Mechanochemical Synthesis of Substituted 4H-3,1-Benzoxazin-4-ones, 2-Aminobenzoxazin-4-ones, and 2-Amino-4H-3,1-benzothiazin-4-ones Mediated by 2,4,6-Trichloro-1,3,5-triazine and Triphenylphosphine

Article abstract of DOI:10.1055/s-0036-1588125

A mild and convenient approach for the synthesis of 2-substituted 4H-3,1-benzoxazin-4-ones, 2-aminobenzoxazin-4-ones, and 2-amino-4H-3,1-benzothiazin-4-ones under solvent-assisted grinding is reported. In the presence of 2,4,6-trichloro-1,3,5-triazine and

Full text of DOI:10.1055/s-0036-1588125

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
M. Pattarawarapan et al.
Letter
Synlett
Mechanochemical Synthesis of Substituted 4H-3,1-Benzoxazin-
4-ones, 2-Aminobenzoxazin-4-ones, and 2-Amino-4H-3,1-benzo-
thiazin-4-ones Mediated by 2,4,6-Trichloro-1,3,5-triazine and
Triphenylphosphine
Mookda Pattarawarapan*
Sirawit Wet-osot
Cl
N
N
O
O
Dolnapa Yamano
Cl
N
Cl
X
OH
X
Wong Phakhodee
PPh3 (cat.), Na2CO3
N
R
NH
Department of Chemistry and Center of Excellence for Innovation
in Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai
50200, Thailand
1–2 min
X = O, S
R = alkyl, aryl, NHR'
(25 examples, up to 98%)
R
mookdap55@gmail.com
Received: 14.10.2016
Accepted after revision: 27.11.2016
Published online: 12.12.2016
the methods still suffer from drawbacks including the need
for expensive reagents, limited availability of substrates,
harsh reaction conditions, and long reaction times.
DOI: 10.1055/s-0036-1588125; Art ID: st-2016-d0690-l
An alternative, simple and relatively straightforward ap-
proach is through cyclization of N-substituted anthranilic
acids in the presence of dehydrating agents such as acetic
anhydride,4,19 di-tert-butyl pyrocarbonate (Boc2O),20 silica-
bound benzoyl chloride,21 thionyl chloride,22 and 2,4,6-tri-
chloro-1,3,5-triazine (TCT).23–25 However, refluxing condi-
tions or microwave irradiation are generally required for
these methods.
Abstract A mild and convenient approach for the synthesis of 2-sub-
stituted 4H-3,1-benzoxazin-4-ones, 2-aminobenzoxazin-4-ones, and 2-
amino-4H-3,1-benzothiazin-4-ones under solvent-assisted grinding is
reported. In the presence of 2,4,6-trichloro-1,3,5-triazine and catalytic
triphenylphosphine, cyclodehydration of N-substituted anthranilic acid
derivatives proceeded rapidly within minutes at room temperature. The
products were also obtained in good to excellent yields by using mini-
mal amounts of solvent and inexpensive reagents.
Recently, our group reported a convenient mechano-
chemical synthesis of 4-arylidene-2-phenyl-5(4H)-oxazolo-
nes from hippuric acid by using TCT in combination with a
catalytic amount of triphenylphosphine (PPh3).26 We envis-
aged that a similar strategy could be applied to the prepara-
tion of 2-substituted benzoxazin-4-ones and other related
derivatives. In a continuation of our ongoing research in-
volving TCT, we wish to report a mild and rapid synthesis of
substituted 4H-3,1-benzoxazin-4-ones, 2-aminobenzoxaz-
in-4-ones, and 2-amino-4H-3,1-benzothiazin-4-ones under
solvent-assisted grinding (Scheme 1).
To optimize the reaction conditions, a solvent-assisted
grinding technique was used to promote the cyclization of
N-benzoylanthranilic acid. Typically, equimolar amounts of
N-benzoylanthranilic acid and TCT were ground together in
a mortar in the presence of two equivalents of base and a
few drops of tetrahydrofuran (THF), either with or without
addition of PPh3. After one minute (the time at which the
starting acid completely disappeared), the cyclized product
was isolated by filtration through a short pad of silica.
According to Table 1, reaction in the presence of an or-
ganic base such as NMM (entry1) gave a low yield of the cy-
clized product, possibly due to decomposition of the qua-
Key words carboxylic acids, chemoselectivity, green chemistry, phos-
phorus, cyclization
4H-3,1-Benzoxazin-4-ones are an important class of N-
heterocycles that are useful precursors for the synthesis of
various pharmaceutically active compounds such as dihyd-
robenzoxazinones,1–3 substituted quinazolinones,4,5 and
isocoumarin derivatives.6 A number of 2-substituted benz-
oxazinone derivatives have been shown to exhibit a range
of useful pharmacological and biological activities such as
anticonvulsant,7 antithrombotic,8 and inhibitors of human
leukocyte elastase,9 human cytomegalovirus protease,10
and serine protease.11,12 Thus, several synthetic methods
have been developed for the preparation of benzoazinones.
Some recent examples include TBHP/CoCl2-mediated oxida-
tive cyclization of N-(2-formylphenyl)amides,13 K2S2O8-me-
diated intramolecular oxidative nitrogenation/oxygenation
in N-aryl benzylic amines,14 palladium-catalysed carbon-
ylation of 2-bromoanilines15 or N-substituted 2-haloani-
lines,16 palladium-catalysed C≡C bond cleavage of azido-
alkynes,17 and copper-catalyzed C–N bond formation/rear-
rangement of N-acyl-2-halobenzamides.18 Nevertheless,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
M. Pattarawarapan et al.
Letter
Synlett
O
OH
Cl
N
O
N
NH
O
N
N
Cl
N
Cl
X
R
X
PPh3
Cl
O
X
Cl
N
N
N
N
X = O, S
R
NH
R = alkyl, aryl, NHR'
Cl
Cl
Cl
N
PPh3
HI
R
Scheme 1 TCT/PPh3 mediated cyclodehydration of N-substituted anthranilic acids
ternary N-triazinylammonium intermediates.27 A slightly
improved yield was observed when using weak inorganic
bases such as sodium bicarbonate or sodium carbonate (en-
tries 2 and 3). However, the best yield was obtained with
the latter base (entry 3). In the absence of PPh3, the reaction
was incomplete, leading to a lower yield of product (entry
4). This result suggested that the reactive triazinylphospho-
nium chloride (I)28 was formed which rapidly activated N-
benzoylanthranilic acid toward cyclization. It should be
noted that when the best conditions were applied under
conventional stirring or using ultrasound (entries 5 and 6),
the product yield decreased significantly, indicating that
the grinding process leads to reaction rate acceleration;
presumably due to an increase in the contact surface area of
the solid reactants.29
studies,15,17 the presence of an electron-withdrawing group
on the N-benzoylanthranilic acid decreased the yield of the
corresponding products (entries 2–4). Considering steric
and electronic effects, it was found that steric hindrance by
the OMe moiety at the ortho-position did not significantly
affect either the yield or the rate of the reaction (entry 5).
Whereas no obvious electronic effect was observed when
the R group contained a strongly electron-donating OMe or
weak electron-withdrawing Cl substituent (entries 6 and
7), significantly lower yields were obtained with electron-
deficient substrates bearing a strongly electron-withdraw-
ing nitro group on R (entries 8 and 9).
Table 2 TCT-Mediated Synthesis of 2-Substituted 4H-3,1-Benzoxazin-
4-ones 2a
O
O
Table 1 Optimization of Reaction Conditionsa
R'
R'
TCT, PPh3
O
OH
O
Na2CO3, grinding
O
O
N
N
R
NH
TCT, PPh3
OH
O
O
R
base, grinding
2
1
NH
Ph
Ph
Entry
R′
R
2
Yield (%)
Ref
31a
31b
31c
31d
31e
31e
31e
31f
1
2
H
Ph
2a
2b
2c
2d
2e
2f
91
87
88
75
81
83
86
75
56
90
85
87
81
71
90
Entry
Base
NMM
Method
Yield (%)
I
Ph
Ph
Ph
1
2
3
4
5
6
grinding
grinding
grinding
grinding
stirringc
55
3
Cl
NO2
H
NaHCO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
61
4
91
5
2-MeOC6H4
4-MeOC6H4
4-ClC6H4
57b
trace
32
6
H
7
H
2g
2h
2i
sonicationc
8
H
3-NO2C6H4
a Reaction conditions: N-benzoylanthranilic acid (0.542 mmol), TCT (0.542
mmol), PPh3 (0.0542 mmol), base (1.084 mmol), a few drops of THF, 1 min.
b Reaction without PPh3.
31e
31g
9
H
4-NO2C6H4
c Reaction performed in THF (2 mL).
10
11
12
13
14
15
H
C6H5CH2
2j
H
4-FC6H4CH2
4-MeOC6H4CH2
2,6-Cl2C6H3CH2
4-HOC6H4CH2
1-naphthylacetyl
2k
2l
16b
H
With the optimized reaction conditions established (Ta-
ble 1, entry 3), we turned our attention to the scope and
generality of this methodology. As summarized in Table 2,
the reaction proceeded well with a variety of N-substituted
anthranilic acid derivatives.30 2-Arylbenzoxazinones con-
taining electron-donating or electron-withdrawing substit-
uents could be prepared in good to excellent yields within
1–2 minutes grinding (entries 1–9). Consistent with other
H
2m
2n
2o
H
31h
H
a Reaction conditions: N-acylanthranilic acid (0.542 mmol), TCT (0.542
mmol), PPh3 (0.0542 mmol), Na2CO3 (1.084 mmol), 1–2 min.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
M. Pattarawarapan et al.
Letter
Synlett
O
O
O
OH
R
X
S
TCT, PPh3 (10 mol%)
Na2CO3, grinding
O
TCT, PPh3 (10 mol%)
Na2CO3, grinding
R
R
N
N
N
N
N
N
H
H
H
H
6
3, X = O
4, X = S
5
5a, R = C6H5 (1 min, 94%)32a
5b, R = 4-MeC6H4 (2 min, 88%)32a
5c, R = 2-MeC6H4 (2 min, 66%)32a
5d, R = 4-BrC6H4 (1 min, 77%)
5e, R = 1-naphthyl (2 min, 86%)32b
5f, R = Bn (3 min, 55%)9
6a, R = C6H5 (1 min, 98%)33a
6b, R = 4-MeC6H4 (2 min, 92%)33b
6c, R = 4-ClC6H4 (2 min, 84%)33b
6d, R = 1-naphthyl (2 min, 82%)
Scheme 2 TCT/PPh3-mediated synthesis of 2-amino-4H-3,1-benzoxazin-4-ones 5 and 2-amino-4H-3,1-benzothiazin-4-ones 6
2-Alkyl substituted benzoxazinones are known to be high-
ly hygroscopic and readily undergo hydrolysis to 2-acet-
aminobenzoic acids during aqueous work-up.23 Since no
aqueous workup was necessary, we were able to synthesize
a series of 2-alkyl substituted benzoxazinone derivatives in
high yields (entries 10–15). Notably, no significant interfer-
ence from bulky groups or the free hydroxy function could
be observed (entries 13–15).
Notably, by using our method, all the cyclized products
were obtained within 1–2 minutes at ambient temperature.
However, the reaction mediated by TCT in the presence of
triethylamine required heating to reflux overnight in anhy-
drous toluene to afford 2a in 83% yield.23 A reaction mediat-
ed by the iminium cation generated from a mixture of TCT
and N,N-dimethylformamide (DMF) required 4 hours in
chloroform/DMF to provide 2a in 86% yield.25
Encouraged by these results, the scope of the reaction
was further extended toward cyclization of 1-aryl-3-(1-
benzene carboxylic acid)carbamides 3 as well as thiocarb-
amides 4. According to Scheme 2, cyclization of 3 proceeded
rapidly to afford 2-aminobenzoxazin-4-ones 5 in good to
excellent yields. Likewise, the thiocarbamide derivatives 4
also underwent rapid cyclization to provide 2-amino-4H-
3,1-benzothiazin-4-ones 6 in comparable yields.
In summary, we have developed a simple and economic
solvent-assisted grinding method that enables convenient
access to heterocycles including 2-substituted 4H-3,1-benz-
oxazin-4-ones, 2-aminobenzoxazin-4-ones, and 2-amino-
4H-3,1-benzothiazin-4-ones from readily available N-sub-
stituted anthranilic acids. Both O- and S-containing sub-
strates underwent rapid cyclization under mild reaction
conditions with high chemoselectivity and wide function-
al-group tolerance.
Acknowledgment
Financial support from the Center of Excellence for Innovation in
Chemistry (PERCH-CIC), Chiang Mai University, Thailand and the Na-
tional Research University Project under Thailand’s Office of the
Higher Education Commission, Ministry of Education are gratefully
acknowledged.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588125.
S
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p
p
ortiInfogrmoaitn
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rmoaitn
References
The conditions were applicable to substrates containing
various functional groups, although sterically hindered
substrate 3c gave a lower yield of the product 5c. Remark-
ably, no product from cyclodesulfurization (to 2-amino-4H-
3,1-benzoxazin-4-one) or cyclization with the NH of the
thiourea moiety (to 3-phenyl-quinazoline-2-thion-4-one)
was observed, indicating that the reaction was highly che-
moselective.
It should be noted that products such as 6 have previ-
ously been prepared by heating 4 to reflux in ethanol for 1
hours without reported yields.33b Acetic anhydride-mediat-
ed cyclization of 4 to 6 also required long reaction times (8–
24 h) at room temperature.34 Additionally, only 2-amino-
4H-3,1-benzoxazin-4-ones were obtained when potassium
salts of 4 were treated with mercury(II) oxide in DMF at
room temperature.32a
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;
1H NMR (400 MHz, CDCl3): δ =
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(neat): 3427, 1761, 1647, 1597, 1518 cm–1 1H NMR (400 MHz,
.
CDCl3): δ = 8.16 (dd, J = 8.0, 1.2 Hz, 1 H), 7.78 (td, J = 8.0, 1.2 Hz,
1 H), 7.59 (d, J = 8.0 Hz, 1 H), 7.49 (td, J = 8.0, 1.2 Hz, 1 H), 7.22
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(1.084 mmol) were mixed and ground together for 1 min,
during which a few drops of THF were added to aid homoge-
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(b) Ingle, A. D. J. Chem. Pharm. Res. 2013, 5, 230.
2-Phenyl-4H-benzo[d][1,3]oxazin-4-one (2a; Table 2, entry
1): Yield: 0.1103 g (0.494 mmol, 91%); white solid; mp 120–
122 °C; Rf 0.38 (EtOAc/hexanes, 10%). 1H NMR (400 MHz,
CDCl3): δ = 8.29 (d, J = 7.2 Hz, 2 H), 8.22 (dd, J = 8.0, 1.2 Hz, 1 H),
7.80 (td, J = 8.0, 1.2 Hz, 1 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.57 (t,
J = 7.2 Hz, 1 H), 7.49 (t, J = 7.2 Hz, 3 H). 13C NMR (100 MHz,
CDCl3): δ = 159.6, 157.2, 147.0, 136.6, 132.7, 130.3, 128.8, 128.7,
128.4, 128.3, 127.3, 117.1.
2-(4-Fluorobenzyl)-4H-benzo[d][1,3]oxazin-4-one (2k; Table
2, entry 11): Yield: 0.1181 g (0.462 mmol, 85%); white solid;
mp 125–127 °C; Rf 0.42 (EtOAc/hexanes, 10%). FTIR (neat):
(34) Haecker, H.-G.; Grundmann, F.; Lohr, F.; Ottersbach, P. A.; Zhou,
J.; Schnakenburg, G.; Guetschow, M. Molecules 2009, 14, 378.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D