3-methoxyphenyl) acetamide were
reacted with 2-chlorophenol, only 35–39% yields were
obtained under our optimised conditions. Improvement of the
yield was attempted by increasing the loading of catalyst,
enhancing the reaction temperature, or prolonging the reaction
time. However, the results obtained were not satisfying. These
results indicated that chloride exhibited much lower reactivity
than that of the bromide, which is consistent with the reported
order.
In conclusion, we have established a Pd-catalysed cascade
process, consisting of intermolecular O-alkylation and
spontaneous intramolecular amidation, for efficient synthesis
of N-substituted 2H-1,4-benzoxazin-3-(4H)-ones. This process
tolerates a range of 2-chloroacetamides to assemble various
products in moderate to excellent yields, which should be
useful in the pharmaceutical and biochemical fields. The
development of other novel cascade protocol towards 2H-1,4-
benzoxazin-3-(4H)-ones is ongoing in our laboratory.
4-(3,5-Dimethylphenyl)-(2H)-1,4-benzoxazin-3-(4H)-one(1c):Yellow-
ish amorphous solid; Rf = 0.67 (25% EtOAc/hexane); IR (film) 1707,
1
1376 cm–1; H NMR (400 MHz, CDCl3) δ 7.09 (s, 1H), 7.03 (dd,
J = 8.0, 1.6 Hz, 1H), 6.98 (ddd, J = 8.0, 8.0, 1.6 Hz, 1H), 6.89 (s, 1H),
6.89 (s, 1H), 6.87–6.83 (m, 1H), 6.45 (dd, J = 8.0, 1.2 Hz, 1H), 4.76
(s, 2H), 2.36 (s, 3H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 164.3, 144.8, 139.9 (×2), 135.5, 130.71, 130.66, 126.2 (×2), 124.0,
122.5, 117.0, 116.9, 68.2, 21.3 (×2); MS (+ESI) m/z 529 (2M+Na+, 9),
702 (100); HRMS (EI) m/z Calcd for C16H15NO2 (M+) 253.1103; found
253.1104.
4-(2,6-Dimethylphenyl)-(2H)-1,4-benzoxazin-3-(4H)-one(1e):Yellow-
ish crystalline solid; m.p. 107–109 °C; Rf = 0.67 (25% EtOAc/hexane);
1
IR (film) 1688, 1370 cm–1; H NMR (400 MHz, CDCl3) δ 7.28 (dd,
J = 8.4, 6.8 Hz, 1H), 7.20 (d, J = 7.2 Hz, 2H), 7.07 (d, J = 8.4 Hz, 1H),
7.00 (ddd, J = 8.4, 8.4, 1.2 Hz, 1H), 6.84 (ddd, J = 8.4, 8.4, 1.2 Hz,
1H), 6.25 (d, J = 8.0 Hz, 1H), 4.79 (s, 2H), 2.01 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 163.3, 144.9, 136.6 (×2), 133.4, 129.1, 128.9
(×2), 128.8, 124.1, 122.9, 117.0, 115.5, 67.9, 17.6 (×2); MS (+ESI)
m/z 276 (M+Na+, 36), 529 (2M+Na+, 21), 702 (100); HRMS (EI) m/z
Calcd for C16H15NO2 (M+) 253.1103; found 253.1101.
4-(4-Chlorophenyl)-(2H)-1,4-benzoxazin-3-(4H)-one (1i): White
crystalline solid; m.p. 158–159 °C; Rf = 0.66 (25% EtOAc/hexane);
1
IR (film) 1677,1379 cm–1; H NMR (400 MHz, CDCl3) δ 7.50 (d,
J = 8.8 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 7.05 (dd, J = 8.0, 2.0 Hz,
1H), 7.01 (ddd, J = 7.6, 7.6, 1.6 Hz, 1H), 6.87 (ddd, J = 8.0, 8.0,
1.6 Hz, 1H), 6.44 (dd, J = 8.0, 1.2 Hz, 1H), 4.76 (s, 2H); 13C NMR
(100 MHz, CDCl3) δ 164.3, 145.0, 134.8, 134.3, 130.3, 130.28 (×2),
130.2 (×2), 124.4, 122.7, 117.2, 116.8, 68.2; MS (+ESI) m/z 298
(M+K+, 28), 539 (100); Anal. Calcd for C14H10ClNO2: C, 64.75; H,
3.88; N, 5.39. Found: C, 64.89; H, 3.96; N, 5.50%.
Experimental
1H and 13C NMR spectra were recorded on a Bruker Advance III 400
MHz spectrometer (400 MHz for 1H or 100 MHz for 13C, respectively)
and using CDCl3 as the solvent with CHCl3 as the internal reference.
IR spectra (film) were recorded on a NEXUS FI/IR spectrometer.
Melting points were taken on Büchi M-560. Elemental analyses and
4-Naphthanyl-(2H)-1,4-benzoxazin-3-(4H)-one (1j): Yellow cryst-
alline solid; m.p. 146–147 °C; Rf = 0.55 (25% EtOAc/hexane);
Scheme 1 Investigation of the reactivity of 2-chlorophenol.

44 JOURNAL OF CHEMICAL RESEARCH 2012
IR (film) 1682, 1370 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J =
8.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.61–7.55 (m, 2H), 7.49–7.39
(m, 3H), 7.07 (d, J = 8.0 Hz, 1H), 6.94 (dd, J = 8.4, 8.4 Hz, 1H), 6.70
(dd, J = 8.0, 8.0 Hz, 1H), 6.20 (d, J = 8.0 Hz, 1H), 4.91 & 4.84 (AB
q, J = 15.6, 15.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 164.6, 144.8,
134.9, 132.3, 130.7, 130.1, 129.8, 128.8, 127.55, 127.52, 126.8, 126.0,
124.2, 122.9, 122.4, 117.1, 116.9, 68.3; MS (+ESI) m/z 298 (M+Na+,
53), 572 (2M+Na+, 100); Anal. Calcd for C18H13NO2: C, 78.53; H,
4.76; N, 5.09. Found: C, 78.56; H, 4.79; N, 4.98%.
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Received 23 November 2011; accepted 7 January 2012
Paper 1101000 doi: 10.3184/174751912X13263685422317
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