An Improved N-Acylation of 1 H-Benzotriazole Using 2,2′-Dipyridyl?-di?-sulfide and Triphenylphosphine

Article abstract of DOI:10.1055/s-0037-1610277

A novel path has been developed for the conversion of carboxylic acids into the corresponding N-acylbenzotriazoles by using 2,2′-dipyridyl disulfide/PPh ₃ in anhydrous dichloromethane in the presence of 1 H-benzotriazole. Mild reaction conditio

Full text of DOI:10.1055/s-0037-1610277

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–G
paper
A
de
A. S. Singh et al.
Paper
Synthesis
An Improved N-Acylation of 1H-Benzotriazole Using 2,2′-Dipyridyl-
disulfide and Triphenylphosphine
Anoop S. Singh
Anand K. Agrahari
Nidhi Mishra
S
N
N
S
S
N
O
O
O
BtH
Mala Singh
PPh3
Bt
OH
Vinod K. Tiwari*
O
PPh3
CH2Cl2, r.t..
alkyl, aryl, glycosyl
Department of Chemistry, Institute of Science, Banaras Hindu
University, Varanasi, 221005, India
tiwari_chem@yahoo.co.in
Yield: up to 84%
Examples: 20
Advantages: One-pot high-yielding method; non-halo reagents;
less toxic environment; mild conditions; scale-up synthesis
vinod.tiwari@bhu.ac.in
This manuscript is dedicated to the late Prof. Alan R. Katritzky
for his contributions to benzotriazole chemistry.
Received: 07.07.2018
Accepted after revision: 23.08.2018
Published online: 17.09.2018
Previous methods:
i) BtH/SOCl2 (4:1), CH2Cl2, 25 °C
DOI: 10.1055/s-0037-1610277; Art ID: ss-2018-z0461-op
ii) BtSO2R, Et3N,THF, reflux, overnight
O
N
O
iii) I2 or NBS or TCT, PPh3, BtH, CH2Cl2,
Abstract A novel path has been developed for the conversion of car-
boxylic acids into the corresponding N-acylbenzotriazoles by using 2,2′-
dipyridyl disulfide/PPh3 in anhydrous dichloromethane in the presence
of 1H-benzotriazole. Mild reaction conditions, short reaction time, easy
in handling, wide substrate scope, availability of reagents involved, and
moreover avoiding the use of base makes this protocol quite useful for
the laboratory practices for N-acylbenzotriazole synthesis.
with or without base
OH
iv) TsCl, BtH, DMAP, Et3N, CH2Cl2
v) EDC or DCC, BtH, CH2Cl2
N
N
This work:
alkyl, aryl,
glycosyl
PyS-SPy, PPh3, BtH, DCM, rt.
Scheme 1 Common approaches for the synthesis of N-acylbenzotri-
azoles from carboxylic acids
Key words N-acylbenzotriazole, coupling reaction, PPh3, PySSPy
N-Acylbenzotriazole derivatives show significant im-
pact in organic chemistry. This class of compounds has re-
markable utility in the form of reagents, ligands, and inter-
mediates in various reactions and produces a large number
of organic and biologically relevant compounds.1–3 N-Acyl-
benzotriazole derivatives are excellent substitute of acid
chlorides in the formation of peptides, amides, esters, acid
azides, diketones, oxazolines, and thiazolines through N-,
O-, S-, and C- acylations under neutral and mild condi-
tions.4–18 Furthermore, it is also used for the synthesis of N-
phenylamides and benzoxazoles by benzotriazole ring
cleavage (BtRC)19–22 and also for the preparation of carba-
mates, ureas, and thiocarbamates by the Curtius rearrange-
ment.23
A number of synthetic routes are available for the trans-
formation of carboxylic acids to N-acylbenzotriazoles,
which mainly include the reaction with thionyl chloride
and BtH (3–4 equiv);24 1-(methanesulfonyl)benzotriazole
in the presence of Et3N;7 I2/PPh3 or NBS/PPh3 or TCT/PPh3
with or without base;25–27 tosyl chloride and BtH in the
presence of base;28 and BtH in the presence of EDC or DCC
(Scheme 1).29
All these transformations mainly involve halogen con-
taining reagents as starting material except the one in
which DCC or EDC is used. But the main drawback associat-
ed with the use of DCC and EDC is its high cost and acute
toxicity in the form of oral, dermal, skin sensitization, and
eye damage.30 We intended to try new less toxic reagents
for this reaction. For this undertaking, we successfully ex-
plored the use of 2,2′-dipyridyl disulfide (PySSPy)/PPh3 as a
suitable alternative and wish to report our results herein.31
Various efforts for the activation of carboxylic acid to
achieve N-acylbenzotriazole are summarized in Scheme 2.
In our investigation, we would like to fulfill two aims, first
to set up and optimize 2,2′-dipyridyl disulfide/PPh3 as acti-
vating reagent for the formation of N-acylbenzotriazoles
and second, to determine the mechanistic path by the 31P
NMR study.
To find out whether the 2,2′-dipyridyl disulfide/PPh3
can act as a reagent for the formation of N-acylbenzotri-
azoles, we proceeded with similar equivalents of reagents
with 1H-benzotriazole (1.0 equiv) as given in literature31
and initiated the reaction by treating benzoic acid (1.0
equiv) with 2,2′-dipyridyl disulfide (1.4 equiv) and PPh3
(1.4 equiv) and after five minutes, added 1H-benzotriazole
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

B
A. S. Singh et al.
Paper
Synthesis
(A) Various methods for the activation of a carboxylic acid to form the corresponding RCOBt
O
O
O
O
Br
I
R
O
R
O
R
O
R
Cl
H
PPh3
(by PPh3, NBS)
PPh3
N
Cy
Cy
N
(Activation of RCOOH
for RCOBt by SOCl2)
(by PPh3, I2)
(by DCC)
(B) Present method for the activation of carboxylic acid to RCOBt using PySSPy
N
O
R
N
S
R
Nu
N
BtH/PySH
R
O
O
N
S
Ph3P
N
O
O
N-acylbenzotriazoles
Ph3P
Ph3P
O
Scheme 2 Various activation methods for carboxylic acid to achieve N-acylbenzotriazoles and the present investigation with the aid of 2,2′-dipyridyl
disulfide
(1.0 equiv) to the reaction mixture. The reaction mixture
was allowed to stir for another three hours to afford N-ben-
zoylbenzotriazole (2q) in 68% yield with a side product 3
(Scheme 3).
aliphatic chain. The crude reaction mass was purified by
flash column chromatography by varying gradient (5–15%)
of ethyl acetate/n-hexane to obtain good yields of the corre-
sponding N-acylbenzotriazoles 2a–s (Scheme 4).
O
O
O
PyS-SPy (1.4 equiv)
PPh3 (1.4 equiv)
OH
N
N
S
N
Table 1 Reaction Optimization Study
+
BtH (1 equiv)
anhyd CH2Cl2
r.t.
N
1q
2q (68%)
3 (21%)
O
O
PyS-SPy, PPh3
N
N
OH
Scheme 3 Prototype reaction for the synthesis of N-acylbenzotriazoles
BtH, solvent, temp
N
1q
2q
To find the best optimized conditions for the prepara-
tion of N-benzoylbenzotriazole (2q) from benzoic acid (1q),
we varied the amounts of 2,2′-dipyridyl disulfide, PPh3, and
BtH (Table 1, entries 1–7) and found that 1.2 equivalents of
2,2′-dipyridyl disulfide, 1.2 equivalents of PPh3, and 2.0
equivalents of BtH (entry 6) afforded the best results. Fur-
thermore, we carried out the solvent optimization with
same quantity used in entry 6 and observed that dichloro-
methane, chloroform, toluene, and benzene show compara-
ble results (entries 7–12). Low boiling point of dichloro-
methane and high solubility of large variety of carboxylic
acid in it made dichloromethane as first preference for our
reaction. Lastly, through temperature optimization we tried
to find out the variation in yields by varying temperature of
reaction from 0–35 °C and observed no change at all in
yields (entries 13–15). This reaction was also tried with
two different disulfides, i.e. p-tolyl disulfide and dibenzyl
disulfide, but both of them gave low yields (36% and 42%
yield, respectively) whereas, with tri(o-tolyl)phosphine
only 47% yield was obtained.
Entrya
PySSPy
(equiv)
PPh3
(equiv)
BtH
(equiv)
Temp
(°C)
Solventb
Yield
(%)c
1
2
1.4
1.2
1.0
2.0
0.5
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.4
1.2
1.0
2.0
1.0
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.0
1.0
1.0
1.0
1.0
2.0
4.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
25
25
25
25
25
25
25
25
25
25
25
25
35
15
0
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CHCl3
DMF
68
67
60
65
51
81
81
80
77
57
3
4
5
6
7
8
9
10
11
12
13
14
15
d
THF
–
benzene
CH2Cl2
CH2Cl2
CH2Cl2
81
80
78
79
After optimization of reaction conditions, we tend to
find out yield variation by changing the starting carboxylic
acid, that is, by using aromatic, aliphatic, or sugar acid. Re-
sults did not show much change in the yields by any substi-
tution on aromatic ring of carboxylic acid and length of the
a Molar amounts of PySSPy, PPh3, and BtH are based on carboxylic acid 1q
(1.0 mmol).
b Anhydrous solvents were used.
c Yields reported after purification by column chromatography (silica gel).
d No product was formed.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

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A. S. Singh et al.
Paper
Synthesis
To increase the synthetic utility of the present method,
the reaction was also carried out in gram scale for quantita-
tive generalization. We applied the optimized reaction con-
ditions for 5 grams of benzoic acid and found that reaction
goes as efficiently as in milligram scale and the final prod-
uct N-benzoylbenzotriazole (2q) was obtained in 79% yield.
This indicates that this modified reaction protocol goes well
in both milligram and gram scales (Scheme 5).
O
O
PyS-SPy (10.8 g), PPh3 (12.9 g)
BtH (10.7 g), anhyd CH2Cl2
OH
N
N
N
1q (5.0 g)
2q (7.2 g, 79%)
Scheme 5 Gram-scale synthesis of N-benzoylbenzotriazole (2q)
For confirmation of the mechanism, a 31P NMR study
was carried out. At first, a blank PPh3 sample was recorded
in CDCl3; the peak was obtained at δ = –4.82, which corre-
sponds to the presence of PPh3 (t = 0 min). After adding
PySSPy and stirring the reaction mixture for five minutes
two new peaks appeared at δ = 29.81 and 43.94 in the 31P
NMR spectrum. The appearance of the latter peak suggests
the formation of a P–S bond. In the same reaction mixture,
when the acid was added and allowed to stir for further 10
minutes, complete disappearance of PPh3 peak at δ = –4.82
and appearance of an intense peak at δ = 29.81 (corre-
sponding to O=PPh3) were observed, which illustrate imme-
diate conversion of PPh3 to O=PPh3 prior to adding benzotri-
azole. 31P NMR spectra after stirring the same reaction mix-
ture for 30 minutes with benzotriazole showed no change
in peaks. Thus, these 31P NMR studies indicate that the reac-
tion moves according to the suggested mechanism (Figure
1). It was noticed that there is a shift in the O=PPh3 peak
with the increase in the acidic nature of the reaction mix-
Scheme 4 Synthesis of N-acylbenzotriazoles. Yields after flash column
chromatography (silica gel).
All the synthesized compounds have been identified by
well-known spectroscopic techniques including mass, 1H,
and 13C NMR studies. Compound 2r was also characterized
by X-ray crystal structure analysis (see the Supporting In-
formation).
Figure 1 31P NMR monitoring studies for determination of mechanism
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

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A. S. Singh et al.
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Synthesis
N
N
N
N
O
PPh3
S
S
N
O
S
S
S
O
S
N
Ph3P
Ph3P
O
PPh3
O
I
II
O
O
O
H
N
H
N
N
Bt
N
N
BtH
S
S
N
S
H
N
O
N
SH
S
2 (N-acyl-
benzotriazoles)
–
2-pyridine
thiol ester
tetrahedral
intermediate
Scheme 6 Possible mechanism for the synthesis of N-acylbenzotriazoles
ture probably due to the formation of acidic compound 2-
mercaptopyridine. The formation of 2-mercaptopyridine
increases the acidity of the reaction mixture which results
into the down-field shift of the peak in31 P NMR spectra.32
The reaction may initiate with the reaction of PySSPy
and PPh3, which gives triphenyl(pyridin-2-ylthio)phospho-
nium ion as intermediate I. This intermediate ion reacts
with carboxylic acid derivatives to give intermediate II. Af-
ter formation of intermediate II, the reaction may follow
the attack of intermediate II by PyS– anion to produce 2-
pyridinethiol ester as an intermediate, which on reaction
with benzotriazole followed by rearrangement produces fi-
nal compound 2 (Scheme 6).
In conclusion, we have established an effective and
practical methodology to synthesize diverse N-acylben-
zotriazoles using a non-halo reagent and less toxic environ-
ment under mild reaction conditions. The path modifica-
tion shows good yields of N-acylbenzotriazoles (up to 84%)
at ambient temperature. The present method has shown
promising applications and found to be equally useful for
the gram-scale synthesis.
N-Acylbenzotriazoles; (1H-1,2,3-Benzotriazole-1-yl)phenylmetha-
none (2q);21 Typical Procedure
2,2′-Dipyridyl disulfide (0.43 g 1.63 mmol, 1.2 equiv) and PPh3 (0.51
g, 1.96 mmol, 1.2 equiv) were dissolved in anhyd CH2Cl2 (5 mL) and
the solution was stirred in a round-bottomed flask for 5 min. Then,
acid 1q (0.2 g, 1.63 mmol, 1.0 equiv) was added to the solution, fol-
lowed by the addition of 1H-benzotriazole (0.39 g, 3.27 mmol, 2.0
equiv). The resultant mixture was stirred for 1 h at r.t. After comple-
tion of reaction (monitored by TLC), the reaction mass was concen-
trated under reduced pressure to complete dryness. Purification of
the residue by flash column chromatography (silica gel) using gradi-
ent mixtures of EtOAc and n-hexane afforded the product 2q in pure
form; white crystalline solid; yield: 0.296 g (81%); mp 110–114 °C
(Lit.21 mp 112 °C); Rf = 0.6 (10% EtOAc/n-hexane).
1H NMR (500 MHz, CDCl3): δ = 8.39 (d, J = 8.5 Hz, 1 H), 8.22 (d, J = 8.0
Hz, 2 H), 8.17 (d, J = 8.5 Hz, 1 H), 7.72–7.67 (m, 2 H), 7.59–7.53 (m, 3
H).
13C NMR (125 MHz, CDCl3): δ = 166.8, 145.8, 133.7, 132.4, 131.8,
131.5, 130.4, 128.5, 126.4, 120.2, 114.8.
(1H-Benzo[d][1,2,3]triazol-1-yl)(p-tolyl)methanone (2a)27
White crystalline solid; yield: 0.268 g (77%); mp 122–124 °C; Rf = 0.5
(5% EtOAc/n-hexane).
1H NMR (300 MHz, CDCl3): δ = 8.39 (d, J = 7.5 Hz, 1 H), 8.18–8.14 (m, 3
H), 7.71 (t, J = 7.5 Hz, 1 H), 7.57–7.53 (m, 1 H), 7.39 (d, J = 7.5 Hz, 2 H),
2.49 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 166.6, 145.8, 144.9, 132.4, 132.0,
130.3, 129.2, 128.7, 126.3, 120.2, 114.9, 21.8.
All solvents and reagents were taken of pure grade. TLC was per-
formed on pre-coated aluminum plates and displayed with either a
UV lamp (δmax = 254 nm) or by spraying with methanolic H2SO4 solu-
tion and subsequent charring by heating at 100 °C (for the carbohy-
drate derivative only). Under reduced pressure solvents were evapo-
rated at temperature <50 °C. Column chromatography was carried out
on silica gel (230–400 mesh, Merck). Distilled n-hexane and EtOAc
were used for the column chromatography. 1H and 13C NMR were re-
corded at 500 and 125 MHz, respectively. Chemical shifts are given in
ppm downfield from internal TMS; J values in Hz. IR spectra were re-
corded as Nujol mulls in KBr palettes.
(1H-Benzo[d][1,2,3]triazol-1-yl)(o-tolyl)methanone (2b)27
White crystalline solid; yield: 0.285 g (82%); mp 110–112 °C; Rf = 0.5
(5% EtOAc/n-hexane).
1H NMR (500 MHz, CDCl3): δ = 8.40 (d, J = 7.5 Hz, 1 H), 8.15 (d, J = 8.5
Hz, 1 H), 7.70 (t, J = 7.5 Hz, 1 H), 7.63 (d, J = 7.5 Hz, 1 H), 7.55–7.48 (m,
2 H), 7.37–7.33 (m, 2 H), 2.44 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 168.3, 146.2, 138.0, 132.3, 131.9,
131.8, 131.1, 130.5, 130.1, 126.5, 125.5, 120.3, 114.6, 20.1.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

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A. S. Singh et al.
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Synthesis
(1H-Benzo[d][1,2,3]triazol-1-yl)(3-methoxyphenyl)methanone
1H NMR (500 MHz, CDCl3): δ = 8.35 (d, J = 8.5 Hz, 1 H), 8.17 (d, J = 8.5
Hz, 1 H), 7.82–7.78 (m, 2 H), 7.74–7.70 (m, 1 H), 7.58–7.55 (m, 1 H),
7.16–7.12 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 164.1, 163.6, 163.5, 161.6, 161.5,
145.8, 134.3, 134.2, 134.1, 132.1, 130.9, 126.8, 120.4, 115.1, 115.0,
114.9 (2 C), 114.8, 109.3, 109.1, 108.9.
(2c)27
White crystalline solid; yield: 0.246 g (74%); mp 80–84 °C; Rf = 0.6
(10% EtOAc/n-hexane).
1H NMR (500 MHz, CDCl3): δ = 8.36 (d, J = 8.5 Hz, 1 H), 8.15 (d, J = 9.0
Hz, 1 H), 7.79 (d, J = 7.5 Hz, 1 H), 7.70–7.67 (m, 2 H), 7.53 (t, J = 7.5 Hz,
1 H), 7.48–7.45 (m, 1 H), 7.22–7.21 (m, 1 H), 3.88 (s, 3 H).
(1H-Benzo[d][1,2,3]triazol-1-yl)[3-(trifluoromethyl)phenyl]meth-
13C NMR (125 MHz, CDCl3): δ = 166.6, 159.5, 145.8, 132.6, 132.4,
130.4, 129.5, 126.4, 124.3, 120.3, 120.2, 116.2, 114.8, 55.6.
anone (2i)27
White crystalline solid; yield: 0.187 g (61%); mp 52–56 °C; Rf = 0.7
(10% EtOAc/n-hexane).
1H NMR (500 MHz, CDCl3): δ = 8.49 (s, 1 H), 8.44 (d, J = 7.5 Hz, 1 H),
8.38 (d, J = 8.0 Hz, 1 H), 8.17 (d, J = 7.5 Hz, 1 H), 7.95 (d, J = 8.5 Hz, 1 H),
7.74–7.71 (m, 2 H), 7.58–7.55 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 165.2, 145.8, 134.9, 132.3, 132.1,
130.8, 130.1 (2 C), 129.1, 128.6 (2 C), 128.5, 126.7, 120.4, 114.8.
(1H-Benzo[d][1,2,3]triazol-1-yl)(2-methoxyphenyl)methanone
(2d)27
Colorless solid; yield: 0.262 g (79%); mp 94–96 °C; Rf = 0.6 (10%
EtOAc/n-hexane).
1H NMR (500 MHz, CDCl3): δ = 8.38 (d, J = 8.5 Hz, 1 H), 8.12 (d, J = 8.5
Hz, 1 H), 7.69–7.66 (m, 1 H), 7.60–7.50 (m, 3 H), 7.11 (t, J = 7.5 Hz, 1
H), 7.05 (m, 1 H), 3.75 (s, 3 H).
(1H-Benzo[d][1,2,3]triazol-1-yl)(3-bromophenyl)methanone (2j)23
13C NMR (125 MHz, CDCl3): δ = 167.0, 157.9, 146.1, 133.6, 131.5,
White solid; yield: 0.198 g (66%); mp 158–162 °C; Rf = 0.6 (5% EtO-
Ac/n-hexane).
130.4, 130.3, 126.2, 122.8, 120.5, 120.1, 114.5, 111.8, 55.9.
(1H-Benzo[d][1,2,3]triazol-1-yl)(3-chlorophenyl)methanone (2e)21
1H NMR (500 MHz, CDCl3): δ = 8.37–8.34 (m, 2 H), 8.17–8.15 (m, 2 H),
7.81 (d, J = 8.0 Hz, 1 H), 7.74–7.70 (m, 1 H), 7.56 (t, J = 7.5 Hz, 1 H)
7.47–7.44 (m, 1 H).
White crystalline solid; yield: 0.250 g (76%); mp 122–124 °C; Rf = 0.5
(10% EtOAc/n-hexane).
13C NMR (125 MHz, CDCl3): δ = 165.3, 145.8, 136.6, 134.4, 133.3,
132.3, 132.2, 131.6, 130.7, 130.3, 130.0, 128.6, 128.5, 126.6, 122.5,
120.3, 114.8.
1H NMR (500 MHz, CDCl3): δ = 8.25 (d, J = 8.5 Hz, 1 H), 8.09–8.04 (m, 2
H), 8.01–7.99 (d, J = 8.5 Hz, 1 H), 7.61–7.58 (m, 1 H), 7.54 (d, J = 8.0 Hz,
1 H), 7.46–7.39 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 165.4, 145.8, 134.6, 133.7, 133.1,
132.2, 131.6, 130.7, 129.9, 129.7, 126.6, 120.3, 114.8.
1-(1H-Benzo[d][1,2,3]triazol-1-yl)dodecan-1-one (2k)27
White crystalline solid; yield: 0.253 g (84%); mp 46–48 °C; Rf = 0.5 (5%
EtOAc/n-hexane).
(1H-Benzo[d][1,2,3]triazol-1-yl)(4-chlorophenyl)methanone (2f)21
1H NMR (500 MHz, CDCl3): δ = 8.29 (d, J = 7.5 Hz, 1 H), 8.11 (d, J = 8.0
Hz, 1 H), 7.66–7.63 (m, 1 H), 7.51–7.48 (m, 1 H), 3.42 (t, J = 7.5 Hz, 2
H), 1.94–1.88 (m, 2 H), 1.51–1.45 (m, 2 H), 1.39–1.26 (m, 14 H), 0.89–
0.86 (m, 3 H).
13C NMR (125 MHz, CDCl3): δ = 172.7, 146.2, 131.2, 130.3, 126.1,
120.1, 114.5, 35.6, 31.9, 29.6, 29.5, 29.4, 29.3, 29.2, 24.5, 22.7, 14.1.
White crystalline solid; yield: 0.273 g (83%); mp 134–138 °C; Rf = 0.5
(10% EtOAc/n-hexane).
1H NMR (500 MHz, CDCl3): δ = 8.39 (d, J = 8.5 Hz, 1 H), 8.22–8.17 (m, 3
H), 7.73 (t, J = 7.5 Hz, 1 H), 7.57 (d, J = 7.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 165.7, 145.8, 140.5, 133.2, 130.6,
129.8, 128.9, 126.6, 120.3, 114.8.
(1H-Benzo[d][1,2,3]triazol-1-yl)(2-chlorophenyl)methanone (2l)27
(1H-Benzo[d][1,2,3]triazol-1-yl)(2,6-difluorophenyl)methanone
(2g)
White crystalline solid; yield: 0.214 g (65%); mp 80–84 °C; Rf = 0.5
(10% EtOAc/n-hexane);
1H NMR (500 MHz, CDCl3): δ = 8.14 (d, J = 7.5 Hz, 1 H), 8.16 (d, J = 8.0
Hz, 1 H), 7.74–7.72 (m, 1 H), 7.65 (d, J = 7.5 Hz, 1 H), 7.58–7.53 (m, 3
H), 7.47–7.44 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 165.9, 146.3, 133.0, 132.6, 132.4,
131.3, 130.7, 130.2 (2 C), 126.8, 126.7, 120.4, 114.5.
White crystalline solid; yield: 0.236 g (72%); mp 120–124 °C; Rf = 0.6
(15% EtOAc/n-hexane).
IR (KBr): 3109, 3060, 2923, 1724, 1625, 1594, 1474, 1386, 1013, 938,
792, 773, 757 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.41 (d, J = 8.5 Hz, 1 H), 8.16 (d, J = 7.5
Hz, 1 H), 7.74 (t, J = 7.5 Hz, 1 H), 7.61–7.55 (m, 2 H), 7.11–7.07 (m, 1
H).
1,2:3,4-Di-O-isopropylidene-α-D-galactopyranuronosylbenzotri-
13C NMR (125 MHz, CDCl3): δ = 161.1, 161.0, 160.0, 159.1, 159.0,
146.4, 133.9, 133.8, 133.7, 131.1, 130.9, 126.9, 120.5, 114.4, 112.2,
112.1, 112.0, 112.0.
HRMS-ESI: m/z [M + H]+ calcd for C13H7F2N3O: 260.0630; found:
260.0626.
azole (2m)25b
White crystalline solid; yield: 0.221 g (81%); mp 174–176 °C; Rf = 0.4
(10% EtOAc/n-hexane).
1H NMR (500 MHz, CDCl3): δ = 8.35 (d, J = 8.5 Hz, 1 H), 8.14 (d, J = 8.5
Hz, 1 H), 7.69 (t, J = 7.5 Hz, 1 H), 7.53 (t, J = 7.5 Hz, 1 H), 5.83–5.79 (m,
2 H), 5.08–5.06 (m, 1 H), 4.79–4.77 (m, 1 H), 4.54–4.52 (m, 1 H), 1.62
(s, 3 H), 1.50 (s, 3 H), 1.40 (s, 3 H), 1.27 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 165.8, 145.9, 131.2, 130.8, 126.5,
120.2, 114.7, 110.8, 109.6, 96.7, 72.7, 71.3, 70.3, 70.1, 26.1, 25.9, 24.9,
24.8.
(1H-Benzo[d][1,2,3]triazol-1-yl)(3,5-difluorophenyl)methanone
(2h)21
White crystalline solid; yield: 0.269 g (82%); mp 114–116 °C; Rf = 0.6
(15% EtOAc/n-hexane).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

F
A. S. Singh et al.
Paper
Synthesis
(1H-Benzo[d][1,2,3]triazol-1-yl)[3,5-bis(prop-2-yn-1-yloxy)phe-
(1H-Benzo[d][1,2,3]triazol-1-yl)(furan-2-yl)methanone (2t)
nyl]methanone (2n)
White solid; yield: 0.243 g (64%); mp 140–142 °C; Rf = 0.5 (5% EtO-
Ac/n-hexane).
White crystalline solid; yield: 0.233 g (81%); mp 118–120 °C; Rf = 0.4
(10% EtOAc/n-hexane).
IR (KBr): 3168, 3140, 3123, 2924, 2854, 1683, 1464, 1449, 1402, 1033,
IR (KBr): 3261, 3251, 3132, 2924, 2853, 2120, 1694, 1603, 1447, 1437,
963, 751 cm–1
.
1352, 1306, 1162, 1061, 801, 754 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.36 (d, J = 8.5 Hz, 1 H), 8.11 (d, J = 10.0
Hz, 2 H), 7.83 (s, 1 H), 7.63–7.62 (m, 1 H), 7.50–7.47 (m, 1 H), 6.69 (m,
1 H).
13C NMR (125 MHz, CDCl3): δ = 155.1, 149.0, 145.6, 144.6, 132.2,
130.5, 126.4, 124.8, 120.2, 114.8, 113.0.
1H NMR (500 MHz, CDCl3): δ = 8.38 (d, J = 8.5 Hz, 1 H), 8.18 (d, J = 9.0
Hz, 1 H), 7.73–7.70 (m, 1 H), 7.56 (t, J = 7.5 Hz, 1 H), 7.48 (d, J = 2.0 Hz,
2 H), 6.96–6.94 (m, 1 H), 4.77 (d, J = 2.5 Hz, 4 H), 2.58–2.57 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 166.1, 158.4, 145.4, 133.2, 132.4,
130.5, 126.5, 120.3, 114.9, 111.3, 108.2, 77.8, 76.3, 56.3.
HRMS-ESI: m/z [M + H]+ calcd for C19H13N3O3: 332.1030; found:
HRMS-ESI: m/z [M + H]+ calcd for C11H7N3O2: 213.0538; found:
213.0535.
332.1032.
S-2-Pyridyl Benzothioate (3)34
(1H-Benzo[d][1,2,3]triazol-1-yl)[2-(methylamino)phenyl]metha-
Pale yellow solid; yield: 0.074 g (21%); mp 48–50 °C.
none (2o)33
1H NMR (500 MHz, CDCl3): δ = 8.69 (d, J = 4.0 Hz, 1 H), 8.02 (d, J = 7.5
Hz, 2 H), 7.79–7.76 (m, 1 H), 8.02 (d, J = 9.0 Hz, 1 H), 7.62–7.59 (m, 1
H), 7.52–7.47 (m, 2 H), 7.34–7.32 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 189.4, 151.3, 150.5, 137.3, 136.6,
134.0, 130.9, 128.9, 127.6, 123.7.
Yellow solid; yield: 0.224 g (67%); mp 52–56 °C; Rf = 0.5.
1H NMR (500 MHz, CDCl3): δ = 8.12 (dd, J = 8.5, 8.0 Hz, 2 H), 8.03 (d, J =
6.5 Hz, 1 H), 7.65–7.64 (br, 1 H), 7.58 (t, J = 7.5 Hz, 1 H), 7.46–7.43 (m,
2 H), 6.75 (d, J = 8.5 Hz, 1 H), 6.68–6.55 (m, 1 H), 2.94 (t, J = 5.5 Hz, 2
H).
13C NMR (125 MHz, CDCl3): δ = 167.5, 153.6, 145.6, 136.1, 135.0,
132.8, 129.6, 125.7, 120.0, 114.7, 111.2, 110.7, 29.8.
Funding Information
(E)-1-(1H-Benzo[d][1,2,3]triazol-1-yl)octadec-9-en-1-one (2p)21
Science and Engineering Research Board (SERB), Department of Sci-
ence & Technology, New Delhi (Grant No. EMR/2016/001123).
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Light yellow colored oil; yield: 0.206 g (76%); Rf = 0.7 (5% EtOAc/n-
hexane).
1H NMR (300 MHz, CDCl3): δ = 8.27 (d, J = 7.5 Hz, 1 H), 8.09 (d, J = 8.5
Hz, 1 H), 7.62 (t, J = 7.5 Hz, 1 H), 7.49–7.46 (m, 1 H), 5.36–5.33 (m, 2
H), 3.42 (t, J = 7.5 Hz, 2 H), 2.07–1.87 (m, 6 H), 1.50–1.25 (m, 20 H),
0.88–0.85 (m, 3 H).
Acknowledgment
The authors sincerely thank CISC-Banaras Hindu University for pro-
viding spectroscopic studies of the developed molecules.
13C NMR (125 MHz, CDCl3): δ = 172.6, 146.1, 131.1, 130.2, 130.0,
129.7, 126.0, 120.1, 114.4, 35.5, 31.9, 29.8, 29.7, 29.6, 29.5, 29.3, 29.2,
29.1, 29.0, 27.3, 27.2, 24.4, 22.7, 14.2.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610277. Copies of 1H and 13C NMR
(1H-Benzo[d][1,2,3]triazol-1-yl)(2-iodophenyl)methanone (2r)21
White solid; yield: 0.203 g (72%); mp 80–82 °C; Rf = 0.5 (5% EtOAc/n-
hexane).
for all the prepared compounds are provided.
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1H NMR (300 MHz, CDCl3): δ = 8.42 (d, J = 8.5 Hz, 1 H), 8.17 (d, J = 7.5
Hz, 1 H), 7.99 (d, J = 7.5 Hz, 1 H),7.76–7.73 (m, 1 H), 7.59–7.52 (m, 3
H), 7.31–7.28 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 167.7, 146.4, 139.8, 138.9, 132.5,
131.5, 130.8, 130.0, 127.9, 126.8, 120.5, 114.6, 93.3.
References
(1) Katritzky, A. R.; Lan, X.; Yang, J. Z.; Denisko, O. V. Chem. Rev.
1998, 98, 409.
(2) Katritzky, A. R.; Rachwal, S. Chem. Rev. 2010, 110, 1564.
(3) Kale, R. R.; Prasad, V.; Mohapatra, P. P.; Tiwari, V. K. Monatsh.
Chem. 2010, 141, 1159.
(3r,5r,7r)-Adamantan-1-yl(1H-benzo[d][1,2,3]triazol-1-yl)metha-
none (2s)
(4) Katritzky, A. R.; Rogovoy, B. V.; Kirichenko, N.; Vvedensky, V.
Bioorg. Med. Chem. Lett. 2002, 12, 1809.
(5) Katritzky, A. R.; Suzuki, K.; Singh, S. K.; He, H-Y. J. Org. Chem.
2003, 68, 5720.
(6) Wang, X.; Zhang, Y. Synth. Commun. 2003, 33, 2627.
(7) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Wang, M. J. Org. Chem.
2003, 68, 4932.
(8) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Wang, M. J. Org. Chem.
2003, 68, 1443.
White solid; yield: 0.249 g (80%); mp 116–120 °C; Rf = 0.5 (5%
EtOAc/n-hexane).
IR (KBr): 2909, 2853, 1719, 1697, 1449, 1345, 1283, 1049, 927, 749
cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.19 (d, J = 7.5 Hz, 1 H), 8.00 (d, J = 8.5
Hz, 1 H), 7.52–7.49 (m, 1 H), 7.38–7.35 (m, 1 H), 2.31 (d, J = 2.0 Hz, 6
H), 2.04 (s, 3 H), 1.81–1.70 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 176.5, 144.6, 132.1, 130.0, 125.7,
119.7, 115.0, 44.9, 38.4, 36.3, 28.0.
(9) Katritzky, A. R.; Shestopalov, A. A.; Suzuki, K. Synthesis 2004,
1806.
(10) Katritzky, A. R.; Cai, C.; Suzuki, K.; Singh, S. K. J. Org. Chem. 2004,
69, 811.
HRMS-ESI: m/z [M + H]+ calcd for C17H19N3O: 282.1601; found:
282.1595.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

G
A. S. Singh et al.
Paper
Synthesis
(11) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Gromova, A. V.; Witek, R.;
Steel, P. J. J. Org. Chem. 2005, 70, 9211.
(26) Agha, K. A.; Abo-Dya, N. E.; Ibrahim, T. S.; Abdel-Aal, E. H.
ARKIVOC 2016, (iii), 161.
(12) Katritzky, A. R.; Suzuki, K.; Wang, Z. Synlett 2005, 1656.
(13) Katritzky, A. R.; Widyan, K.; Kirichenko, K. J. Org. Chem. 2007,
72, 5802.
(14) Lim, D.; Fang, F.; Zhou, G.; Coltart, D. M. Org. Lett. 2007, 9, 4139.
(15) Wang, X.; Wang, W.; Wen, Y.; He, L.; Zhu, X. Synthesis 2008,
3223.
(16) Zhou, G.; Lim, D.; Fang, F.; Coltart, D. M. Synthesis 2009, 3350.
(17) Li, J.; Sun, Y.; Chen, Z.; Su, W. Synth. Commun. 2010, 40, 3669.
(18) Xia, Z.; Lv, X.; Wang, W.; Wang, X. Tetrahedron Lett. 2011, 52,
4906.
(19) Kale, R. R.; Prasad, V.; Tiwari, V. K. Lett. Org. Chem. 2010, 7, 136.
(20) Singh, A. S.; Singh, M.; Mishra, N.; Mishra, S.; Agrahari, A. K.;
Tiwari, V. K. ChemistrySelect 2017, 2, 154.
(27) Singh, A. S.; Agrahari, A. K.; Singh, M.; Mishra, N.; Tiwari, V. K.
ARKIVOC 2017, (v), 80.
(28) Wet-osot, S.; Duangkamol, C.; Pattarawarapan, M.; Phakhodee,
W. Monatsh. Chem. 2015, 146, 959.
(29) Kanışkan, N.; Kökten, S.; Çelik, İ. ARKIVOC 2012, (viii), 198.
(30) N,N′-Dicyclohexylcarbodiimide, MSDS. No. D80002 [online];
Sigma-Aldrich; Bangalore, India, May 07, 2018.
(31) (a) Nicolaou, K. C.; Papahatjis, D. P.; Claremon, D. A.; Magolda, R.
L.; Dolle, R. E. J. Org. Chem. 1985, 50, 1440. (b) Corey, E. J.;
Nicolaou, K. C.; Melvin, L. S. J. Am. Chem. Soc. 1975, 97, 653.
(c) Tohda, K.; Suzuki, K.; Kosuge, N.; Watanabe, K.; Nagashima,
H.; Inoue, H.; Shirai, T. Anal. Chem. 1990, 62, 936. (d) Corey, E. J.;
Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614. (e) Mukaiyama,
T.; Matsueda, R.; Suzuki, M. Tetrahedron Lett. 1970, 1901. (f) Lu,
Y.; Yao, D.; Chen, C. Metabolites 2013, 3, 993.
(21) Singh, A. S.; Kumar, D.; Mishra, N.; Tiwari, V. K. ChemistrySelect
2017, 2, 224.
(22) Singh, A. S.; Kumar, D.; Mishra, N.; Tiwari, V. K. RSC Adv. 2016, 6,
84512.
(23) Singh, A. S.; Mishra, N.; Kumar, D.; Tiwari, V. K. ACS Omega 2017,
2, 5044.
(24) Katritzky, A. R.; Zhang, Y.; Singh, S. K. Synthesis 2003, 2795.
(25) (a) Duangkamol, C.; Wangngae, S.; Pattarawarapan, M.;
Phakhodee, W. Eur. J. Org. Chem. 2014, 7109. (b) Singh, M.;
Agrahari, A. K.; Mishra, N.; Singh, A. S.; Tiwari, V. K. Ind. J. Het-
erocycl. Chem. 2018, 28, 125.
(32) Wang, S.; Zhuang, H.; Shabha, H. K.; Glass, T. E.; Sankarapandian,
M.; Ji, Q.; Shultz, A. R.; Mcgrath, J. E. Macromolecule 2001, 34,
8051.
(33) Pramanik, M. M. D.; Rastogi, N. Org. Biomol. Chem. 2016, 14,
1239.
(34) Scardovi, N.; Garner, P. P.; Protasiewicz, J. D. Org. Lett. 2003, 5,
1633.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G