An efficient synthesis, characterization and antimicrobial screening of N-substituted 2-(piperidin-4-yl)-2H-benzo[d] [1,2,3] triazoles

Article abstract of DOI:10.2174/157018012800389304

A new series N-substituted -2-piperidine-4-yl-2H-benzotriazole (6a-6r) have been synthesized from 4-oxopiperidine-1-carbaxylic acid tert-butyl ester. The new compounds were screened for their antibacterial activity against Gram positive bacteria (Bacillus subtilis, Bacillus megaterium, Bacillus pumilis, Staphylococcus aurius, Enterobactor aerogens and Streptococcus pyrogens) and Gram negative bacteria (Escherichia coli, Proteus vulgaris, Proteus mirabilis and Klebsiella pneumonia). Compounds 6a, 6b, 6g, 6h, 6k, 6q and 6r showed significant anti bacterial activity. The compounds have also been screened for antifungal activity viz Candida albicance, Fusarium oxysporum, Drechslera halodes,and Colletotrichum falcatum. Compounds 6a, 6b, 6d, 6g, 6h and 6r showed significant antifungal activity.

Full text of DOI:10.2174/157018012800389304

Letters in Drug Design & Discovery, 2012, 9, 471-478
471
An Efficient Synthesis, Characterization and Antimicrobial Screening of
N-substituted 2-(piperidin-4-yl)-2H-benzo[d] [1, 2, 3] Triazoles
Jalapathi Pochampalli*,a, Devender Mandalaa,b, Nalla Umapathireddya,b and Pompu Rajakomuraiahc
aDepartment of chemistry, PG College of Science, Osmania University, Hyderabad- 500004, India
bAllied Fabrichem Pvt. Ltd, Plot No-185, Phase-II, IDA Mallapur, Hyderabad-500076, India
cDepartment of Microbiology, Kakatiya University, Warangal-506009, India
Received December 28, 2011: Revised February 20, 2012: Accepted February 21, 2012
Abstract: A new series N-substituted -2-piperidine-4-yl-2H-benzotriazole (6a-6r) have been synthesized from 4-oxo-
piperidine-1-carbaxylic acid tert-butyl ester. The new compounds were screened for their antibacterial activity against
Gram positive bacteria (Bacillus subtilis, Bacillus megaterium, Bacillus pumilis, Staphylococcus aurius, Enterobactor
aerogens and Streptococcus pyrogens) and Gram negative bacteria (Escherichia coli, Proteus vulgaris, Proteus mirabilis
and Klebsiella pneumonia). Compounds 6a, 6b, 6g, 6h, 6k, 6q and 6r showed significant anti bacterial activity. The
compounds have also been screened for antifungal activity viz Candida albicance, Fusarium oxysporum, Drechslera
halodes,and Colletotrichum falcatum. Compounds 6a, 6b, 6d, 6g, 6h and 6r showed significant antifungal activity.
Keywords: Antibacterial activity, Antifungal activity, Benzotriazole, Broth method, Gram positive bacteria, Piperidine.
1. INTRODUCTION
2. MATERIALS AND METHODS
Benzotriazole derivatives act as precursors in many
organic syntheses [1, 2] and have proven to be fertile sources
of medicinal agents. Recent study showed that several
benzotriazoles and 1, 2, 4-triazole derivatives were
represented in an interesting class of heterocyclic’s [3] and
became the most rapidly expanding group of antifungal
compounds with the advantage of low toxicity high oral
bioavailability and broad spectrum activity[4-7]. N-alkylated
benzotriazole derivatives show antibacterial and antifungal
activity [8].
Thin Layer Chromatography (TLC) was performed on
E.Merk AL Silica gel 60 F254 plates and visualized under a
UV light. The infrared (IR) spectra were determined in a
1
Perkin-Elmer Fourier transform (FDIR spectrum). H-NMR
spectra were recorded on Varian EM-360 (400MHz mercury
plus) spectrometer in DMSO-d6 or CDCl3 and calibrated
using solvent signals [7.25(CDCl3) and 2.50(DMSO-d6)].
All chemical shifts were recorded in δ (ppm) using TMS as
an internal standard. The mass spectra were recorded on
Agilent ion trap MS. Spectrometer at the energy of ionizing
electron equal to 70ev.
Benzotriazole and its derivatives have pharmaceutical
importance such as being involved in the production of
corrosion inhibitors, antibacterial [9,10], antifungal [11,12],
antihistaminic, antitubercular [13] and several chemothera-
peutic agents and are also used as anti-fading agent for
metals, antiseptic, anticoagulant agent, anti-fog for
photograph, anti-freeze agent, photoconductor, copying
systems, pesticide products, and other speciality chemicals.
2.1. Antibacterial Activity
The invitro antibacterial activities of the compounds 6a-
6r were assayed with two concentrations (600 and 900
mcg/ml) against six representative Gram-positive bacteria
and four Gram-negative bacteria. The broth dilution method
was recommended by the national committee for clinical
laboratory standards. Bacteria were grown overnight in Luria
Bertani (LB) broth at 37°C, harvested by centrifugation and
then washed twice with sterile distilled water. Stock
solutions of the total compounds were prepared in DMSO.
Each stock solution was diluted with standard broth method.
The inhibition of microorganisms under standardized
conditions was utilized to demonstrate the antibacterial
action of compounds. Almost all the synthesized compounds
were showing better activity than standard (Streptomycin). It
is suggested that the entire molecular system is significant
for activity. The functional groups which are responsible for
antibacterial activity are chloro, cyclopropyl, hydroxyethyl
and ethyl propionyl. However, the compounds 6b, 6d, 6g
and 6h are found to be more active against B. pumilis and S.
pyrogens. The remaining compounds showed moderate to
good activity against all organisms employed except 6a, 6d,
Piperidine and its derivatives have a high impact on
medicinal field due to thire wide variety of pharmacological
actions viz antifungal [14], K+ ion channel blocker [15],
hypoglycemic, hypolipidimic [16], anti-acetyl cholinesterase
activity [17] and opioid receptor antagonist [18], etc. Since
several years, we have been working on the design and
synthesis of novel bio active heterocyclic molecules [19]. In
this connection, we report synthesis and antimicrobial
activity of new molecules which contain piperidine and
benzotriazole moieties within the framework.
*Address correspondence to this author at the Department of Chemistry, PG
College of Science, Osmania University, Hyderabad- 500004, India;
E-mail: pochampallij@gmail.com
1875-628X/12 $58.00+.00
© 2012 Bentham Science Publishers

472 Letters in Drug Design & Discovery, 2012, Vol. 9, No. 5
Jalapathi et al.
O
S
OH
N
O
N
O
O
N
N
N
O
O
N
N
N
(b)
(c)
(a)
N
N
+
76%, 24h
73%, 18h
90%, 4h
(3)
O
O
O
O
O
O
N
O
O
(4a)
(4b)
(1)
(2)
Reagents & Conditions: (a) NaBH4/MeOH; (b) Mesyl chloride, Et3N/ACN; (c) Benzotriazole(3), K2CO3/ACN
Scheme 1.
6g and 6r against Staph. Aurius, S.pyogens and B. subtilis,
respectively. It is interesting to note that the cyclopropyl
substituted compound (6b) is responsible for the highest
activity against E.coli. It may be attributed to the
hydrophobic nature of cyclopropyl moiety. However, the
benzyl and allyl substituents are also leading the good
activity.
benzotriazole (5) and halo/other substituted reactants. 4-
hydroxy-piperidine-1-carbaxylic acid tert-butyl ester (1) was
prepared from the reduction of tert-butyl 4-oxopiperidine-1-
carboxylate with sodium borohydride in methanol. The
compound (1) was protected with methanesulfonyl chloride
in the presence of triethylamine, acetonitrile to give
methanesulfonyloxy-piperidin-1-carbaxylic acid-tert-butyl
ester [20, 21] (2). This compound was again treated with
benzotriazole (3) using K2CO3-acetonitrile to yield two
benzotriazole isomers (4a, 4b), because benzotriazole exists
in two isomeric forms (1H-benzotriazole and 2H-
benzotriazole). The compounds 4a & 4b are regioisomers
[22]; these two isomers were separated by column
chromatography, in aromatic region of different chemical
Further substitution on 2-piperidin-4-yl-2H-benzotriazole
increases the antibacterial activity, primarily ethyl propionyl
and ethyl oxolyl showing two folds greater potency than the
standard and also 3-hydroxy butyl substituted compound
faintly increasing the activity more than the standard. The
compound with N, N-dimethyl oxolyl substituent has been
showing very good activity against Klebsiella pneumonia,
Enterobactor aerogens. The detailed numerical data is listed
in Table 2.
1
shifts in H-NMR spectral data of compound (4a) & (4b),
indicating that these are regioisomers. The compound (4a)
was deprotected with methanolic- HCl in DCM to produce
2-piperidin-4-yl-2H-benzotriazole
(5),
and
it
was
2.2. Antifungal Activity
individually allowed to react with halo/other substituted
compounds to produce the corresponding N-alkyl piperidyl
benzotriazoles (6a-6r).
Piperidine and its derivatives have high impact on
medical field due to their versatile pharmacological action.
Invitro antifungal activities of the N-substituted 2-piperidine-
4-yl-2H-benzotrizoles (6a-6r) were assayed against fungal
organisms viz Candida albicance, Fusarium oxysporum,
Drechslera halodes,and Colletotrichum falcatum which were
grown for 48 hrs at 25°C in a YPD broth (1% yeast extract,
2% peptone and 2% dextrose), harvested by centrifugation
and then washed with sterile distilled water.
All the products are purified by column chromatography
using silica gel (60-120mesh); The structures of the
compounds were confirmed by 13C & 1H-NMR using CDCl3
and DMSO-d6 as solvents and also Mass & HRMS spectral
analysis.
3.1. Experimental Procedures
The fungal activity was determined by using Itrazole as
standard, and all the prepared compounds were showed good
to moderate activity. The N, N-dimethyl oxamide substituted
compound (6r) showed premier activity. The N-methyl and
ethyl oxolyl substituents are responsible for superior activity
against Candida albicance and Drechslera halodes,
respectively. It may be attributed that polar groups in have
been playing a vital role in activity. It is found that the
compounds 6d, 6e, 6g and 6q were not showing any activity
against Candida albicance. The detailed numerical data is
listed in Table 3.
Preparation of 4-Hydroxy-piperidine-1-carbaxylic acid tert-
butyl ester (1)
Sodium borohydride (186mg, 5.025mmol) was added to
a solution of 4-Oxo-piperidine-1-carbaxylic acid tert-butyl
ester (1.0g, 5.025mmol) in methanol (10mL) at 0°C. Then
the reaction mixture was wormed to room temperature and
stirred for 4h. The mixture evaporated to 1/3 of its volume,
then quenched with ice-cold water and extracted with ethyl
acetate (3x25mL). The combined organic layers were
washed with water and brine solution, evaporated by rotary
to afford 910mg (90%) of 4-Hydroxy-piperidine-1-
carbaxylic acid tert-butyl ester (1) as oily liquid.
3. RESULTS AND DISCUSSION
1H-NMR-(400MHz) in CDCl3: δ 3.86-3.81 (m, 3H);
3.06-2.99 (m, 2H); 1.85 (t, 2H); 1.56 (t, 2H); 1.47 (s, 9H).
Several piperidyl substituted benzotriazoles were
synthesized by the reaction between 2-piperidin-4-yl-2H-

An Efficient Synthesis, Characterization
Letters in Drug Design & Discovery, 2012, Vol. 9, No. 5 473
N
N
(d)
(e)
N
4a
N
NH
N
N
R
95%,18h
N
(5)
Reagents & Condiotions: (d) Methanolic HCl, (e) Halo and other compounds(6a-6r).
(6a-6r)
Scheme 2.
(M+H, FT-IR in cm-1: 3421, 2975, 1695, 1425, 1356, 1120;
m/z: 202 (100%) +Ve Scan.
1H-NMR-(400MHz) in CDCl3: (4b); δ8.08 (d, 1H); 7.58
(d, 1H); 7.56(d, 1H); 7.37 (d, 1H) 4.88-4.80 (m, 1H); 4.34
(bs, 2H); 3.06-3.00 (bs, 2H); 2.36 (q, 2H); 2.17 (q, 2H); 1.50
(s, 9); 13C-NMR in DMSO-d6: δ 28.78, 30.42, 40.05, 43.06,
53.12, 110.82, 119.50, 124.34, 127.82, 132.50, 145.62. ESI-
MS m/z: 303 (M+H) +.
Preparation
of
4-methanesulfonyloxy-piperidine-1-
carbaxylic acid tert-butyl ester (2)
To a solution of 4-Hydroxy-piperidine-1-carbaxylic acid
tert-butyl ester (1) (1.1g, 5.47mmol) in acetonitrile (10mL),
we added triethylamine (1.47mL, 10.94mmol) followed by
methanesulfonylchloride (0.93g, 8.20mmol) at 0 °C. The
reaction mixture was allowed to reach room temperature and
was stirred for 24 h. The solvent was evaporated under
reduced pressure and the residue was diluted with water (20
mL). The aqueous solution was extracted with ethyl acetate
(25 mL x 3). The combined organic layers were washed with
water (20 mL x 3), dried over anhydrous Na2SO4 and
evaporated under reduced pressure to give 1.16g (76%) of 4-
Methanesulfonyloxy-piperidne-1-carbaxylic acid tert-butyl
ester (2) as a pale yellow solid.
Preparation of 2-piperidin-4-yl-2H-benzotriazole (5)
To
a
solution of 4-benzotriazol-2-yl-piperidine-1-
carbaxylic acid tert-butyl ester(4a) (4.0g, 13.24mmol) in
DCM (5vol, 20mL) was added methanol-HCl (1vol, 4mL) at
0 °C. The reaction mixture was allowed to reach to room
temperature and and stirred for 18 h. The reaction mass was
flushed with nitrogen to remove the excess HCl gas. The
solvent was evaporated under reduced pressure and basified
with saturated NaHCO3 solution, then extracted with
dichloromethane (3x50mL). The combined organic layers
were washed with water (20 mL x 3), dried over anhydrous
Na2SO4 and evaporated under reduced pressure to give a
crude product. This crude product was washed with acetone
(5mL) and diethyl ether (25mL), dried under high vacuum to
afford 3.0g (94.9%) of 2-piperidin-4-yl-2H-benzotriazole as
a off white solid.
1H-NMR-(400MHz) in CDCl3: δ 4.87-4.82 (m, 1H);
3.68 (d, 2H); 3.30-3.24 (m, 2H); 3.01 (s, 3H); 1.96-1.91 (m,
2H); 1.83-1.74 (m, 2H); 1.45 (s, 9H): m/z: 180 (M-boc) -Ve
Scan.
Preparation of 4-Benzotriazol-2-yl-piperidine-1-carbaxylic
acid tert-butyl ester (4a) & 4-benzotriazole-1yl-piperdine-1-
carbaxylic acid tert-butyl ester (4b)
1H-NMR-(400MHz) in DMSO-d6: δ8.10 (d, 1H); 7.62
(d, 1H); 7.56(d, 1H); 7.37 (d, 1H) 4.88-4.80 (m, 1H); 4.34
(bs, 2H); 3.06-3.00 (bs, 2H); 2.36 (q, 2H); 2.17 (q, 2H): 13C-
NMR in DMSO-d6: δ24.76, 44.88, 58.30, 120.32, 131.40,
To a solution of benzotriazole (3) (7.0g, 5.88mmol) in
acetonitrile, we added K2CO3 (16.2g, 11.77mmol), followed
by 4-methanesulfonyloxy-piperidne-1-carbaxylic acid tert-
butyl ester (18.5g, 6.47mmol) (2) at room temperature. The
reaction mixture was heated at 100°C for 18h. The solvent
was removed under reduced pressure and the residue was
diluted with water (30 mL). The aqueous solution was
extracted with ethyl acetate (3x50 mL). The combined
organic layers were washed with water (20 mL x 3), dried
over anhydrous Na2SO4 and evaporated under reduced
pressure to give a mixture of compounds. This mixture of
compounds was separated by column chromatography (silica
gel, 60-120 mesh) using 8-12% ethyl acetate in pet-ether as a
mobile phase to get 13.0g (73.19%) of two regio isomers
which are 4-Benzotriazol-2-yl-piperidine-1-carbaxylic acid
tert-butyl ester [4a, 8.6g, 64%] and 4-benzotriazol-1-yl-
piperidine-1-carbaxylic acid tert-butyl ester [4b, 4.4g, 36%)
as off white solids.
1H-NMR-(400MHz) in CDCl3: (4a); δ 7.86 (d, 2H);
7.40 (d, 2H); 4.94-4.91 (m, 1H); 4.25 (bs, 2H); 3.04 (bs, 2H);
2.32-2.28 (m, 4H); 1.46 (s, 9); 13C-NMR in CDCl3: δ 28.36,
31.88, 42.46, 63.50, 79.87, 117.95, 126.24, 143.92, 154.46.
FT-IR in cm-1: 2925, 1696, 1451, 1321, 1158, 746; ESI-
MS: m/z: 303 (M+H) +; ESI-HRMS: m/z calcd. For
C16H22N4O2 [M+H] +303.1452; Found: 303.1422.
+
131.40, 145.66; ESI-MS: m/z: 203 (M+H) ; ESI-HRMS:
m/z Calcd. For C11H14N4 [M+H] +203.1291; Found:
203.1295.
Preparation of 2-(1-Methyl-piperdin-4-yl)-2H-benzotriazole
(6a)
A solution of 2-piperidin-4-yl-2H-benzotriazole (100mg,
0.495mmol) in 37% of formaldehyde (2mL) and 100% of
formic acid (2mL) was heated to 100°C for 4h. Then the
reaction mixture was cooled to room temperature and
evaporated the volatiles, basified with saturated NaHCO3
solution and extracted with ethyl acetate (3x25mL). The
combined organic layers were washed with water (25mL x
3), brine solution and dried over anhydrous Na2SO4. The
solvent was removed under reduced pressure to give 81g (87
%) of 2-(1-Methyl-piperdin-4-yl)-2H-benzotriazole as a
white color solid.
1H-NMR-(400MHz) in CDCl3: δ 7.87 (d, 2H); 7.38 (d,
2H); 4.78-4.70(m, 1H); 3.04(d, 2H); 2.50(t, 2H); 2.36 (s,
3H); 2.24 (t, 4H); 13C-NMR in DMSO-d6: δ 23.78, 42.12,
51.60, 59.80, 118.54, 128.40, 142.50; ESI- MS: m/z: 217
(M+H) +; ESI-HRMS: m/z Calcd. For C12H16N4 [M+H]
+217.1448; Found: 217.1444.

474 Letters in Drug Design & Discovery, 2012, Vol. 9, No. 5
Jalapathi et al.
Table 1. Synthesis of N-Alkyl Derivatives of - 2-piperidin-4-yl-2H-benzotriazole (6a-6r)
Product
code
% of
yields
Entries
Reagents R=
Products
Reaction Time
N
N
N
HCOOH/HCOOH
1
6a
N
4h.
87%
OEt
N
N
2
6b
N
N
2h.
44.5%
OSiMe3
OH
B
N
N
3
4
6c
N
24h.
3h.
78%
93%
N
OH
N
Br
6d
N
N
N
N
N
N
N
Cl
Br
5
6
6e
6f
4h.
3h.
88%
96%
Cl
N
Br
N
N
HO
N
OH
O
N
N
N
N
Br
7
8
6g
6h
2.5h.
6h.
93%
87%
O
O
O
N
N
N
O
Cl
N
O
O
O
N
Br
9
6i
6j
N
N
2h.
5h
98%
95%
N
N
Br
N
N
10
N
N
OH
N
N
OH
11
12
6k
6l
12h
6h
76%
73%
N
Cl
N
O
S
N
N
O
N
S
Cl
Cl
O
O
Cl
O
N
O
N
N
13
6m
4h.
65%
NH
N
Cl
Cl
N

An Efficient Synthesis, Characterization
Letters in Drug Design & Discovery, 2012, Vol. 9, No. 5 475
(Table 1). Contd…..
Reagents R=
Products
Entries
Reaction Time
Product
code
% of
yields
O
Cl
14
6n
2.5h.
88%
N
N
O
N
N
N
N
N
Br
N
15
16
6o
6p
1h
98%
90%
O2N
NO2
N
Br
N
N
N
1.5h.
NO2
NO2
N
Br
O
N
N
O
N
17
18
6q
6r
4h.
2h.
96%
76%
O
O
O
N
N
O
N
N
Cl
NHMe2
Cl
N
O
O
Preparation of 2-(1-cyclopropyl-piperidin-4-yl)-2H-ben-
zotriazole (6b)
The reaction mixture was stirred for 24h, filtered with the
reaction mixture and washed with DCM. The combined
organic layers were washed with water (10mL) and brine
solution (10mL). The organic solvents were evaporated by
rotary to get 80 mg (78%) of 2-(1-Phenyl-piperidin-4-yl)-
2H-benzotriazole as a pale blue color solid.
1H-NMR-(400MHz) in CDCl3: δ 7.98 (d, 2H); 7.44 (d,
2H); 7.04-6.88 (m, 5H) 4.78-4.70(m, 1H); 3.24(d, 2H);
2.56(t, 2H); 2.38 (t, 4H); m/z: 279 (M+H) +.
(1-ethoxy-1-cyclopropyloxy)-trimethyl-silane (0.12mL,
0.627mmol) was added to a solution of 2-piperidin-4-yl-2H-
benzotriazole (100mg, 0.495mmol) in acetic acid (2mL) and
stirred for 15 min, then sodium cyano borohydride (38mg,
0.627mmol) was added to the reaction mixture and heated to
60°C for 2h. Then the reaction mixture was cooled to room
temperature and evaporated with the solvent and basified
with saturated NaHCO3 solution extracted with ethyl acetate
(3x25mL). The combined organic layers were washed with
water (25mL) and brine solution (25mL). The organic layers
were evaporated by rotary to give a crude product which is
purified by column chromatography using 60-120 silica
mesh. The pure product elute at 2% methanol was washed in
chloroform to afford 45mg (44.5%) of 2-(1-cyclopropyl-
piperidin-4-yl)-2H-benzotriazole as a colorless liquid.
General Procedure for Preparation of Compounds (6d-6r,
Table 1)
Triethylamine (1.5eq) and the corresponding halo
compound (1.2eq) were added to a solution of 2-piperidin-4-
yl-2H-benzotriazole (1.0eq) in dichloromethane at 0°C. Then
the reaction mixture was allowed to reach room temperature
for 1-12h. The mixture was washed with water and brine
solution and extracted with DCM. The organic layers were
dried over Na2SO4, evaporated by rotary to afford the
corresponding products (Table 1). All the products were
1H-NMR-(400MHz) in CDCl3: δ 7.86 (d, 2H); 7.34 (d,
2H); 4.78-4.70(m, 1H); 3.04(d, 2H); 2.50(t, 2H); 2.20 (t,
4H); 1.43 (m, 1H); 0.67-0.63 (m, 2H); 0.58-0.41 (m, 1H);
1
confirmed by TLC, Mass, FT-IR , H-NMR and 13C-NMR
+
ESI- MS: m/z: 243(M+H) ; ESI-HRMS: m/z Calcd. For
spectral analyses.
C14H18N4 [M+H] + 243.1604 Found: 243.1611.
Spectral Data for Compounds (6d-6r)
Preparation of 2-(1-Phenyl-piperidin-4-yl)-2H-benzotri-
azole (6c)
Analysis of 2-(1-propyl-piperidin-4-yl)-2H-benzotriazole
(6d)
1H-NMR-(400MHz) in CDCl3: δ 7.85 (d, 2H); 7.38 (d,
2H); 4.72-4.66(m, 1H); 3.04(d, 2H); 2.50(t, 2H); 2.38 (t,
2H); 2.24 (t, 4H) 1.62-1.54 (m, 2H); 1.08 (q, 3H): ESI- MS:
Phenyl boronic acid (60mg, 0.501mmol), pyridine
(0.1mL) and Cu (OAC)2 (91mg, 0.501mmol) were added to
a solution of 2-piperidin-4-yl-2H-benzotriazole (100mg,
0.495mmol) in dichloromethane (6mL) at room temperature.

476 Letters in Drug Design & Discovery, 2012, Vol. 9, No. 5
Jalapathi et al.
Table 2. Antibacterial Activity of Chemical Compounds
Zone of inhibition (in mm)
Name of the
compound.
Con
mcg/ml
E.coli
B.
B.
B.
Proteus.
vulgaris
Proteus
Staph.
aureus
K.pneumonia
Entero.
S.
subtilis
megatherium
pumilis
.mirabilis
aerogens
pyogens
600
900
2.23
4.5
6.32
5.56
5.92
2.03
3.27
2.65
4.29
NA
NA
3.23
6.24
3.42
6.84
5.32
2-(1-propyl-piperidin-
4-yl)-2H-
benzotriazole(6d)
12.17
10.63
10.69
10.24
600
900
1.98
3.75
2.12
3.80
5.92
7.42
4.45
8.60
4.32
8.49
6.62
12.0
3.15
6.28
5.19
6.18
2-[1-(3-Chloro-
propyl)-piperidin-4-
yl)-2H-
11.29
14.80
10.28
13.21
benzotriazole(6e)
600
900
3.26
6.50
6.19
3.15
6.89
6.10
1.12
2.45
2.12
4.28
5.03
10.2
2.13
4.25
6.19
NA
NA
1-(4-benzotriazol-2-yl-
piperidin-1-yl)-2-
phenyl-ethanone(6g)
13.12
11.20
13.45
600
900
6.32
5.32
5.12
6.32
13.0
4.25
8.46
6.13
5.92
6.12
5.25
5.16
3-(4-benzotriazol-2-yl-
piperidin-1-yl)-
propionic acid ethyl
ester(6q)
12.40
10.80
10.22
12.06
11.02
12.02
10.28
10.20
600
900
1.15
2.78
NA
NA
5.26
2.26
5.25
4.26
8.55
5.52
5.69
11.2
5.31
6.18
5.26
2-(4-benzotriazol-2-yl-
piperidin-1-yl)-N, N-
dimethyl-2-oxo-
10.24
10.25
10.22
11.25
10.48
acetamide(6r)
600
900
2.26
4.90
5.21
10.2
5.52
3.35
6.25
4.92
9.04
4.95
3.65
7.25
3.26
6.29
2.25
4.25
4.86
9.42
2-(4-benzotriazol-2-yl-
piperidin-1-yl)-
ethanol(6f)
11.27
10.25
600
900
3.36
6.85
5.52
11.2
6.12
5.21
5.12
5.59
4.56
8.67
2.26
5.45
6.12
4.26
8.67
4-(4-Benzotriazol-2yl-
piperidin-1-yl)-butan-
2-ol(6k)
12.06
10.29
10.11
11.25
12.50
600
900
1.45
2.24
2.36
4.25
6.15
NA
NA
4.25
8.49
4.52
8.25
5.68
2.26
4.47
6.91
3.65
6.47
2-(1-Methyl-piperdin-
4-yl)-2H-
benzotriazole(6a)
13.45
10.25
13.39
600
900
5.52
6.69
5.56
2.26
4.26
3.36
6.80
3.21
6.50
5.59
3.36
6.28
6.16
2.25
4.27
(4-benzotriazol-2-yl-
piperidin-1-yl)-oxo-
acetic acid ethyl
ester(6h)
10.02
13.02
11.25
11.90
12.49
600
900
6.96
12.9
3.36
6.24
5.26
1.98
3.75
5.05
2.98
4.00
6.69
5.05
2.45
4.47
2.78
4.22
2-(1-cyclopropyl-
piperidin-4-yl)-2H-
benzotriazole(6b)
10.28
10.45
12.49
10.24
600
900
3.06
6.14
8.44
6.23
7.25
8.90
12.82
20.34
10.34
20.01
3.24
6.54
4.47
8.76
8.91
Standard:
Streptomycin
16.22
12.80
14.50
16.09
16.47
+
+
m/z: 245 (M+H) ; ESI-HRMS: m/z Calcd. For C14H20N4
[M+H] +245.2748; Found: 245.2742:
3409, 2925, 1456, 1171, 1054. ESI- MS: m/z: 247 (M+H) ;
+
ESI-HRMS: m/z Calcd. For C13H18N4O [M+H] 247.1671
Found: 247.1678.
Analysis of 2-[1-(3-Chloro-propyl)-piperidin-4-yl)-2H-
benzotriazole (6e):
Analysis of 1-(4-benzotriazol-2-yl-piperidin-1-yl)-2-phenyl-
ethanone (6g)
1H-NMR-(400MHz) in CDCl3: δ 8.10 (d, 2H); 7.96 (d,
2H); 7.66 (t, 1H); 7.48 (m, 2H) 7.40 (m, 2H); 4.84-4.79(m,
1H); 3.90(s, 2H); 3.14(t, 2H); 2.60-2.47(m, 4H); 2.36 (t, 2H);
FT-IR in cm-1: 3058, 2939, 1674, 1448, 1277; ESI- MS:
1H-NMR-(400MHz) in CDCl3: δ 7.85 (d, 2H); 7.37 (d,
2H); 4.82-4.73(m, 1H); 3.63(t, 2H); 3.12(d, 2H); 2.64(t, 2H);
2.54 (t, 2H); 2.44-2.36 (m, 4H); 1.98 (q, 2H): m/z: 279
+ 13
(M+H) . C-NMR in CDCl3: δ 29.64, 31.16, 43.05, 51.56,
55.89, 63.55, 117.95, 126.12, 143.
+
m/z: 321 (M+H) ; ESI-HRMS: m/z Calcd. For C19H20N4O
Analysis of 2-(4-benzotriazol-2-yl-piperidin-1-yl)-ethanol
(6f)
[M+H] + 321.1710 Found: 321.1717.
Analysis of (4-benzotriazol-2-yl-piperidin-1-yl)-oxo-acetic
acid ethyl ester(6h)
1H-NMR-(400MHz) in CDCl3: δ 7.90 (d, 2H); 7.40 (d,
2H); 5.09-5.02(m, 1H); 4.35(q, 2H); 3.42(t, 2H); 3.24(t, 2H);
1H-NMR--(400MHz) in DMSO d6: δ 7.85 (d, 2H); 7.40
(d, 2H); 4.85-4.80(m, 1H); 3.66(t, 2H); 3.12(d, 2H); 2.68(t,
2H); 2.46-2.38 (m, 6H); 13C-NMR in CDCl3: δ 32.04,
51.90, 59.01, 63.49, 117.91, 126.15, 143. 85; FT-IR in cm-1:

An Efficient Synthesis, Characterization
Letters in Drug Design & Discovery, 2012, Vol. 9, No. 5 477
Table 3. Anti-Fungal Activity of Chemical Compounds
Zone of inhibition (in mm)
Name of the
compound.
Con
mcg/ml
Candida albucance
Fusarium oxysporium
Dreschleria halides
Colletotrichum falcatum
2-(1-propyl-piperidin-
4-yl)-2H-
benzotriazole(6d)
600
900
NA
NA
10.25
20.05
7.50
8.05
14.25
15.24
2-[1-(3-Chloro-propyl)-
piperidin-4-yl)-2H-
benzotriazole(6e)
600
900
NA
NA
9.50
2.25
5.38
7.05
18.24
13.25
1-(4-benzotriazol-2-yl-
piperidin-1-yl)-2-
phenyl-ethanone(6g)
600
900
NA
NA
5.59
8.56
5.62
10.25
16.39
10.28
3-(4-benzotriazol-2-yl-
piperidin-1-yl)-
propionic acid ethyl
ester(6q)
600
900
NA
NA
7.62
7.82
6.05
14.25
14.54
11.90
2-(4-benzotriazol-2-yl-
piperidin-1-yl)-N, N-
dimethyl-2-oxo-
600
900
6.05
5.59
3.82
6.59
5.59
12.49
10.25
10.62
acetamide(6r)
2-(4-benzotriazol-2-yl-
piperidin-1-yl)-
ethanol(6f)
600
900
5.52
4.54
9.25
5.82
3.45
6.42
10.25
11.25
4-(4-Benzotriazol-2yl-
piperidin-1-yl)-butan-
2-ol(6k)
600
900
5.52
4.26
8.28
4.21
8.24
2.35
4.49
11.06
2-(1-Methyl-piperdin-
4-yl)-2H-benzotriazole
600
900
600
900
5.59
3.32
6.25
4.82
8.50
3.26
6.25
8.52
16.25
3.49
7.25
5.26
10.05
12.50
5.25
(4-benzotriazol-2-yl-
piperidin-1-yl)-oxo-
acetic acid ethyl
ester(6h)
10.05
2-(1-cyclopropyl-
piperidin-4-yl)-2H-
benzotriazole(6b)
600
900
4.52
8.42
5.52
7.45
6.92
10.25
14.82
13.24
Standard: Itrazole
600
900
5.35
10.80
20.03
7.56
9.34
12.01
14.76
18.26
2.38-2.32 (m, 4H); 1.36 (t, 3H); FT-IR in cm-1: 3056, 2937,
1.36 (d, 3H); FT-IR in cm-1: 3418, 2930, 1711, 1454, 1375
+
+
1746, 1653, 1454, 1371; ESI- MS: m/z: 303 (M+H) ; ESI-
and 1273; ESI- MS: m/z: 275 (M+H) ; ESI-HRMS: m/z
+
HRMS: m/z Calcd. For C15H18N4O3 [M+H] 303.1816:
Calcd. For C15H22N4O [M+H] + 275.1866 Found: 275.2102;
Found: 303.1811.
Analysis
of
2-(-4-Benzotriazol-2-yl
piperidin-1-yl)-
Analysis of 2-(1-Allyl-piperidin-4-yl)-2H-benzotriazol(6i)
ethanesulfonyl chloride(6l)
1H-NMR-(400MHz) in CDCl3: δ 7.86 (d, 2H); 7.48 (d,
2H); 5.88(m, 1H); 5.26(dd, 2H); 5.06-5.01 (m, 1H); 3.42(t,
2H); 3.24(t, 2H); 2.38-2.32 (m, 4H); 13C-NMR in CDCl3: δ
24.60, 44.88, 56.80, 58.60, 116.08, 117.90, 128.40, 132.30,
143.34; m/z: 243 (M+H) +Ve Scan.
1H-NMR-(400MHz) in CDCl3: δ 7.92 (d, 2H); 7.51 (d,
2H); 5.04-4.98 (m, 1H); 3.62 (t, 2H); 3.46(t, 2H); 3.32(t,
2H); 2.98 (t, 2H); 2.38-2.32 (m, 4H); m/z: 329 (M+H) +Ve
Scan
Analysis of 1-(-4-Benzotriazol-2-yl piperidin-1-yl)-3-
dimethylamino-propan-1-one(6m)
Analysis
of
2-(1-Prop-2-ynyl-piperidin-4-yl)-2H-
benzotriazol(6j)
1H-NMR-(400MHz) in DMSOd6: δ 7.96 (d, 2H); 7.39
(d, 2H); 5.07-4.91 (m, 1H); 3.46(t, 2H); 3.32(t, 2H); 2.72-
2.65 (m, 4H); 2.43-2.35 (m, 4H); 2.34 (s, 6H): m/z: 302
(M+H) +Ve Scan
1H-NMR-(400MHz) in CDCl3: δ 7.86 (d, 2H); 7.48 (d,
2H); 5.06-5.01 (m, 1H); 3.42(t, 2H); 3.24(t, 2H); 2.38-2.32
(m, 4H); 2.06 (s, 1H):m/z: 239 (M-H) .
Analysis of 4-(4-Benzotriazol-2yl-piperidin-1-yl)-butan-2-
ol(6k)
Analysis of 2-[1-(4-Methoxy-benzyl)-piperidin-4-yl]-2H-
benzotriazole(6n)
1H-NMR-(400MHz) in CDCl3: δ 7.86 (d, 2H); 7.48 (d,
2H); 5.06-5.01 (m, 1H); 4.02-3.94 (M, 1H); 3.62 (t, 2H);
3.42(t, 2H); 3.24(t, 2H); 2.38-2.32 (m, 4H); 2.06 (t, 2H):
1H-NMR-(400MHz) in CDCl3: δ 7.96 (d, 2H); 7.42 (d,
2H); 7.12 (d, 2H); 6.90 (d, 2H); 5.07-4.91 (m, 1H); 3.98 (s,

478 Letters in Drug Design & Discovery, 2012, Vol. 9, No. 5
Jalapathi et al.
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Antonio, C.; Michele, P.; Gianpiero, B.; Bernardetta, B.; Marta,
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3H); 3.72 (s, 2H); 3.46(t, 2H); 3.32(t, 2H); 2.43-2.35 (m,
4H): m/z: 301 (M-H) -Ve Scan
Analysis
of
2-[1-(4-Nitro-benzyl)-piperidin-4-yl]-2H-
benzotriazole(6o)
[5]
[6]
[7]
1H-NMR-(400MHz) in CDCl3: δ 7.96 (d, 2H); 7.42 (d,
2H); 7.20 (d, 2H); 6.92 (d, 2H); 5.07-4.91 (m, 1H); 4.28 (s,
2H); 3.46(t, 2H); 3.32(t, 2H); 2.43-2.35 (m, 4H): m/z: 336
(M-H) -Ve Scan.
Analysis
of
2-[1-(3-Nitro-benzyl)-piperidin-4-yl]-2H-
[8]
[9]
benzotriazole(6p)
1H-NMR-(400MHz) in CDCl3: δ8.12 (d, 2H); 7.96 (d,
2H); 7.45-7.40 (m, 2H); 6.92 (d, 2H); 5.08-4.90 (m, 1H);
4.68 (s, 2H); 3.52(t, 2H); 3.30(t, 2H); 2.43-2.35 (m, 4H):
m/z: 338 (M+H) +Ve Scan
[10]
[11]
[12]
Analysis of 3-(4-benzotriazol-2-yl-piperidin-1-yl)-propionic
acid ethyl ester(6q)
1H-NMR-(400MHz) in CDCl3: δ7.87 (d, 2H); 7.40 (d,
2H); 4.77-4.72 (m, 1H); 4.14(q, 2H); 3.06(t, 2H); 2.77(t,
2H); 2.58 (t, 2H); 2.45-2.35 (m, 4H); 13C-NMR in CDCl3:
δ14.80, 22.34, 24.30, 33.90, 49.64, 50.12, 57.17, 60.13,
117.12, 128.14, 143.84, 162.19; ESI- MS: m/z: 303 (M+H)
N. Lebouvier.; F. Pagniez.; M. Duflos.; P. Le pape.; Y. M. Na.; G.
Le Baut.; M. Le Borngne.; Bioorg. Med. Chem. Let., 2007, 17,
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P. Sanna, A. Carta, M. E. R. Nikookar. Synthesis and antitubercular
activity of 3-aryl substituted-3-[1H (2H) benzotriazole-1-(2)-yl]
[13]
acrylonitriles. Eur. J. Med Chem., 2000, 35(5), 535-543.
Balasubramanian, S.; Ramalingan, C.; Aridoss, G.; Cavilan, S.;
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Daniel, T.; Smoth.; Rivi, S.; Richard, B. B.; Jennifer, M. M.;
Kevin, J.; Stephen, R. B.; 2005, Eur. J. Med. Chem., 40, 908-917.
Hong Woo, L.; Bok Young, K.; JoongBok, A.; Sung, K. K.; Jung,
H. L.; Jae, S. S., Sang, J. L., Seung, S. Y., 2005, Eur. J. Med.
Chem., 40, 862-874
ꢀ
[14]
[15]
[16]
+
+; ESI-HRMS: m/z Calcd. For C16H22N4O2 [M+H]
321.1812; Found: 321.1816.
Analysis of 2-(4-benzotriazol-2-yl-piperidin-1-yl)-N, N-
dimethyl-2-oxo-acetamide(6r)
1H-NMR-(400MHz) in DMSO-d6: δ7.87 (d, 2H); 7.40
(d, 2H); 4.98 (quintet, 1H); 3.38(t, 4H); 2.98(s, 6H); 2.42 (t,
4H); FT-IR in cm-1: 3441, 2924, 1644, 1433, 1271,
1174.m/z: 302 (M+H) +Ve Scan.
[17]
[18]
[19]
Jae, S. S.; Soon, K. A.; sang, J. L.; Swung, S. Y.; 2005, Eur.J. Med.
Chem., 40, 862-874.
Hachiro, S.; Shin, A.; Yoshiharu, Y.; Kiyomi, Y.; 1990, J. Med.
Chem., 33, 1880-1881.
Sanjeeva Reddy, CH.; Jalapathi, P.; Nagaraj, A. A new and
efficient method for the synthesis of 5-aryl methelene-pyrimidine-
2, 4, 6-trione under solvent and catalyst free conditions. Indian
Journal of Chemistry, 2007, 46B, 660-663.
CONFLICT OF INTEREST
[20]
[21]
James, B. T.; Robert, N. A.; Richard, B. R.; Scott, E. F. S.; Wayne,
M.; Ariane, A. V.; Heng, X.; Christina, M. D.; Lu, Y. F.; Buddy, E.
C.; Dennis, M. Z.; Ivy, C. F.; 2001, J. Med. Chem., 44, 2687-2690.
Jason, D. Katz.; James, P. Jewell.; David, J.; Guerin.;
JongwonLim.; Christopher, J.; Dinsmore.; Sujal, V.; Desghmukh,
Bo-sheng pan, C.; Gary Marshall.; Wei Lu.; Michael, D.; Altman.;
William, K.; Dahlberg.; Lenora Davis.; Danielle Falcone.; Ana E.;
Declared none.
ACKNOWLEDGEMENTS
Declared none.
Gabarda.; Gaozhen Hang. Discovery of
a
5H-benzo[4,5]
cycloheptal[1,2-b]pyridine-5-one(MK-2461)inhibitor of c-Met
kinase for the treatment of cancer. J. Med. Chem., 2011, 54, 12,
4092-4108.
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