Saccharin and tert-Butyl Nitrite: Cheap and Efficient Reagents for the Synthesis of 1,2,3-Benzotriazine-4-(3H)-ones from 2-Aminobenzamides under Metal-Free Conditions

Article abstract of DOI:10.1071/CH17590

A mild and eco-friendly protocol for the synthesis of 1,2,3-benzotriazine-4-(3H)-ones is described using saccharin as a cheap and efficient catalyst and tert-butyl nitrite as a diazotization reagent for the first time. The current method has advantages su

Full text of DOI:10.1071/CH17590

CSIRO PUBLISHING
Aust. J. Chem. 2018, 71, 186–189
Communication
https://doi.org/10.1071/CH17590
Saccharin and tert-Butyl Nitrite: Cheap and Efficient
Reagents for the Synthesis of 1,2,3-Benzotriazine-4-(3H)-
ones from 2-Aminobenzamides under Metal-Free Conditions
A B
,
A
A
Nader Ghaffari Khaligh,
Mohad Rafie Johan, and Juan Joon Ching
A
Nanotechnology and Catalysis Research Center, 3rd Floor, Block A, Institute of
Postgraduate Studies, University of Malaya, 50603 Kuala Lumpur, Malaysia.
Corresponding author. Email: ngkhaligh@gmail.com
B
A mild and eco-friendly protocol for the synthesis of 1,2,3-benzotriazine-4-(3H)-ones is described using saccharin as a
cheap and efficient catalyst and tert-butyl nitrite as a diazotization reagent for the first time. The current method has
advantages such as cost effectiveness, energy efficiency, and simple experimental procedure, good yield of the desired
product, and metal-free and environmentally benign conditions.
Manuscript received: 15 November 2017.
Manuscript accepted: 30 January 2018.
Published online: 14 February 2018.
The reduction of environmental, human health, and safety risks
of chemicals and synthetic procedures is the foremost goal of
green chemistry, which can be achieved by redesigning toxic
molecules, synthetic routes, and industrial processes. Reducing
the amount of waste generated in reactions, recycling certain
reagents, improving energy efficiency, minimizing potential
accidents, preparing biodegradable or recyclable products,
using sustainable raw materials, and avoiding molecules linked
to toxicity are some routes in green chemistry. New catalysts and
reagents and low-risk solvents, as well as new experimental
processes, are developed by green chemistry researchers.[1]
1,2,3-Benzotriazine-4-(3H)-ones are an important active
scaffold in bioorganic and medicinal chemistry owing to their
potential pharmacological properties, such as sedative, diuretic,
anaesthetic, antiarthritic, antitumour, and antitubercular activi-
ties.[2] 1,2,3-Benzotriazine-4-(3H)-ones are often prepared by
diazotization of methyl anthranilates[3,4] or 2-aminobenzamides[5]
in the presence of NaNO2 and a strong acid (HCl or H2SO4) at low
temperature.
Recently, an efficient anunulation of 2-aminobenzamides
was reported in the presence of tert-butyl nitrite and tetrabuty-
lammonium iodide (Scheme 1a).[6] On the basis of the reported
protocol, tetra-n-butylammonium iodide (n-Bu4NI) was used as
a catalyst. Although the substrate scope was broad and the
desired products were afforded in good yield, it should be noted
that diazotization–iodination products could also be formed
slowly and in lower yields as by-products in the presence of
tetra-n-butylammonium iodide.[7] Furthermore, the formation
iodine and gaseous products are expected because active com-
pounds such as HNO2 and NOþ can partially oxidize iodide ions to
iodine.[8] According to its material safety data sheet, n-Bu4NI has
an LD50 (lethal dose 50: the amount of a toxic agent (as a poison,
virus, or radiation) that is sufficient to kill 50 % of a population of
animals, usually within a certain time) of 1990 mg kgꢀ1 (rat) and
Previous work (a)
tBuONO (3.0 equiv.), n-Bu4NI (5.0 mol-%)
O
N
O
MeCN, 60ЊC, 12 h
R
R
N
N
N
H
NH2
tBuONO (1.5 equiv.), Sac-H (10 mol-%)
EtOH, 50ЊC, 6 h
Present work (b)
Scheme 1. The previously reported route (a); and the present strategy (b)
for the synthesis of 1,2,3-benzotriazine-4-(3H)-ones.
can cause skin, eye, and lung irritation. The price for 500 g of
n-Bu4NI is US$215 (Tokyo Chemical Industry Co., Ltd) and
temperature and reaction time were 608C and 12 h, which limited
further industrial-scale applications in organic synthesis because
cost effectiveness and energy efficiency are very important factors
for industrial processes. Therefore, the use of a cheap disposable
reagent and establishing a reaction at low temperature with a short
reaction time would be highly beneficial.
In continuation of our studies on simple, efficient, and environ-
mentally benign methods under mild reaction conditions,[9,10]
very recently, the telescopic synthesis of azo compounds was
reported via stable arenediazonium bis(trifluoromethylsulfonyl)
imides using tert-butyl nitrite.[11] To the best of our knowledge,
few reports exist concerning the use of saccharin (Sac-H) for
organic reactions[12–14] and there are no reports on the utilization
of Sac-H as catalyst for multicomponent reactions. Sac-H (pKa ¼
1.31)[15] is a cheap artificial sweetener and a calorie-free additive
that is widely used in the food and drug industries.[16] We were
interested to explore the potential of saccharin in combination
Journal compilation Ó CSIRO 2018
www.publish.csiro.au/journals/ajc

Saccharin as Efficient Catalyst in Organic Transformations
187
Table 1. The optimization of reaction conditions for annulation of
2-amino-N-(2-methoxyphenyl)-benzamide in the presence of TBN
and Sac-H
Table 2. The annulation of 2-amino-N-(2-methoxyphenyl)-benzamide
in the presence of TBN and Sac-H
Reaction conditions: 2-amino-N-(aryl)-benzamide (1) (2.0 mmol), tert-butyl
nitrile (0.40 mL, ,3.0 mmol), Sac-H (0.2 mmol), EtOH (5 mL), 6 h
Reaction conditions: 2-amino-N-(2-methoxyphenyl)-benzamide (1a)
(2.0 mmol), solvent (5 mL), 6 h. Optimised reaction conditions shown
in bold
Entry
R (1)
Product 2
Yield [%]A
Melting point [8C]
ReportedB
Found
Entry Amount of
TBN
Amount of
Sac-H
Solvent Temperature Yield
[%]A
1
2
2-MeO–
4-MeO–
H–
a
b
c
d
e
f
80
92
96
90
96
78
89
88
80
90
135–137
150–152
127–129
153–155
136–138
113–115
155–157
173–175
116–118
150–151
134–136
151–153
127–129
153–155
139–141
113–115
158–160
178–180
122
[8C]
[equiv.]
[mol-%]
3
1
1.5
1.5
1.5
2
10
10
10
10
20
20
–
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
EtOH
tBuOH
r.t
60
50
50
50
50
50
50
50
50
48
78
78
80
78
79
43B
4
2-Me–
4-Me–
2-CF3–
4-CF3–
4-Cl–
2
5
3
6
4
7
g
h
i
5
1.5
2
8
6
9
2-Cl–
7
1.5
–
10
4-F–
j
151–153
B
8
10
10
10
–
AIsolated yield.
BAll known products were identical in respects of melting point, FTIR, and
NMR spectra to those previously reported.[8,27–30]
9
1.5
1.5
80
10
75
.
AIsolated yield.
BReaction time was 12 h.
with tert-butyl nitrite for the preparation 1,2,3-benzotriazine-4-
(3H)-ones via annulation of 2-aminobenzamides. Our prediction
oftheireffectivenessasacatalystwascorrectandthesynthesisof
1,2,3-benzotriazine-4-(3H)-ones was efficiently performed in
the presence of saccharin and tert-butyl nitrite. Our strategy has
the potential to be an efficient and green alternative to the
previously reported methods as no hazardous data have been
reported or are available for saccharin; thus, saccharin is safer
than tetra-n-butylammonium iodide (TBAI). Furthermore, reac-
tiontemperatureandreactiontimewere508Cand6 hrespectively,
and the price for 500 g saccharin is only US$71 from the same
supplier. In the present method, tert-butyl nitrite was employed as
the diazotizing reagent owing to its easy handling, commercial
availability, and high safety profile.[17–26]
transformed and afforded the desired products in good yields.
The yields were apparently affected by the electronic properties
and steric demands of the substituents of the 2-amino-N-
arylbenzamides.
2-Amino-N-arylbenzamides bearing electron-donating
groups (Table 2, entries 2 and 5) gave higher yields than those
with electron-withdrawing groups (Table 2, entry 7) and ortho-
substituted 2-amino-N-arylbenzamides showed lower reactivity
and afforded lower yields compared with para-substituted
owing to steric effects (Table 2, entries 1, 4, 6 and 9). The
macro-scale scope of this protocol was studied using 20 mmol of
2-amino-N-phenyl-benzamide (1c) under the aforementioned
optimized conditions and 3-phenyl-3H-benzo[d][1,2,3]triazin-
4-one was obtained in 80 % isolated yield.
Initially, 2-amino-N-(2-methoxyphenyl)-benzamide (1a) was
added with slow stirring to a mixture of Sac-H and tert-butyl
nitrite in dry acetonitrile (5mL) over 5 min at room temperature
and the stirring was continued for 6 h (Scheme 1b). The solvent,
by-product tert-BuOH, and excess tert-BuONO were evaporated
under reduced pressure after completion of the reaction (moni-
tored by TLC). The crude residue was purified by column
chromatography to give the pure product in 48% yield (Table 1,
entry 1). The reaction yield increased to 78 % when the reaction
temperature was raised to 50 and 608C (Table 1, entries 2 and 3).
Increasing the amount of tert-BuONO to 2 equiv. and Sac-H to 20
mol-% produced no significant improvement in the yield of 2a
(Table 1, entries 4–6). In the absence of saccharin, 2a was
obtained in 43 % yield after 12 h (Table 1, entry 7) and the
reaction did not proceed in the absence of tert-butyl nitrite (TBN)
(Table 1, entry 8). Then, solvent effect on the yield of 2a under
the optimal conditions was examined. A slight improvement was
observed in the yield of 2a when the reaction was performed in
ethanolwhereas the yieldof 2a decreased in tert-butanol (Table 1,
entries 9 and 10). Therefore, optimal conditions were chosen as
shown in entry 9 in Table 1.
On the basis of result reports in the literature,[6,20,25]
a
possible mechanism is illustrated in Scheme 2. The following
mechanism shows that the azo coupling reaction proceeds in
two steps. In the first step, the mild electrophile nitrosonium
(þN=O 2 NꢁOþ) is formed from Sac-H and tert-butyl nitrite.
The amine nitrogen of the aryl amine reacts with the mild
electrophile nitrosonium (þN=O 2 NꢁOþ) in Lewis acid–
base fashion to form arenediazonium saccharinate. It seems that
extensive delocalization of the charge over the CO–N–SO2
framework of the anion makes [Sacꢀ] and the corresponding salt
highly resonance-stabilized. Then, intramolecular substitution
gives intermediate I, which further gives 1,2,3-benzotriazine-4-
(3H)-ones by recycling Sac-H.
In summary, an efficient telescopic metal-free synthesis of
1,2,3-benzotriazine-4-(3H)-ones using tert-butyl nitrite in com-
bination with saccharin in ethanol was developed. The current
method has advantages including no competitive reactions, use of
a cheaper and safer reagent, lower temperature and a shorter
reaction time, i.e. energy efficiency and cost effectiveness are
superior in this strategy compared with previously reported
methods. A simple experimental and environmentally benign
procedure, broad substrate scope, good yield, and metal-free
conditions are other advantages of the present strategy. Owing
to the aforementioned advantages, the present method is expected
to find applications in academic and industrial processes.
Then, a variety of 1,2,3-benzotriazine-4-(3H)-ones (2a–j) was
synthesized under the optimized conditions (Scheme 1b). The
results showed that 2-amino-N-arylbenzamides (1a–j) contain-
ing electron-donating and withdrawing groups were smoothly

188
N. G. Khaligh, M. R. Johan, and J. J. Ching
Ϫ
O
O
O
ϩ
ϩ
Ϫ
NH
N
H
N
ϩ
H
ϩ
S
S
S
O
O
O
O
O
O
Ϫ
[Sac]
Sac-H
Sac-H
ϩ
Ϫ
ϩ
Ϫ
ϩ
N
t-Bu
[Sac]
t-Bu
N
t-BuOH
N
O
ϩ
[Sac]
N
O
ϩ
O
O
O
O
H
O
O
NH
O
NH
N
O
H
NH
H
NH
Ϫ
N
O
Ϫ
ϩ
ϩ
O
N
N
H
[Sac]
ϩ
[Sac]
N
O
N
ϩ
NH2
O
N
H
(I)
Sac-H
1c
Sac-H
H
O
N
O
H
O
N
Oϩ
ϩ
H2O
N
Ϫ
N
N
N
N
H
H
ϩ
[Sac]
Ϫ
N
N
Sac-H
[Sac]
R
2c
Scheme 2. Possible reaction mechanism.
Experimental
Characterization Data of Some Derivatives
3-(2-Chlorophenyl)benzo[d][1,2,3]triazin-4
(3H)-one (2i)[3]
General
Unless specified, all chemicals were analytical grade and
purchased from Fluka AG, Sigma–Aldrich, and Synthetic
Chemicals Ltd. The purity determination of the substrates and
isolated products were confirmed by their showing one spot on
TLC plates (silica gel SIL G/UV 254). 1H NMR spectra were
recorded on a Bruker Avance 400 MHz instrument. Fourier-
transform (FT)IR spectra were obtained using a PerkinElmer
spectrometer 781 and Bruker Equinox 55 using KBr pellets for
samples in the range of 400–4000 cmꢀ1. Mass spectra
were recorded on a PESciex model API 3000 instrument.
Microanalyses were performed on a PerkinElmer 240-B
microanalyser.
Yellow solid. nmax (KBr)/cmꢀ1 1651, 1588, 1329, 1169,
1121, 1071. dH (400 MHz, CDCl3) 8.47 (dd, J 7.8, 1.1, 1H),
8.27 (d, J 8.4, 1H), 8.04–8.01 (m, 1H), 7.93–7.84 (m, 1H), 7.67–
7.64 (m, 1H), 7.58–7.49 (m, 3H). dC (100 MHz, CDCl3) 154.8,
143.8, 136.4, 135.2, 132.9, 132.3, 131.0, 130.4, 129.5, 128.7,
127.8, 125.6, 120.2. m/z (high-resolution mass spectroscopy
(HRMS) electron impact (EIþ)); calc. for C13H9ClN3O, m/z
257.0350 [M þ Hþ].
3-(4-Fluorophenyl)benzo[d][1,2,3]triazin-4
(3H)-one (2j)[3]
Yellow solid. nmax (KBr)/cmꢀ1 2951, 1685, 1611, 1593,
1510, 1250, 1022. dH (400 MHz, CDCl3) 8.44 (dd, J 8.0 and
0.9, 1H), 8.23 (d, J 8.0, 1H), 8.04–7.99 (m, 1H), 7.91–7.85
(m, 1H), 7.67–7.63 (m, 2H), 7.29–7.25 (m, 2H). dC (100 MHz,
CDCl3) 162.5 (d, J 247.4), 155.2, 143.6, 135.2, 134.7 (d, J 3.1),
132.9, 128.6, 127.9 (d, J 8.8), 125.6, 120.2, 116.0 (d, J 22.8). m/z
( HRMS EIþ) 242.0721; calc. for C13H9FN3O, m/z 242.0724
[M þ Hþ].
Typical Procedure for the Synthesis
of 1,2,3-Benzotriazine-4-(3H)-ones
Initially, 2-amino-N-(arylphenyl)-benzamide (0.484g, 2.0mmol)
(1) was added with slow stirring to a mixture of Sac-H (0.037g,
0.2 mmol) and tert-butyl nitrite (0.40 mL, ,3.0 mmol) in dry
ethanol (5mL) for 5 min at room temperature. Then, stirring was
continued for 6 h. The solvent, by-product tert-BuOH, and excess
tert-BuONO were evaporated under reduced pressure after
completion of the reaction (monitored by TLC). The crude resi-
due was purified by column chromatography on silica gel with
light petroleum/ethyl acetate (8: 2 to 7 : 3 v/v) to give the pure
products.
Conflicts of Interest
The authors declare no conflicts of interest.

Saccharin as Efficient Catalyst in Organic Transformations
189
Acknowledgements
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This work was supported by a High Impact Research Grant (no. RP025A/B/
C-14AET) for Scientific Research from the University of Malaya, Malaysia.
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