Imidazolium-supported benzotriazole: an efficient and recoverable activating reagent for amide, ester and thioester bond formation in water

Article abstract of DOI:10.1039/c5ra18749d

An efficient and recyclable imidazolium-supported benzotriazole reagent (Im-CH₂-BtH) as a novel synthetic auxiliary has been synthesized and its utility as a carboxyl group activating reagent via the formation of stable imidazolium-supported acyl benzotriazoles was explored for the synthesis of amides, esters and thioesters in water under microwave conditions. The reagent was reused five times without any noticeable loss in activity. It is moisture insensitive and highly stable under thermal and aerobic conditions. The application of imidazolium-supported N-acetyl benzotriazole leads to synthesis of paracetamol on the gram scale under greener conditions in 93% yield.

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SHAKOOR, S. Sunita Choudhary, K. Bajaj, M. K. Muthyala, A. Kumar and R. SAKHUJA, RSC Adv., 2015, DOI:
10.1039/C5RA18749D.
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ARTICLE
Imidazolium-supported benzotriazole: An efficient and
recoverable activating reagent for amide, ester and thioester
bond formation in water§
Received 00th January 20xx,
Accepted 00th January 20xx
S. M. Abdul Shakoor,a Sunita Choudhary,a Kiran Bajaj,a Manoj Kumar Muthyala,a Anil Kumara and
Rajeev Sakhuja*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient and recyclable imidazolium-supported benzotriazole reagent (Im-CH2-BtH) as a novel synthetic auxiliary has
been synthesized and its utility as carboxyl group activating reagent via the formation of stable imidazolium-supported
acyl benzotriazoles was explored for the synthesis of amides, esters and thioesters in water under microwave conditions.
The reagent was reused five times without any noticeable loss in activity. It is moisture insensitive and highly stable under
thermal and aerobic conditions. The application of imidazolium-supported N-acetyl benzotriazole leads to synthesis of
paracetamol on gram scale under greener conditions in 93% yield.
and high yields of the N-, S- and O-acylated products.10
Katritzky’s pioneer work on the applications of N-
acylbenzotriazoles has led to the synthesis of libraries of
Introduction
Amide, ester and thioesters functionalities are highly
desirable synthetic targets that form an integral component
of numerous natural products and biologically active
synthetic molecules. Amide bond itself accounts its
presence in more than 25% of known drugs as per the
Comprehensive Medicinal Chemistry (CMC) database
analysis.1 Amide and ester linkages are introduced as an
essential component to synthetic drugs such as Procaine,
Lidocaine, Tocainide to increase their metabolic stability.2
These groups impose degradable character and good
thermal and mechanical properties to biodegradable
poly(ester amide)s (PEAs) polymers.3 Glycolamide esters of
Aspirin,4 Ibuprofen,5 Niflumic acid,6 Scutellarin7 and
Nimesulide8 have also been used as biolabile prodrugs due
to their ability to undergo quick cleavage in human plasma.
Similarly, thioesters have been extensively used in native
chemical ligation for the synthesis of many biologically
active small- and medium-sized peptides and proteins.9
Acid-activation as acyl halides, acyl azides,
acylimidazoles, anhydrides, esters and acyl benzotriazoles,
followed by nucleophilic substitution are among the most
common strategies employed for construction of amide,
ester and thioester bonds. N-Acylbenzotriazoles has
surpasses most of the aforementioned reagents due to
their relative stability, ease of formation, higher reactivity
novel peptides and peptidomimetics.11 However, the N-
acylbenzotriazole methodology suffers one or more
hindrances in term of green chemistry perspective such as
use of organic solvents in the acylation reaction, non-
reusability of benzotriazole, and sometimes purification of
the acylated product by column chromatography.12 Efforts
to overcome some of these drawbacks have been
undertaken by Paio,13a Showalter,13b Fang13c and
Katritzky13d-e leading to the synthesis of polymer-supported
benzotriazole reagents. Although, polymer-supported
benzotriazoles have overcome some of these limitations
but they have their own issues such as low loading capacity,
elaborate purification procedures, low swelling properties,
limited solubility and scope of the reagents.13
In past decade, there has been a great attention on the
synthesis of functionalized imidazolium-supported reagents
and their use as alternative soluble support in solution-
phase parallel synthesis14 and in facilitating the separation
process (Figure 1).15
Figure 1 Some imidazolium-supported reagents used in organic synthesis
Tuneable chemical and physical properties, higher
loading capacity, reactions under homogeneous conditions
and use of conventional methods for the analysis of
reaction progress has proved them as ideal support for the
reagents16 in the synthesis of small molecule libraries,17
peptides,18 and oligosaccharides.19 With our interest in
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application of benzotrioazole in acylation reactions and
imidazolium-supported reagents we envisioned that
supporting benzotriazole on imidazolium support can
generate a soluble-supported benzotriazole auxiliary that
can have high efficiency and can be easily recycled. In this
article, we report synthesis of imidazolium-supported
benzotriazole and its application as reusable carboxyl group
activating reagent for amide, ester and thioester bond
formation in aqueous media under microwave irradiation.
temperature. It is worth mentioning that 6 has not shown
any sign of decomposition or loss of reactivity even after
storing for more than two month at room temperature. The
TGA of
6 indicated the first weight loss to be around 254 °C
and the full degradation centered around 366 °C (Figure 2,
right curve) suggesting that 6 is thermally stable.
O
O
SOCl2/EtOH
N
LAH/THF
N
N
N
N
N
HO
HO
EtO
N
N
reflux, 6 h
reflux, 12 h
95%
N
97%
H
H
H
2
1
3
SOCl2/toluene
r.t., 5 h
Results and discussion
70%
N
-
PF6
Our work commenced with the synthesis of
imidazolium-supported benzotriazole reagent connected
Cl-
N
N
N
N
N
N
KPF6/acetone
Cl
N
N
N
N
N
Neat/80 oC
98%
N
reflux, 24 h
96%
N
N
via methylene linker (Im-CH2-BtH,
1. Esterification of commercially available benzotriazole-5-
carboxylic acid ( ), followed by reduction with lithium
aluminium hydride (LAH) in THF yielded 5-
6) as depicted in Scheme
H
H
H
4
6
5
Scheme 1 Synthesis of imidazolium-supported benzotriazole (Im-CH2-BtH) (6)
1
hydroxymethylbenzotriazole (
thionyl chloride in
chloromethylbenzotriazole (
Reaction of with 1,2-dimethylimidazole under solvent free
heating condition afforded imidazolium methylene linked
benzotriazole chloride salt ( ), as a gummy product in 98%
yield. Based on the H NMR analysis, it was found that is
3
).20 Chlorination of
toluene furnished
3
with
5-
4
) in 70% as a single isomer.
4
5
1
5
isomeric mixture of N1- and N3-isomers with major amounts
of N1-isomer. It was used as such for the next step without
further purification.
Figure 2 DSC and TGA curves for 6.
For tuning the solubility, the counter anion in
5 was
After successful synthesis and characterization of
focused our attention to investigate the carboxylic acid
activating capability of to synthesize amides, esters and
thioesters. Thus, we initially attempted the activation of
benzoic acid (7a) with . It is important to mention that
initially the activation of 7a was attempted with the
reagent
(Im-CH2-BtH, Cl- salt), however due to difficulty in
6, we
exchanged with PF6 anion by reacting with KPF6 in dry
acetone under refluxing condition to yield methylene linked
imidazolium benzotriazole potassium hexafluorophosphate
6
(
6
) as a brown solid in 96% yield. Initially the exchange of Cl-
6
-
by PF6 was attempted in water at room temperature but
the reaction never goes on completion and the product
5
remains soluble along with
the reaction goes to completion only on refluxing in dry
acetone. The 1H NMR of indicated the presence of N1- and
5 in water. On the other hand,
the weighing because of gummy nature of the reagent and
comparatively lower reactivity, we switched to activation
(Im-CH2-BtH, PF6- salt
using 6 ).
6
N2-isomers in the ratio 2:1. Three characteristic singlet at δ
5.58, 3.76 and 2.64 for the methylene (2H), N-methyl (3H)
and C-methyl (3H) protons were observed for N1-isomer
along with three singlets at δ 6.17, 3.66 and 2.44 for N2-
Various coupling reagents viz. DCC, EDC.HCl, HBTU and
HATU were screened in tetrahydrofuran (THF) and
acetonitrile (CH3CN) for the activation of benzoic acid (7a
)
isomer. Peaks for equivalent aromatic protons were
1
with 6 (Table 1). Other polar solvents such as DMF and
DMSO were discarded due to difficulty of removing them
after the reaction. Among all the trials, DCC (1.2 eq.) in
CH3CN using a catalytic amounts of DMAP at room
temperature gave best yield (75%) of imidazolium-
supported N-benzoyl benzotriazole (8a) (Table 1, entry 3). A
number of spots were visible on the TLC when the reaction
was carried under refluxing conditions and subsequently
leads to declination in the isolated yield of 8a under similar
experimental conditions (Table 1, entry 5) Interestingly due
to high polarity of 8a, the DCU was easily removed from the
reaction mixture by simple washing with ethyl acetate and
thereafter precipitation with methanol yielded 8a as pure
product. Catalytic amounts of DMAP was enough and
observed in the region δ 7.37-8.07 in the H NMR of
6. We
were successful in isolating N1-isomer by recrystallization
of the brown solid from methanol. Thus, the overall
strategy provides a straight forward high yielding method
for the synthesis of imidazolium-supported benzotriazole,
avoiding protection and de-protection steps as usually
required in polymer-supported benzotriazole synthesis.
The thermal stability profile of the synthesized reagent
6
was studied using differential scanning calorimetry (DSC)
and thermogravimetric analysis (TGA). The DSC experiment
showed that the exothermic decomposition temperature of
6
is above 150 °C (Figure 2, left curve)) with an initiation
temperature of 151.81 °C and end point at 185.81 °C. We
recommend the use of
6 well below its decomposition
2 | J. Name., 2012, 00, 1-3
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necessary for the reaction as its absence leads to
We next investigated benzoylation of p-toluidine (9A
)
tremendous decrease in the yield of 8a (Table 1, entry 4).
with imidazolium-supported N-benzoyl benzotriazole (8a
)
using DMAP and K2CO3 as bases under classical and
microwave conditions in a number of solvents such as
CH3CN, THF, EtOH and water. To our delight, the reaction in
CH3CN and water proceeded smoothly under microwave
irradiation giving 10aA in 85% and 90% yields, respectively
(Scheme 3). On the other hand, it took 12-14 h for
completion of reaction under reflux conditions in
acetonitrile and water with almost comparable yields.
The substrate scope of other imidazolium-supported N-
Table 1. Optimization of reaction conditions for the synthesis of 8a
Entry
Coupling reagents
Solvent
Reaction
conditions
r.t, 26 h
Yield of
8a (%)
50
1
2
3
4
5
5
DCC (1.2 eq.) /DMAP (cat.)
DCC (2 eq.)/DMAP (cat.)
DCC (1.2 eq.)/DMAP (cat.)
DCC (1.2 eq.)
THF
acyl benzotriazoles
conditions with
(
8b-g
) was checked under similar
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
r.t., 20 h
r.t., 20 h
r.t., 20 h
reflux, 8 h
r.t., 20 h
76
a
variety of aliphatic, aromatic and
75
heteroaromatic amines as N-nucleophilic substrates (9A-E).
For all substrates, the reaction proceeded with quantitative
conversion in water by applying 15-30 minutes of
microwave irradiation, and 80-95% isolated yield of the
corresponding amides (10) were obtained (Scheme 3).
Interestingly, a simple extraction of the concentrated
reaction mixture with ethyl acetate followed by washing
with 1N HCl (to remove the un-reacted N-nucleopilic
substrate and DMAP) yielded pure amides 10, avoiding any
use of column chromatography. Apart from aromatic and
40
55a
DCC (1.2 eq.)/DMAP (cat.)
EDC.HCl (1.5 eq.)/DMAP
(cat.)
65
6
HBTU (1.5 eq.)/DMAP
(cat.)
CH3CN
r.t., 20 h
45
7
HATU (1 eq.)/DMAP (cat.)
CH3CN
r.t., 20 h
52
aA number of spots on TLC appeared on refluxing and subsequently the yield
of 8a decreased.
With these optimized conditions in hand, we studied
the substrate scope of this reaction and successfully
activated six more aromatic and heteroaromatic acids (7b-
heteroaromatic N-nucleophiles, the acylation using
worked quite well with aliphatic amines such as propyl
amine 9D and benzyl amine 9E), yielding the
8
(
)
(
g
) with imidazolium-supported benzotriazole auxiliary
corresponding amides 10aD and 10gE in 88% and 90%
yields, respectively. Similarly the acetylation of benzyl
amine (9E) with 8h proceeded in 15 minutes under similar
experimental conditions yielding 10hE in 84% yield.
yielding their corresponding stable imidazolium-supported
benzotriazole acyl reagents (Im-CH2-Bt-COAr, 8b-g) in 65-
80% yields (Scheme 2) either in pure N1-isomeric form or
enriched N1-isomer with small amounts of N3-isomer. Apart
from aromatic and heteroaromatic acids, acetic acid also
got efficiently activated by our synthesized reagent
6
yielding corresponding imidazolium-supported
benzotriazole acetyl reagent (8h) in 85% isolated yield,
under similar experimental conditions in 16 h. It is
noteworthy that the loss in yield of
8 is solely during the
isolation process due to its partial solubility in methanol.
Scheme 3 Imidazolium-supported acyl benzotriazole (8a-g) mediated
synthesis of amides (10) in aqueous media under MW irradiation.
We further utilized imidazolium-supported N-acyl
benzotriazoles (8a-g) for the thioester bond formation by
reacting with thiophenol (11A) and 2-naphthalenethiol
Scheme 2 Synthesis of imidazolium-supported acyl benzotriazole reagents
(Im-CH2-Bt-COR) (8)
(
11B) under similar conditions (Scheme 4). Here again,
DMAP was found to be the optimum base for the reactions
in water and acetonitrile and the reaction worked
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comparatively slow with K2CO3. Longer reaction time and
lower yield of the product (12aA) was obtained under
classical reflux conditions in water and acetonitrile. Both
thiophenols reacted smoothly with 8a-g and the reaction
completed in 10-30 minute of microwave irradiation.
Extraction of the concentrated reaction mixture with ethyl
acetate followed by washing of organic filterate with water
(to remove DMAP) and recrystallization with hexanes
yielded pure thioesters (12) in 85-96% yields.
O
O
O
O
O
O
O
O
O
O
O
O
14aA
14bA
14cA
84%
14dA
80%
MeO
O
80%
75%
Cl
OMe
O
MW, 45 min.
MW, 35 min.
MW, 50 min.
MW, 40 min.
O
O
O
O
O
14eA
73%
14gA
70%
MW, 50 min.
MW, 50 min.
Scheme
synthesis of esters (14) in aqueous media under MW irradiation.
5
Imidazolium-supported acyl benzotriazole
(
8a-g) mediated
-
PF6
N
N
DMAP/H2O
O
R1SH
N
+
Recovery and reusability of imidazolium-supported
benzotriazole reagent
R1
+
6
MW, 100 oC,
10-30 min.
N
N
R
S
11A-B
Recovered
O
8
12
R
Recoverability of Im-CH2-BtH was studied in all the
O
O
S
O
S
S
O
S
three cases of reactions. The insolubility of Im-CH2-BtH (6)
in ethyl acetate provided a simple procedure for separating
it from crude reaction mixture. In case of amide and
12aB
12aA
12bB
12cA
93%
MeO
O
90%
MW, 25 min.
96%
MW, 10 min.
86%
MW, 20 min.
Cl
OMe
MW, 10 min.
thioester synthesis, pure Im-CH2-BtH (6) was obtained after
O
O
S
O
S
S
washing of concentrated reaction mass with ethyl acetate
followed by high vacuum drying whereas in case of ester
S
O
O
12dB
92%
12gA
12dA
93%
MW, 10 min.
12gB
85%
MW, 30 min.
synthesis an additional washing with water was required to
88%
MW, 30 min.
1
MW, 10 min.
remove t-BuOK to yield pure
of the recovered Im-CH2-BtH (
initially synthesized reagent ( ) is shown in Figure 3. From
the H NMR it is very clear that the chemical structure of
recovered is identical to that of original compound.
6. Comparison of the H NMR
Scheme 4 Imidazolium-supported acyl benzotriazole (8a-g) mediated
synthesis of thioesters (12) in aqueous media under MW irradiation
6) reagent with that of
6
1
After the success of amide and thioester bond
formation in aqueous medium, we then turned our
attention towards ester bond formation using imidazolium-
6
supported N-acyl benzotriazoles
(8a-g). When 3-
methoxyphenol (13) was allowed to react with 8a under the
standardized condition for amide bond formation,
corresponding ester 14a was only formed in 26% yield. This
may be attributed to the lower nucelophilicity of phenols
compare to amines and thiols However, use of t-BuOK
instead of DMAP resulted in formation of 14a in 80%
isolated yield after 40 minutes of MW irradiation. Next,
when other imidazolium-supported acyl benzotriazole (8b-
g) were reacted with 3-methoxyphenol (13A) in water
under microwave irradiation using t-BuOK as base to give
corresponding esters 14aA-gA (Scheme 5). Extraction of the
concentrated reaction mixture with ethyl acetate followed
by washing of organic filterate with 2N NaOH yielded pure
esters (14aA-gA) in 73-84% isolated yields.
Figure 3 Comparison of 1H NMR of
6 and recovered 6.
The reusability of the recovered reagent
evaluated towards the synthesis of 8a. Delightfully the
recovered reagent ( ) has not shown any significant change
(6) was
-
6
PF6
OH
O
N
N
t-BuOK/H2
O
N
+
N
6
+
in the chemical reactivity and for five cycles 75, 75, 73, 72
N
MW, 100 oC,
35-50 min.
R
O
O
Recovered
O
and 70% isolated yield of 8a was obtained based on the
O
14
8
R
13
6 examples
70-84%
amount of recovered Im-CH2-BtH (
6) (Figure 4). It is worth
to mention that the recovery process is very simple and less
arduous. However, due to inevitable loss of Im-CH2-BtH (
6
)
during the activation step, the amount of amide (10aA
)
formed in each subsequent cycle’s decreases (percentage
yield remain same) due to use of lesser amount of
nucleophile in the subsequent cycles.
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amide (10aA) was isolated in 92% yield by usual work up
procedure without employing
column chromatography, along
Reusability of Im-CH2-BtH (6)
with almost recovery of Im-
CH2-BtH ( ) (98% of its starting
6
material). Thus, the step-wise
synthetic strategy leads to the
synthesis of amide (10aA) in
comparable yields, with or
without the isolation of Im-CH2-
BtCOPh.
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
75%
75%
73%
72%
70%
1
2
3
4
5
Figure 4
6)
Recyclability and reusability of Im-CH -BNtH (o. of Cycles
2
O
One-pot and sequential synthesis of amide without
isolating Im-CH2-BtCOR
Ph
-
OH
O
-
PF6
7a
+
H2
N
N
H
Ph
DCC (1 eq.)/DMAP (cat.)
CH3CN, r.t., 20 h
N
N
N
N
10aA
PF6
N
DMAP (1.2 eq.)/H2
MW, 100 oC, 20 min.
O
92%
+
To overcome the loss in yield during the synthesis of
imidazolium-supported acyl benzotriazole reagents (Im-
N
N
O
8a
not isolated
N
Ph
N
N
Im-CH2-BtH (6)
Recovered
H
6
CH2-Bt-COR) (
economical, we planned to perform the synthesis of amide
10aA) in one-pot fashion. It is important to mention that
since the activation step does not proceed in water,
therefore benzoic acid (7a) and Im-CH2-BtH ( ) were
8) and to make the process more efficient and
(
Scheme
supported acyl benzotriazole (8a
6
Sequential synthesis of 10aA without isolating Imidazolium-
)
6
Application of imidazolium-supported acetyl benzotriazole
(8h) for the synthesis of paracetamol
allowed to react in acetonitrile at room temperature for 20
h using DCC (1.2 eq.)/DMAP (5 mol %), after which p-
toluidine (1.0 eq.), additional DMAP (1.2 eq.) were added to
the same pot and the reaction mixture was subjected to
microwave irradiation for 20 minutes. After the two
Lastly, we applied the chemical utility of imidazolium
supported benzotriazole reagent towards the synthesis of
paracetamol. Paracetamol (N-(4-hydroxyphenyl)acetamide)
is a mild painkiller and reduces the temperature of patients
with fever, and thus widely used OTC drug in many
countries either in different pharmaceutical formulations,
alone or in combination with other active pharmaceutical
ingredients. Many synthetic routes have been explored for
the paracetamol production but all those involve the
acetylation of p-aminophenol using acetic anhydride at the
final stage. We attempted to substitute corrosive acetic
anhydride by imidazolium-supported N-acetyl benzotriazole
8h for preparing paracetamol in a cleaner and safer way.
8h effectively and selectively acetylated amino group of p-
aminophenol (9F) using DMAP in water under microwave
irradiation in 15 minutes yielding paracetamol (10hF) in
sequential reactions in one-pot, the reagent Im-CH2-BtH (6)
was almost completely recovered (97% of its starting
amount) by washing the concentrated and dried reaction
mixture with ethyl acetate and decanting the organic
filterate to separate the product along with by-products
such as DCU, DMAP and un-reacted acid from 6. However,
the isolation of the product 10aA in 82% yield from this
organic filterate (ethyl acetate) required tedious separation
procedure including acid-base work up followed by column
chromatography.
In order to exploit the synthetic advantage of the
reagent (Im-CH2-BtCOR) to effectively undergo acylation in
water, we also attempted the sequential synthesis of amide
93% yield, along with the easy recovery of Im-CH2-BtH (6) in
(
10aA) by (i) carrying the activation step in acetonitrile in
pure form as described for other products. In order to
evaluate the potential of this process on a larger scale, a
one gram batch production of paracetamol from 3.95 g of
8h and 1.0 g of p-aminophenol was successfully achieved
under optimized conditions (Scheme 7).
the usual manner at room temperature, (ii) removing the
side products (DCU) by washing the concentrated and dried
residue with ethyl acetate and (iii) using this concentrated
residue for the benzoylation of p-toluidine in water using
DMAP (1.2 eq) under microwave irradiation. In this case,
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extracted with ethyl acetate (4
×
100 mL). Drying and
concentrating the organic layer under reduced pressure
afforded in 95%. m.p: 147-149
C (Lit.20 m.p: 149-150 oC).
3
°
Scheme 7 Synthesis of paracetamol on gram scale using 6.
Synthesis of 5-(chloromethyl)-1H-benzo[d][1,2,3]triazole (4)
Thionyl chloride (0.36 mol) was slowly added to a solution
of (1H-benzo[d][1,2,3]triazol-5-yl)methanol (3) (0.026 mol)
Experimental
in toluene (100 mL), and the mixture was stirred vigorously
for 5 h. The resulting solid was filtered and washed with
Materials and methods
hexanes to give pure 3. White solid; yield: 70%; m.p: 162-
All the chemicals were purchased from “Sigma-Aldrich”,
Alfa Aesar, and Spectrochem India Pvt. Ltd and were used
without further purification. The solvents used were
purchased from Merck (India) and were distilled and dried
before use. Nuclear magnetic resonance spectra were
recorded on Bruker Avance™ 400 spectrometer. All 1H NMR
experiments were reported in δ units, parts per million
(ppm), and were measured relative to residual chloroform
(7.26 ppm) or DMSO (2.5 ppm) in the deuterated solvent.
All 13C NMR spectra were reported in ppm relative to
deuterochloroform (77.0 ppm) or [D6]- DMSO (39.5 ppm).
All coupling constants J were reported in Hz. The following
abbreviations were used to describe peak splitting patterns
when appropriate: s = singlet, d = doublet, t = triplet, dd =
doublet of doublet, m = multiplet and br s = broad singlet.
Melting points were determined on a capillary point
apparatus equipped with a digital thermometer and are
uncorrected. Mass spectra were recorded on an AB SCIEX
TOF/TOF 5800 spectrometer. The reactions were carried in
a CEM Discover BenchMate reactor in 10mL pressure vials
at 80 W. DSC was recorded on Perkin Elmer DSC 4000 at a
163 oC; 1H NMR (400 MHz, CDCl3 + DMSO-d6) δ 7.86 (s, 1H),
7.80 (d, J = 8.5 Hz, 1H), 7.41 (dd, J = 8.6, 1.3 Hz, 1H), 4.79 (s,
2H); 13C NMR (100 MHz, CDCl3 + DMSO-d6) δ 143.3, 143.0,
140.3, 131.7, 120.1, 119.5, 51.0.
Synthesis of 3-((1H-benzo[d][1,2,3]triazol-5-yl)methyl)-1,2-
dimethyl-1H-imidazol-3-ium Chloride (5)
A mixture of 1,2–dimethylimidazole (0.019 mol) and 5-
(chloromethyl)-1H-benzo[d][1,2,3]triazole (0.017 mol) were
heated at 80
reaction mixture was washed with ethyl acetate (3
yielding
. Brown gummy semi-solid (N1+N3); yield: 98%; 1H
°C for 3 h. Upon completion of reaction, the
×
25 mL)
5
NMR (400 MHz, CDCl3 + DMSO-d6) δ 16.08 (s, 1H), 7.95 (s,
1H), 7.91 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.71 (d,
J = 1.9 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H), 5.62 (s, 2H), 3.79 (s,
3H), 2.66 (s, 3H); 13C NMR (100 MHz, CDCl3 + DMSO-d6) δ
144.46, 144.08, 132.68, 131.21, 125.22, 122.63, 121.20,
117.69, 50.78, 33.68, 9.42.
Synthesis of 3-((1H-benzo[d][1,2,3]triazol-5-yl)methyl)-1,2-
dimethyl-1H-imidazol-3-ium hexafluorophosphate (6)
heating rate of 10
°C/min. using nitrogen as the carrier gas
in the range 0 °C to 280
analysis (TGA) was obtained using the Perkin Elmer TGA
4000 in the presence of nitrogen flow at a linear heating of
°
C. Similarly, thermogravimetric
In a round bottom flask, 3-((1H-benzo[d][1,2,3]triazol-5-
yl)methyl)-1,2-dimethyl-1H-imidazol-3-ium chloride
(5)
(0.017 mol) was refluxed with potassium
10 °C/min starting from 25 °C to 500 °C
hexafluorophosphate (0.018 mol) in dry acetone (40 mL) for
24 h under an inert atmosphere of nitrogen gas. Upon
completion of reaction, the excess potassium
hexafluorophosphate was filtered off and the mother liquor
was concentrated under reduced pressure, dried in high
vacuum pump, precipitated with methanol to result
Synthesis of ethyl 1H-benzo[d][1,2,3]triazole-5-carboxylate (2)
To a solution of benzotriazole-5-carboxylic acid (0.1 mol) in
ethanol (80 mL), thionyl chloride (0.3 mol) was added drop-
wise, at 0 oC. The reaction mixture was refluxed for about 6
h until the consumption of the starting material. The
reaction mixture was concentrated under reduced pressure
1
compound 6. Brown solid (N1 + N2 isomers); yield: 96%; H
NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.96 (d, J = 10.6
Hz, 2H), 7.90 (s, 0.5H), 7.75 (s, 1H), 7.67 (s, 1H), 7.44 (d, J =
7.6 Hz, 1H), 7.37 (s, 1H), 6.17 (s, 1H, CH2-N2-isomer), 5.58 (s,
2H, CH2-N2-isomer), 3.76 (s, 3H, N-CH3-N1-isomer), 3.66 (s,
1.5H, N-CH3-N2-isomer), 2.64 (s, 3H, C-CH3-N1-isomer), 2.44
(s, 1.5H, C-CH3-N2-isomer); 13C NMR (100 MHz, DMSO-d6) δ
145.26, 139.68, 138.69, 132.36, 126.00, 123.16, 121.62,
and extracted with ethyl acetate and water (3 × 100 mL).
The combined organic layer was dried over Na2SO4 and
concentration of the solvent yielded
oC (Lit20 m.p: 108-109 oC).
2 in 97%. m.p: 106-108
Synthesis of 1H-benzo[d][1,2,3]triazol-5-yl)methanol (3)
116.02, 115.59, 51.55(
isomer), 35.22 (N-
H3-N1-isomer), 33.71(N-
11.35 (C-
H3-N2-isomer), 9.88 (C- H3-N1-isomer).
Recrystallization in methanol yielded pure N1-isomer of
C
H2-N3-isomer), 51.02(
C
H2-N1-
To a suspension of lithium aluminium hydride (0.09 mol) in
C
C
H3-N2-isomer),
dry THF (100 mL) in a round bottom flask, ethyl 1H-
C
C
benzo[d][1,2,3]triazole-5-carboxylate (
2) (0.03 mol) was
6
.
slowly added from a dropping funnel at 0
°C under an
White solid (N1-isomer); m.p: 172-173 oC; 1H NMR (400
MHz, DMSO-d6) δ 15.86 (s, 1H), 7.94 (s, 2H), 7.71 (d, J = 34.9
Hz, 2H), 7.43 (d, J = 7.0 Hz, 1H), 5.57 (s, 2H), 3.76 (s, 3H),
2.63 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 145.20,
atmosphere of nitrogen. The reaction mixture was refluxed
for 12 h. The reaction mixture was then quenched in ice-
cold water, acidified with 1N HCl, filtered through celite,
6 | J. Name., 2012, 00, 1-3
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140.39, 139.40, 131.61, 125.34, 123.15, 121.66, 116.04,
115.39, 51.15, 35.28, 9.97; HRMS (ESI-TOF) (m/z) calculated
for C12H15N5+ 229.1327; found 229.1326 [M+1-PF6]+
72%; m.p: 122-124 oC; 1H NMR (400 MHz, DMSO-d6) δ 8.43 –
8.23 (m, 2H), 7.83 (dd, J = 17.4, 5.1 Hz, 1H), 7.78 – 7.64 (m, 3H),
7.59 (t, J = 8.4 Hz, 1H), 7.49 – 7.38 (m, 2H), 5.74 – 5.66 (m, 2H),
3.79 (s, 3H), 2.66 (s, 3H), 2.37 (2s, 3H total, for N1+N3-isomers);
13C NMR (100 MHz, DMSO-d6) δ 168.09, 146.21, 145.81, 145.47,
138.03, 137.69, 134.05, 132.39, 131.61, 131.21, 130.62, 127.10,
125.93, 121.73, 121.25, 119.74, 115.36, 114.46, 51.06, 50.73,
35.34, 19.84, 10.00, 9.98; HRMS (ESI-TOF) (m/z) calculated for
C20H21N5O+ 347.1746; found 347.1764 [M+1-PF6]+.
General procedure for synthesis of imidazolium-supported
acylbenzotriazole reagents (8a-h)
A 50 mL round bottom flask containing a mixture of DCC
(1.2 mmol), carboxylic acid (1.2 mmol),
6 (1 mmol) and
dimethylaminopyridine (5 mol %) in dry acetonitrile (10 mL)
was stirred for 20-40 h. After the completion of reaction,
the solvent was concentrated under reduced pressure, and
the crude reaction mixture was washed with ethyl acetate
(50 mL). The residue was dried for under high vacuum and
washing of the residual solid with minimum amount of
(E)-3-((1-Cinnamoyl-1H-benzo[d][1,2,3]triazol-5-yl)methyl)-1,2-
dimethyl-1H-imidazol-3-ium hexaflurophosphate (8e): Brown
solid (N1-isomer); yield: 72%; m.p: 214-216 oC; 1H NMR (400
MHz, DMSO-d6) δ 8.36 (d, J = 8.5 Hz, 1H), 8.13 (s, 1H), 8.09 (s,
1H), 8.01 (dd, J = 16.3, 2.9 Hz, 1H), 7.82 (d, J = 3.7 Hz, 1H), 7.72
(dd, J = 27.4, 2.6 Hz, 4H), 7.56 (s, 1H), 7.46 (s, 2H), 5.62 (s, 2H),
3.81 (s, 3H), 2.65 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 163.84,
158.88, 149.04, 146.37, 145.48, 134.22, 133.94, 132.21, 131.17,
129.70, 123.34, 121.68, 119.75, 116.35, 115.39, 50.60, 35.35,
34.60, 10.02; HRMS (ESI-TOF) (m/z) calculated for C21H21N5O+
359.1746; found 359.1767 [M+1-PF6]+.
methanol yielded pure 8 in 65-80% yields. The products
8a-h) were analyzed by 1H & 13C NMR and HRMS.
(
3-((1-Benzoyl-1H-benzo[d][1,2,3]triazol-5-yl)methyl)-1,2-
dimethyl-1H-imidazol-3-ium hexaflurophosphate (8a): White
solid (N1-isomer); yield: 75%; m.p: 164-166 oC; 1H NMR (400
MHz, DMSO-d6 + CDCl3) δ 8.37 (d, J = 8.6 Hz, 1H), 8.25 (s, 1H),
8.16 – 8.12 (m, 2H), 7.84 – 7.79 (m, 1H), 7.77 (dd, J = 4.8, 2.6 Hz,
2H), 7.68 (d, J = 2.1 Hz, 1H), 7.65 (t, J = 7.8 Hz, 2H), 5.68 (s, 2H),
3.82 (s, 3H), 2.68 (s, 3H); 13C NMR (100 MHz, DMSO-d6 + CDCl3) δ
166.06, 145.43, 133.64, 133.05, 131.30, 130.98, 130.33, 128.27,
122.79, 121.25, 119.21, 114.99, 50.26, 34.84, 9.48; HRMS (ESI-
TOF) (m/z) calculated for C19H19N5O+ 333.1589; found 333.1614
[M+1-PF6]+.
3-((1-Isonicotinoyl-1H-benzo[d][1,2,3]triazol-5-yl)methyl)-1,2-
dimethyl-1H-imidazol-3-ium hexafluorophosphate (8f): White
o
1
solid (N1+N3-isomer); yield: 65%; m.p: 181-184 C; H NMR (400
MHz, DMSO-d6) δ 9.23 (s, 1H), 8.92 (d, J = 2.7 Hz, 1H), 8.49 (d, J =
7.5 Hz, 1H), 8.44 – 8.24 (m, 2H), 7.89 – 7.58 (m, 4H), 5.75 – 5.67
(m, 2H), 3.79 (s, 3H), 2.65 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
δ 165.72, 154.02, 151.91, 146.21, 145.26, 139.47, 138.14,
134.17, 131.87, 131.21, 128.30, 127.19, 123.89, 123.36, 121.74,
121.28, 119.69, 115.47, 114.49, 50.87, 50.59, 35.35, 9.99; HRMS
(ESI-TOF) (m/z) calculated for C18H18N6O+ 334.1542; found
334.1561 [M+1-PF6]+.
3-((1-(4-Chlorobenzoyl)-1H-benzo[d][1,2,3]triazol-5-yl)methyl)-
1,2-dimethyl-1H-imidazol-3-ium hexaflurophosphate (8b):
Brown solid (N1+N3-isomer); yield: 70%; m.p: 142-146 oC ; 1H
NMR (400 MHz, DMSO-d6) δ 8.37 (dd, J = 9.8, 6.5 Hz, 1H), 8.27
(s, 1H), 8.15 (d, J = 8.3 Hz, 2H), 7.86 – 7.80 (m, 1H), 7.76 (d, J =
8.4 Hz, 2H), 7.70 (s, 1H), 7.60 (d, J = 8.3 Hz, 1H), 5.75 – 5.65 (m,
2H), 3.78 (s, 3H), 2.65 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ
166.01, 145.40, 139.24, 133.77, 131.61, 131.10, 130.57, 129.14,
123.28, 121.75, 121.24, 119.65, 115.54, 114.58, 50.95, 50.59,
35.33, 10.19; HRMS (ESI-TOF) (m/z) calculated for C19H18ClN5O+
367.1199; found 367.1219 [M+1-PF6]+.
3-((1-(Furan-2-carbonyl)-1H-benzo[d][1,2,3]triazol-5-
yl)methyl)-1,2-dimethyl-1H-imidazol-3-ium
hexafluorophosphate (8g): White solid (N1+N3-isomer); yield:
68%; m.p: 220-224 oC; 1H NMR (400 MHz, DMSO-d6) δ 8.34 (dd, J
= 13.0, 8.6 Hz, 2H), 8.27 (s, 1H), 8.07 (d, J = 3.5 Hz, 1H), 7.86 –
7.74 (m, 2H), 7.69 (s, 1H), 6.94 (dd, J = 3.6, 1.6 Hz, 1H), 5.73 –
5.64 (m, 2H), 3.79 (s, 3H), 2.65 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) δ 154.80, 151.00, 145.65, 145.36, 144.24, 137.97,
133.91, 132.40, 132.00, 131.13, 126.94, 125.63, 123.33, 121.72,
121.26, 119.75, 115.34, 114.42, 113.96, 50.88, 50.59, 35.33,
9.98; HRMS (ESI-TOF) (m/z) calculated for C17H17N5O2+ 323.1382;
found 323.1410 [M+1-PF6]+.
3-((1-(3,4-Dimethoxybenzoyl)-1H-benzo[d][1,2,3]triazol-5-
yl)methyl)-1,2-dimethyl-1H-imidazol-3-ium (8c): White Solid
(N1+N3-isomer); yield: 80%; m.p: 223-227 oC; 1H NMR (400 MHz,
DMSO-d6) δ 8.33 (dd, J = 15.0, 6.3 Hz, 1H), 8.28 (d, J = 11.0 Hz,
1H), 7.86 (dd, J = 8.5, 1.8 Hz, 1H), 7.83 – 7.73 (m, 2H), 7.71 (s,
2H), 7.23 (d, J = 8.7 Hz, 1H), 5.73 – 5.65 (m, 2H), 3.92 (s, 3H),
3.85 (s, 3H), 3.78 (s, 3H), 2.64 (d, J = 7.3 Hz, 3H); 13C NMR (101
MHz, DMSO-d6) δ 165.66, 154.35, 148.77, 145.75, 145.41,
137.71, 133.74, 132.76, 132.37, 130.82, 127.38, 126.79, 123.36,
123.21, 121.73, 121.11, 119.61, 115.47, 114.47, 111.48, 56.43,
56.18, 50.90, 50.61, 35.34, 9.99; HRMS (ESI-TOF) (m/z)
3-((1-Acetyl-1H-benzo[d][1,2,3]triazol-5-yl)methyl)-1,2-
dimethyl-1H-pyrazol-2-ium (8h): White solid (N1-isomer); yield:
1
85%; m.p: 198-200 oC; H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J
= 7.5 Hz, 1H), 8.21 (s, 1H), 7.75 (s, 2H), 7.69 (s, 1H), 5.66 (s, 2H),
3.77 (s, 3H), 2.94 (s, 3H), 2.63 (s, 3H).; 13C NMR (100 MHz,
DMSO-d6) δ 170.26, 146.25, 145.85, 145.46, 137.85, 133.64,
130.99, 126.69, 123.33, 121.65, 121.14, 119.59, 115.06, 114.22,
50.70, 35.33, 23.61, 9.97.
+
calculated for C21H23N5O3 393.1800; found 393.1827 [M+1-
PF6]+.
1,2-Dimethyl-3-((1-(2-methylbenzoyl)-1H-
General procedure for synthesis of amides, thioesters and
esters (10, 12, 14) and recovery of reagent 6
benzo[d][1,2,3]triazol-5-yl)methyl)-1H-imidazol-3-ium
hexafluorophosphate (8d): White solid (N1+N3-isomer); yield:
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Journal Name
In a microwave capped tube, N- S- or O--nucleophilic
Procedure for sequential synthesis of amide (10aA)
without isolating Im-CH2-BtCOR
aromatic/heteroaromatic
substrates
(1.2
mmol),
imidazolium supported N-acyl benzotriazole reagent (8a-g
)
A 25 mL round bottom flask containing a mixture of DCC
(1 mmol) and DMAP (1.5 mmol) (t-BuOK for O-nucleophilic
substrate) were mixed in water (2 mL). The tube was
irradiated in a CEM microwave synthesizer for 10-50
(1.2 mmol), benzoic acid (1.2 mmol),
6 (1 mmol) and DMAP
(5 mol %) in dry acetonitrile (8 mL) was stirred for 20 h at
20 oC. After the completion of reaction, the mixture was
concentrated and dried under vacuum and washed with
ethyl acetate (2 x 20 mL) to remove DCU, DMAP and un-
reacted acid. The residue was charged with p-toluidine (1.2
mmol), additional DMAP (1.2 mmol) and water (4 mL) and
the mixture was subjected to microwave irradiation for 20
minutes. After completion of the reaction, reaction mixture
o
minutes at 100 C, 50 W and the progress of the reaction
was monitored via TLC. After completion of the reaction,
reaction mixture was concentrated in a 25 ml round bottom
flask to give a gummy reaction mass. Subsequently, ethyl
acetate (2 × 20 mL) was added to this mixture and stirred
for 15 minutes and decanted. The product (amide, thioester
and ester) got dissolved in organic filterate leaving behind
was concentrated, dried and washed with ethyl acetate (2
×
the regenerated reagent
6 as semi-solid (in case of N- & S-
20 mL). The organic filterate was decanted and washed
with 1N HCl, dried with Na2SO4 and concentrated to yield
pure amide 10aA in 92% yield. The left over residue was
nucleophilc substrates. While in case of O-nuclephlic
substrates, washing with water (5 mL) was required to
remove t-BuOK to regenerate pure 6.
dried under vacuum to give pure Im-CH2-BtH (
starting material).
6) (98% of its
For N-nucleophilic substrates, the organic filterate was
washed with 1N HCl, dried with Na2SO4 and concentrated
to yield pure amides 10.
For S-nucleophilic substrates, the organic filterate was
washed with water, concentrated and recrystallized with
hexane to yield pure thioesters 12.
Conclusions
In summary, we have synthesized and characterized
imidazolium-supported benzotriazole reagent as a novel
synthetic auxiliary and explored its utility as greener
carboxyl group activating reagent for the synthesis of
amides, esters and thioesters in aqueous microwave
conditions via the formation of stable imidazolium-
supported acyl benzotriazoles. The reagent is moisture
insensitive and highly stable under thermal and aerobic
conditions. The use of an aqueous medium and microwave
energy in the acylation reaction, high yield of the amides,
esters and thioesters in short reaction times,
chromatography free purification and easy recyclability and
reusability of imidazolium-supported benzotriazole makes it
For O-nucleophilic substrates, the organic filterate was
washed with 2N NaOH, dried with Na2SO4 and concentrated
to yield pure esters 14.
Reusability of 3-((1H-benzo[d][1,2,3]triazol-5-yl)methyl)-1,2-
dimethyl-1H-imidazol-3-ium hexafluorophosphate (6)
After the first run of the reaction and work up procedure as
mentioned above, regenerated semi-solid
6 was dried
under vacuum for 10-12 h and was reused for the next
cycle of the reaction, following the same procedures.
a
greener, economical and environmentally friendly
Procedure for one-pot synthesis of amide (10aA) without
isolating Im-CH2-BtCOR
activating reagent. The other applications of this reagent
are in progress.
A 25 mL round bottom flask containing a mixture of DCC
(1.2 mmol), benzoic acid (1.2 mmol),
6 (1 mmol) and DMAP
(5 mol %) in dry acetonitrile (8 mL) was stirred for 20 h at
20 oC. After the completion of reaction, p-toluidine (1.2
mmol), additional DMAP (1.2 mmol) were added to the
same pot and the reaction mixture was subjected to
microwave irradiation for 20 minutes. After the two
sequential reactions in one-pot, reaction mixture was
concentrated and dried under high vacuum for 5-6 h and
the residue was washed with ethyl acetate (2 × 20 mL) and
the organic filterate was decanted to separate the product
along with by-products such as DCU, DMAP and un-reacted
Acknowledgements
The authors acknowledge BITS Pilani for providing research
grant (BITS Seed Grant) for the work. The authors SMAS
thank UGC, New Delhi, India for providing BSR fellowship.
The author SC thanks CSIR, New Delhi for senior research
fellowship.
Notes and references
1
A. K. Ghose, V. N. Viswanadhan and J. J. Wendoloski, J.
Comb. Chem., 1999, , 55.
acid from
6. The un-dissolved semi-solid was dried under
1
vacuum to give pure Im-CH2-BtH (
6) (97% of its starting
2
T. Nogrady and D. F. Weaver, Medicinal Chemistry: A
Molecular and Biochemical Approach, Oxford University
Press, 2005.
amount). The organic filterate was washed with 1N HCl and
then with 2N NaOH. Purification of this residue by column
chromatography over silica gel using EtOAc: hexane (1: 9,
v/v) as eluent yielded 10aA in 82% yield.
3
4
A. Rodriguez-Galan, L. Franco and J. Puiggali, Polym.,
2011, 3, 65.
N. M. Nielsen and H. Bundgaard, J. Med. Chem., 1989,
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8 | J. Name., 2012, 00, 1-3
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