A phosgene and peroxide-free one-pot tandem synthesis of isatoic anhydrides involving anthranilic acid, boc anhydride and 2-chloro-N-methyl pyridinium iodide

Article abstract of DOI:10.1016/j.tetlet.2013.10.034

A phosgene and peroxide-free approach for the synthesis of isatoic anhydrides has been described. The synthesis involves the carbamate formation with boc anhydride followed by in situ cyclization to afford the isatoic anhydride. The importance of this synthetic strategy is in the ease of operation, scalability and preparation from readily available raw materials.

Full text of DOI:10.1016/j.tetlet.2013.10.034

Tetrahedron Letters 54 (2013) 6897–6899
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Tetrahedron Letters
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A phosgene and peroxide-free one-pot tandem synthesis of isatoic
anhydrides involving anthranilic acid, Boc anhydride, and 2-chloro-
N-methyl pyridinium iodide
⇑
Chhaya Verma, Somesh Sharma, Arunendra Pathak
Jubilant Chemsys Limited, B-34, Sector-58, Noida 201301, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A phosgene and peroxide-free approach for the synthesis of isatoic anhydrides has been described. The
synthesis involves the carbamate formation with Boc anhydride followed by in situ cyclization to afford
the isatoic anhydride. The importance of this synthetic strategy is in the ease of operation, scalability, and
preparation from readily available raw materials.
Received 18 July 2013
Revised 7 October 2013
Accepted 8 October 2013
Available online 14 October 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Isatoic anhydrides
2-Chloromethylpyridinium iodide
Mukaiyama reagent
Cl
1H-Benzo[d][1,3]oxazine-2,4-dione commonly known as isatoic
anhydride is a widely used intermediate in organic synthesis. It is
used as a precursor for the synthesis of various five and six mem-
bered heterocyclic compounds such as quinazolinones, quinazol-
ones, benzimidazolones, phthalimides, pyrroloquinazolones,
quinazolinediones, oxazolones, indoles, and their derivatives.1,2
The synthesis of isatoic anhydride relies mainly on following meth-
ods (i) cyclization of anthranilic acid with phosgene, alkylchloro-
formate or carbonyldiimidazole3 (ii) oxidation of isatin with
chromic acid or peroxy acid4 and (iii) rearrangement of phthalic
acid derivative.5
O
N
O
N
O
Cl
N
I
O
OH
NH
O
O
NH
O
O
O
O
1
2
3
O
H+
O
+
N
H
O
The other reported methods are transmetalation of o-bromo-
phenyl isocyante with n-BuLi followed by reaction with carbon
dioxide.6 Although all these methods are widely used for the syn-
thesis of isatoic anhydrides, they have some drawbacks due to the
toxicity of reagents. Recently, green synthesis of isatoic anhydride
from isatin has been described using ultrasound.7 However, this
method lacks the practical applicability at a bigger scale.
In this Letter, we report a one-pot two-step synthesis of isatoic
anhydrides from anthranilic acid and Boc anhydride (di-tert-butyl
dicarbonate) in the presence of 2-chloromethylpyridinium iodide
(CMPI, Mukaiyama reagent) around the concept of enolization of
carbamate (2) as illustrated in Scheme 1.
4
Scheme 1. Plausible mechanism for the formation of isatoic anhydride.
O-(benzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium tetrafluoro-
borate imidazolidinium chloride (TBTU), propylphosphonic anhy-
dride
(T3P),
benzotriazole-1-yl-oxy-tris-(dimethylamino)-
phosphonium hexafluorophosphate (BOP) etc.8 It was anticipated
that Boc protected anthranilic acid (1) under basic condition will
enolize and initiate in situ cyclization with active ester (2,
Scheme 1).
The chemistry started with the synthesis of Boc anthranilic acid
from anthranilic acid under standard condition (THF/H2O/NaOH),
which on treatment with coupling reagents led to the formation
of intermediate 3 and subsequently to desired product 4 under
acidic work-up (Scheme 2). All efforts to isolate intermediate 3
were unsuccessful.
The formation of active esters like 2 is well documented with
coupling reagents viz. dimethylimidazolidinium chloride (DMC),
⇑
Corresponding author.
E-mail addresses: pathakarunendra@gmail.com, arunendra_pathak@jchemsys.
com (A. Pathak).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.034

6898
C. Verma et al. / Tetrahedron Letters 54 (2013) 6897–6899
O
O
O
Table 2 (continued)
i) coupling reagent,
ACN, rt
Boc2O, NaOH
OH
NH2
Yielda (%)
72f
O
OH
NH
Entry
Anthranilic acid
Cl
Product
Cl
ii) H+, 87%
H2O, THF, 75 %
N
H
O
O
O
O
O
O
OH
NH2
4
5
1
5
N
H
O
13
Scheme 2. Formation of isatoic anhydride and screening of coupling reagents.
O
O
Cl
Cl
O
OH
6
7
8
9
71b
90b
62c
67c
N
H
O
NH2
O
Table 1
Coupling reagents scope in cyclization
14
O
Entry
Coupling reagent
Time (h)
Yielda (%) of 4
O2N
O2N
OH
NH2
O
1
2
3
4
5
DMC
TBTU
BOP
T3P
CMPI
0.17
5
12
24
0.17
92
58
27
N
H
O
15
O
O
No conversion
93
OH
NH2
O
a
Br
Br
Br
Br
N
H
O
Yield based on crude LCMS.
16
O
O
OH
NH2
O
O
O
O
N
H
O
O
17
Boc2O, TEA
OH
i) CMPI
OH
O
O
rt, 10 min
ii) H+
NH
N
H
O
NH2
ACN, DMAP, 2 h
OH
NH2
O
10
56g
O
O
F
F
F
F
4
N
H
O
1
Overall Yield 95%
18
F
F
TEA, Boc2O
ACN, DMAP
CMPI
O
O
O
NH
O
F
F
O
OH
NH2
11
12
13
72b
80
N
H
O
O
HN
19
6
O
O
F
F
F
F
OH
NH2
O
Scheme 3. One pot two-step synthesis of isatoic anhydride.
N
H
20
O
O
O
O
N
O
CMPI, ACN
rt, 10 min
H+
OH
O
OH
NH
O
OH
75h,i
R
95%
NH
O
N
O
O
O
O
NH
21
R
R
O
O
O
O
7
7
8
R = -CH3, -C2H5 or -CH2Ph
O
OH
NH
14
96h,i
N
Scheme 4. Mechanistic consideration of formation of isatoic anhydride.
22
a
b
c
d
e
f
Table 2
Isolated yield (calculated over 2 steps).
Ref. 7.
Ref. 10a.
Ref. 10b.
Ref. 10c.
Ref. 10d.
Ref. 10e.
Ref. 10f.
CMPI-catalyzed synthesis of substituted isatoic anhydrides (9–22)
Entry
Anthranilic acid
Product
Yielda (%)
77b
O
O
OH
NH2
O
g
h
i
1
N
H
O
9
Boc protection in 2 h.
O
O
OH
NH2
O
2
3
4
94c
55d
58e
N
H
O
O
O
For optimization of the cyclization step, five coupling reagents
10
were explored as depicted in Table 1. We were delighted to ob-
serve the efficient formation of isatoic anhydride in excellent yield
in the case of DMC and CMPI (Table 1, entries 1 and 5). However,
we chose CMPI as a reagent of preference for further exploration
due to its chemical stability, cost, and ease of handling.
With the successful outcome of these results, we thought of
doing one-pot two-step conversion of anthranilic acid to isatoic
anhydride by adding CMPI to the same reaction mixture. However,
there was no product formation observed. This might be due to the
hydrolysis of active ester (2) under strong aqueous basic condition.
O
O
OH
NH2
O
N
H
11
O
O
OH
O
N
H
NH2
O
12
O

C. Verma et al. / Tetrahedron Letters 54 (2013) 6897–6899
6899
Then, the formation of carbamate (1) was optimized under anhy-
References and notes
drous basic condition (Scheme 3). To this reaction mass (without
isolation of 1) was added CMPI, and subsequent acidic work-up
afforded isatoic anhydride in good yield.9
1. Katritzky, A. R.; Boulton, J. (Eds.), Adv. Heterocyclic Chem.; Isatoic Anhydrides and
Their Uses in Heterocyclic Synthesis; Kappe, T., Stadlbauer, W., Eds.; Academic
Press: New York, London, 1981. Vol. 28.
On the success of this result, we tried to develop one pot one
step strategy by adding all reagents (Boc anhydride, DMAP, CMPI,
and TEA) in one shot; however, it led to the formation of undesired
product 6.
To understand the mechanism of the reaction, we prepared
methoxy, ethoxy, and benzyloxy carbamates of anthranilic acid
(Scheme 4).
On treatment with CMPI, the cyclized intermediates (8) formed
were quite stable in comparison to 3 (Scheme 1). These on acidic
work-up were converted to starting material (7) instead to isatoic
anhydride, reflecting the preference of cyclic ester hydrolysis over
acidolysis of the alkoxy group in intermediate 8. These results sup-
port the proposed plausible mechanism in Scheme 1, where the
protonation of t-butoxy group leads to the formation of isatoic
anhydride.
Finally, we evaluated the versatility of this approach by synthe-
sizing substituted isatoic anhydrides under optimized conditions
(Table 2).
These examples clearly demonstrate the applicability of this
strategy for the synthesis of substituted isatoic anhydrides. The
key advantage of this convergent approach is the use of Boc anhy-
dride (a cheap, readily available, and less toxic raw material), ease
of operation and great scalability potential with no hazardous
effect.
2. Shvekhgeimer, M.-G. A. Chem. Heterocycl. Compd. 2001, 37, 385.
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9. General experimental procedure: to
a solution of anthranilic acid (0.5 g,
3.64 mmol) in acetonitrile (10 mL) were added TEA (0.73 g, 7.28 mmol), Boc
anhydride (0.95 g, 4.37 mmol), and DMAP (0.044 g, 0.36 mmol). The mixture
was stirred at rt for 2.0 h. CMPI (1.1 g, 4.36 mmol) was added in one lot to the
reaction mixture. The reaction mixture was stirred at rt for 10 min. 1 N HCl
(20 mL) was added to the reaction and the mixture was extracted two times
with EtOAc. The combined organic layers were washed with brine, dried with
anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The
resulting solid was crystallized in DCM and MeOH to afford 0.56 g (95%) of 1H-
benzo[d][1,3]oxazine-2,4-dione as an off white solid. 1H NMR (400 MHz,
DMSO) d 7.14–7.16 (d, J = 8 Hz, 1H), 7.23–7.27 (t, J = 16 Hz,1H), 7.72–7.74 (t,
J = 8 Hz, 1H), 7.90–7.92 (d, J = 8 Hz,1H), 11.72 (s, 1H). 13C NMR (100 MHz,
DMSO-d6) d 110.6, 115.7, 123.9, 129.3, 137.3, 141.8, 147.5, 160.3. IR (thin film)
3461, 3173, 2937, 1984, 1753, 1604, 1486, 1358, 1258, 1138, 1009, 765, 673,
492. ES–MS (m/z): 161.8 (M+-H). MP (°C): 236°.
In conclusion, we have developed an efficient and work-friendly
method for the synthesis of substituted and N-alkylated isatoic
anhydrides.
Acknowledgment
We are extremely thankful to the Jubilant Chemsys manage-
ment for providing financial support and analytical facilities for
the execution of this research work.
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Supplementary data
Supplementary data associated (experimental detail, reaction
conditions and characterisation of products depicted in Table 2)
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2013.10.034.