One-pot synthesis ofN-substituted benzannulated triazolesviastable arene diazonium salts

Article abstract of DOI:10.1039/d1ob00968k

A mild and effective one-pot synthesis of 1,2,3-benzotriazin-4(3H)-ones and benzothiatriazine-1,1(2H)-dioxide analogues has been developed. The method involves the diazotisation and subsequent cyclisation of 2-aminobenzamides and 2-aminobenzenesulfonamidesviastable diazonium salts, prepared using a polymer-supported nitrite reagent andp-tosic acid. The transformation was compatible with a wide range of aryl functional groups and amide/sulfonamide-substituents and was used for the synthesis of pharmaceutically important targets. The synthetic utility of the one-pot diazotisaton-cyclisation process was further demonstrated with the preparation of an α-amino acid containing 1,2,3-benzotriazin-4(3H)-one.

Full text of DOI:10.1039/d1ob00968k

Organic &
Biomolecular Chemistry
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One-pot synthesis of N-substituted benzannulated
triazoles via stable arene diazonium salts†
Cite this: Org. Biomol. Chem., 2021,
19, 6127
Rochelle McGrory, Réka J. Faggyas and Andrew Sutherland
*
A mild and effective one-pot synthesis of 1,2,3-benzotriazin-4(3H)-ones and benzothiatriazine-1,1(2H)-
dioxide analogues has been developed. The method involves the diazotisation and subsequent cyclisation
of 2-aminobenzamides and 2-aminobenzenesulfonamides via stable diazonium salts, prepared using a
polymer-supported nitrite reagent and p-tosic acid. The transformation was compatible with a wide
range of aryl functional groups and amide/sulfonamide-substituents and was used for the synthesis of
pharmaceutically important targets. The synthetic utility of the one-pot diazotisaton–cyclisation process
was further demonstrated with the preparation of an α-amino acid containing 1,2,3-benzotriazin-4(3H)-one.
Received 19th May 2021,
Accepted 21st June 2021
DOI: 10.1039/d1ob00968k
rsc.li/obc
The importance of 1,2,3-benzotriazin-4(3H)-ones and 1,2,3-
benzothiatriazine-1,1(2H)-dioxides have resulted in the devel-
Introduction
Benzotriazin-4(3H)-ones and benzothiatriazine-1,1(2H)-diox- opment of a wide range of methods for their synthesis.1
ides are privileged heterocyclic moieties in medicinal chem- Traditionally, these compounds were prepared from 2-amino-
istry and are key components of a wide range of pharmaceu- benzamides or 2-aminobenzenesulfonamides by reaction with
tically-relevant compounds (Fig. 1).1,2 For example, benzotria- sodium nitrite and hydrochloric acid (Scheme 1a).2b,12 Due to
zin-4(3H)-one 1 bearing a naphthalene-substituted piperazine the harsh acidic conditions that limits substrate scope,
side-chain was found to be a high affinity agent for the unstable diazonium salts and the use of sodium nitrite that
5-HT1A receptor.2d Benzotriazin-4(3H)-one 3 is a potent anaes- can lead to the release of toxic nitrogen oxides, milder
thetic with an IC50 value comparable to lidocaine,2c while reagents and reaction conditions for this transformation have
benzothiatriazine-1,1(2H)-dioxide 4 is a well-known diuretic been reported.13 In addition, new approaches have been devel-
agent.2a Benzannulated triazoles have also been widely used oped for the preparation of 1,2,3-benzotriazin-4(3H)-ones
for other applications, such as rubber components, dyes and and 1,2,3-benzothiatriazine-1,1(2H)-dioxides.14 For example,
as photoluminescence agents.1 Furthermore, these benzannu-
lated heterocycles are useful synthetic precursors in organic
chemistry.1 The groups of Murakami,3 Liu,4 and Cheng5 have
shown that these compounds can undergo nickel-catalysed
denitrogenative insertion reactions, with alkenes, alkynes and
allenes, while palladium-catalysed denitrogenation and sub-
sequent reaction with isocyanides6a or alkynes6b have allowed
the preparation of 3-isoindolin-1-ones and o-alkynylated ben-
zamides, respectively. Other nickel-catalysed denitrogentative
substitution processes7 and visible-light-activated annulation
reactions have also been reported.8 Specific reactions of ben-
zothiatriazine-1,1(2H)-dioxides have been described for the
synthesis of biaryl sultams, using thermal,9 visible light10 or
acid-promoted11 methods.
School of Chemistry, The Joseph Black Building, University of Glasgow,
Glasgow G12 8QQ, UK. E-mail: Andrew.Sutherland@glasgow.ac.uk
†Electronic supplementary information (ESI) available: Experimental procedures
and data for starting materials, 1H and 13C NMR spectra for all compounds. See
DOI: 10.1039/d1ob00968k
Fig. 1 Biologically active benzotriazin-4(3H)-ones and benzothiatria-
zine-1,1(2H)-dioxides.
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(Scheme 1d). As well as demonstrating the scope of these
processes, we describe the application of this transformation
for the synthesis of various biologically active compounds,
including the synthesis of an α-amino acid containing 1,2,3-
benzotriazin-4(3H)-one.
Results and discussion
The study began with the optimisation of a one-pot diazotisa-
tion and cyclisation of 2-aminobenzamide (6a) for the prepa-
ration of 1,2,3-benzotriazin-4(3H)-one (7a) (Table 1). Following
our previous work,19–21 a polymer-supported nitrite reagent,
readily prepared by the ion exchange of Amberlyst A-26 with an
aqueous solution of sodium nitrite, was used in combination
with p-tosic acid.18c,d The reaction was initially trialled using
one equivalent of both reagents and methanol as the reaction
solvent (entry 1). While the transformation proceeded at room
temperature, a reaction time of 48 hours was required for com-
pletion and gave 7a in 39% yield (entry 1). Using three equiva-
lents of both reagents led to a substantial improvement, gener-
ating 7a in 87% yield after 2 hours (entry 2). A further increase
in the number of equivalent of reagents resulted in a faster,
but less efficient process (entry 3). A solvent screen was also
performed (entries 4–6), and while these reactions gave 7a in
good yields, methanol was deemed the optimal solvent. It
should be noted that as well as avoiding toxic reagents and
harsh conditions, an advantage of this process is the simple
work-up procedure and purification of products. On reaction
completion, the polymer resin is removed by filtration (and
recycled), and the product then purified by flash column
Scheme 1 Methods for the synthesis of benzotriazin-4(3H)-ones and
benzothiatriazine-1,1(2H)-dioxides.
Chandrasekhar and Sankararaman reported the preparation of
N-substituted 1,2,3-benzotriazin-4(3H)-ones via the palladium(0)-
catalysed carbonylation of 1,3-diaryltriazenes (Scheme 1b),15
while Cui and co-workers prepared both series of compounds
by a redox cyclisation of amides and sulfonamides with
nitrous oxide (Scheme 1c).16 The Song group have reported the
preparation of 1,2,3-benzotriazin-4(3H)-ones by the oxidative
rearrangement of 3-aminoindazoles.17
Despite the wide range of approaches now developed for
the synthesis of these heterocycles, there is still a need for a
mild and general approach from readily available starting
materials, that avoids the requirement of harsh acidic or
strongly oxidising conditions and precious transition metal
catalysis. In recent years, issues associated with standard dia-
zonium salt formation (NaNO2, HCl) of aromatic compounds
have been overcome with the use of polymer-supported
nitrite reagents and milder acids.18 For example, Filimonov
and co-workers demonstrated that aryl diazonium tosylate
salts could be prepared using nitrite supported on a tetraalk-
ylammonium functionalised resin, such as Amberlyst A-26, in
the presence of p-tosic acid.18c,d As well as the mild reaction
conditions, the aryl diazonium tosylate salts were found to
have high thermal and aging stability. Our group have
exploited this safe and mild approach for aryl diazonium salt
formation in one-pot processes for (radio)iodination,19 Heck–
Matsuda reactions,20 and the synthesis of benzotriazoles.21
We now report the one-pot synthesis of 1,2,3-benzotriazin-4
(3H)-ones and 1,2,3-benzothiatriazine-1,1(2H)-dioxides via
stable aryl diazonium salts, by reaction of readily available
2-aminobenzamides and 2-aminobenzenesulfonamides with
Table 1 Optimisation of the one-pot diazotisation and cyclisation of
2-aminobenzamide (6a)
Entry
Reagentsa (equiv.)
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7c
1
3
6
3
3
3
3
MeOH
MeOH
MeOH
MeCN
THF
EtOAc
MeOH
48
2
1
2
2
2
2.5
39
87
62
55
73
65
56
a Polymer supported nitrite and p-tosic acid. b Isolated yield. c Reaction
was performed using sodium nitrite.
a
polymer-supported nitrite reagent and p-tosic acid
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chromatography. By comparison, if the polymer-supported the corresponding 1,2,3-benzotriazin-4(3H)-ones 7a–7k in
nitrite reagent is replaced with sodium nitrite in this process, 53–91% yields. For the majority of the 2-aminobenzamides,
while the reaction is completed in a similar time, the require- the transformation proceeded at room temperature in reaction
ment of performing a work-up involving aqueous washes to times of 2–4.5 h. Only methoxy-substituted 2-aminobenzamide
remove p-TsOH, results in the isolation of 7a in 56% yield 6i required both elevated temperatures (65 °C) and a long reac-
(entry 7).
Following optimisation, the scope of the reaction was nature of the diazo intermediate prior to cyclisation.
explored for the preparation of other N-unsubstituted 1,2,3- The next stage of the project investigated the application of
tion time (76 h). This is likely due to the reduced electrophilic
benzotriazin-4(3H)-ones (Scheme 2). 2-Aminobenzamides 6a– the one-pot method for the synthesis of N-substituted 1,2,3-
6k bearing a range of o-, m- and p-substituted functional benzotriazin-4(3H)-ones (Scheme 2). Unlike most of the simple
groups were found to be substrates for the reaction, providing 2-aminobenzamides used in the first part of this study that
were commercially available, many of the N-alkyl and N-aryl
substituted benzamides required synthesis. These were pre-
pared in one-step by the reaction of isatoic anhydride with
various amines.22,23 Reaction of N-alkyl benzamides with
polymer-supported nitrite reagent and p-tosic acid, under opti-
mised conditions gave the corresponding N-alkyl 1,2,3-benzo-
triazin-4(3H)-ones 7l–7p in 54–89% yields. With these com-
pounds, it was found that cyclisation of more sterically hin-
dered secondary amides required more forcing conditions. For
example, N-cyclohexyl benzamide 6n required a reaction time
of 49 hours and a reaction temperature of 65 °C, while a
t-butyl analogue demonstrated the limitation of this approach
with no reaction observed. N-Aryl benzamides also required
slightly elevated temperatures (40 °C) but all substrates investi-
gated were converted to the corresponding N-aryl 1,2,3-benzo-
triazin-4(3H)-ones (7q–7x). The process was efficient for the
preparation of 1,2,3-benzotriazin-4(3H)-ones bearing both elec-
tron-rich and electron-deficient N-aryl substituents and was
also compatible with N-heterocyclic moieties (e.g. 7x). The syn-
thesis of 7r demonstrates that ortho-substituted N-aryl groups
are also tolerated during the cyclisation step.
The research programme then examined the scope of the
one-pot diazotisation and cyclisation for the preparation of
N-substituted
1,2,3-benzothiatriazine-1,1(2H)-dioxides
9
(Scheme 3). The N-substituted benzenesulfonamides 8 were
prepared in two steps by reaction of 2-nitrobenzenesulfonyl
chloride with an amine, under basic conditions, followed by
reduction of the nitro-group with tin dichloride.23 The
N-substituted 2-aminobenzenesulfonamides 8 were found to
be more reactive to diazotisation and cyclisation than the
corresponding benzamides 6. Reactions proceeded at 0 °C or
room temperature and with relatively short reaction times
(2–4.5 h). For 2-amino-N-methylbenzenesulfonamide (8a) and
N-ethyl analogue 8b, room temperature reactions led to deni-
trogenation of the diazo intermediates and isolation of the
deaminated N-alkylbenzenesulfonamides as the major pro-
ducts. However, performing these reactions at 0 °C, allowed
clean transformations and the isolation of 8a and 8b in 51%
and 75% yields, respectively. Reaction of the other
N-alkylbenzenesulfonamides proceeded smoothly at room
temperature and gave 1,2,3-benzothiatriazine-1,1(2H)-dioxides
9c–9f, in 60–85% yields. A demonstration of the increased reac-
tivity of this class of compound was the synthesis of t-butyl
analogue 9d. While the corresponding 2-aminobenzamide
gave no product, 9d was isolated in 60% yield. Similarly, the
Scheme 2 Reaction scope for the synthesis of 1,2,3-benzotriazin-4
(3H)-ones.
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Scheme 3 Reaction scope for the synthesis of 1,2,3-benzothiatriazine-
1,1(2H)-dioxides.
Scheme 4 Synthesis of biologically active benzannulated triazoles 3, 5
and 10.
reaction of 2-amino-N-arylbenzenesulfonamides also pro-
ceeded at 0 °C or room temperature and gave the corres-
ponding N-aryl 1,2,3-benzothiatriazine-1,1(2H)-dioxides 9g–9k tial pesticide with low-toxicity.2e Initially, amine 12 was pre-
in 59–71% yields. Several of the compounds prepared in this pared in two steps.23 N-Benzoylpiperazine was alkylated with
part of the study are used for the production of materials. For N-(2-bromoethyl)phthalimide and this was followed by
example, 9a, 9d and 9g are blowing agents for the formation removal of the phthalimide protecting group with hydrazine.
of cellular rubber,24 while 9a and 9g are also used as catalysts Reaction of 12 with 2-nitrobenzenesulfonyl chloride and nitro-
for free-radical polymerisation.25
group reduction with zinc/acetic acid gave sulfonamide 14 in
We next examined the application of the one-pot process high yields. Application of the one-pot diazotisation and cycli-
for the synthesis of biologically active benzannulated triazoles. sation method with 14, proceeded at room temperature and
Initially, the optimised conditions for diazotisation and cycli- after a reaction time of 2 hours, gave nematicidal agent 5 in
sation (Table 1, entry 2) were used for the gram scale synthesis 72% yield.
of 1,2,3-benzotriazin-4(3H)-one (7a). This gave 7a in 64% yield
We have an interest in the development of novel α-amino
(Scheme 4). Copper(II)-catalysed N-arylation of 7a with acids that can be used as biological probes.27 Thus, as a proof-
naphthalene-2-boronic acid under basic conditions completed of-concept experiment, we were interested in exploring
the two-step synthesis of chorismate mutase inhibitor 10.26 whether the one-pot diazotisation and cyclisation procedure
1,2,3-Benzotriazin-4(3H)-one (7a) was also used for the three- could be used for the preparation of an α-amino acid bearing a
step synthesis of anaesthetic compound 3, which has similar 1,2,3-benzotriazin-4(3H)-one side-chain. Key intermediate 16
activity to lidocaine.2c N-Alkylation of 7a with ethyl bromoace- was prepared by the reaction of known L-3-aminoalanine
tate, followed by aminolysis with N,N-diethylethylenediamine derivative 1528 with isatoic anhydride (Scheme 5).
gave 3 in good overall yield. As well as the synthesis of biologi- Diazotisation and cyclisation of 16 was complete in 3 hours
cally active 1,2,3-benzotriazin-4(3H)-ones, the one-pot method and gave 1,2,3-benzotriazin-4(3H)-one 17 in 87% yield. Despite
was also used for a new synthesis of benzothiatriazine-1,1(2H)- the use of p-tosic acid, no Boc-group deprotection was
dioxide 5, a compound with nematicidal activity and a poten- observed under the mild diazotisation reaction conditions.
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ppm relative to tetramethylsilane as the internal standard,
multiplicity (integration, s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet or overlap of non-equivalent reso-
nances). 13C NMR spectra were recorded on a Bruker DPX
spectrometer at either 101 or 126 MHz and data are reported
as follows: chemical shift in ppm relative to tetramethylsilane
or the solvent as internal standard (CDCl3: δ 77.0 ppm,
CD3OD: δ 49.0 ppm, DMSO-d6: δ 39.5 ppm), multiplicity with
respect to hydrogen (deduced from DEPT experiments, C, CH,
CH2 or CH3). Infrared spectra were recorded on a Shimadzu
FTIR-84005 spectrometer; wavenumbers are indicated in
cm−1. Mass spectra were recorded using a JEOL JMS-700
Spectrometer or
a Bruker microTOFq High Resolution
Mass Spectrometer. Melting points were determined on
a Gallenkamp melting point apparatus and are reported
uncorrected.
Scheme 5 Synthesis of α-amino acid 18.
General procedure for preparation of polymer supported
nitrite resin
Ester hydrolysis with caesium carbonate at room temperature,
followed by acid-mediated removal of the Boc-protecting group
gave parent amino acid 18.
To a stirred solution of sodium nitrite (5.50 g, 80.0 mmol) in
water (200 mL) was added Amberlyst A26 hydroxide form resin
(10.0 g, 40.0 mmol). The reaction mixture was stirred at rt for
1 h. The polymer-supported resin was filtered and washed
with water until the filtrate was of neutral pH. The content of
the polymer-supported nitrite was 3.5 mmol of NO2 per g.18
Conclusions
In summary, a mild and general one-pot process has been
developed for the synthesis of both 1,2,3-benzotriazin-4(3H)-
ones and 1,2,3-benzothiatriazine-1,1(2H)-dioxides via stable
General Procedure for synthesis of 1H-benzotriazinones
To a stirred solution of the 2-aminobenzamides (1 equiv.) in
methanol (10 mL mmol−1) at 0 °C was added polymer-sup-
ported nitrite (containing 3.0 equiv. of NO2) and p-toluenesul-
fonic acid monohydrate (3 equiv.). The reaction mixture was
stirred for 1 h at 0 °C. The reaction mixture was then warmed
to room temperature and stirred until completion. The resin
was filtered and washed with methanol (20 mL mmol−1). The
reaction mixture was concentrated in vacuo. Purification by
flash column chromatography gave the 1H-benzotriazinones.
1,2,3-Benzotriazin-4(3H)-one (7a).30 The reaction was carried
out as described in the general procedure using 2-aminobenza-
mide (6a) (0.303 g, 2.20 mmol), polymer-supported nitrite
(1.89 g, containing 6.60 mmol of NO2) and p-toluenesulfonic
acid monohydrate (1.26 g, 6.60 mmol). The reaction mixture
was stirred at 0 °C for 1 h, warmed to room temperature and
stirred for 1 h. Purification by flash column chromatography,
eluting with 35% ethyl acetate in hexane gave 1,2,3-benzo-
aryl diazonium tosylate salts. The use of
a polymer-
supported nitrite reagent and p-tosic acid facilitated the
rapid diazotisation and cyclisation of 2-aminobenzamides
and 2-aminobenzenesulfonamides, yielding the target com-
pounds in good yields. The process was found to be com-
patible for a wide range of substrates,29 bearing N-aryl or
N-alkyl substituted amides or sulfonamides. The mild nature
of this transformation allowed the preparation of various
agents for rubber and polymer production, as well as the
synthesis of medicinally important compounds. The use of
this process for the preparation of a benzotriazin-4(3H)-one
derived amino acid serves as a platform for future work
and the synthesis of more complex analogues for chemical
biology applications.
Experimental
triazin-4(3H)-one (7a) (0.294 g, 87%) as
a white solid.
All reagents and starting materials were obtained from com- Mp 212–215 °C (lit.30 215–217 °C); δH (400 MHz, DMSO-d6)
mercial sources and used as received. All dry solvents were pur- 7.91 (1H, br t, J 7.7 Hz, 7-H), 8.08 (1H, br t, J 7.7 Hz, 6-H), 8.18
ified using a PureSolv 500 MD solvent purification system. (1H, br d, J 7.7 Hz, 8-H), 8.22 (1H, br d, J 7.7 Hz, 5-H), 14.94
Brine refers to a saturated aqueous solution of sodium chlor- (1H, br s, NH); δC (101 MHz, DMSO-d6) 120.2 (C), 124.3 (CH),
ide. Flash column chromatography was performed using 127.8 (CH), 132.6 (CH), 135.5 (CH), 144.2 (C), 155.6 (C); m/z
Merck Geduran Si 60 (35–70 µm) silica gel. Merck aluminium- (EI) 147 (M+. 100%), 104 (22), 92 (69), 76 (72), 63 (83).
backed plates pre-coated with silica gel 60F254 were used for
5-Fluoro-1,2,3-benzotriazin-4(3H)-one (7b). The reaction was
thin layer chromatography and were visualised with a UV lamp carried out as described in the general procedure using
or by staining with KMnO4 or ninhydrin. 1H NMR spectra were 6-fluoro-2-aminobenzamide (6b) (0.200 g, 1.30 mmol),
recorded on a Bruker DPX spectrometer at either 400 or polymer-supported nitrite (1.11 g, containing 3.89 mmol of
500 MHz and data are reported as follows: chemical shift in NO2) and p-toluenesulfonic acid monohydrate (0.740 g,
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3.89 mmol). The reaction mixture was stirred at 0 °C for 1 h, DMSO-d6) 8.12 (1H, d, J 8.6 Hz, 8-H), 8.24 (1H, dd, J 8.6, 2.2
warmed to room temperature and stirred for 1 h. Purification Hz, 7-H), 8.31 (1H, d, J 2.2 Hz, 5-H), 15.10 (1H, br s, NH); δC
by flash column chromatography, eluting with 70% diethyl (101 MHz, DMSO-d6) 121.7 (C), 125.6 (C), 126.5 (CH), 130.1
ether in hexane gave 5-fluoro-1,2,3-benzotriazin-4(3H)-one (7b) (CH), 138.3 (CH), 142.9 (C), 154.3 (C); m/z (EI) 227 (M+. 23%),
(0.144 g, 67%) as a white solid. Mp 200–204 °C; νmax/cm−1 225 (23), 184 (22), 182 (21), 156 (17), 154 (18), 78 (78), 63 (100).
(neat) 3161 (NH), 2975 (CH), 2160, 2012, 1700 (CvO), 1480,
6-Iodo-1,2,3-benzotriazin-4(3H)-one (7f). The reaction was
1262, 815; δH (500 MHz, DMSO-d6) 7.68 (1H, dd, J 10.5, 9.0 Hz, carried out as described in the general procedure using
6-H), 8.00 (1H, br d, J 8.0 Hz, 8-H), 8.07 (1H, ddd, J 10.5, 8.0, 2-amino-5-iodobenzamide (6f) (0.150 g, 0.570 mmol), polymer-
5.0 Hz, 7-H), 14.97 (1H, br s, NH); δC (126 MHz, DMSO-d6) supported nitrite (0.497 g, containing 1.72 mmol of NO2) and
2
2
109.9 (C, JCF = 8.8 Hz), 118.6 (CH, d, JCF = 20.2 Hz), 124.0 p-toluenesulfonic acid monohydrate (0.372 g, 1.72 mmol). The
4
3
(CH, JCF = 3.8 Hz), 136.5 (CH, JCF = 10.1 Hz), 145.7 (C), 152.7 reaction mixture was stirred for 1 h at 0 °C and then heated
(C, JCF = 1.3 Hz), 158.7 (C, d, JCF = 264.6 Hz); m/z (ESI) under reflux for 18 h. Purification by flash column chromato-
166.0410 (MH+. C7H5FN3O requires 166.0411).
graphy, eluting with 40% ethyl acetate in hexane gave 6-iodo-
3
1
6-Fluoro-1,2,3-benzotriazin-4(3H)-one (7c).17 The reaction 1,2,3-benzotriazin-4(3H)-one (7f) (0.0910 g, 58%) as a white
was carried out as described in the general procedure using solid. Mp 127–130 °C; νmax/cm−1 (neat) 3071 (NH), 2945 (CH),
2-amino-5-fluorobenzamide (6c) (0.150 g, 0.970 mmol), 1672 (CvO), 1227, 1188; δH (400 MHz, CD3OD) 7.90 (1H, d, J
polymer-supported nitrite (0.836 g, containing 2.92 mmol of 8.6 Hz, 8-H), 8.37 (1H, dd, J 8.5, 2.0 Hz, 7-H), 8.64 (1H, d, J 2.0
NO2) and p-toluenesulfonic acid monohydrate (0.556 g, Hz, 5-H); δC (101 MHz, CD3OD) 99.5 (C), 122.8 (C), 130.5 (CH),
2.92 mmol). The reaction mixture was stirred at 0 °C for 1 h, 134.6 (CH), 145.2 (C), 145.6 (CH), 156.6 (C); m/z (ESI) 295.9288
warmed to room temperature and stirred for 1.5 h. Purification (MNa+. C7H4IN3NaO requires 295.9291).
by flash column chromatography, eluting with 30% ethyl
6-Nitro-1,2,3-benzotriazin-4(3H)-one (7g).33 The reaction was
acetate in hexane gave 6-fluoro-1,2,3-benzotriazin-4(3H)-one carried out as described in the general procedure using
(7c) (0.125 g, 78%) as a white solid. Spectroscopic data were 2-amino-5-nitrobenzamide (6g) (0.0800 g, 0.442 mmol),
consistent with the literature.17 Mp 206–208 °C; δH (400 MHz, polymer-supported nitrite (0.378 g, containing 1.32 mmol of
DMSO-d6) 7.91–8.00 (2H, m, 5-H and 7-H), 8.31 (1H, ddd, J 8.8, NO2) and p-toluenesulfonic acid monohydrate (0.252 g,
5.0, 0.4 Hz, 8-H), 15.04 (1H, br s, NH); δC (101 MHz, DMSO-d6) 1.32 mmol). The reaction mixture was stirred for 1 h at 0 °C
2
3
109.5 (CH, JCF = 24.0 Hz), 122.4 (C, JCF = 9.4 Hz), 123.9 (CH, and heated under reflux for 7 h. Purification by flash column
d, 2JCF = 24.4 Hz), 131.6 (CH, d, JCF = 9.5 Hz), 141.5 (C, d, JCF chromatography, eluting with 60% diethyl ether in hexane
= 2.2 Hz), 155.0 (C, d, JCF = 3.1 Hz), 163.2 (C, d, JCF = 253.4 gave 6-nitro-1,2,3-benzotriazin-4(3H)-one (7g) (0.0480 g, 56%)
Hz); m/z (EI) 165 (M+. 20%), 122 (10), 94 (21), 78 (88), 63 (100). as a yellow solid. Mp 189–194 °C (lit.33 194 °C); δH (400 MHz,
3
4
4
1
6-Chloro-1,2,3-benzotriazin-4(3H)-one (7d).31 The reaction DMSO-d6) 8.42 (1H, dd, J 8.9, 0.5 Hz, 8-H), 8.76 (1H, dd, J 8.9,
was carried out as described in the general procedure using 2.6 Hz, 7-H), 8.82 (1H, dd, J 2.6, 0.5 Hz, 5-H), 15.42 (1H, br s,
2-amino-5-chlorobenzamide (6d) (0.150 g, 0.880 mmol), NH); δC (101 MHz, DMSO-d6) 120.3 (CH), 121.1 (C), 129.4 (CH),
polymer-supported nitrite (0.759 g, containing 2.65 mmol of 130.1 (CH), 146.4 (C), 148.5 (C), 154.8 (C); m/z (EI) 192 (M+.
NO2) and p-toluenesulfonic acid monohydrate (0.504 g, 28%), 149 (28), 84 (82), 66 (100).
2.65 mmol). The reaction mixture was stirred at 0 °C for 1 h,
6-Methyl-1,2,3-benzotriazin-4(3H)-one (7h).34 The reaction
warmed to room temperature and stirred for 1 h. Purification was carried out as described in the general procedure using
by flash column chromatography, eluting with 35% ethyl 2-amino-5-methylbenzamide (6h) (0.100 g, 0.660 mmol),
acetate in hexane gave 6-chloro-1,2,3-benzotriazin-4(3H)-one polymer-supported nitrite (0.573 g, containing 2.00 mmol of
(7d) (0.145 g, 91%) as a white solid. Mp 190–192 °C (lit.31 NO2) and p-toluenesulfonic acid monohydrate (0.380 g,
195–196 °C); δH (400 MHz, DMSO-d6) 8.12 (1H, dd, J 8.7, 2.4 2.00 mmol). The reaction mixture was stirred at 0 °C for 1 h,
Hz, 7-H), 8.18 (1H, d, J 2.4 Hz, 5-H), 8.22 (1H, d, J 8.7 Hz, 8-H), warmed to room temperature and stirred for 3.5 h. Purification
15.11 (1H, br s, NH); δC (101 MHz, DMSO-d6) 121.7 (C), 123.5 by flash column chromatography, eluting with 30% ethyl
(CH), 130.2 (CH), 135.6 (CH), 136.9 (C), 142.8 (C), 154.6 (C); acetate in petroleum ether gave 6-methyl-1,2,3-benzotriazin-4
m/z (EI) 181 (M+. 18%), 138 (7), 110 (11), 78 (88), 63 (100).
(3H)-one (7h) (0.0570 g, 53%) as a white solid. Mp 219–220 °C
6-Bromo-1,2,3-benzotriazin-4(3H)-one (7e).32 The reaction (lit.34 217–218 °C); δH (400 MHz, DMSO-d6) 2.54 (3H, s, 6-CH3),
was carried out as described in the general procedure using 7.89 (1H, dd, J 8.2, 1.6 Hz, 7-H), 8.01 (1H, br s, 5-H), 8.07 (1H,
2-amino-5-bromobenzamide (6e) (0.150 g, 0.700 mmol), d, J 8.2 Hz, 8-H), 14.86 (1H, br s, NH); δC (101 MHz, DMSO-d6)
polymer-supported nitrite (0.601 g, containing 2.10 mmol of 21.3 (CH3), 120.1 (C), 123.6 (CH), 127.8 (CH), 136.7 (CH), 142.6
NO2) and p-toluenesulfonic acid monohydrate (0.399 g, (C), 143.4 (C), 155.6 (C); m/z (EI) 161 (M+. 8%), 104 (8), 89 (6),
2.10 mmol). The reaction mixture was stirred at 0 °C for 1 h, 78 (82), 63 (100).
warmed to room temperature and stirred for 1 h. Purification
6-Methoxy-1,2,3-benzotriazin-4(3H)-one (7i). The reaction
by flash column chromatography, eluting with 25% ethyl was carried out as described in the general procedure using
acetate in hexane gave 6-bromo-1,2,3-benzotriazin-4(3H)-one 5-methoxy-2-aminobenzamide (6i) (0.100 g, 0.600 mmol),
(7e) (0.129 g, 82%) as a white solid. Spectroscopic data were polymer-supported nitrite (0.515 g, containing 1.80 mmol of
consistent with the literature.32 Mp 207–209 °C; δH (400 MHz, NO2) and p-toluenesulfonic acid monohydrate (0.342 g,
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1.80 mmol). The reaction mixture was stirred for 1 h at room by flash column chromatography, eluting with 25% ethyl
temperature and then heated under reflux for 75 h. acetate in petroleum ether gave N-methyl-1,2,3-benzotriazin-4
Purification by flash column chromatography, eluting with (3H)-one (7l) (0.144 g, 89%) as a white solid. Mp 115–117 °C
40% ethyl acetate in hexane gave 6-methoxy-1,2,3-benzotriazin- (lit.16 118–120 °C); δH (500 MHz, DMSO-d6) 3.93 (3H, s, 3-CH3),
4(3H)-one (7i) (0.0560 g, 53%) as a white solid. Mp 190–192 °C; 7.89–7.95 (1H, m, 6-H), 8.05–8.10 (1H, m, 7-H), 8.19 (1H, dd, J
νmax/cm−1 (neat) 3159 (NH), 2959 (CH), 1662 (CvO), 1296, 8.1, 1.0 Hz, 8-H), 8.24 (1H, dd, J 8.1, 1.0 Hz, 5-H); δC (126 MHz,
1141, 895, 833; δH (400 MHz, DMSO-d6) 3.96 (3H, s, 6-OCH3), DMSO-d6) 37.0 (CH3), 119.2 (C), 124.3 (CH), 127.9 (CH), 132.8
7.55 (1H, d, J 2.8 Hz, 5-H), 7.62 (1H, dd, J 9.0, 2.8 Hz, 7-H), (CH), 135.2 (CH), 143.9 (C), 155.1 (C); m/z (EI) 161 (M+. 6%), 78
8.12 (1H, d, J 9.0 Hz, 8-H), 14.79 (1H, br s, NH); δC (101 MHz, (82), 63 (100).
DMSO-d6) 56.2 (CH3), 104.2 (CH), 122.0 (C), 124.6 (CH), 130.1
N-Propyl-1,2,3-benzotriazin-4(3H)-one (7m).35 The reaction
(CH), 139.4 (C), 155.6 (C), 161.9 (C); m/z (EI) 177.0534 (M+. was carried out as described in the general procedure using
C8H7N3O2 requires 177.0538), 134 (12%), 106 (38), 78 (79), 63 2-amino-N-propylbenzamide (6m) (0.150 g, 0.840 mmol),
(100).
polymer-supported nitrite (0.721 g, containing 2.52 mmol of
7-Trifluoromethyl-1,2,3-benzotriazin-4(3H)-one (7j). The NO2) and p-toluenesulfonic acid monohydrate (0.479 g,
reaction was carried out as described in the general 2.52 mmol). The reaction mixture was stirred at 0 °C for 1 h,
procedure using 2-amino-4-trifluorobenzamide (6j) (0.150 g, warmed to room temperature and stirred for 1 h. Purification
0.730 mmol), polymer-supported nitrite (0.630 g, containing by flash column chromatography, eluting with 20% ethyl
2.20 mmol of NO2) and p-toluenesulfonic acid monohydrate acetate in hexane gave N-propyl-1,2,3-benzotriazin-4(3H)-one
(0.418 g, 2.20 mmol). The reaction mixture was stirred at 0 °C (7m) (0.136 g, 86%) as a white solid. Mp 50–55 °C (lit.35
for 1 h, warmed to room temperature and stirred for 2 h. 56–57 °C); δH (500 MHz, DMSO-d6) 0.92 (3H, t, J 7.3 Hz, 3′-H3),
Purification by flash column chromatography, eluting with 1.83 (2H, sextet, J 7.3 Hz, 2′-H2), 4.33 (2H, t, J 7.3 Hz, 1′-H2),
30% ethyl acetate in petroleum ether gave 7-trifluoromethyl- 7.88–7.93 (1H, m, 6-H), 8.04–8.09 (1H, m, 7-H), 8.16 (1H, br d,
1,2,3-benzotriazin-4(3H)-one (7j) (0.130 g, 82%) as a white J 8.0 Hz, 8-H), 8.22 (1H, dd, J 8.0, 1.0 Hz, 5-H); δC (126 MHz,
solid. Mp 185–187 °C; νmax/cm−1 (neat) 3136 (NH), 1694 DMSO-d6) 10.9 (CH3), 22.7 (CH2), 50.7 (CH2), 119.2 (C), 124.5
(CvO), 1651 (CvC), 1319, 1134, 864; δH (400 MHz, DMSO-d6) (CH), 127.9 (CH), 132.8 (CH), 135.3 (CH), 143.6 (C), 154.7 (C);
8.20 (1H, br d, J 8.3 Hz, 6-H), 8.40 (1H, br d, J 8.3 Hz, 5-H), m/z (ESI) 212 (MNa+. 100%).
8.57 (1H, br s, 8-H), 15.25 (1H, br s, NH); δC (101 MHz, DMSO-
N-Cyclohexyl-1,2,3-benzotriazin-4(3H)-one (7n).13c The
reaction was carried out as described in the general
1
3
d6) 123.1 (C, q, JCF = 273.4 Hz), 123.1 (C), 125.2 (CH, q, JCF
=
3
3.2 Hz), 126.3 (CH), 128.1 (CH, q, JCF = 3.2 Hz), 134.8 (C, d, procedure using 2-amino-N-cyclohexylbenzamide (6n) (0.150 g,
2JCF = 33.1 Hz), 143.9 (C), 154.8 (C); m/z (EI) 215.0301 (M+. 0.690 mmol), polymer-supported nitrite (0.590 g, containing
C8H4F3N3O requires 215.0306), 172 (6%), 160 (8), 144 (9), 78 2.06 mmol of NO2) and p-toluenesulfonic acid monohydrate
(81), 63 (100).
(0.392 g, 2.06 mmol). The reaction mixture was stirred at room
3H-Naphtho[2,3-d][1,2,3]triazin-4-one (7k). The reaction was temperature for 1 h and then heated under reflux for 48 h.
carried out as described in the general procedure using 2-ami- Purification by flash column chromatography, eluting with
nonaphthalene-3-carboxamide (6k) (0.0330 g, 0.177 mmol), 25% ethyl acetate in hexane gave N-cyclohexyl-1,2,3-benzotria-
polymer-supported nitrite (0.152 g, containing 0.532 mmol of zin-4(3H)-one (7n) (0.0850 g, 54%) as a yellow solid. Mp
NO2) and p-toluenesulfonic acid monohydrate (0.101 g, 130–133 °C (lit.13c 129–131 °C); δH (500 MHz, CD3OD)
0.532 mmol). The reaction mixture was stirred at 0 °C for 1 h 1.30–1.42 (1H, m, CHH), 1.49–1.62 (2H, m, CH2), 1.76–1.84
and heated to 40 °C for 2 h. Purification by flash column (1H, m, CHH), 1.92–2.07 (6H, m, 3 × CH2), 4.95–5.06 (1H, m,
chromatography, eluting with 80% ethyl acetate in hexane with 1′-H), 7.89 (1H, td, J 8.1, 1.0 Hz, 6-H), 8.02–8.07 (1H, m, 7-H),
1% triethylamine gave 3H-naphtho[2,3-d][1,2,3]triazin-4-one 8.15 (1H, br d, J 8.1 Hz, 8-H), 8.31 (1H, dd, J 8.1, 1.0 Hz, 5-H);
(7k) (0.0290, 83%) as a white solid. Mp 254–257 °C; νmax/cm−1 δC (126 MHz, CD3OD) 26.5 (CH2), 26.9 (2 × CH2), 32.9 (2 ×
(neat) 3006 (NH), 2850 (CH), 2325, 2072, 1823, 1667 (CvO), CH2), 58.2 (CH), 120.6 (C), 126.0 (CH), 129.0 (CH), 133.7 (CH),
1203, 747; δH (400 MHz, DMSO-d6) 7.73–7.86 (2H, m, 7-H and 136.4 (CH), 145.2 (C), 156.6 (C); m/z (EI) 229 (M+. 68%), 172
8-H), 8.27–8.38 (2H, m, 6-H and 9-H), 8.84 (1H, s, 10-H), 8.91 (43), 158 (69), 148 (75), 130 (40), 105 (76), 78 (100), 63 (100).
(1H, s, 5-H), 14.64 (1H, s, NH); δC (101 MHz, DMSO-d6) 117.7
N-(Benzyl)-1,2,3-benzotriazin-4(3H)-one (7o).14 The reaction
(C), 125.8 (CH), 127.9 (CH), 128.9 (CH), 129.1 (CH), 129.3 (CH), was carried out as described in the general procedure using
129.4 (CH), 133.7 (C), 135.7 (C), 140.5 (C), 155.8 (C); m/z (ESI) 2-amino-N-(4-benzyl)benzamide (6o) (0.0500 g, 0.221 mmol),
198.0662 (MH+. C11H8N3O requires 198.0662).
polymer-supported nitrite (0.190 g, containing 0.663 mmol of
N-Methyl-1,2,3-benzotriazin-4(3H)-one (7l).16 The reaction NO2) and p-toluenesulfonic acid monohydrate (0.126 g,
was carried out as described in the general procedure using 0.663 mmol). The reaction mixture was stirred at 0 °C for 1 h
2-amino-N-methylbenzamide (6l) (0.150 g, 1.00 mmol), and then heated to 40 °C for 4 h. Purification by flash column
polymer-supported nitrite (0.850 g, containing 3.00 mmol of chromatography, eluting with 30% ethyl acetate in hexane gave
NO2) and p-toluenesulfonic acid monohydrate (0.571 g, N-(benzyl)-1,2,3-benzotriazin-4(3H)-one (7o) (0.0370 g, 71%) as
3.00 mmol). The reaction mixture was stirred at 0 °C for 1 h, a white solid. Mp 115–119 °C (lit.14 118–120 °C); δH (400 MHz,
warmed to room temperature and stirred for 5.5 h. Purification CDCl3) 5.63 (2H, s, PhCH2), 7.26–7.37 (3H, m, 3′-H, 4′-H and
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5′-H), 7.50–7.55 (2H, m, 2′-H and 6′-H), 7.74–7.80 (1H, m, 6-H), (CH3), 120.4 (C), 125.6 (CH), 127.1 (CH), 127.8 (CH), 128.7
7.89–7.95 (1H, m, 7-H), 8.14 (1H, br d, J 8.2 Hz, 8-H), 8.33 (1H, (CH), 129.9 (CH), 131.2 (CH), 132.8 (CH), 135.2 (CH), 135.6 (C),
dd, J 8.0, 1.0 Hz, 5-H); δC (101 MHz, CDCl3) 53.5 (CH2), 120.2 138.0 (C), 144.1 (C), 155.2 (C); m/z (ESI) 260 (MNa+. 100%).
(C), 125.3 (CH), 128.3 (CH), 128.5 (CH), 128.9 (2 × CH), 129.0
(2 × CH), 132.5 (CH), 134.9 (CH), 135.9 (C), 144.5 (C), 155.5 (C); reaction was carried out as described in the general procedure
m/z (ESI) 260 (MNa+. 100%).
using 2-amino-N-(4′-methylphenyl)benzamide (6s) (0.285 g,
N-(4′-Methylphenyl)-1,2,3-benzotriazin-4(3H)-one (7s).14 The
N-(Methoxycarbonylmethyl)-1,2,3-benzotriazin-4(3H)-one (7p).13c 1.26 mmol), polymer-supported nitrite (1.09 g, containing
To a stirred solution of 2-amino-N-(methoxycarbonylmethyl) 3.78 mmol of NO2) and p-toluenesulfonic acid monohydrate
benzamide (6p) (0.127 g, 0.601 mmol) in methanol (6 mL) was (0.719 g, 3.78 mmol). The reaction mixture was stirred at 0 °C
added polymer-supported nitrite (0.516 g, containing for 1 h and then heated to 40 °C for 4 h. The reaction mixture
1.80 mmol of NO2) and p-toluenesulfonic acid monohydrate was cooled to room temperature and concentrated in vacuo.
(0.342 g, 1.80 mmol). The reaction mixture was stirred at 0 °C The reaction mixture was diluted in dichloromethane (20 mL)
for 1 h and then heated to 40 °C for 4 h. The reaction mixture and washed with 1 M aqueous sodium hydroxide (6 × 20 mL).
was cooled to room temperature and concentrated in vacuo. The organic layer was dried (MgSO4), filtered and concentrated
The reaction mixture was diluted in ethyl acetate (20 mL) and in vacuo to give N-(4′-methylphenyl)-1,2,3-benzotriazin-4(3H)-
washed with water (4 × 20 mL). The organic layer was dried one (7s) (0.272 g, 91%) as an orange solid. Mp 137–140 °C
(MgSO4), filtered and concentrated in vacuo to give N-(methoxy- (lit.14 139–141 °C); δH (400 MHz, CDCl3) 2.45 (3H, s, 4′-CH3),
carbonylmethyl)-1,2,3-benzotriazin-4(3H)-one (7p) (0.110 g, 7.33–7.39 (2H, m, 3′-H and 5′-H), 7.50–7.56 (2H, m, 2′-H and
84%) as a white solid. Mp 128–130 °C (lit.13c 128–130 °C); δH 6′-H), 7.82–7.87 (1H, m, 6-H), 7.96–8.01 (1H, m, 7-H), 8.22 (1H,
(400 MHz, CDCl3) 3.81 (3H, s OCH3), 5.21 (2H, s, CH2CO2CH3), br d, J 8.1 Hz, 8-H), 8.44 (1H, dd, J 7.9, 1.4 Hz, 5-H); δC
7.80–7.86 (1H, m, 6-H), 7.95–8.02 (1H, m, 7-H), 8.19 (1H, br d, (101 MHz, CDCl3) 21.4 (CH3), 120.6 (C), 125.8 (CH), 126.0 (2 ×
J 8.1 Hz, 8-H), 8.37 (1H, dd, J 7.9, 1.1 Hz, 5-H); δC (101 MHz, CH), 128.6 (CH), 129.8 (2 × CH), 132.8 (CH), 135.1 (CH), 136.5
CDCl3) 50.9 (CH2), 52.8 (CH3), 119.9 (C), 125.4 (CH), 128.8 (C), 139.2 (C), 143.9 (C), 155.5 (C); m/z (ESI) 260 (MNa+. 100%).
(CH), 132.8 (CH), 135.3 (CH), 144.5 (C), 155.7 (C), 167.7 (C);
N-(4′-Methoxyphenyl)-1,2,3-benzotriazin-4(3H)-one (7t).14
The reaction was carried out as described in the general pro-
m/z (ESI) 242 (MNa+. 100%).
N-Phenyl-1,2,3-benzotriazin-4(3H)-one (7q).13c The reaction cedure using 2-amino-N-(4′-methoxyphenyl)benzamide (6t)
was carried out as described in the general procedure using (0.0500 g, 0.206 mmol), polymer-supported nitrite (0.177 g,
2-amino-N-phenylbenzamide (6q) (0.0500 g, 0.236 mmol), containing 0.619 mmol of NO2) and p-toluenesulfonic acid
polymer-supported nitrite (0.202 g, containing 0.707 mmol of monohydrate (0.118 g, 0.619 mmol). The reaction mixture was
NO2) and p-toluenesulfonic acid monohydrate (0.135 g, stirred at 0 °C for 1 h and then heated to 40 °C for 4 h.
0.707 mmol). The reaction mixture was stirred at 0 °C for 1 h Purification by flash column chromatography, eluting with
and then heated to 40 °C for 18 h. Purification by flash 70% diethyl ether in hexane gave N-(4′-methoxyphenyl)-1,2,3-
column chromatography, eluting with 25% ethyl acetate in benzotriazin-4(3H)-one (7t) (0.0370 g, 71%) as a yellow solid.
hexane gave N-phenyl-1,2,3-benzotriazin-4(3H)-one (7q) Mp 147–150 °C (lit.14 151–153 °C); δH (400 MHz, CDCl3) 3.88
(0.0330 g, 62%) as a white solid. Mp 150–153 °C (lit.13c (3H, s, 4′-OCH3), 7.02–7.09 (2H, m, 3′-H and 5′-H), 7.52–7.60
150–152 °C); δH (400 MHz, CDCl3) 7.49 (1H, tt, J 7.4, 1.3 Hz, 4′- (2H, m, 2′-H and 6′-H), 7.84 (1H, td, J 8.0, 1.0 Hz, 6-H),
H), 7.53–7.59 (2H, m, 3′-H and 5′-H), 7.63–7.68 (2H, m, 2′-H 7.94–8.01 (1H, m, 7-H), 8.21 (1H, br d, J 8.1 Hz, 8-H), 8.43 (1H,
and 6′-H), 7.83–7.88 (1H, m, 6-H), 7.96–7.03 (1H, m, 7-H), 8.23 dd, J 8.0, 1.0 Hz, 5-H); δC (101 MHz, CDCl3) 55.7 (CH3), 114.4
(1H, br d, J 8.1 Hz, 8-H), 8.45 (1H, dd, J 7.9, 1.1 Hz, 5-H); δC (2 × CH), 120.5 (C), 125.7 (CH), 127.4 (2 × CH), 128.6 (CH),
(101 MHz, CDCl3) 120.6 (C), 125.8 (CH), 126.2 (2 × CH), 128.7 131.9 (C), 132.8 (CH), 135.1 (CH), 143.9 (C), 155.5 (C), 160.0
(CH), 129.1 (CH), 129.2 (2 × CH), 132.9 (CH), 135.2 (CH), 139.0 (C); m/z (ESI) 276 (MNa+. 100%).
(C), 143.9 (C), 155.4 (C); m/z (ESI) 246 (MNa+. 100%).
N-(4′-Fluorophenyl)-1,2,3-benzotriazin-4(3H)-one (7u).14 The
N-(2′-Methylphenyl)-1,2,3-benzotriazin-4(3H)-one (7r).13b reaction was carried out as described in the general procedure
The reaction was carried out as described in the general pro- using 2-amino-N-(4′-fluorophenyl)benzamide (6u) (0.0500 g,
cedure using 2-amino-N-(2′-methylphenyl)benzamide (6r) 0.217 mmol), polymer-supported nitrite (0.187 g, containing
(0.100 g, 0.442 mmol), polymer-supported nitrite (0.379 g, con- 0.652 mmol of NO2) and p-toluenesulfonic acid monohydrate
taining 1.33 mmol of NO2) and p-toluenesulfonic acid mono- (0.124 g, 0.652 mmol). The reaction mixture was stirred at 0 °C
hydrate (0.252 g, 1.33 mmol). The reaction mixture was stirred for 1 h and then heated to 40 °C for 4 h. Purification by flash
at 0 °C for 1 h and then heated to 40 °C for 4 h. Purification by column chromatography, eluting with 30% ethyl acetate in
flash column chromatography, eluting with 100% dichloro- hexane gave N-(4′-fluorophenyl)-1,2,3-benzotriazin-4(3H)-one
methane gave N-(2′-methylphenyl)-1,2,3-benzotriazin-4(3H)- (7u) (0.0320 g, 60%) as a white solid. Mp 136–139 °C (lit.14
one (7r) (0.0810 g, 77%) as a white solid. Mp 158–160 °C (lit.13b 138–140 °C); δH (400 MHz, CDCl3) 7.20–7.28 (2H, m, 2′-H and
153–155 °C); δH (500 MHz, CDCl3) 2.21 (3H, s, 2′-CH3), 6′-H), 7.61–7.68 (2H, m, 3′-H and 5′-H), 7.82–7.89 (1H, m, 6-H),
7.33–7.49 (4H, m, 3′-H, 4′-H, 5′-H and 6′-H), 7.86 (1H, br t, J 7.5 7.96–8.01 (1H, m, 7-H), 8.22 (1H, br d, J 8.0 Hz, 8-H), 8.43 (1H,
Hz, 6-H), 8.01 (1H, br t, J 7.5, 7-H), 8.25 (1H, br d, J 7.5 Hz, dd, J 8.0, 1.1 Hz, 5-H); δC (101 MHz, CDCl3) 116.1 (2 × CH, d,
3
8-H), 8.45 (1H, br d, J 7.5 Hz, 5-H); δC (126 MHz, CDCl3) 17.8 2JC–F = 23.0 Hz), 120.4 (C), 125.8 (CH), 128.0 (2 × CH, d, JC–F
=
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4
8.8 Hz), 128.7 (CH), 133.0 (CH), 134.9 (C, d, JC–F = 3.3 Hz), (CH), 129.5 (CH), 133.8 (CH), 135.9 (CH), 140.2 (CH), 142.6 (C),
1
135.3 (CH), 143.8 (C), 155.4 (C), 162.7 (C, d, JC–F = 249.1 Hz); 154.3 (C), 156.3 (C); m/z (ESI) 253 (MNa+. 100%).
m/z (ESI) 264 (MNa+. 100%).
General procedure for synthesis of 2H-benzothiatriazin-
N-(4′-Chlorophenyl)-1,2,3-benzotriazin-4(3H)-one (7v).13b
1,1-dioxides
The reaction was carried out as described in the general
procedure using 2-amino-N-(4′-chlorophenyl)benzamide (6v) To a stirred solution of 2-aminobenzenesulfonamides (1
(0.150 g, 0.608 mmol), polymer-supported nitrite (0.522 g, con- equiv.) in methanol (10 mL mmol−1) at 0 °C was added
taining 1.82 mmol of NO2) and p-toluenesulfonic acid mono- polymer-supported nitrite (containing 3.0 equiv. of NO2) and
hydrate (0.347 g, 1.82 mmol). The reaction mixture was stirred p-toluenesulfonic acid monohydrate (3 equiv.). The reaction
at 0 °C for 1 h and then heated to 40 °C for 4 h. The reaction mixture was stirred at 0 °C until completion or stirred at 0 °C
mixture was cooled to room temperature and concentrated in for 1 h and then warmed to room temperature and stirred
vacuo. The reaction mixture was diluted in ethyl acetate until completion. The resin was filtered and washed with
(20 mL) and washed with 1 M aqueous sodium hydroxide (6 × methanol (20 mL mmol−1). The reaction mixture was concen-
20 mL). The organic layer was dried (MgSO4), filtered and con- trated in vacuo. Purification by flash column chromatography
centrated in vacuo to give N-(4′-chlorophenyl)-1,2,3-benzotria- gave the 2H-benzothiatriazin-1,1-dioxides.
zin-4(3H)-one (7v) (0.102 g, 65%) as a yellow solid. Mp
N-Methyl-1,2,3,4-benzothiatriazin-1,1(2H)-dioxide (9a).16 To
174–176 °C (lit.13b 173–175 °C); δH (400 MHz, CDCl3) 7.50–7.55 a stirred solution of 2-amino-N-(methyl)benzenesulfonamide
(2H, m, 2′-H and 6′-H), 7.61–7.67 (2H, m, 3′-H and 5′-H), (8a) (0.0840 g, 0.451 mmol) in methanol (6 mL) was added
7.84–7.90 (1H, m, 6-H), 7.98–8.03 (1H, m, 7-H), 8.23 (1H, br d, polymer-supported nitrite (0.387 g, containing 1.35 mmol of
J 8.2 Hz, 8-H), 8.44 (1H, dd, J 7.9, 1.2 Hz, 5-H); δC (101 MHz, NO2) and p-toluenesulfonic acid monohydrate (0.257 g,
CDCl3) 120.4 (C), 125.8 (CH), 127.4 (2 × CH), 128.8 (CH), 129.4 1.35 mmol). The reaction mixture was stirred at 0 °C for 2 h.
(2 × CH), 133.1 (CH), 135.0 (C), 135.4 (CH), 137.4 (C), 143.7 (C), The reaction mixture was diluted with ethyl acetate (30 mL)
155.3 (C); m/z (ESI) 280 (MNa+. 100%).
and washed with water (4 × 30 mL). The organic layer was
N-(4′-Iodophenyl)-1,2,3-benzotriazin-4(3H)-one (7w).14 The dried (MgSO4), filtered and concentrated in vacuo. Purification
reaction was carried out as described in the general procedure by flash column chromatography, eluting with 50% diethyl
using 2-amino-N-(4′-iodophenyl)benzamide (6w) (0.0900 g, ether in hexane gave N-methyl-1,2,3,4-benzothiatriazin-1,1(2H)-
0.266 mmol), polymer-supported nitrite (0.229 g, containing dioxide (9a) (0.0450 g, 51%) as a yellow solid. Mp 70–72 °C
0.799 mmol of NO2) and p-toluenesulfonic acid monohydrate (lit.16 68–72 °C); δH (400 MHz, CDCl3) 3.91 (3H, s, NCH3), 7.79
(0.152 g, 0.799 mmol). The reaction mixture was stirred at 0 °C (1H, td, J 7.7, 1.2 Hz, 7-H), 7.87–7.92 (1H, m, 6-H), 8.02–8.07
for 1 h and then heated to 40 °C for 18 h. Purification by flash (2H, m, 5-H and 8-H); δC (101 MHz, CDCl3) 34.0 (CH3), 120.6
column chromatography, eluting with 25% ethyl acetate in (CH), 125.4 (C), 129.5 (CH), 132.8 (CH), 134.3 (CH), 141.8 (C);
hexane gave N-(4′-iodophenyl)-1,2,3-benzotriazin-4(3H)-one m/z (ESI) 220 (MNa+. 100%).
(7w) (0.0740 g, 80%) as a white solid. Mp 187–190 °C (lit.14
N-Ethyl-1,2,3,4-benzothiatriazin-1,1(2H)-dioxide (9b).36 To a
191–193 °C); δH (400 MHz, CDCl3) 7.42–7.47 (2H, m, 2′-H and stirred solution of 2-amino-N-(ethyl)benzenesulfonamide (8b)
6′-H), 7.83–7.92 (3H, m, 6-H, 3′-H and 5′-H), 7.97–8.04 (1H, m, (0.0500 g, 0.250 mmol) in methanol (2.5 mL) was added
7-H), 8.23 (1H, br d, J 8.1 Hz, 8-H), 8.44 (1H, dd, J 7.9, 1.0 Hz, polymer-supported nitrite (0.215 g, containing 0.749 mmol of
5-H); δC (101 MHz, CDCl3) 94.5 (C), 120.4 (C), 125.8 (CH), 127.8 NO2) and p-toluenesulfonic acid monohydrate (0.142 g,
(2 × CH), 128.8 (CH), 133.1 (CH), 135.4 (CH), 138.4 (2 × CH), 0.749 mmol). The reaction mixture was stirred at 0 °C for 2 h.
138.7 (C), 143.7 (C), 155.2 (C); m/z (ESI) 372 (MNa+. 100%).
The reaction mixture was diluted with ethyl acetate (30 mL)
N-(Thiazol-2′-yl)-1,2,3-benzotriazin-4(3H)-one (7x).13c The and washed with water (4 × 30 mL). The organic layer was
reaction was carried out as described in the general procedure dried (MgSO4), filtered and concentrated in vacuo. Purification
using N-(2-aminobenzoyl)-2-aminothiazole (6x) (0.147 g, by flash column chromatography, eluting with 25% ethyl
0.670 mmol), polymer-supported nitrite (0.578 g, containing acetate in hexane gave N-ethyl-1,2,3,4-benzothiatriazin-1,1(2H)-
2.01 mmol of NO2) and p-toluenesulfonic acid monohydrate dioxide (9b) (0.0410 g, 75%) as
a dark orange solid.
(0.387 g, 2.01 mmol). The reaction mixture was stirred at 0 °C Spectroscopic data were consistent with the literature.36 Mp
for 1 h and then heated to 40 °C for 4 h. The reaction mixture 75–78 °C; δH (400 MHz, CDCl3) 1.59 (3H, t, J 7.2 Hz, 2′-H3),
was cooled to room temperature and concentrated in vacuo. 4.34 (2H, q, J 7.2 Hz, 1′-H2), 7.77 (1H, td, J 7.8, 1.1 Hz, 6-H),
The reaction mixture was diluted in ethyl acetate (20 mL) and 7.88 (1H, td, J 7.8, 1.4 Hz, 7-H), 8.01 (1H, dd, J 7.8, 1.4 Hz,
washed with 1 M aqueous sodium hydroxide (6 × 20 mL). The 5-H), 8.03 (1H, dd, J 7.8, 1.1 Hz, 8-H); δC (101 MHz, CDCl3)
organic layer was dried (MgSO4), filtered and concentrated in 16.0 (CH3), 43.7 (CH2), 120.4 (CH), 125.7 (C), 129.3 (CH), 132.6
vacuo to give N-(thiazol-2′-yl)-1,2,3-benzotriazin-4(3H)-one (7x) (CH), 134.1 (CH), 141.8 (C); m/z (ESI) 234 (MNa+. 100%).
(0.0800 g, 52%) as an orange solid. Mp 170–173 °C (lit.13c
N-Propyl-1,2,3,4-benzothiatriazin-1,1(2H)-dioxide (9c). To a
174–176 °C); δH (400 MHz, CDCl3) 7.44 (1H, d, J 3.5 Hz, 5′-H), stirred solution of 2-amino-N-(propyl)benzenesulfonamide (8c)
7.89 (1H, d, J 3.5 Hz, 4′-H), 7.88–7.95 (1H, m, 6-H), 8.02–8.09 (0.0650 g, 0.303 mmol) in methanol (3 mL) was added
(1H, m, 7-H), 8.32 (1H, br d, J 8.1 Hz, 8-H), 8.51 (1H, dd, J 7.9, polymer-supported nitrite (0.261 g, containing 0.910 mmol of
1.4 Hz, 5-H); δC (101 MHz, CDCl3) 119.1 (CH), 119.4 (C), 126.0 NO2) and p-toluenesulfonic acid monohydrate (0.173 g,
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0.910 mmol). The reaction mixture was stirred at 0 °C for 1 h, benzenesulfonamide (8f) (0.0700 g, 0.293 mmol) in methanol
warmed to room temperature and stirred for a further 1 h. The (2 mL) was added polymer-supported nitrite (0.206 g, contain-
reaction mixture was diluted with ethyl acetate (20 mL) and ing 0.718 mmol of NO2) and p-toluenesulfonic acid monohy-
washed with water (4 × 30 mL). The organic layer was dried drate (0.137 g, 0.718 mmol). The reaction mixture was stirred
(MgSO4), filtered and concentrated in vacuo to give N-propyl- at 0 °C for 1 h, warmed to room temperature and stirred for a
1,2,3,4-benzothiatriazin-1,1(2H)-dioxide (9c) (0.0560 g, 82%) as further 3.5 h. The reaction mixture was diluted with ethyl
a red solid. Mp 83–86 °C; νmax/cm−1 (neat) 2967 (CH), 1573 acetate (20 mL) and washed with water (4 × 20 mL). The
(CvC), 1471, 1446, 1329, 1313, 1185, 1160, 1111, 946, 766; δH organic layer was dried (MgSO4), filtered and concentrated in
(400 MHz, CDCl3) 1.04 (3H, t, J 7.4 Hz, 3′-H3), 2.01 (2H, sext, J vacuo to give N-(4′-methoxybenzyl)-1,2,3,4-benzothiatriazin-1,1
7.4 Hz, 2′-H2), 4.23 (2H, t, J 7.4 Hz, 1′-H2), 7.77 (1H, td, J 7.8, (2H)-dioxide (9f) (0.0610 g, 85%) as a red solid. Spectroscopic
1.1 Hz, 6-H), 7.88 (1H, td, J 7.8, 1.4 Hz, 7-H), 8.02 (1H, dd, J data were consistent with the literature.36 Mp 92–95 °C; δH
7.8, 1.4 Hz, 5-H), 8.04 (1H, dd, J 7.8, 1.1 Hz, 8-H); δC (101 MHz, (400 MHz, CDCl3) 3.79 (3H, s, 4′-OCH3), 5.36 (2H, s, NCH2),
CDCl3) 11.2 (CH3), 23.7 (CH2), 50.0 (CH2), 120.5 (CH), 125.7 6.85–6.91 (2H, m, 3′-H and 5′-H), 7.40–7.46 (2H, m, 2′-H and
(C), 129.3 (CH), 132.6 (CH), 134.1 (CH), 141.8 (C); m/z (ESI) 6′-H), 7.76 (1H, td, J 7.8, 1.2 Hz, 7-H), 7.86 (1H, td, J 7.8, 1.4
248.0468 (MNa+. C9H11N3NaO2S requires 248.0464).
Hz, 6-H), 8.01 (1H, dd, J 7.8, 1.2 Hz, 5-H), 8.03 (1H, dd, J 7.8,
N-(tert-Butyl)-1,2,3,4-benzothiatriazin-1,1(2H)-dioxide (9d).16 1.4 Hz, 8-H); δC (101 MHz, CDCl3) 51.0 (CH2), 55.4 (CH3), 114.3
To a stirred solution of 2-amino-N-(tert-butyl)benzenesulfona- (2 × CH), 120.6 (CH), 126.1 (C), 127.5 (C), 129.5 (CH), 130.6 (2
mide (8d) (0.0260 g, 0.114 mmol) in methanol (1.1 mL) was × CH), 132.7 (CH), 134.2 (CH), 141.8 (C), 159.9 (C); m/z (ESI)
added polymer-supported nitrite (0.0980 g, containing 326 (MNa+. 100%).
0.342 mmol of NO2) and p-toluenesulfonic acid monohydrate
N-Phenyl-1,2,3,4-benzothiatriazin-1,1(2H)-dioxide (9g).37 To
(0.0650 g, 0.342 mmol). The reaction mixture was stirred at a stirred solution of 2-amino-N-(phenyl)benzenesulfonamide
0 °C for 1 h, warmed to room temperature and stirred for a (8g) (0.0390 g, 0.157 mmol) in methanol (1.5 mL) was added
further 1 h. The reaction mixture was diluted with ethyl acetate polymer-supported nitrite (0.135 g, containing 0.471 mmol of
(10 mL) and washed with water (4 × 10 mL). The organic layer NO2) and p-toluenesulfonic acid monohydrate (0.0900 g,
was dried (MgSO4), filtered and concentrated in vacuo. 0.471 mmol). The reaction mixture was stirred at 0 °C for 2 h.
Purification by flash column chromatography, eluting with The reaction mixture was diluted with ethyl acetate (20 mL)
20% ethyl acetate in hexane gave N-(tert-butyl)-1,2,3,4-ben- and washed with water (4 × 20 mL). The organic layer was
zothiatriazin-1,1(2H)-dioxide (9d) (0.0160 g, 60%) as an orange dried (MgSO4), filtered and concentrated in vacuo. Purification
solid. Mp 78–82 °C (lit.16 78–82 °C); δH (400 MHz, CDCl3) 1.82 by flash column chromatography, eluting with 50% diethyl
(9H, s, NC(CH3)3), 7.74 (1H, td, J 7.8, 1.2 Hz, 7-H), 7.85 (1H, td, ether in hexane gave N-phenyl-1,2,3,4-benzothiatriazin-1,1(2H)-
J 7.8, 1.4 Hz, 6-H), 7.96–8.03 (2H, m, 5-H and 8-H); δC dioxide (9g) (0.0290 g, 71%) as an orange solid. Mp 111–115 °C
(101 MHz, CDCl3) 30.5 (3 × CH3), 67.9 (C), 120.4 (CH), 126.3 (lit.37 111 °C); δH (400 MHz, CDCl3) 7.51–7.60 (3H, m, 3′-H, 4′-
(C), 128.6 (CH), 132.3 (CH), 134.0 (CH), 141.2 (C); m/z (ESI) 262 H and 5′-H), 7.62–7.69 (2H, m, 2′-H and 6′-H), 7.84 (1H, td, J
(MNa+. 100%).
7.7, 1.1 Hz, 7-H), 7.94 (1H, td, J 7.7, 1.4 Hz, 6-H), 8.10–8.15
N-Benzyl-1,2,3,4-benzothiatriazin-1,1(2H)-dioxide (9e).36 To (2H, m, 5-H and 8-H); δC (101 MHz, CDCl3) 121.1 (CH), 126.6
a stirred solution of 2-amino-N-benzylbenzenesulfonamide (C), 128.1 (2 × CH), 129.7 (2 × CH), 129.8 (CH), 130.1 (CH),
(8e) (0.130 g, 0.496 mmol) in methanol (5 mL) was added 133.2 (CH), 134.4 (CH), 135.0 (C), 141.4 (C); m/z (ESI) 282
polymer-supported nitrite (0.426 g, containing 1.49 mmol of (MNa+. 100%).
NO2) and p-toluenesulfonic acid monohydrate (0.283 g,
N-(4′-Methylphenyl)-1,2,3,4-benzothiatriazin-1,1(2H)-dioxide
1.49 mmol). The reaction mixture was stirred at 0 °C for 1 h, (9h).36 To a stirred solution of 2-amino-N-(4′-methylphenyl)
warmed to room temperature and stirred for a further 1 h. The lbenzenesulfonamide (8h) (0.0650 g, 0.248 mmol) in methanol
reaction mixture was diluted with ethyl acetate (20 mL) and (2.5 mL) was added polymer-supported nitrite (0.213 g, con-
washed with water (4 × 20 mL). The organic layer was dried taining 0.743 mmol of NO2) and p-toluenesulfonic acid mono-
(MgSO4), filtered and concentrated in vacuo to give N-benzyl- hydrate (0.141 g, 0.743 mmol). The reaction mixture was
1,2,3,4-benzothiatriazin-1,1(2H)-dioxide (9e) (0.104 g, 76%) as stirred at 0 °C for 1 h, warmed to room temperature and
an orange solid. Spectroscopic data were consistent with the stirred for a further 2.5 h. The reaction mixture was diluted
literature.36 Mp 99–102 °C; δH (400 MHz, CDCl3) 5.42 (2H, s, with ethyl acetate (20 mL) and washed with water (4 × 20 mL).
PhCH2), 7.30–7.38 (3H, m, 3′-H, 4′-H and 5′-H), 7.46–7.51 (2H, The organic layer was dried (MgSO4), filtered and concentrated
m, 2′-H and 6′-H), 7.77 (1H, td, J 7.7, 1.2 Hz, 6-H), 7.87 (1H, td, in vacuo. Purification by flash column chromatography, eluting
J 7.7, 1.4 Hz, 7-H), 8.01 (1H, dd, J 7.7, 1.4 Hz, 5-H), 8.04 (1H, with 20% ethyl acetate in hexane gave N-(4′-methylphenyl)-
dd, J 7.7, 1.2 Hz, 8-H); δC (101 MHz, CDCl3) 51.3 (CH2), 120.6 1,2,3,4-benzothiatriazin-1,1(2H)-dioxide (9h) (0.0440 g, 65%) as
(CH), 126.1 (C), 128.6 (CH), 128.9 (2 × CH), 129.0 (2 × CH), an orange solid. Spectroscopic data were consistent with the
129.5 (CH), 132.8 (CH), 134.2 (CH), 135.4 (C), 141.8 (C); m/z literature.36 Mp 100–102 °C; δH (400 MHz, CDCl3) 2.45 (3H, s,
(ESI) 296 (MNa+. 100%).
4′-CH3), 7.35 (2H, br d, J 8.0 Hz, 3′-H and 5′-H), 7.50–7.55 (2H,
N-(4′-Methoxybenzyl)-1,2,3,4-benzothiatriazin-1,1(2H)-dioxide m, 2′-H and 6′-H), 7.83 (1H, td, J 7.6, 1.2 Hz, 6-H), 7.93 (1H, td,
(9f).36 To a stirred solution of 2-amino-N-(4′-methoxybenzyl) J 7.6, 1.4 Hz, 7-H), 8.08–8.14 (2H, m, 5-H and 8-H); δC
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(101 MHz, CDCl3) 21.4 (CH3), 121.1 (CH), 126.7 (C), 128.1 (2 × 1,2,3,4-benzothiatriazin-1,1(2H)-dioxide (9k) (0.0720 g, 59%) as
CH), 129.7 (CH), 130.3 (2 × CH), 132.3 (C), 133.1 (CH), 134.4 an orange solid. Mp 115–118 °C; νmax/cm−1 (neat) 1570 (CvC),
(CH), 140.5 (C), 141.5 (C); m/z (ESI) 296 (MNa+. 100%).
1472, 1454, 1338, 1182, 1159, 1128, 808, 762; δH (400 MHz,
N-(4′-Methoxyphenyl)-1,2,3,4-benzothiatriazin-1,1(2H)-dioxide CDCl3) 7.37–7.41 (2H, m, 2′-H and 6′-H), 7.83–7.91 (3H, m,
(9i).38 To a stirred solution of 2-amino-N-(4′-methoxyphenyl) 6-H, 3′-H and 5′-H), 7.96 (1H, td, J 7.8, 1.4 Hz, 7-H), 8.12 (1H,
benzenesulfonamide (8i) (0.0550 g, 0.197 mmol) in methanol dd, J 7.8, 1.4 Hz, 5-H), 8.14 (1H, dd, J 7.8, 1.2 Hz, 8-H); δC
(2 mL) was added polymer-supported nitrite (0.170 g, contain- (101 MHz, CDCl3) 96.0 (C), 121.1 (CH), 126.6 (C), 129.6 (2 ×
ing 0.592 mmol of NO2) and p-toluenesulfonic acid monohy- CH), 130.0 (CH), 133.4 (CH), 134.6 (CH), 134.8 (C), 138.9 (2 ×
drate (0.113 g, 0.592 mmol). The reaction mixture was stirred CH), 141.3 (C); m/z (ESI) 407.9274 (MNa+. C12H8IN3NaO2S
at 0 °C for 1 h, warmed to room temperature and stirred for a requires 407.9274).
further 1.3 h. The reaction mixture was diluted with ethyl
N-Naphthyl-1,2,3-benzotriazin-4(3H)-one (10).26
To
a
acetate (20 mL) and washed with water (4 × 20 mL). The stirred solution of 1,2,3-benzotriazin-4(3H)-one (7a) (0.100 g,
organic layer was dried (MgSO4), filtered and concentrated in 0.680 mmol), 2-naphthaleneboronic acid (0.175 g, 1.02 mmol)
vacuo. Purification by flash column chromatography, eluting and copper acetate (0.123 g, 0.680 mmol) in dichloroethane
with 50% diethyl ether in hexane gave N-(4′-methoxyphenyl)- (7 mL) was added triethylamine (188 µL, 1.36 mmol). The reac-
1,2,3,4-benzothiatriazin-1,1(2H)-dioxide (9i) (0.0390 g, 68%) as tion was stirred at room temperature for 3 h and then heated
a yellow solid. Mp 77–82 °C (lit.38 83–84 °C); δH (400 MHz, to 45 °C for a further 2.5 h. The reaction mixture was cooled to
CDCl3) 3.88 (3H, s, 4′-OCH3), 7.05 (2H, br d, J 8.8 Hz, 3′-H and room temperature and filtered through a pad of Celite®. The
5′-H), 7.56 (2H, br d, J 8.8 Hz, 2′-H and 6′-H), 7.80–7.87 (1H, m, reaction mixture was concentrated in vacuo. Purification by
6-H), 7.90–7.97 (1H, m, 7-H), 8.08–8.17 (2H, m, 5-H and 8-H); flash column chromatography, eluting with 60% diethyl ether
δC (101 MHz, CDCl3) 55.8 (CH3), 114.9 (2 × CH), 121.1 (CH), in hexane gave N-naphthyl-1,2,3-benzotriazin-4(3H)-one (10)
126.5 (C), 127.1 (C), 129.7 (CH), 130.0 (2 × CH), 133.1 (CH), (0.118 g, 64%) as a yellow solid. Mp 169–173 °C (lit.26
134.4 (CH), 141.4 (C), 161.1 (C); m/z (ESI) 284 (MNa+ − N2. 173–175 °C); δH (400 MHz, CDCl3) 7.53–7.61 (2H, m, 4′-H and
100%).
5′-H), 7.76 (1H, dd, J 8.8, 2.1 Hz, 8′-H), 7.85–7.90 (1H, m, 6-H),
N-(4′-Bromophenyl)-1,2,3,4-benzothiatriazin-1,1(2H)-dioxide 7.91–7.97 (2H, m, 3′-H and 6′-H), 7.98–8.04 (2H, m, 7-H and 7′-
(9j). To a stirred solution of 2-amino-N-(4′-bromoophenyl)ben- H), 8.18 (1H, d, J 2.1 Hz, 2′-H), 8.26 (1H, br d, J 8.1 Hz 8-H),
zenesulfonamide (8j) (0.100 g, 0.306 mmol) in methanol 8.48 (1H, dd, J 8.0, 1.5 Hz, 5-H); δC (101 MHz, CDCl3) 120.6 (C),
(3.1 mL) was added polymer-supported nitrite (0.263 g, con- 123.8 (CH), 125.1 (CH), 125.8 (CH), 126.9 (CH), 127.2 (CH),
taining 0.917 mmol of NO2) and p-toluenesulfonic acid mono- 127.9 (CH), 128.6 (CH), 128.7 (CH), 129.1 (CH), 133.0 (CH),
hydrate (0.174 g, 0.917 mmol). The reaction mixture was 133.2 (C), 133.3 (C), 135.3 (CH), 136.4 (C), 143.9 (C), 155.6 (C);
stirred at 0 °C for 2 h. The reaction mixture was diluted with m/z (ESI) 296 (MNa+. 100%).
ethyl acetate (20 mL) and washed with water (4 × 20 mL). The
N-(Ethoxycarbonylmethyl)-1,2,3-benzotriazin-4(3H)-one (11).2c
organic layer was dried (MgSO4), filtered and concentrated in To a stirred solution of 1,2,3-benzotriazin-4(3H)-one (7a)
vacuo. Purification by flash column chromatography, eluting (0.150 g, 1.02 mmol) in acetonitrile (10 ml) was added ethyl
with 40% diethyl ether in hexane gave N-(4′-bromophenyl)- bromoacetate (0.113 mL, 1.02 mmol) and potassium carbonate
1,2,3,4-benzothiatriazin-1,1(2H)-dioxide (9j) (0.0700 g, 68%) as (0.141 g, 1.02 mmol). The reaction mixture was heated under
an orange solid. Mp 107–112 °C; νmax/cm−1 (neat) 2981 (CH), reflux for 18 h. The reaction mixture was cooled to room temp-
1572 (CvC), 1471, 1448, 1337, 1168, 904, 759; δH (400 MHz, erature, diluted in chloroform (30 mL) and washed with water
CDCl3) 7.50–7.56 (2H, m, 2′-H and 6′-H), 7.65–7.71 (2H, m, 3′- (3 × 30 mL). The organic layer was dried (MgSO4), filtered and
H and 5′-H), 7.85 (1H, td, J 7.7, 1.2 Hz, 6-H), 7.95 (1H, td, J 7.7, concentrated in vacuo. Purification by flash column chromato-
1.3 Hz, 7-H), 8.12 (1H, dd, J 7.7, 1.3 Hz, 5-H), 8.13 (1H, dd, J graphy, eluting with 25% ethyl acetate in hexane gave N-(ethox-
7.7, 1.2 Hz, 8-H); δC (101 MHz, CDCl3) 121.1 (CH), 124.4 (C), ycarbonylmethyl)-1,2,3-benzotriazin-4(3H)-one (11) (0.140 g,
126.6 (C), 129.5 (2 × CH), 129.9 (CH), 132.9 (2 × CH), 133.4 59%) as an off-white solid. Mp 107–111 °C (lit.2c 114–116 °C);
(CH), 134.1 (C), 134.6 (CH), 141.3 (C); m/z (ESI) 359.9408 δH (400 MHz, CDCl3) 1.31 (3H, t, J 7.1 Hz, OCH2CH3), 4.28 (2H,
(MNa+. C12H879BrN3NaO2S requires 359.9413).
q, J 7.1 Hz, OCH2CH3), 5.19 (2H, s, CH2CO2Et), 7.83 (1H, ddd, J
N-(4′-Iodophenyl)-1,2,3,4-benzothiatriazin-1,1(2H)-dioxide 8.8, 7.9, 1.2 Hz, 6-H), 7.98 (1H, ddd, J 8.8, 8.2, 1.5 Hz, 7-H),
(9k). To a stirred solution of 2-amino-N-(4′-iodophenyl)benze- 8.19 (1H, ddd, J 8.2, 1.2, 0.6 Hz, 8-H), 8.37 (1H, ddd, J 7.9, 1.5,
nesulfonamide (8k) (0.119 g, 0.318 mmol) in methanol 0.6 Hz, 5-H); δC (101 MHz, CDCl3) 14.3 (CH3), 51.0 (CH2), 62.2
(3.2 mL) was added polymer-supported nitrite (0.273 g, con- (CH2), 119.9 (C), 125.4 (CH), 128.7 (CH), 132.8 (CH), 135.3
taining 0.954 mmol of NO2) and p-toluenesulfonic acid mono- (CH), 144.5 (C), 155.7 (C), 167.2 (C); m/z (ESI) 256 (MNa+.
hydrate (0.182 g, 0.954 mmol). The reaction mixture was 100%).
stirred at 0 °C for 2 h. The reaction mixture was diluted with
N-(2′-Diethylaminoethyl)acetamide-1,2,3-benzotriazin-4(3H)-
ethyl acetate (30 mL) and washed with water (4 × 30 mL). The one (3).2c To a stirred solution of N-(ethoxycarbonylmethyl)-
organic layer was dried (MgSO4), filtered and concentrated in 1,2,3-benzotriazin-4(3H)-one (11) (0.100 g, 0.430 mmol) in
vacuo. Purification by flash column chromatography, eluting anhydrous methanol (4 mL) was added dropwise N,N-diethyl-
with 50% diethyl ether in hexane gave N-(4′-iodophenyl)- ethylenediamine (0.0610 mL, 0.430 mmol). The reaction
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mixture was heated under reflux for 18 h. The reaction mixture (CH2), 53.9 (CH2), 57.3 (2 × CH2), 117.2 (CH), 118.3 (CH), 121.7
was cooled to room temperature and concentrated in vacuo. (C), 128.0 (2 × CH), 129.7 (2 × CH), 130.6 (CH), 131.1 (CH),
Purification by flash column chromatography, eluting with 135.0 (CH), 136.7 (C), 147.7 (C), 172.3 (C); m/z (ESI) 411.1463
10% methanol in dichloromethane gave N-(2′-diethyl- (MNa+. C19H24N4NaO3S requires 411.1461).
aminoethyl)acetamide-1,2,3-benzotriazin-4(3H)-one
(3)
N-[2′-(4″-Benzoylpiperazin-1-yl)ethyl]-1,2,3,4-benzothiatriazin-
(0.0940 g, 72%) as a white solid. Mp 147–150 °C (lit.2c 1,1(2H)-dioxide (5). To a stirred solution of N-[2′-(4″-benzoylpi-
155–156 °C); δH (400 MHz, CDCl3) 0.97 (6H, t, J 7.1 Hz, 2 × perazin-1-yl)ethyl]-2-aminobenzenesulfonamide (14) (0.0760 g,
NCH2CH3), 2.55 (4H, q, J 7.1 Hz, 2 × NCH2CH3), 2.61 (2H, t, J 0.196 mmol) in methanol (2 mL) was added polymer-sup-
5.7 Hz, Et2NCH2), 3.39 (2H, q, J 5.7 Hz, CONHCH2), 5.13 (2H, ported nitrite (0.164 g, containing 0.587 mmol of NO2) and
s, CH2CONH), 6.85 (1H, br s, NH), 7.79–7.85 (1H, m, 6-H), p-toluenesulfonic acid monohydrate (0.112 g, 0.587 mmol).
7.94–8.00 (1H, m, 7-H), 8.19 (1H, dd, J 8.2, 0.5 Hz, 8-H), 8.36 The reaction mixture was stirred at 0 °C for 1 h, warmed to
(1H, dd, J 7.9, 1.5 Hz, 5-H); δC (101 MHz, CDCl3) 11.4 (2 × room temperature and stirred for a further 1 h. The reaction
CH3), 36.9 (CH2), 46.9 (2 × CH2), 51.5 (CH2), 52.8 (CH2), 120.0 mixture was filtered and the resulting resin was washed with
(C), 125.3 (CH), 128.7 (CH), 132.7 (CH), 135.2 (CH), 144.5 (C), methanol (10 mL). The reaction mixture was concentrated in
155.8 (C), 166.1 (C); m/z (ESI) 304 (MNa+. 100%).
vacuo. Purification by flash column chromatography, eluting
N-[2′-(4″-Benzoylpiperazin-1-yl)ethyl]-2-nitrobenzenesulfon- with 60% ethyl acetate in hexane (with 1% triethylamine) gave
amide (13). 2-Nitrobenzenesulfonyl chloride (0.0560 g, N-[2′-(4″-benzoylpiperazin-1-yl)ethyl]-1,2,3,4-benzothiatriazin-
0.253 mmol) was dissolved in dichloromethane (0.2 mL) and 1,1(2H)-dioxide (5) (0.0560 g, 72%) as a yellow solid. Mp
added dropwise to a stirred solution of 1-benzoyl-4-[2′-amino- 60–65 °C; νmax/cm−1 (neat) 2939 (CH), 1630 (CvO), 1575
ethyl]piperazine (12) (0.0550 g, 0.236 mmol) and triethylamine (CvC), 1433, 1337, 1188, 1013, 761; δH (500 MHz, CD3OD)
(0.0340 mL, 0.248 mmol) in dichloromethane (0.4 mL) at 0 °C. 2.53 (2H, br s, 2″-H2), 2.66 (2H, br s, 6″-H2), 2.93 (2H, t, J 6.5
The reaction mixture was warmed to room temperature and Hz, 2′-H2), 3.41 (2H, br s, 3″-H2), 3.74 (2H, br s, 5″-H2), 4.41
stirred for 2 h. The reaction mixture was concentrated in vacuo. (2H, t, J 6.5 Hz, 1′-H2), 7.36–7.50 (5H, m, Ph), 7.91 (1H, td, J
Purification by flash column chromatography, eluting with 1% 7.7, 1.4 Hz, 7-H), 8.01 (1H, td, J 7.7, 1.2 Hz, 6-H), 8.06–8.11
methanol in dichloromethane gave N-[2′-(4″-benzoylpiperazin- (2H, m, 5-H and 8-H); δC (126 MHz, CD3OD) 43.2 (CH2), 46.2
1-yl)ethyl]-2-nitrobenzenesulfonamide (13) (0.0880 g, 83%) as (CH2), 54.0 (CH2), 54.2 (CH2), 58.0 (2 × CH2), 121.2 (CH), 127.3
a colourless oil. νmax/cm−1 (neat) 3335 (NH), 2941 (CH), 1627 (C), 128.0 (2 × CH), 129.7 (2 × CH), 130.3 (CH), 131.1 (CH),
(CvO), 1576 (CvC), 1539, 1437, 1364, 1166, 1012, 759; δH 134.4 (CH), 135.6 (CH), 136.8 (C), 142.9 (C), 172.4 (C); m/z (ESI)
(500 MHz, CD3OD) 2.39 (2H, br s, 2″-H2), 2.49 (2H, br s, 6″-H2), 422.1253 (MNa+. C19H21N5NaO3S requires 422.1257).
2.54 (2H, br t, J 6.1 Hz, 2′-H2), 3.21 (2H, br t, J 6.1 Hz, 1′-H2),
Methyl
(2S)-2-(tert-butoxycarbonylamino)-3-(2′-aminoben-
3.37 (2H, br s, 3″-H2), 3.68 (2H, br s, 5″-H2), 7.35–7.51 (5H, m, zoyl)aminopropanoate (16). To a stirred solution of methyl
Ph), 7.79–7.86 (2H, m, 4-H and 6-H), 7.90 (1H, br t, J 5.3 Hz, (2S)-2-(tert-butoxycarbonylamino)-3-aminopropanoate (15)
5-H), 8.10–8.15 (1H, m, 3-H); δC (126 MHz, CD3OD) 41.1 (CH2), (0.0900 g, 0.412 mmol) in ethyl acetate (1.5 mL) was added
43.0 (CH2), 53.4 (CH2), 54.0 (CH2), 57.5 (2 × CH2), 126.1 (CH), isatoic anhydride (0.0740 g, 0.454 mmol). The reaction was
128.0 (2 × CH), 129.7 (2 × CH), 131.2 (CH), 131.7 (CH), 133.7 heated to 90 °C and stirred for 18 h. After cooling to room
(CH), 134.7 (C), 135.1 (CH), 136.6 (C), 149.6 (C), 172.4 (C); m/z temperature, the reaction mixture was concentrated in vacuo.
(ESI) 441.1211 (MNa+. C19H22N4NaO5S requires 441.1203).
Purification by flash column chromatography, eluting with
N-[2′-(4″-Benzoylpiperazin-1-yl)ethyl]-2-aminobenzenesulfon- 40% ethyl acetate in hexane with 1% triethylamine gave
amide (14). To a stirred solution of N-[2′-(4″-benzoylpiperazin- methyl (2S)-2-(tert-butoxycarbonylamino)-3-(2′-aminobenzoyl)
1-yl)ethyl]-2-nitrobenzenesulfonamide (13) (0.0830 g, aminopropanoate (16) (0.0664 g, 48%) as a white solid. Mp
0.198 mmol) in methanol (2 mL) was added zinc powder 120–124 °C; νmax/cm−1 (neat) 3360 (NH), 2976 (CH), 2928 (CH),
(0.129 g, 1.98 mmol) and acetic acid (0.113 mL, 1.98 mmol). 1741 (CvO), 1705 (CvO), 1522, 1368, 1256, 1161; [α]1D9 +25.6 (c
The reaction was stirred at room temperature for 5 h. The reac- 0.3, CHCl3); δH (400 MHz, CDCl3) 1.43 (9H, s, 3 × CH3),
tion mixture was filtered through a pad of Celite® and washed 3.67–3.85 (5H, m, OCH3 and 3-H2), 4.45–4.55 (1H, m, 2-H),
with methanol (50 mL). The reaction mixture was concentrated 5.51 (2H, br s, 2′-NH2), 5.60 (1H, br d, J 4.8 Hz, 2-NH),
in vacuo. Purification by flash column chromatography, eluting 6.58–6.69 (2H, m, 3′-H and 5′-H), 6.78 (1H, br s, 3-NH), 7.19
with 5% methanol in dichloromethane gave N-[2′-(4″-benzoyl- (1H, br t, J 7.8 Hz, 4′-H), 7.33 (1H, br d, J 7.8 Hz, 6′-H); δC
piperazin-1-yl)ethyl]-2-aminobenzenesulfonamide (14) (0.0650 g, (101 MHz, CDCl3) 28.4 (3 × CH3), 42.5 (CH2), 52.9 (CH), 53.9
84%) as a colourless solid. Mp 65–70 °C; νmax/cm−1 (neat) 3373 (CH3), 80.6 (C), 115.5 (C), 116.8 (CH), 117.4 (CH), 127.5 (CH),
(NH), 2944 (CH), 1617 (CvO), 1575 (CvC), 1454, 1305, 1146, 132.7 (CH), 148.8 (C), 156.1 (C), 169.9 (C), 171.3 (C); m/z (ESI)
1012, 711; δH (500 MHz, CD3OD) 2.29 (2H, br s, 2″-H2), 360.1532 (MNa+. C16H23N3NaO5 requires 360.1530).
2.35–2.47 (4H, m, 2′-H2 and 6″-H2), 2.96 (2H, br t, J 6.4 Hz,
Methyl (2S)-2-(tert-butoxycarbonylamino)-3-[1′,2′,3′-benzo-
1′-H2), 3.39 (2H, br s, 3″-H2), 3.71 (2H, br s, 5″-H2), 6.70 (1H, br triazin-4′(3H)-one]propanoate (17). To a stirred solution of
t, J 8.1 Hz, 5-H), 6.84 (1H, br d, J 8.1 Hz, 3-H), 7.29 (1H, td, methyl (2S)-2-(tert-butoxycarbonylamino)-3-(2′-aminobenzoyl)
J 8.1, 1.2 Hz, 4-H), 7.35–7.51 (5H, m, Ph), 7.62 (1H, dd, J 8.1, aminopropanoate (16) (0.100 g, 0.297 mmol) in methanol
1.2 Hz, 6-H); δC (126 MHz, CD3OD) 40.6 (CH2), 43.1 (CH2), 53.4 (3 mL) at 0 °C was added polymer-supported nitrite (0.256 g,
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containing 0.890 mmol of NO2) and p-toluenesulfonic acid 1122, 784; [α]1D9 −5.4 (c 0.2, MeOH); δH (400 MHz, CD3OD) 4.63
monohydrate (0.169 g, 0.890 mmol). The reaction mixture was (1H, dd, J 7.2, 4.4 Hz, 2-H), 4.94 (1H, dd, J 14.6, 7.2 Hz, 3-HH),
stirred at 0 °C for 1 h and then 2 h at room temperature. The 5.11 (1H, dd, J 14.6, 4.4 Hz, 3-HH), 7.95 (1H, td, J 8.1, 1.2 Hz,
reaction mixture was filtered and the resulting resin was 6′-H), 8.10 (1H, td, J 8.1, 1.2 Hz, 7′-H), 8.21 (1H, br d, J 8.1 Hz,
washed with methanol (10 mL). The reaction mixture was con- 8′-H), 8.35 (1H, dd, J 8.1, 1.2 Hz, 5′-H); δC (101 MHz, CD3OD)
centrated in vacuo. The reaction mixture was diluted in ethyl 49.7 (CH2), 53.3 (CH), 120.9 (C), 126.0 (CH), 129.6 (CH), 134.4
acetate (20 mL) and washed with water (4 × 20 mL). The (CH), 136.8 (CH), 145.4 (C), 157.8 (C), 169.1 (C); m/z (ESI)
organic layer was dried (MgSO4), filtered and concentrated in 257.0643 ([MNa − HCl]+. C10H10N4NaO3 requires 257.0645).
vacuo. Purification by flash column chromatography, eluting
with 60% diethyl ether in hexane gave methyl (2S)-2-(tert-
butoxycarbonylamino)-3-[1′,2′,3′-benzotriazin-4′(3H)-one]pro-
panoate (20) (0.0900 g, 87%) as a colourless oil. νmax/cm−1
(neat) 3333 (NH), 2976 (CH), 2928 (CH), 1746 (CvO), 1713
(CvO), 1688 (CvO), 1508, 1368, 1302, 1163; [α]1D8 −18.2 (c 0.2,
CHCl3); δH (400 MHz, CDCl3) 1.32 (9H, s, 3 × CH3), 3.80 (3H, s,
OCH3), 4.72 (1H, dd, J 12.8, 6.8 Hz, 3-HH), 4.85–5.00 (2H, m,
2-H and 3-HH), 5.43 (1H, br d, J 6.4 Hz, 2-NH), 7.81 (1H, br t, J
8.0 Hz, 6′-H), 7.95 (1H, td, J 8.0, 0.9 Hz, 7′-H), 8.14 (1H, br d, J
8.0 Hz, 8′-H), 8.35 (1H, dd, J 8.0, 0.9 Hz, 5′-H); δC (101 MHz,
CDCl3) 28.3 (3 × CH3), 50.7 (CH2), 52.9 (CH), 53.0 (CH3), 80.4
(C), 119.8 (C), 125.4 (CH), 128.5 (CH), 132.7 (CH), 135.1 (CH),
144.2 (C), 155.2 (C), 156.2 (C), 170.5 (C); m/z (ESI) 371.1323
(MNa+. C16H20N4NaO5 requires 371.1326).
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Financial support from the University of Glasgow (student-
ships to R. M. and R. J. F.) is gratefully acknowledged.
Notes and references
1 Z. Khalid, H. A. Ahmad, M. A. Munawar, M. A. Khan and
S. Gul, Heterocycles, 2017, 94, 3.
(2S)-2-(tert-Butoxycarbonylamino)-3-[1′,2′,3′-benzotriazin-4′(3H)-
one]propanoic acid. To a stirred solution of methyl (2S)-2-(tert-
butoxycarbonylamino)-3-[1′,2′,3′-benzotriazin-4′(3H)-one]pro-
panoate (17) (0.0700 g, 0.201 mmol) in methanol (3.5 mL),
dioxane (1.75 mL) and water (1.75 mL) was added caesium car-
bonate (0.0850 g, 0.261 mmol). The reaction mixture was
stirred at room temperature for 18 h. The reaction mixture was
concentrated in vacuo, diluted in water (30 mL) and acidified
to pH 1 using 1 M aqueous hydrochloric acid. The reaction
mixture was extracted with dichloromethane (3 × 30 mL). The
organic layers were combined, dried (MgSO4), filtered and con-
centrated in vacuo to give (2S)-2-(tert-butoxycarbonylamino)-3-
[1′,2′,3′-benzotriazin-4′(3H)-one]propanoic acid (0.0660 g, 99%)
as a colourless oil. νmax/cm−1 (neat) 3351 (NH), 2973 (CH),
1689 (CvO), 1394, 1367, 1301, 1164, 779; [α]1D9 −52.5 (c 0.2,
MeOH); δH (400 MHz, CD3OD) 1.23 (9H, s, 3 × CH3), 4.62 (1H,
dd, J 13.2, 9.6 Hz, 3-HH), 4.79 (1H, dd, J 9.6, 4.4 Hz, 2-H), 5.02
(1H, dd, J 13.2, 4.4 Hz, 3-HH), 7.89 (1H, br t, J 7.9 Hz, 6′-H),
8.04 (1H, br t, J 7.9 Hz, 7′-H), 8.13 (1H, br d, J 7.9 Hz, 8′-H),
8.33 (1H, br d, J 7.9 Hz, 5′-H); δC (101 MHz, CD3OD) 28.5 (3 ×
CH3), 52.3 (CH2), 54.8 (CH), 80.6 (C), 120.8 (C), 125.9 (CH),
129.1 (CH), 133.8 (CH), 136.4 (CH), 145.5 (C), 157.5 (C), 157.6
(C), 173.0 (C); m/z (ESI) 357.1164 (MNa+. C15H18N4NaO5
requires 357.1169).
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νmax/cm−1 (neat) 3372 (NH), 3220 (CH), 1679 (CvO), 1651,
This journal is © The Royal Society of Chemistry 2021
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Organic & Biomolecular Chemistry
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