Cascade reaction between methyl 3-dehydroshikimate, arylamines, and 2-chloroalkyl esters under microwave conditions: A practical and biomass-based synthesis of N -aryl-1,4-benzoxazin-3-ones

Article abstract of DOI:10.1055/s-0033-1338606

A biomass-based, metal- and ligand-free assembly of N-aryl-1,4-benzoxazin- 3-ones from methyl 3-dehydroshikimate (3-MHDS), involving aliphatic to aromatic transformation followed by C-O and C-N forming reactions, is presented. A variety of N-aryl-1,4-benzoxazin-3-ones were efficiently synthesized in a one-pot consecutive manner under microwave conditions. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1338606

PAPER
▌1167
paper
Cascade Reaction between Methyl 3-Dehydroshikimate, Arylamines, and
2-Chloroalkyl Esters under Microwave Conditions: A Practical and Biomass-
Based Synthesis of N-Aryl-1,4-benzoxazin-3-ones
Biomass-Involved Practical Approach to N-Aryl-1,4-benzoxazin-3-ones
Ensheng Zhang,a,b Tianlong Xu,a,b Wen Wei,a Tongkun Huang,a Mu Yuan,c Wei Zeng,d Yong Zou*a,c
a
Guangzhou Institute of Chemistry, Chinese Academy of Sciences, Guangzhou 510650, P. R. of China
Fax +86(20)85231119; E-mail: zouyong@gic.ac.cn
b
University of Chinese Academy of Sciences, Beijing 100039, P. R. of China
c
Guangzhou Medical University, Guangzhou 510182, P. R. of China
d
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510641, P. R. of China
Received: 23.12.2013; Accepted after revision: 17.02.2014
method still suffered from drawbacks such as the require-
Abstract: A biomass-based, metal- and ligand-free assembly of N-
ments for transition-metal catalysts, phosphine ligands,
aryl-1,4-benzoxazin-3-ones from methyl 3-dehydroshikimate (3-
and high temperatures (150 °C). Moreover, from the per-
spective of sustainable chemistry, the utilization of renew-
MHDS), involving aliphatic to aromatic transformation followed by
C–O and C–N forming reactions, is presented. A variety of N-aryl-
1,4-benzoxazin-3-ones were efficiently synthesized in a one-pot able biomass, the construction of platform compounds,
consecutive manner under microwave conditions.
and the development of cost-efficient methods to convert
platform compounds into various value-added chemicals,
are fundamental tasks for chemists.12 To the best of our
knowledge, no metal- and ligand-free protocol for the
synthesis of N-aryl-1,4-benzoxazin-3-ones has been re-
ported that is based on renewably sourced materials.
Therefore, an alternative method that is facile, efficient,
and makes use of biomass-derived starting materials to ac-
cess N-substituted 1,4-benzoxazin-3-ones is of genuine
interest.
Key words: methyl 3-dehydroshikimate, N-aryl-1,4-benzoxazin-3-
ones, metal-free, cascade reaction, cyclization
N-Substituted 1,4-benzoxazin-3-ones are an intriguing
class of privileged scaffold for a variety of biologically in-
teresting molecules, ranging from potential drugs, natural
products, and agrochemicals.1 For example, various bio-
active molecules (Figure 1) such as mineralocorticoid re-
ceptor modulating agents,2 SGLT2 inhibitors,3 thrombin
inhibitors,4 and the herbicide flumioxazin,5 are all charac-
terized by the N-substituted 1,4-benzoxazin-3-one motif.
As a result, considerable efforts have been made to syn-
thesize these compounds.6 Generally, methods to access
this scaffold involve the treatment of 2-halophenols and 2-
aminophenols with bifunctional reagents such as 2-halo-
amides,7 2-haloalkanoyl halides,8 or excess 2-
bromoalkanoates9 through palladium- or copper-cata-
lyzed and ligand-involved processes. The reaction of 2-ni-
trophenols with a bifunctional reagent can also lead to 1,4-
benzoxazin-3-ones, but a reductive process is further re-
quired to convert the nitro group into an amino group.10
However, the aforementioned methods for the assembly
of N-aryl-1,4-benzoxazin-3-ones are indirect, require pre-
formed coupling partners such as 2-(2-halophenoxy)al-
kanoates or N-aryl-2-haloacetamides, and use transition-
metal catalysts.7,9b In addition, iodo-substituted precur-
sors and long reaction times are required to obtain satis-
factory yields.7b Very recently, the Qi group reported an
impressive, one-pot, three-component protocol for the
construction of N-aryl-1,4-benzoxazin-3-ones through
palladium(II) acetate and XPhos-catalyzed reactions be-
tween 2-halophenols, ethyl 2-bromoalkanoates, and aryl-
amines under microwave conditions.11 However, this
O
H2N
O
R
O
R1
N
O
R2
N
N
Ar
R3
N
N
mineralocorticoid receptor-modulating agents
SGLT2 inhibitors
F
O
N
R
O
O
NH2
N
O
N
O
CH2C CH
CH3
NH
O
thrombin inhibitors
flumioxazin
Figure 1 Examples of bioactive N-substituted 1,4-benzoxazin-3-
ones
Over the past few years, a novel strategy to access to N-
substituted anilines from nonaromatic cyclohexenones via
sequential amination/aromatization reactions has
emerged as an effective and alternative synthetic path-
way.13 Our group has also recently demonstrated the fea-
sibility of a biomass-derived, cost-competitive cyclohex-
enone, methyl 3-dehydroshikimate (3-MDHS, 1), in the
facile synthesis of N-substituted 2-aminophenols via tan-
dem cross-coupling and aromatization reactions.14a In the
course of our study, we envisioned that this aliphatic
to aromatic methodology for generating N-substituted
2-aminophenols could further be exploited for the syn-
SYNTHESIS 2014, 46, 1167–1176
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DOI: 10.1055/s-0033-1338606; Art ID: SS-2013-H0833-OP
© Georg Thieme Verlag Stuttgart · New York

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thesis of N-aryl-1,4-benzoxazin-3-ones 3 through a cas- excellent yields (entries 6 and 11), while other bases such
cade process by using inexpensive and readily accessible as triethylamine, pyridine, DBU, sodium methoxide, and
3-MDHS (1), primary amines, and bifunctional reagents, sodium hydroxide delivered low to moderate yields (en-
such as chloroacetyl chloride or 2-chloroalkyl esters, as tries 14–18). In contrast, the desired product 3a was not
the reactants (Scheme 1). This approach may be metal- obtained and only the intermediate 4a was isolated in the
and ligand-free, for the pivotal CAr-NH-CAr′ subunit is absence of a base (entry 19). Temperature studies showed
generated by the formation of N-arylated 2-aminophenols that 110 °C was favorable for this two-step conversion
4 in the absence of a metal catalyst and ligand.14a Hence, (entries 6, 20, and 21). In addition, results showed that mi-
these N-arylated 2-aminophenols, which are generated in crowave irradiation was advantageous over conventional
situ and highly functionalized, could serve as platform heating in terms of yield and reaction time (entry 6 vs. 22).
compounds for further transformations. In continuation of Therefore, the optimized reaction conditions consist of 1
our work on the development of novel and practical meth- (2.2 mmol) and arylamine 2 (2.0 mmol) in N,N-dimethyl-
ods for biomass conversion and utilization,14 we herein formamide (3 mL) using 4-toluenesulfonic acid (0.10
describe a facile, metal- and ligand-free protocol utilizing mmol) as the catalyst for step 1, and methyl chloroacetate
3-MDHS (1) for the one-pot synthesis of N-aryl-1,4-ben- (2.4 mmol) using potassium carbonate (4.0 mmol) as the
zoxazin-3-ones under microwave irradiation.
base for step 2, both under microwave conditions at 110
°C (entry 6).
Ar
N
With the optimized reaction conditions in hand, a variety
of arylamines were examined to explore the scope of the
substrates. As summarized in Table 2, this one-pot, two-
step transformation showed good compatibility with vari-
ous functional groups such as Me, OMe, F, Cl, Br, I, NO2,
CF3, Ac, and CO2Me, affording the desired products in
moderate to high yields. In general, electron-rich anilines
required shorter reaction times and afforded higher yields
compared to electron-deficient substrates. For example,
anilines possessing an electron-donating group such as
methyl or methoxy gave excellent yields of 3b and 3c (en-
tries 2 and 3), whereas substrates bearing electron-with-
drawing groups such as acetyl, nitro, methoxycarbonyl,
and trifluoromethyl afforded moderate yields of products
MeO2C
O
1. ArNH2, p-TsOH
2. bifunctional reagent, base
MeO2C
O
MW
OH
O
R1
OH
3
1
Ar
step 1
step 2
MeO2C
NH
MW
bifunctional reagent
MW
ArNH2, p-TsOH
OH
4
microwave-assisted one-pot process
Scheme 1 Strategy utilizing 3-MDHS (1) for the construction of
N-aryl-1,4-benzoxazin-3-ones
Based on an improved method from our previous 3h,i,q,r,t (entries 8, 9, 17, 18, and 20). No reaction took
findings14a for the synthesis of 1 (see the Supporting Infor- place when 2,4-dinitroaniline was used as the substrate,
mation), we started our investigation by using aniline (2a) which might be due to the reduced nucleophilicity of the
as a model substrate in the reaction with 1 and 2-haloge- corresponding substrate (entry 16). It could be concluded
nated bifunctional reagents (Table 1). As expected, the that the reactivity of halogen-substituted anilines de-
cascade reaction between 1 and aniline (2a) catalyzed by creased in the order I > Br > Cl > F by comparing the prod-
4-toluenesulfonic acid under microwave conditions in uct yields of 3d–g, respectively (entries 4–7). The steric
N,N-dimethylformamide, dimethyl sulfoxide, or N-meth- effect of the substrates was also observed. For instance,
ylpyrrolidin-2-one gave intermediate 4a (Step 1), fol- the ortho-substituted anilines afforded lower yields of the
lowed by subsequent metal-free C–O and C–N forming desired products 3j–m compared to the substrates bearing
reaction with chloroacetyl chloride to afford the desired the same substituents at the para-position 3b,c,e,f (entries
product 3a in good yields (entries 1–3). Although chloro- 10–13 vs. 2, 3, 5, 6). Moreover, 2,4,6-trimethylaniline ex-
acetyl chloride seemed to be highly reactive and effective hibited relative low reactivity in this reaction and gave 3o
in this process, it is a moisture-sensitive, corrosive, and ir- in 68% yield. It was noteworthy that the diamino substrate
ritating substrate. Alternatively, we then carried out the 4,4′-benzidine reacted smoothly with two equivalents of
reaction by using the more benign methyl chloroacetate as 3-MDHS (1) and methyl chloroacetate to afford the corre-
the bifunctional reagent and ethanol as the solvent. To our sponding symmetrical bi-N-aryl-1,4-benzoxazin-3-one 3v
delight, 3a was obtained in 69% isolated yield (entry 4). (entry 22). Additionally, benzophenone hydrazone and 1-
Subsequently, various solvents such as dimethyl sulfox- naphthylamine also readily underwent this consecutive
ide, N,N-dimethylformamide, N-methylpyrrolidin-2-one, transformation and gave the desired products 3w,x, re-
N,N-dimethylacetamide, PEG-200, PEG-400, and 1,4-di- spectively, in high yields (entries 23 and 24). Notably, the
oxane were screened. We were pleased to find that the de- workup procedure of the reaction is simple; the desired
sired product 3a could be obtained in these solvents with products 3 could substantially be separated in pure form
yields ranging from 52–93%, among which N,N-dimeth- from the reaction mixture by precipitating with water.
ylformamide was optimal (entries 4–10). The effect of
Finally, the scope and generality of our protocol was fur-
different bases on step 2 was also investigated. Results
ther explored by using methyl 2-chloropropanoate as the
showed that both potassium and cesium carbonate gave
bifunctional reagent (Table 3). Gratifyingly, methyl 2-
Synthesis 2014, 46, 1167–1176
© Georg Thieme Verlag Stuttgart · New York

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Biomass-Involved Practical Approach to N-Aryl-1,4-benzoxazin-3-ones
1169
chloropropanoate coupled readily with 3-MDHS (1) and tions and afforded the desired product in 82% yield (entry
arylamines in this one-pot, two-step process, affording the 6). In addition, high yields were obtained when polycyclic
corresponding N-aryl-2-methyl-1,4-benzoxazin-3-ones 5 arylamines such as 4′-chlorobiphenyl-4-ylamine and 1-
rapidly and efficiently (entries 1–8). Both electron-rich naphthylamine were used as substrates (entries 7 and 8).
(entry 2) and electron-deficient (entries 3–5) arylamines It is worth mentioning that compound 5h existed as dia-
1
gave the corresponding products in satisfactory yields. It stereoisomers in a 1:1 molar ratio as confirmed by H
was notable that the carbonyl group survived the condi- NMR spectroscopy, probably owing to the steric hin-
Table 1 Optimization of the Reaction Conditionsa
NH2
step 1
p-TsOH
MW
step 2
MeO2C
O
bifunctional reagent, base
+
MeO2C
N
O
O
MeO2C
NH
OH
OH
MW
OH
1
2a
3a
4a
Entry
Solvent
Base
Step 1b
Step 2b
Yieldc (%)
1
DMF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Na2CO3
110 °C, 8 min
110 °C, 8 min
110 °C, 8 min
78 °C, 25 min
110 °C, 8 min
110 °C, 8 min
110 °C, 10 min
110 °C, 10 min
110 °C, 10 min
100 °C, 20 min
110 °C, 10 min
110 °C, 10 min
110 °C, 10 min
110 °C, 10 min
110 °C, 10 min
110 °C, 10 min
110 °C, 10 min
110 °C, 10 min
110 °C, 10 min
90 °C, 16 min
130 °C, 8 min
110 °C, 240 min
110 °C, 8 min
60 °C, 90 min
60 °C, 90 min
60 °C, 90 min
78 °C, 30 min
110 °C, 5 min
110 °C, 5 min
110 °C, 5 min
110 °C, 15 min
110 °C, 15 min
100 °C, 5 min
110 °C, 5 min
110 °C, 10 min
110 °C, 10 min
110 °C, 8 min
110 °C, 10 min
110 °C, 10 min
110 °C, 10 min
110 °C, 10 min
110 °C, 110 min
90 °C, 10 min
130 °C, 10 min
110 °C, 5 h
90d
87d
89d
69
2
DMSO
NMP
3
4
EtOH
5
DMSO
DMF
80
6
93
7
NMP
90
8
PEG-200
PEG-400
65
9
56
10
11
12
13
14
15
16
17
18
19
20
21
22
23
1,4-dioxane
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
52
93
85
NaHCO3
Et3N
trace
45
pyridine
DBU
40
38
NaOMe
NaOH
–
75
60
e
–
K2CO3
K2CO3
K2CO3
K2CO3
85
89
83f
90d
60 °C, 1.5 h
a Typical procedure under microwave conditions: step 1: 1 (0.41 g, 2.2 mmol), 2a (2.0 mmol), p-TsOH (0.10 mmol), solvent (3.0 mL); step 2:
add methyl chloroacetate (2.4 mmol), K2CO3 (4.0 mmol), stir.
b The ramp time is included as part of the reaction time.
c Isolated yield.
d Chloroacetyl chloride was used as the bifunctional reagent for step 2 under conventional heating.
e Not detected, only intermediate 4a was obtained.
f Reaction was carried out in an oil bath.
© Georg Thieme Verlag Stuttgart · New York
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E. Zhang et al.
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drance of the bulky α-naphthyl group that hampers the in- the sequential reaction between 3-MDHS (1), anilines,
version of the configuration and the rotation of the C–N and bifunctional 2-chloroalkyl esters has been developed.
bond.
Various N-aryl-1,4-benzoxazin-3-ones were readily syn-
thesized in moderate to excellent yields. Notable features
In conclusion, a facile and metal-free protocol for the one-
pot assembly of N-aryl-1,4-benzoxazin-3-ones through
Table 2 Microwave-Assisted One-Pot Synthesis of N-Aryl-1,4-benzoxazin-3-onesa
Ar
N
MeO2C
O
O
p-TsOH, then base
MeO2C
O
Cl
+
+
ArNH2
MeO
OH
MW
O
OH
1
2
3
Entry
Ar
T1b (min)
T2b (min)
Product
Yieldc (%)
1
2
Ph
8
8
5
5
5
6
6
7
8
7
6
6
7
7
6
10
8
0
7
7
5
7
6
9
5
6
3a
3b
3c
3d
3e
3f
93
97
96
90
87
83
78
85
82
89
82
75
90
72
68
4-MeOC6H4
4-MeC6H4
4-IC6H4
3
8
4
8
5
4-BrC6H4
8
6
4-ClC6H4
10
8
7
4-FC6H4
3g
3h
3i
8
4-AcC6H4
8
9
4-O2NC6H4
2-MeC6H4
2-BrC6H4
12
10
12
12
8
10
11
12
13
14
15
16
17
18
19
20
21
22e
23
24
3j
3k
3l
2-ClC6H4
2-MeOC6H4
2,5-Cl2C6H3
2,4,6-Me3C6H2
2,4-(O2N)2C6H3
3-MeO2CC6H4
3-F3CC6H4
3-MeC6H4
3-O2NC6H4
3-ClC6H4
3m
3n
3o
3p
3q
3r
3s
13
12
20
8
d
–
80
71
92
83
85
88
87
90
8
8
8
3t
8
3u
3vg
3w
3x
f
4-(4-H2NC6H4)C6H4
1-naphthyl
12
8
N=CPh2
8
a Reactions conditions: 1 (0.41 g, 2.2 mmol), 2 (2.0 mmol), p-TsOH (0.10 mmol), DMF (3.0 mL), methyl chloroacetate (2.4 mmol), K2CO3 (4.0
mmol), microwaves, 110 °C; step 1: T1; step 2: T2.
b The ramp time is included as part of the reaction time.
c Isolated yield.
d Not detected.
e Reactions condition: 1 (0.82 g, 4.4 mmol), 4,4′-benzidine (2.0 mmol), p-TsOH (0.20 mmol), DMF (8.0 mL), methyl chloroacetate (6.0 mmol),
K2CO3 (8.0 mmol) under typical procedures.
f Aniline was 4,4′-benzidine.
g Product is N,N′-biphenylbis[6-(methoxycarbonyl)-2H-1,4-benzoxazin-3(4H)-one].
Synthesis 2014, 46, 1167–1176
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Biomass-Involved Practical Approach to N-Aryl-1,4-benzoxazin-3-ones
1171
Table 3 Expanding of Substrate Scope Using Methyl 2-chloropropanoate as the Bifunctional Reagenta
Ar
N
MeO2C
O
O
p-TsOH, then base
MeO2C
O
Cl
+
+
ArNH2
MeO
OH
MW
O
OH
5
1
2
Entry
Ar
Ph
T1b (min)
T2b (min)
Product
Yieldc (%)
1
2
3
4
5
6
7
8
8
8
5
5
8
6
7
8
6
6
5a
5b
5c
5d
5e
5f
92
93
75
83
72
82
87
85d
4-MeC6H4
4-FC6H4
8
4-BrC6H4
8
4-O2NC6H4
4-AcC6H4
12
8
4-(4-ClC6H4)C6H4
1-naphthyl
8
5g
5h
8
a Reactions conditions: methyl 2-chloropropanoate was used as bifunctional reagent according to the typical microwave procedures.
b The ramp time is included as part of the reaction time.
c Isolated yield.
d 1H NMR spectrum showed that 5h existed as diastereoisomers in a 1:1 molar ratio, which may be due to the steric hindrance of the bulky α-
naphthyl group, hindering the inversion of the configuration and the rotation of the C–N bond (see the Supporting Information for details).
mmol) were added to the mixture and it was irradiated (240 W, 110
°C) with stirring for the indicated time (T2). Upon cooling, the mix-
ture was poured into H2O, the resulting solid was filtered and dried
to furnish the desired product in pure form in most cases. If neces-
sary, these products could be further purified by recrystallization
(EtOAc–PE) or column chromatography (silica gel, 200–300,
EtOAc–PE).
such as the biomass-involved transformation, metal- and
ligand-free reaction conditions, step-efficient procedures,
and broad substrate scope have made this protocol a prac-
tical alternative to the existing transition-metal-catalyzed
methods.
(–)-Shikimic acid (chromatography grade) was kindly provided as
a natural product by Guangxi Wan Shan Spice Co. Ltd. (–)-Methyl
3-dehydroshikimate was readily prepared from (–)-shikimic acid
through an improved method based on our previously reported pro-
tocol (see the Supporting Information for details). Petroleum ether
(PE) was boiling fraction 60–90 °C. Other reagents and solvents
were purchased from commercial sources and used without further
purification unless otherwise stated. Reactions were monitored by
TLC. Column chromatography was performed with silica gel (200–
300 mesh) using a EtOAc–PE system as eluent. Melting points were
measured on a Thiele apparatus and are uncorrected. Microwave
experiments were carried out with a scientific WBFY microwave
reactor in a flask connected with a condenser under atmosphere
pressure. This microwave reactor was a monomode device with a
tunable power controller. Reaction temperature was detected using
an infrared thermometer and the ramp time is included as part of the
reaction time. 1H NMR and 13C NMR spectra were measured on a
400 MHz spectrometer (1H 400 MHz, 13C 100 MHz) using CDCl3
or DMSO-d6 as the solvent at r.t. calibrated using residual undeuter-
ated solvent as an internal reference. HRMS spectra were recorded
on a LC-Q-TOF (ESI) apparatus. MS spectra were measured on a
Shimadzu GC-MS QP5050A in EI mode or a Thermo Finnigan
LCQ DECA XP ion trap mass spectrometer in ESI mode.
Methyl 3-Oxo-4-phenyl-3,4-dihydro-2H-1,4-benzoxazine-6-
carboxylate (3a)
White needles; yield: 0.53 g (93%); mp 161–163 °C; Rf = 0.51
(EtOAc–PE, 1:3).
1H NMR (400 MHz, DMSO-d6): δ = 7.62 (dd, J = 8.4, 1.6 Hz, 1 H),
7.60–7.53 (m, 3 H), 7.37 (d, J = 7.6 Hz, 2 H), 7.18 (d, J = 8.4 Hz, 1
H), 6.85 (d, J = 1.6 Hz, 1 H), 4.92 (s, 2 H), 3.69 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 165.3, 163.3, 148.2, 135.4,
130.6, 130.1, 129.0, 129.0, 125.2, 123.5, 116.9, 116.6, 67.4, 52.1.
MS (EI): m/z (%) = (283 [M]+, 100), 252 ([M – OCH3]+, 23), 224
([M – COOCH3]+, 5), 198 (11), 178 (10), 77 (18).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H13NNaO4:
306.0737; found: 306.0735.
Methyl 4-(4-Methoxyphenyl)-3-oxo-3,4-dihydro-2H-1,4-ben-
zoxazine-6-carboxylate (3b)
White solid; yield: 0.61 g (97%); mp 151–153 °C; Rf = 0.52
(EtOAc–PE, 1:3).
1H NMR (400 MHz, DMSO-d6): δ = 7.60 (dd, J = 8.4, 2.0 Hz, 1 H),
7.27 (d, J = 9.2 Hz, 2 H), 7.16 (d, J = 8.4 Hz, 1 H), 7.12 (d, J = 9.2
Hz, 2 H), 6.90 (d, J = 2.0 Hz, 1 H), 4.89 (s, 2 H), 3.83 (s, 3 H), 3.71
(s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 165.3, 163.4, 159.2, 148.2,
130.8, 130.1, 127.6, 125.1, 123.5, 116.8, 116.6, 115.2, 67.5, 55.4,
52.1.
MS (EI): m/z (%) = 313 ([M]+, 100), 284 (73), 228 (10), 178 (8), 77
(10).
Methyl 4-Aryl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-car-
boxylates 3a–o,q–x; General Procedure
To a mixture of 3-MDHS (1; 0.41 g, 2.2 mmol) and p-TsOH (0.10
mmol) in DMF (3 mL) was added arylamine 2 (2.0 mmol). The
flask was then placed in the microwave synthesizer and the mixture
was irradiated (240 W, 110 °C) with stirring for the indicated time
(T1). Then, K2CO3 (0.55 g, 4 mmol) and methyl chloroacetate (2.4
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E. Zhang et al.
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HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H15NNaO5:
336.0842; found: 336.0838.
1H NMR (400 MHz, DMSO-d6): δ = 7.62 (dd, J = 8.4, 1.6 Hz, 1 H),
7.44 (d, J = 6.8 Hz, 4 H), 7.18 (d, J = 8.4 Hz, 1 H), 6.84 (d, J = 1.6
Hz, 1 H), 4.91 (s, 2 H), 3.71 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 165.3, 163.4, 161.8 (d,
1JFC = 245 Hz, 4′C), 148.2, 131.5 (d, 4JFC = 2.2 Hz, 1′C), 131.3 (d,
3JFC = 8.9 Hz, 2′C), 130.6, 125.3, 123.6, 117.2, 117.0 (d, 2JFC = 22
Hz, 3′C), 116.9, 67.4, 52.1.
MS (EI): m/z (%) = 301 ([M]+, 100), 272 ([M – OCH3]+, 98), 216
(7), 178 (8).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H12FNNaO4:
Methyl 4-(4-Methylphenyl)-3-oxo-3,4-dihydro-2H-1,4-benzox-
azine-6-carboxylate (3c)
White solid; yield: 0.57 g (96%); mp 174–176 °C; Rf = 0.43
(EtOAc–PE, 1:4).
1H NMR (400 MHz, DMSO-d6): δ = 7.60 (dd, J = 8.4, 2.0 Hz, 1 H),
7.39 (d, J = 8.4 Hz, 2 H), 7.23 (d, J = 8.4 Hz, 2 H), 7.16 (d, J = 8.4
Hz, 1 H), 6.88 (d, J = 2.0 Hz, 1 H), 4.90 (s, 2 H), 3.70 (s, 3 H), 2.40
(s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 165.3, 163.3, 148.2, 138.5,
132.7, 130.6, 128.6, 125.1, 123.5, 116.9, 116.8, 116.6, 67.4, 52.1,
20.8.
MS (EI): m/z (%) = 297 ([M]+, 91), 268 (100), 266 ([M – OCH3]+,
18), 240 (9), 178 (10), 77 (23).
324.0643; found: 324.0636.
Methyl 4-(4-Acetylphenyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxa-
zine-6-carboxylate (3h)
White solid; yield: 0.55 g (85%); mp 160–162 °C; Rf = 0.32
(EtOAc–PE, 1:2.5).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H15NNaO4:
320.0893; found: 320.0887.
1H NMR (400 MHz, DMSO-d6): δ = 8.16 (d, J = 8.4 Hz, 2 H), 7.63
(dd, J = 8.4, 2.00 Hz, 1 H), 7.55 (d, J = 8.4 Hz, 2 H), 7.21 (d, J = 8.4
Hz, 1 H), 6.85 (d, J = 2.0 Hz, 1 H), 4.93 (s, 2 H), 3.70 (s, 3 H), 2.66
(s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 197.3, 165.2, 163.3, 148.4,
139.5, 137.0, 130.2, 130.0, 129.4. 125.5, 123.6, 117.1, 116.6, 67.5,
52.1, 26.9.
MS (EI): m/z (%) = 325 ([M]+, 100), 294 ([M – OCH3]+, 14), 254
(9), 178 (6).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C18H15NNaO5:
348.0842; found: 348.0839.
Methyl 4-(4-Iodophenyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxa-
zine-6-carboxylate (3d)
Off-white solid; yield: 0.74 g (90%); mp 165–167 °C; Rf = 0.62
(EtOAc–PE, 1:3).
1H NMR (400 MHz, DMSO-d6): δ = 7.98 (d, J = 8.8 Hz, 2 H), 7.64
(dd, J = 8.4, 1.6 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 2 H), 7.18 (d, J = 8.4
Hz, 1 H), 6.88 (d, J = 2.0 Hz, 1 H), 4.92 (s, 2 H), 3.74 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 165.3, 163.3, 148.3, 139.0,
135.2, 131.3, 130.2, 125.4, 123.6, 117.0, 116.5, 95.4, 67.4, 52.1.
MS (EI): m/z (%) = 409 ([M]+, 100), 380 (73), 316 (18), 77 (18).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H12INNaO4:
Methyl 4-(4-Nitrophenyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxa-
zine-6-carboxylate (3i)
Faint yellow solid; yield: 0.54 g (82%); mp 183–185 °C; Rf = 0.52
(EtOAc–PE, 1:2.5).
431.9703; found: 431.9696.
1H NMR (400 MHz, DMSO-d6): δ = 8.47 (d, J = 8.8 Hz, 2 H), 7.74
(d, J = 8.8 Hz, 2 H), 7.66 (dd, J = 8.4, 2.0 Hz, 1 H), 7.24 (d, J = 8.4
Hz, 1 H), 6.88 (d, J = 2.0 Hz, 1 H), 4.96 (s, 2 H), 3.72 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 165.2, 163.4, 148.4, 147.4,
141.3, 130.6, 129.9, 125.6, 125.3, 123.7, 117.2, 116.5, 67.5, 52.1.
Methyl 4-(4-Bromophenyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxa-
zine-6-carboxylate (3e)
White solid; yield: 0.63 g (87%); mp 166–168 °C; Rf = 0.47
(EtOAc–PE, 1:4).
1H NMR (400 MHz, DMSO-d6): δ = 7.80 (dd, J = 6.8, 2.0 Hz, 2 H),
7.62 (dd, J = 8.4, 2.0 Hz, 1 H), 7.36 (dd, J = 6.8, 2.0 Hz, 2 H), 7.18
(d, J = 8.4 Hz, 1 H), 6.85 (d, J = 2.0 Hz, 1 H), 4.91 (s, 2 H), 3.71 (s,
3 H).
MS (EI): m/z (%) = 328 ([M]+, 100), 297 ([M – OCH3]+, 18), 269
([M – COOCH3]+, 7), 178 (6), 77 (4).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H12N2NaO6:
351.0588; found: 351.0583.
13C NMR (100 MHz, DMSO-d6): δ = 165.3, 163.3, 148.3, 134.7,
133.2, 131.3, 130.3, 125.4, 123.6, 122.2, 117.0, 116.4, 67.4, 52.1.
MS (EI): m/z (%) = 363 ([M + 2]+, 100), 361 ([M]+, 99), 332 ([M –
Methyl 4-(2-Methylphenyl)-3,4-dihydro-2H-1,4-benzoxazine-6-
OCH3]+, 73), 178 (18), 77 (8).
carboxylate (3j)
White solid; yield: 0.53 g (89%); mp 93–95 °C; Rf = 0.66 (EtOAc–
PE, 1:3).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H1279BrNNaO4:
383.9842; found 383.9832.
1H NMR (400 MHz, DMSO-d6): δ = 7.63 (dd, J = 8.4, 2.0 Hz, 1 H),
7.49–7.39 (m, 3 H), 7.29 (d, J = 7.6 Hz, 1 H), 7.20 (d, J = 8.4 Hz, 1
H), 6.73 (d, J = 2.0 Hz, 1 H), 4.95 (q, J = 27.60 Hz, 2 H), 3.69 (s, 3
H), 2.02 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 165.3, 162.9, 148.3, 136.3,
134.1, 131.5, 129.7, 129.5, 129.2, 127.8, 125.4, 123.8, 117.0, 116.1,
67.4, 52.1, 16.8.
Methyl 4-(4-Chlorophenyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxa-
zine-6-carboxylate (3f)
White solid; yield: 0.53 g (83%); mp 156–158 °C; Rf = 0.61
(EtOAc–PE, 1:3).
1H NMR (400 MHz, DMSO-d6): δ = 7.67 (d, J = 8.8 Hz, 2 H), 7.63
(dd, J = 8.4, 2.0 Hz, 1 H), 7.43 (d, J = 8.8 Hz, 2 H), 7.19 (d, J = 8.4
Hz, 1 H), 6.85 (d, J = 2.0 Hz, 1 H), 4.91 (s, 2 H), 3.71 (s, 3 H).
MS (EI): m/z (%) = 297 ([M]+, 100), 268 ([M – OCH3]+, 38), 240
13C NMR (100 MHz, DMSO-d6): δ = 165.3, 163.4, 148.2, 134.3,
133.6, 131.0, 130.3, 130.2, 125.3, 123.6, 117.0, 116.4, 67.4, 52.1.
([M – COOCH3]+, 9), 178 (5), 77 (7).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H15NNaO4:
320.0893; found: 320.0896.
MS (EI): m/z (%) = 319 ([M + 2]+, 100), 317 ([M]+, 33), 286 ([M –
OCH3]+, 14), 240 (9), 178 (10).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H1235ClNNaO4:
340.0347; found: 340.0340.
Methyl 4-(2-Bromophenyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxa-
zine-6-carboxylate (3k)
Off-white solid; yield: 0.59 g (82%); mp 81–83 °C; Rf = 0.54
(EtOAc–PE, 1:3).
1H NMR (400 MHz, DMSO-d6): δ = 7.91 (dd, J = 8.4, 1.2 Hz, 1 H),
7.67–7.63 (m, 2 H), 7.62–7.58 (m, 1 H), 7.56–7.50 (m, 1 H), 7.23
Methyl 4-(4-Fluorophenyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxa-
zine-6-carboxylate (3g)
White solid; yield: 0.47 g (78%); mp 140–142 °C; Rf = 0.40
(EtOAc–PE, 1:4).
Synthesis 2014, 46, 1167–1176
© Georg Thieme Verlag Stuttgart · New York

PAPER
Biomass-Involved Practical Approach to N-Aryl-1,4-benzoxazin-3-ones
1173
(d, J = 8.4 Hz, 1 H), 6.71 (d, J = 2.0 Hz, 1 H), 4.96 (s, 2 H), 3.70 (s,
3 H).
MS (EI): m/z (%) = 325 ([M]+, 100), 294 ([M – OCH3]+, 9), 266 ([M
– COOCH3]+, 6), 238 (11), 77 (8).
13C NMR (100 MHz, DMSO-d6): δ = 165.2, 162.9, 148.2, 134.2,
133.9, 131.7, 131.5, 129.7, 129.2, 125.6, 123.8, 122.8, 117.2, 115.9,
67.4, 52.2.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C19H19NNaO4:
348.1206; found: 348.1215.
Methyl 4-[3-(Methoxycarbonyl)phenyl]-3-oxo-3,4-dihydro-2H-
1,4-benzoxazine-6-carboxylate (3q)
White solid; yield: 0.54 g (80%); mp 119–121 °C; Rf = 0.48
(EtOAc–PE, 1:2.5).
MS (EI): m/z (%) = 363 ([M + 2]+, 27), 361 ([M]+, 25), 332 ([M –
OCH3]+, 9), 282 (100), 75 (18).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H12BrNNaO4:
1H NMR (400 MHz, DMSO-d6): δ = 8.11 (d, J = 8.0 Hz, 1 H), 7.98
(s, 1 H), 7.76 (t, 1 H), 7.69 (d, J = 8.0 Hz, 1 H), 7.62 (dd, J = 8.4,
2.0 Hz, 1 H), 7.19 (d, J1 = 8.4 Hz, 1 H), 6.79 (d, J = 1.6 Hz, 1 H),
4.93 (s, 2 H), 3.87 (s, 3 H), 3.69 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 165.4, 165.2, 163.5, 148.3,
135.9, 133.9, 131.6, 130.8, 130.4, 130.0, 129.7, 125.4, 123.6, 117.0,
116.4, 67.5, 52.4, 52.1.
383.9842; found: 383.9844.
Methyl 4-(2-Chlorophenyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxa-
zine-6-carboxylate (3l)
White solid; yield: 0.47 g (75%); mp 106–108 °C; Rf = 0.63
(EtOAc–PE, 1:2.5).
1H NMR (400 MHz, DMSO-d6): δ = 7.78–7.75 (m, 1 H), 7.65 (dd,
J = 8.4, 2.0 Hz, 1 H), 7.61–7.59 (m, 3 H), 7.22 (d, J = 8.4 Hz, 1 H),
6.74 (d, J = 2.0 Hz, 1 H), 4.97 (s, 2 H), 3.71 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 165.2, 163.0, 148.2, 132.5,
132.3, 131.7, 131.4, 130.7, 129.3, 129.2, 125.7, 123.9, 117.2, 115.8,
67.3, 52.2.
MS (EI): m/z (%) = 341 ([M]+, 100), 310 ([M – OCH3]+, 16), 282
([M – COOCH3]+, 3), 178 (5).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C18H15NNaO6:
364.0792; found: 364.0792.
MS (EI): m/z (%) = 319 ([M + 2]+, 18), 317 ([M]+, 55), 286 ([M –
Methyl 3-Oxo-4-[3-(trifluoromethyl)phenyl]-3-oxo-3,4-di-
hydro-2H-1,4-benzoxazine-6-carboxylate (3r)
White solid; yield: 0.50 g (71%); mp 108–110 °C; Rf = 0.40
(EtOAc–PE, 1:4).
OCH3]+, 9), 282 (100), 240 (5), 178 (7), 75 (14).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H12ClNNaO4:
340.0347; found: 340.0349.
1H NMR (400 MHz, DMSO-d6): δ = 7.94–7.73 (m, 4 H), 7.63 (dd,
J = 8.4, 1.6 Hz, 1 H), 7.20 (d, J = 8.4 Hz, 1 H), 6.80 (d, J = 1.6 Hz,
1 H), 4.93 (s, 2 H), 3.71 (s, 3 H).
Methyl 4-(2-Methoxyphenyl)-3,4-dihydro-2H-1,4-benzoxazine-
6-carboxylate (3m)
White solid; yield: 0.56 g (90%); mp 148–150 °C; Rf = 0.29
(EtOAc–PE, 1:4).
1H NMR (400 MHz, DMSO-d6): δ = 7.60 (dd, J = 8.4, 2.0 Hz, 1 H),
7.53 (m, 1 H), 7.33 (dd, J = 8.0, 1.6 Hz, 1 H), 7.28 (dd, J = 8.0, 0.8
Hz, 1 H), 7.12–7.17 (m, 2 H), 6.83 (d, J = 2.0 Hz, 1 H), 4.91 (s, 2
H), 3.70 (s, 6 H).
13C NMR (100 MHz, DMSO-d6): δ = 165.3, 163.1, 155.2, 148.2,
130.9, 130.6, 130.3, 125.2, 123.7, 123.1, 121.4, 116.9, 116.2, 113.0,
67.3, 55.8, 52.1.
13C NMR (100 MHz, DMSO-d6): δ = 165.2, 163.5, 148.2, 136.3,
2
133.5, 131.5, 130.9 (q, JCF = 34 Hz, 1 C), 130.2, 126.3, 126.0,
1
125.9, 125.4, 123.6 (q, JCF = 274 Hz, CF3), 117.1, 116.3, 67.4,
52.1.
MS (EI): m/z (%) = 351 ([M]+, 100), 320 ([M – OCH3]+, 18), 292
([M – COOCH3]+, 3), 178 (6).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H12F3NNaO4:
374.0611; found: 374.0602.
MS (EI): m/z (%) = 313 ([M]+, 100), 282 ([M – OCH3]+, 23), 254
Methyl 4-(3-Methylphenyl)-3,4-dihydro-2H-1,4-benzoxazine-6-
carboxylate (3s)
White solid; yield: 0.55 g (92%); mp 137–139 °C; Rf = 0.44
(EtOAc–PE, 1:4).
([M – COOCH3]+, 6), 178 (4), 75 (7).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H15NNaO5:
336.0842; found: 336.0845.
1H NMR (400 MHz, DMSO-d6): δ = 7.60 (dd, J = 8.4, 2.0 Hz, 1 H),
7.48 (t, 1 H), 7.34 (d, J = 8.0 Hz, 1 H), 7.15 (t, 3 H), 6.88 (d, J = 2.0
Hz, 1 H), 4.91 (s, 2 H), 3.70 (s, 3 H), 2.37 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 165.3, 163.3, 148.3, 139.8,
135.3, 130.6, 129.9, 129.7, 129.3, 125.9, 125.2, 123.6, 116.9, 116.7,
67.5, 52.1, 20.8.
Methyl 4-(2,5-Dichlorophenyl)-3-oxo-3,4-dihydro-2H-1,4-benz-
oxazine-6-carboxylate (3n)
White solid; yield: 0.51 g (72%); mp 136–138 °C; Rf = 0.71
(EtOAc–PE, 1:3).
1H NMR (400 MHz, DMSO-d6): δ = 7.87 (d, J = 2.4 Hz, 1 H), 7.83
(d, J = 8.8 Hz, 1 H), 7.72 (dd, J = 8.8, 2.4 Hz, 1 H), 7.67 (dd,
J = 8.4, 2.0 Hz, 1 H), 7.24 (d, J = 8.4 Hz, 1 H), 6.77 (d, J = 2.0 Hz,
1 H), 5.03–4.93 (dd, J = 15.2 Hz, 2 H), 3.75 (s, 3 H).
MS (EI): m/z (%) = 297 ([M]+, 100), 266 ([M – OCH3]+, 73), 238
([M – COOCH3]+, 5), 178 (9), 77 (6).
13C NMR (100 MHz, DMSO-d6): δ = 165.1 (C=O), 163.0 (C=O),
148.0, 133.7, 132.8, 132.0, 131.8, 131.6, 131.4, 128.9, 125.8, 123.9,
117.3, 115.6, 67.2, 52.2.
MS (EI): m/z (%) = 351 ([M]+, 25), 320 ([M – OCH3]+, 7), 316
(100), 178 (7).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H15NNaO4:
320.0893; found: 320.0894.
Methyl 4-(3-Nitrophenyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxa-
zine-6-carboxylate (3t)
White solid, yield: 0.54 g (83%); mp >200 °C; Rf = 0.44 (EtOAc–
PE, 1:2.5).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H1135Cl2NNaO4:
1H NMR (400 MHz, DMSO-d6): δ = 8.40 (m, 2 H), 7.90 (d, J = 4.8
Hz, 2 H), 7.64 (dd, J = 8.4, 2.0 Hz, 1 H), 7.21 (d, J = 8.4 Hz, 1 H),
6.82 (d, J = 1.6 Hz, 1 H), 4.93 (s, 2 H), 3.70 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 165.3, 163.6, 148.8, 148.3,
136.5, 136.0, 131.6, 130.2, 125.5, 124.7, 124.1, 123.7, 117.2, 116.4,
67.5, 52.2.
373.9957; found: 373.9951.
Methyl 3-Oxo-4-(2,4,6-trimethylphenyl)-3,4-dihydro-2H-1,4-
benzoxazine-6-carboxylate (3o)
White solid; yield: 0.44 g (68%); mp 120–122 °C; Rf = 0.57
(EtOAc–PE, 1:4).
1H NMR (400 MHz, DMSO-d6): δ = 7.63 (dd, J = 8.4, 2.0 Hz, 1 H),
7.21 (d, J = 8.4 Hz, 1 H), 7.10 (s, 2 H), 6.71 (d, J = 2.0 Hz, 1 H),
4.98 (s, 2 H), 3.71 (s, 3 H), 2.32 (s, 3 H), 1.95 (s, 6 H).
MS (EI): m/z (%) = 328 ([M]+, 100), 297 ([M – OCH3]+, 23), 253
(18).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1167–1176

1174
E. Zhang et al.
PAPER
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H12N2NaO6:
351.0588; found: 351.0585.
Methyl 4-Aryl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxa-
zine-6-carboxylates 5a–h; General Procedure
To a mixture of 3-MDHS (1; 0.41 g, 2.2 mmol) and p-TsOH (0.10
mmol) in DMF (3 mL) was added arylamine 2 (2.0 mmol). The
flask was then placed into the microwave synthesizer and the mix-
ture was irradiated (240 W, 110 °C) with stirring for the indicated
time (T1). Then, K2CO3 (0.55 g, 4 mmol) and methyl 2-chloropro-
panoate (2.4 mmol) were added to the mixture and it was irradiated
(240 W, 110 °C) with stirring for the indicated time (T2). Upon cool-
ing, the mixture was poured into H2O, the resulting solid was fil-
tered and dried to furnish the desired product in pure form.
Methyl 4-(3-Chlorophenyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxa-
zine-6-carboxylate (3u)
White solid; yield: 0.54 g (85%); mp 146–148 °C; Rf = 0.62
(EtOAc–PE, 1:3).
1H NMR (400 MHz, DMSO-d6): δ = 7.64–7.51 (m, 3 H), 7.58 (s, 1
H), 7.40–7.38 (m, 1 H), 7.18 (d, J = 8.4 Hz, 1 H), 6.84 (d, J = 2.0
Hz, 1 H), 4.91 (s, 2 H), 3.72 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 165.2, 163.4, 148.2, 136.8,
134.0, 131.7, 130.3, 129.3, 129.3, 128.0, 125.4, 123.6, 117.0, 116.4,
67.4, 52.2.
Methyl 2-Methyl-4-phenyl-3-oxo-3,4-dihydro-2H-1,4-benzoxa-
zine-6-carboxylate (5a)
White solid; yield: 0.55 g (92%); mp 145–147 °C; Rf = 0.65
(EtOAc–PE, 1:4).
1H NMR (400 MHz, DMSO-d6): δ = 7.62 (dd, J = 8.4, 2.0 Hz, 1 H),
7.58 (t, J = 8.0 Hz, 2 H), 7.53 (t, J = 7.2 Hz, 1 H), 7.35 (d, J = 7.2
Hz, 2 H), 7.19 (d, J = 8.0 Hz, 1 H), 6.85 (d, J = 2.0 Hz, 1 H), 5.03
(q, J = 6.8 Hz, 1 H), 3.69 (s, 3 H), 1.54 (d, J = 6.80 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 165.5, 165.3, 147.8, 135.8,
130.9, 130.1, 129.0, 128.9, 125.2, 123.7, 117.2, 116.6, 73.5, 52.1,
16.2.
MS (EI): m/z (%) = 297 ([M]+, 76), 266 ([M – OCH3]+, 9), 254
(100).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H15NNaO4:
320.0893; found: 320.0894.
MS (EI): m/z (%) = 319 ([M + 2]+, 33), 317 ([M]+, 100), 286 ([M –
OCH3]+, 98), 258 ([M – COOCH3]+, 3), 178 (9).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H12ClNNaO4:
340.0347; found: 340.0348.
N,N′-Biphenylbis[6-(methoxycarbonyl)-2H-1,4-benzoxazin-
3(4H)-one] (3v)
White solid; yield: 0.99 g (88%); mp >200 °C; Rf = 0.24 (EtOAc–
PE, 1:2).
1H NMR (400 MHz, DMSO-d6): δ = 8.03 (d, J = 8.4 Hz, 4 H), 7.64
(dd, J = 8.4, 2.0 Hz, 2 H), 7.53 (d, J = 8.4 Hz, 4 H), 7.21 (t, J = 8.4
Hz, 2 H), 6.98 (d, J = 2.0 Hz, 2 H), 4.96 (s, 4 H), 3.71 (s, 6 H).
13C NMR (100 MHz, DMSO-d6): δ = 165.3, 163.4, 148.4, 139.5,
135.1, 130.5, 129.7, 128.6, 125.4, 123.6, 117.0, 116.7, 67.5, 52.1.
MS (ESI): m/z = 565 [M + H]+.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C32H24N2NaO8:
Methyl 2-Methyl-4-(4-methylphenyl)-3-oxo-3,4-dihydro-2H-
1,4-benzoxazine-6-carboxylate (5b)
White solid; yield: 0.58 g (93%); mp 141–143 °C; Rf = 0.49
(EtOAc–PE, 1:5).
587.1425; found: 587.1416.
1H NMR (400 MHz, DMSO-d6): δ = 7.62 (dd, J = 8.4, 2.0 Hz, 1 H),
7.38 (d, J = 8.4 Hz, 2 H), 7.21 (d, J = 8.0 Hz, 2 H), 7.18 (d, J = 8.4
Hz, 1 H), 6.88 (d, J = 2.0 Hz, 1 H), 5.01 (q, J = 6.8 Hz, 1 H), 3.70
(s, 3 H), 2.40 (s, 3 H), 1.53 (d, J = 6.8 Hz, 3 H).
Methyl 4-(1-Naphthyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-
6-carboxylate (3w)
Pink crystals; yield: 0.58 g (87%); mp 157–159 °C; Rf = 0.53
(EtOAc–PE, 1:3).
1H NMR (400 MHz, CDCl3): δ = 8.02 (d, J = 8.4 Hz, 1 H), 7.95 (d,
J = 8.0 Hz, 1 H), 7.69 (dd, J = 8.4, 2.0 Hz, 1 H), 7.62 (t, J = 8.0 Hz,
1 H), 7.43–7.56 (m, 4 H), 7.12 (d, J = 8.4 Hz, 1 H), 6.91 (d, J = 2.0
Hz, 1 H), 5.00–4.89 (dd, J = 15.2 Hz, 2 H), 3.68 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 165.9, 163.7, 148.3, 134.9, 131.4,
130.4, 130.1, 129.8, 128.8, 127.5, 127.4, 126.7, 126.1, 125.9, 124.9,
121.8, 118.0, 116.9, 68.0, 52.0.
MS (EI): m/z (%) = 333 ([M]+, 100), 302 ([M – OCH3]+, 9), 291 (8),
244 (9), 178 (7), 77 (9).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C20H15NNaO4:
356.0893; found: 356.0888.
13C NMR (100 MHz, DMSO-d6): δ = 165.5, 165.3, 147.8, 138.4,
133.1, 130.9, 130.6, 128.6, 125.2, 123.7, 117.1, 116.7, 73.5, 52.1,
20.7, 16.2.
MS (EI): m/z (%) = 311 ([M]+, 71), 296 ([M – CH3]+, 2), 280 ([M –
OCH3]+, 5), 268 (100), 240 (6), 182 (4).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C18H17NNaO4:
334.1050; found: 334.1052.
Methyl 4-(4-Fluorophenyl)-2-methyl-3-oxo-3,4-dihydro-2H-
1,4-benzoxazine-6-carboxylate (5c)
White solid; yield: 0.47 g (75%); mp 119–121 °C; Rf = 0.62
(EtOAc–PE, 1:4).
1H NMR (400 MHz, DMSO-d6): δ = 7.62 (dd, J = 8.4, 2.0 Hz, 1 H),
7.44 (d, J = 7.2 Hz, 4 H), 7.20 (d, J = 8.4 Hz, 1 H), 6.84 (d, J = 2.0
Hz, 1 H), 5.01 (q, J = 6.8 Hz, 1 H), 3.71 (s, 3 H), 1.54 (d, J = 6.8 Hz,
3 H).
Methyl 4-[(Diphenylmethylene)amino]-3-oxo-3,4-dihydro-2H-
1,4-benzoxazine-6-carboxylate (3x)
White solid; yield: 0.69 g (90%); mp 146–148 °C; Rf = 0.68
(EtOAc–PE, 1:3).
1H NMR (400 MHz, DMSO-d6): δ = 7.84 (d, J = 2.0 Hz, 1 H), 7.77–
7.73 (m, 3 H), 7.56–7.52 (m, 1 H), 7.44–7.30 (m, 5 H), 7.20–7.17
(m, 2 H), 6.96 (d, J = 8.4 Hz, 1 H), 4.42 (s, 2 H), 3.86 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 179.2, 166.3, 155.9, 147.8, 136.0,
134.7, 132.1, 129.9, 129.8, 129.1, 128.3, 128.1, 127.4, 126.3, 124.9,
116.6, 116.3, 67.5, 52.1.
13C NMR (100 MHz, DMSO-d6): δ = 165.7, 165.3, 161.8 (d,
1JFC = 245 Hz, 4′C), 147.8, 132.0 (d, 4JFC = 2.5 Hz, 1′C), 131.3 (d,
3JFC = 8.1 Hz, 2′C), 130.9, 125.3, 123.7, 117.3, 117.2 (d, 2JFC = 22.6
Hz, 3′C), 116.6, 73.5, 52.1, 16.3.
MS (EI): m/z (%) = 315 ([M]+, 65), 284 ([M – OCH3]+, 7), 272
(100), 254 (2).
MS (ESI): m/z (%) = 386 ([M]+, 21), 355 ([M – OCH3]+, 3), 180
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H14FNNaO4:
(100), 77 (53).
338.0799; found: 338.0802.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C23H18N2NaO4:
409.1159; found: 409.1152.
Methyl 4-(4-Bromophenyl)-2-methyl-3-oxo-3,4-dihydro-2H-
1,4-benzoxazine-6-carboxylate (5d)
White solid; yield: 0.62 g (83%); mp 152–154 °C; Rf = 0.51
(EtOAc–PE, 1:5).
Synthesis 2014, 46, 1167–1176
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Biomass-Involved Practical Approach to N-Aryl-1,4-benzoxazin-3-ones
1175
1H NMR (400 MHz, DMSO-d6): δ = 7.79 (d, J = 8.4 Hz, 2 H), 7.63
(dd, J = 8.4, 1.6 Hz, 1 H), 7.35 (d, J = 8.4 Hz, 2 H), 7.20 (d, J = 8.4
Hz, 1 H), 6.85 (d, J = 2.0 Hz, 1 H), 5.01 (q, J = 6.8 Hz, 1 H), 3.72
(s, 3 H), 1.54 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 165.5, 165.3, 147.8, 135.2,
133.1, 131.3, 130.6, 125.4, 123.8, 122.0, 117.3, 116.5, 73.5, 52.1,
16.2.
H), 5.15 (q, J = 6.8 Hz, 1 H), 3.60 (s, 6 H), 1.64 (d, J = 6.8 Hz, 3 H),
1.60 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 165.9, 165.7, 165.2, 147.9,
147.7, 134.2, 129.7, 128.8, 128.7, 128.0, 127.7, 127.6, 127.3, 126.9,
126.8, 126.3, 126.3, 125.5, 125.4, 122.2, 121.3, 117.3, 117.2, 116.4,
116.4, 73.8, 73.5, 52.0, 16.4, 16.2.
MS (EI): m/z (%) = 347 ([M]+, 69), 316 ([M – OCH3]+, 4), 304
(100), 77 (5).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C21H17NNaO4:
370.1050; found: 370.1054.
MS (EI): m/z (%) = 377 ([M + 2]+, 69), 375 ([M]+, 65), 346 ([M –
OCH3]+, 8), 334 (100), 332 (98), 253 (6).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H14BrNNaO4:
397.9998; found: 397.9998.
Methyl 4-(4-Nitrophenyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-
benzoxazine-6-carboxylate (5e)
Gray solid; yield: 0.49 g (72%); mp 151–153 °C; Rf = 0.36 (EtOAc–
PE, 1:5).
1H NMR (400 MHz, DMSO-d6): δ = 8.43 (d, J = 8.8 Hz, 2 H), 7.71
(d, J = 8.4 Hz, 2 H), 7.65 (dd, J = 8.4, 2.0 Hz, 1 H), 7.24 (d, J = 8.4
Hz, 1 H), 6.87 (d, J = 1.6 Hz, 1 H), 5.01 (q, J = 6.8 Hz, 1 H), 3.70
(s, 3 H), 1.56 (d, J = 6.8 Hz, 3 H).
Acknowledgment
This work was supported by the National Natural Science Founda-
tion of China (21272280, 81201716, 81301890), Science & Tech-
nology Program of Guangdong Province and Guangzhou City
(2011A081401002, 2012J4300097), Guangdong Natural Science
Foundation (S2013010014278), National Significant New Drugs
Development (2011ZX09202-101-07). The authors also thank
Guangxi Wanshan Spice Co. Ltd for giving high-quality (–)-shi-
kimic acid as a gift.
MS (EI): m/z (%) = 342 ([M]+, 82), 311 ([M – OCH3]+, 9), 299
(100), 253 (41).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H14N2NaO6:
365.0744; found: 365.0746.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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Methyl 4-(4-Acetylphenyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-
benzoxazine-6-carboxylate (5f)
Yellow solid; yield: 0.56 g (82%); mp 193–195 °C; Rf = 0.38
(EtOAc–PE, 1:4).
1H NMR (400 MHz, DMSO-d6): δ = 8.15 (d, J = 8.8 Hz, 2 H), 7.64
(dd, J1 = 8.4, 2.0 Hz, 1 H), 7.54 (d, J = 8.0 Hz, 2 H), 7.22 (d, J = 8.4
Hz, 1 H), 6.86 (d, J = 2.0 Hz, 1 H), 5.03 (q, J = 6.8 Hz, 1 H), 3.70
(s, 3 H), 2.65 (s, 3 H), 1.55 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 197.3, 165.4, 165.2, 147.9,
140.0, 136.9, 130.5, 129.9, 129.3, 125.5, 123.8, 117.3, 116.6, 73.5,
52.1, 26.9, 16.1.
MS (EI): m/z (%) = 339 ([M]+, 65), 308 ([M – OCH3]+, 8), 296
(100), 253 (8), 77 (9).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C19H17NNaO5:
362.0999; found: 362.1001.
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© Georg Thieme Verlag Stuttgart · New York