Devender Mandala et al.

/ Journal of Pharmacy Research 2012,5(7),3848-3854

Research Article Available online through
ISSN: 0974-6943 www.jpronline.info
Facile Synthesis, Characterization and Antimicrobial Evaluation of
N-Substituted-1-Piperidin-4-yl-1H-Benzotriazole
Devender Mandalaa, b, Jalapathi Pochampallia *, Sravanthi Chada a , Umapathi Nallaa , Rajakomuraiah.Tc
a
Department of Chemistry, PG College of Science, Osmania University, Hyderabad-500004, India
b
Allied Fabrichem Pvt. Ltd, Plot No-185, Phase-II, IDA-Mallapur, Hyderabad-500076, India
c
Department of Microbiology, Kakatiya University, Warangal-506009, India
Received on:07-04-2012; Revised on: 12-05-2012; Accepted on:16-06-2012

ABSTRACT
N-substituted 1- piperidin-4-yl-1H-benzotriazole (6a-6q) have been synthesized from 4-hydroxy piperidine-1-carbaxylic acid tert-butyl ester. The newly
synthesized compounds were screened for their anti bacterial activity against six gram-positive bacteria viz. (Bacillus subtilis, Bacillus megaterium, Bacillus
pumilis, Staphylococcus aurius, Enterobactor aerogens and Streptococcus pyrogens) and four Gram negative bacteria (Escherichia coli, Proteus vulgaris,
Proteus mirabilis and Klebsiella pneumonia). The compounds were also screened for their antifungal activity viz Candida albicance, Fusarium oxysporum,
Drechslera halodes and Colletotrichum falcatum.

KEY WORDS: Antibacterial activity, Antifungal activity, Benzotriazole, Halo compounds, Piperidine derivatives.

INTRODUCTION:
Benzotriazole derivatives have occupied a unique position for their biologi- signals [7.25(CDCl3 ) and 2.50(DMSO-d6 )]. All chemical shifts recorded in
cal, chemical and industrial importance. These derivatives exhibit a excellent (ppm) using TMS as an internal standard. The mass spectra were re-
degree of analgesic, anti-inflammatory [1] diuretic, antiviral and antihyper- corded on Agilent ion trap MS. Spectrometer at energy of ionizing electron
tensive activities [2-4]. Synthesis and biological activity of benzotriazole equal to 70ev. All the reagents were purchased from Aldrich, Merck and
derivatives as antiprotozoal agents [5] have been reported in the literature. Acros Organics and used without further purification.
Benzotriazoles acts as a precursor in many organic synthesis [6, 7] and has
proven to be fertile source of medicinal agents such as antimicrobial [8], RESULTS AND DISCUSSION:
anticonvulsant and anti-tumor [9] etc. Recent study reveals that several N- The novel N-alkyl piperidine benzotriazoles were synthesized from com-
alkyl benzotriazole derivatives represented an interesting class of heterocy- mercially available and low cost material 4-oxo-piperidine-1-carboxylic acid
clic [10] and became the most rapidly expanding group of antibacterial and tert-butyl ester. The reduction of this 4-oxo-piperidine-1-carboxylic acid
antifungal compounds with the advantage of low toxicity, high oral tert-butyl ester with sodium borohydride in methanol to yielded 4-hy-
bioavailability and broadspectrum activity [11-13]. droxy-piperdine-1-carbaxylic acid tert-butyl ester and followed by pro-
tected with methanesulfonyl chloride in presence of Et N/acetonitrile to
Many piperidine derivatives have been mentioned in preclinical and clini- afforded 4-Methanesulfonyloxy-piperidine-1-carbaxylic 3acid tert-butyl es-
cal studies [14]. Besides the interesting structural features, these derivatives ter (2). The reaction between 4-Methanesulfonyloxy-piperidine-1-carbaxylic
are also of pharmaceutical interest as exhibit a wide range of biological acid tert-butyl ester (2)& benzotriazole (3) in presence of K2 CO3 in DMF
activities [15]. Nevertheless, the variety of functionality and substitution to give two regioisomers of piperidine benzotriazoles 4a & 4b, because N-
patterns found in piperidine targets and widely accepted concept that the substituted benzotriazoles exist as two isomeric forms 1H- and 2H-substi-
biological properties are highly dependent on the type and location of tuted, however the energy difference between the two isomers is very
substitution on the heterocyclic ring [16]. Since several years we have been little[18], and according to Alan R Katritzky [19] while using polar solvents in
working on design and synthesis of novel bio active heterocyclic molecules reaction medium the 1H-isomeric form will predominated. The compound
[17]
. In this connection we report synthesis and microbial activity of new 4a and 4b was separated by column chromatography and characterized by
molecules which contain piperidine and benzotriazole moieties within the 1 H-NMR & 13 C NMR. From this the compounds (4a) & (4b) are regioisomers
[20]
framework. . The compound 4a deprotected with methanol in HCl to produce 1-
Piperidin-4-yl-1H-benzotriazole (5), which was individually allowed to
MATERIALS & METHODS: react with halo/other substituted compounds to produce the corresponding
Thin Layer Chromatography (TLC) was performed on E.Merk AL Silica N-substituted piperidyl benzotriazoles (6a-6q). In case of 6b the yield is
gel 60 F254 plates and visualized under UV light. The infrared (IR) spectra low compared to all other compounds because in this reaction the byproduct
were determined in a perkin-Elmer Fourier transform (FDIR spectrum). is opened cyclopropyl ring to form 1-(1-propyl-piperidin-4-yl)-1H-
1 +
1
H-NMR spectra were recorded on Varian EM-360 (400MHz mercury benzotriazole). It is confirmed by H-NMR and Mass (m/z: 245, M+H ).
plus) spectrometer in DMSO-d6 or CDCl3 and calibrated using solvent
All the products were purified by column chromatography using silica gel
*Corresponding author. (60-120mesh) the structures of the compounds were confirmed by 13 C &
Jalapathi Pochampalli, 1
H-NMR using CDCl3 and DMSO-d6 as solvents and also Mass & HRMS
Dept. of Chemistry, spectral analysis.
PG College of Science,
Osmania University,
Saifabad-500004

Journal of Pharmacy Research Vol.5 Issue 7.July 2012 3848-3854

 Devender Mandala et al. / Journal of Pharmacy Research 2012,5(7),3848-3854
Experimental procedures:
Preparation of 4-Methanesulfonyloxy-piperidne-1-carbaxylic acid tert-
butyl ester (2):
To a solution of compound 4-Hydroxy-piperidine-1-carbaxylic acid tert-
butyl ester (1.1g, 5.47mmol) in acetonitrile (10mL), added triethylamine
(1.47mL, 10.94mmol) followed by methanesulfonylchloride (0.93g,
8.20mmol) at 0 C. The reaction mixture was allowed to come to room
temperature and stirred for 24 h. The solvent was evaporated under re-
duced pressure and the residue was diluted with water (20 mL). The aque-
ous solution was extracted with ethyl acetate (25 mL x 3). The combined
organic layers was washed with water (20 mL x 3), dried over anhydrous
Na2 SO4 and evaporated under reduced pressure to gave 1.16g (76%) of 4-
Methanesulfonyloxy-piperidne-1-carbaxylic acid tert-butyl ester (2) as a
pale yellow solid.
1
H-NMR-(400MHz) in CDCl3 : 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-100) -
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):
To a solution of benzotriazole (3) (7.0g, 5.88mmol) in DMF, added K 2 CO3
(16.2g, 11.77mmol) followed by 4-Methanesulfonyloxy-piperidne-1-
carbaxylic acid tert-butyl ester (2) (18.5g, 6.47mmol) at room temperature.
The reaction mixture was heated at 100 C for 18 h. Then solvent was
removed under reduced pressure and the residue was diluted with water
(30mL). The aqueous solution was extracted with ethyl acetate (50 mL x 3).
The combined organic layers was washed with water (20mL x 3), dried over
anhydrous Na2 SO4 and evaporated under reduced pressure to get crude
compound. The crude compound was purified by column chromatography
using silica gel, (60-120 mesh), the pure compound elute at 8-12% ethyl
acetate in pet-ether as a mobile phase to afforded 13.0g (73.19%) of two
regio isomers in which 8.4g, (65%) of 4-benzotriazol-1-yl-piperidine-1-
carbaxylic acid tert-butyl ester (4a) and 4.6g, (35%) of 4-Benzotriazol-2-
yl-piperidine-1-carbaxylic acid tert-butyl ester (4b) as a off white solids.
1
H-NMR-(400MHz) in CDCl3 : (4a); 8.08 (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); 13 C-NMR in CDCl3 : 29.56, 32.22,
44.46, 65.25, 82.23, 112.95, 119.98, 128.24, 136.02 146.12, 162.34. FT-IR
in cm-1 : 2978, 1688, 1460, 1375, 1108, 750; MS: m/z: 303 (M+H) +; ESI-
HRMS: m/z calcd. For C16 H22 N4 O2 [M+H] +303.1758; Found: 303.1762.
1
H-NMR-(400MHz) in CDCl3 : (4b); 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);
13
C-NMR in CDCl3 : 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 C16 H22 N4 O2 [M+H]
+
303.1452; Found: 303.1422.
Preparation of 1- piperidin-4-yl-1H-benzotriazole (5):
To a solution of 4-benzotriazol-1-yl-piperidine-1-carbaxylic acid tert-bu-
tyl ester (4a) (4.0g, 13.24mmol) in dichloromethane (5vol, 20mL) was
added methanol-HCl (1vol, 4mL) at 0C. The reaction mixture was allowed
to come to room temperature and stirred for 18 h. The reaction mass was
flushed with nitrogen to remove excess HCl gas. The solvent was evapo-
rated under reduced pressure and basified with saturated NaHCO3 solution
Journal of Pharmacy Research Vol.5 Issue 7.July 2012
and extracted with 10% Methanol in dichloromethane (3x50mL). The
crude product was washed acetone (5mL) and diethyl ether (25mL),
dried under high vacuum to afford 3.0g (94.9%) of 1- piperidin-4-yl-
1H-benzotriazole (5) as off white solid.
1
H-NMR-(400MHz) in DMSO-d6 : 8.10 (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): MS-m/z: 203 (M+H) +; ESI-HRMS: m/z
Calcd. For C11 H14 N4 [M+H] +203.1291; Found: 203.1295.
Preparation of 1-(1-cyclopropyl-piperidin-4-yl)-1H-benzotriazole
(6b):
(1-ethoxy-1-cyclopropyloxy)-Trimethyl-silane (0.12mL, 0.627mmol)
was added to solution of 1- piperidin-4-yl-1H-benzotriazole (5) (100mg,
0.418mmol) in acetic acid (2mL) stirred for 15min. then sodium cyano
borohydride (38mg, 0.627mmol) added to the reaction mixture and heated
to 60C for 2h. Then the reaction mixture cool to room temperature and
evaporated the solvent and basified with saturated NaHCO3 solution
extracted with ethyl acetate (3x25mL). The combined organic layers
washed with water (25mL), brine solution (25mL). The organic layers
evaporated by rotary to give crude product which is purified by column
chromatography using 60-120 silica mesh. The pure product elute at
2%methanol in chloroform to afford 45mg (44.7%) of 1-(1-cyclopropyl-
piperidin-4-yl)-1H-benzotriazole (6b) as a color less liquid.
1
H-NMR-(400MHz) in CDCl3 : 8.04 (d, 1H); 7.65(d, 1H); 7.38 (t,
1H); 7.32 (t, 1H); 4.78-4.70(m, 1H); 3.08(d, 2H); 2.62(t, 2H); 2.28 (t,
4H); 1.43 (m, 1H); 0.67-0.63 (m, 2H); 0.58-0.41 (m, 1H); MS-m/z:243
(M+H) + , ESI-HRMS: m/z calcd. For C14 H 18 N4 [M+H] +243.2107;
Found: 243.2112.
Preparation of 1-(1-Phenyl-piperidin-4-yl)-1H-benzotriazole (6c)
Phenyl boronic acid (60mg, 0.501mmol), pyridine (0.1mL) and
Cu(OAC)2 (91mg, 0.501mmol) was added to a solution of 1- piperidin-
4-yl-1H-benzotriazole (5) (100mg, 0.418mmol) in dichloromethane (6mL)
at room temperature. The reaction mixture stirred for 24h, filtered the
reaction mixture and washed with DCM. The combined organic layers
washed with water (10mL) and brine solution (10mL). The organic
solvents were evaporated by rotary to get 80mg (78%) of 1-(1-Phenyl-
piperidin-4-yl)-2H-benzotriazole (6c) as pale blue color solid.
1
H-NMR-(400MHz) in CDCl3 : 8.04 (d, 1H); 7.65(d, 1H); 7.38 (t,
1H); 7.32 (t, 1H); 7.12(d, 2H) 6.98 (d, 2H); 6.78 (m, 1H); 4.80-4.75(m,
1H); 3.31(d, 2H); 2.56(t, 2H); 2.38 (t, 4H); 13 C-NMR in CDCl3 :
26.78, 46.08, 53.52, 114.34, 119.65, 127.86, 131.96, 133.20, 145.71,
150.34; MS-m/z: 279 (M+H) +, ESI-HRMS: m/z calcd. For C17 H18 N4
[M+H] +279.1527; Found: 279.1510.
General preparation methods for N-alkyl derivatives of 1- piperidin-
4-yl-1H-benzotriazole (6d -6q):
Triethylamine (1.5eq) and corresponding halo compound (1.1eq) was
added to a solution of 1- piperidin-4-yl-1H-benzotriazole (5) (1.0eq) in
dichloromethane at 0C. Then the reaction mixture allow to room tem-
perature for 1-12h. The mixture was washed with water and brine solu-
tion and extracted with dichloromethane. The organic layers dried over
Na 2 SO 4 , evaporated by rotary to afford corresponding products, the
products were purified by column chromatography using ethyl acetate
in pet ether as mobile phase. The products were confirmed by 1 H-
NMR, 13 C-NMR, FT-IR, Mass and HRMS spectral analysis.
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 Devender Mandala et al. / Journal of Pharmacy Research 2012,5(7),3848-3854
Table 1: synthesis of N-alkyl derivatives of - 1-piperidin-4-yl-1H-benzotriazole (6a-6q):
Entries Reagents R= Product code Products Time % of yields

N N
1 HCOOH/HCHO 6a N 4h 76%
N

OEt N N
2 6b N N 2h 45%

O S iM e 3

OH N N
3 B 6c N N 24h 78%

OH

N N
4 Br 6d
N 1.5 97%
N

N N
5 6e N N 6h 98%
Cl Br
Cl

N N
6 Br 6f N 12h 76%
HO N
OH
O
Br N N
7 6g N N 12h 87%

O
N N
8 6h O 6h 87%

O N N
Cl
O
O
O

N N
9 Br 6i
N
1h 98%

Br N N
N N
10 6j 2h 98%

Journal of Pharmacy Research Vol.5 Issue 7.July 2012 3848-3854

 Devender Mandala et al. / Journal of Pharmacy Research 2012,5(7),3848-3854
Entries Reagents R= Product code Products Time % of yields

OH N N
11 6k
N N OH 12h 55%

Cl

O N N
N N
12 S 6l
O 7h 58%
C l Cl S
O O Cl

N N
O
N O
13
Cl
,
Cl
6m N 8h 83%
N
NH

Cl N N
N
14 6n O 3.5h 80%
O N

Br N N
N NO2
15 6o N 2h 76%
O 2N

Br
16 6p N N NO2 9h 92%
N
NO N
2

N N
17 Br O N O
6q 4h 96%
N
O O

Antibacterial activity:
Antibacterial activity testing was carried out by using broth dilution method.
Each purified compound is dissolved in dimenthylsulfoxide (DMSO), steril-
ized by filtration using sintered glass filter and store at 37C. All the newly
synthesized compounds (6a-6q) were evaluated for in vitro antibacterial
activity against six gram positive bacteria (Bacillus subtilis, Bacillus
megaterium,Bacillus pumilis, Staphylococcus aurius, Enterobactor aerogens
and Streptococcus pyrogens), four Gram-negative bacteria (Escherichia
coli, Proteus vulgaris, Proteus mirabilis and Klebsiella pneumonia) at con-
centration of 600 and 900 mcg/mL, the bacterial liquid cultures were pre-
pared in infusion broth for their activity tests. The compounds were dis-
solved in DMSO and antibacterial activity of DMSO against the test organ-
isms was investigated, was found to nil. Antibacterial activity was deter-
mined by measuring the diameter of inhibition zone, activity of each com-
pound was compared with Streptomycin as standards.
The newly synthesized compounds showing better activity than standard
in which, proparginyl (6j), propyl (6d) and allyl (6i) were showing better
Journal of Pharmacy Research Vol.5 Issue 7.July 2012
activity against all bacteria. The compounds (6l) are found to be more active
against Klebsiella pneumonia, because it is having chloro sulfonyl moiety. It
is interesting to note that N-methyl substituted compound (6a) is showing
two fold greater potency than the standard against the E.coli bacteria in two
concentrations because of its hydrophobic nature. The remaining compounds
showed moderate to good activity against all organisms and these results are
summarized in table-2
Anti fugal activity:
The antifungal activities of the N-substituted 2-piperidine-4-yl-1H-
benzotrizoles (6a-6q) were screened against fungal organisms viz Candida
albicance, Fusarium oxysporum, Drechslera halodes and Colletotrichum
falcatum was grown for 48hrs at 25C in YPD broth (1% yeast extract, 2%
peptone and 2% dextrose), harvested by centrifugation and then washed
with sterile distilled water. The fungal activity was determined by using
Itrazole as standard, and the newly synthesized compounds were showed
good to moderate activity in which the compounds having 3-hydroxy butyl
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 Devender Mandala et al. / Journal of Pharmacy Research 2012,5(7),3848-3854
Conc. Zone of inhibition (in mm)
Name of the compound. mcg/m E. B. B. B. Proteus P. Staph. K. Entero. S.
coli subtilis megatherium pumilis vulgaris mirabilis aureus pneumonia aerogens pyogens

1-(1-Methyl-piperdin-4-yl)-1H-benzotriazole( 6a) 600 6.96 3.36 5.26 1.98 5.05 2.98 6.69 5.05 2.45 2.78
900 12.9 6.24 10.28 3.75 10.45 4.00 12.49 10.24 4.47 4.22

1-(1-propyl-piperidin-4-yl)-1H-benzotriazole (6d) 600 1.45 2.36 6.15 NA 4.25 4.52 5.68 2.26 6.91 3.65
900 2.24 4.25 13.45 NA 8.49 8.25 10.25 4.47 13.39 6.47

(4-benzotriazol-1-yl-piperidin-1-yl)-oxo-acetic acid ethyl ester (6h) 600 6.32 5.32 5.12 6.32 4.25 6.13 5.92 6.12 5.25 5.16
900 12.40 10.80 10.22 13.0 8.46 12.06 11.02 12.02 10.28 10.20

1-(1-Allyl-piperidin-4-yl)-1H-benzotriazole (6i)
600 2.01 5.29 4.26 4.52 2.35 2.21 4.98 5.52 6.02 2.05
900 3.45 10.11 8.45 8.60 4.28 4.55 9.20 10.47 11.25 4.52

1-(1-Prop-2-ynyl-piperidin-4-yl)-2H-benzotriazole (6j) 600 1.13 5.12 2.56 2.25 6.15 2.12 5.05 6.26 6.74 5.50
900 2.09 10.24 4.25 4.52 12.52 4.28 10.28 12.49 13.45 10.25

4-(4-Benzotriazol-1yl-piperidin-1-yl)-butan-2-ol (6k) 600 2.06 4.45 4.26 5.26 5.21 5.50 3.30 2.60 2.05 4.95
900 4.25 8.21 8.98 10.25 10.45 10.55 6.25 4.28 4.25 9.29

2-(-4-Benzotriazol-1-yl piperidin-1-yl)-ethanesulfonyl chloride (6l) 600 2.05 5.56 2.56 2.35 6.65 4.45 3.25 6.65 6.89 3.64
900 3.9 10.25 4.25 4.27 12.49 8.52 6.42 13.42 11.25 6.25

1-(-4-Benzotriazol-1-yl piperidin-1-yl)-3-dimethylamino-propan-1-one (6m) 600 5.52 6.69 5.56 2.26 3.36 3.21 5.59 3.36 6.16 2.25
900 10.02 13.02 11.25 4.26 6.80 6.50 11.90 6.28 12.49 4.27

600 2.25 3.25 5.50 4.56 5.36 4.95 5.92 2.35 4.56 5.65
1-[1-(4-Nitro-benzyl)-piperidin-4-yl]-1H-benzotriazole (6o)
900 4.25 6.28 10.25 8.25 10.85 9.52 11.25 4.29 9.25 10.27

3-(4-benzotriazol-1-yl-piperidin-1-yl)-propionic acid ethyl ester (6q) 600 3.78 NA 5.23 3.90 NA 10.89 8.80 NA 6.42 NA
900 7.16 NA 9.11 8.10 NA 19.98 16.90 NA 11.23 NA

Standard: Streptomycin 600 3.06 8.44 6.23 7.25 8.90 12.82 10.34 3.24 4.47 8.91
900 6.14 16.22 12.80 14.50 16.09 20.34 20.01 6.54 8.76 16.47

(6k) substitution and N, N-dimethyl oxamide (6m) substituents were show
ing more activity against Candida albicance. It may be attributated that polar
groups have been played vital role in that. The compounds having ethyl
oxolyl (6h) and chloro sulfonyl (6l) substituents were responsible for supe-
rior activity against Drechslera halodes, and the compounds 6d, 6h, 6o and
6q were showing moderate activity against Drechslera halodes and Fusarium
oxysporum respectively. 6d and 6h were not showing any activity against
Candida albicance. The detailed numerical data listed in table-3.
Analysis of 1-(1-propyl-piperidin-4-yl)-1H-benzotriazole(6d):1 H-NMR-
(400MHz) in CDCl3 : 8.08 (d, 1H); 7.62 (d, 1H); 7.49 (t, 1H); 7.38 (t, 1H);
4.76-4.66(m, 1H); 3.14(d, 2H); 2.54(q, 2H); 2.42 (q, 2H); 2.28-2.18 (m, 4H)
1.62-1.54 (m, 2H); 0.96 (q, 3H): MS-m/z: 245 (M+H) +; ESI-HRMS: m/z
Calcd. For C14 H20 N4 [M+H] +245.2738; Found: 245.2732
Analysis of 1-[1-(3-Chloro-propyl)-piperidin-4-yl]-1H-benzotriazole
(6e): 1 H-NMR-(400MHz) in CDCl3 : 8.08 (d, 1H); 7.62 (d, 1H); 7.40 (t,
1H); 7.38 (t, 1H); 4.76-4.66(m, 1H); 3.40 (t, 2H); 3.14(d, 2H); 2.54(q, 2H);
2.42 (q, 2H); 2.28-2.18 (m, 4H) 1.62-1.54 (m, 2H); 13 C-NMR in CDCl3 :
24.28, 32.32, 45.76, 49.80, 51.98, 53.52, 118.35, 128.12, 133.46, 147.71;
MS-m/z:279 (M+H) +.
Analysis of 2-(4-benzotriazol-1-yl-piperidin-1-yl)-ethanol (6f): 1 H-
NMR-(400MHz) in DMSO-d6 : 8.09 (d, 1H); 7.82 (d, 1H); 7.40 (t, 1H);
7.38 (t, 1H); 5.02-4.92(m, 1H); 3.94 (t, 2H); 3.14(t, 2H); 2.54(t, 2H); 2.42
(q, 2H); 2.28-2.18 (m, 4H); FT-IR in cm-1 : 3410, 2950, 1450, 1175, 1055;
MS-m/z 247 (M+H) +; ESI-HRMS: m/z Calcd. For C13 H18 N4 O [M+H] +
247.1671 Found: 247.1678.
Analysis of 1-(4-benzotriazol-1-yl-piperidin-1-yl)-2-phenyl-ethanone
(6g): 1 H-NMR-(400MHz) in CDCl3 : 8.12 (d, 1H); 7.86 (d, 1H); 7.40 (t,
1H); 7.38 (t, 1H); 7.32-7.24 (m, 5H); 4.83-4.76(m, 1H); 3.99 (s, 2H); 3.18(t,
2H); 2.58(t, 2H); 2.28-2.18 (m, 4H); 13 C-NMR in CDCl3 : 26.10, 39.62,
43.54, 59.80, 117.75, 126.46, 127.86, 129.98, 133.46, 140.01, 145.21, 192.38;
m/z: 321 (M+H) +, ESI-HRMS: m/z Calcd. For C19 H20 N 4 O [M+H] +
321.1675: Found: 321.1679.
Analysis of (4-benzotriazol-1-yl-piperidin-1-yl)-oxo-acetic acid ethyl
ester(6h): 1 HNMR-(400MHz) in CDCl3 : 8.09 (d, 1H); 7.86 (d, 1H); 7.40
(t, 1H); 7.38 (t, 1H); 4.99-4.86(m, 1H); 4.32 (q, 2H); 3.38 (t, 2H); 3.18(t,
2H); 2.28-2.18 (m, 4H); 1.38 (t, 3H); 13 C-NMR in CDCl3 : 14.23, 28.22,
39.62, 57.66, 59.32, 119.55, 128.86, 133.46, 142.98, 161.20, 162.98; FT-IR
in cm-1 : 3050, 2935, 1747, 1686, 1450, 1371; MS: m/z: 303 (M+H) +; ESI-
HRMS: m/z Calcd. For C15 H18 N4 O3 [M+H] + 303.1816: Found: 303.1811.
Analysis of 1-(1-Allyl-piperidin-4-yl)-1H-benzotriazole(6i): 1 HNMR-
(400MHz) in CDCl3 : 8.08 (d, 1H); 7.64 (d, 1H); 7.48 (t, 1H); 7.38 (t,
1H); 5.96-5.89 (m, 1H); 5.20 (dd, 2H); 4.78-4.71(m, 1H); 3.17 (q, 4H); 3.56
(q, 2H); 2.26-2.18 (m, 4H); MS-m/z: 243 (M+1) +; ESI-HRMS: m/z Calcd.
For C14 H18 N4 [M+H] + 243.1608: Found: 243.1604.
Analysis of 1-(1-Prop-2-ynyl-piperidin-4-yl)-2H-benzotriazole(6j):
1
HNMR-(400MHz) in CDCl3 : 8.08 (d, 1H); 7.64 (d, 1H); 7.48 (t, 1H);
7.38 (t, 1H); 4.96-4.89 (m, 1H); 3.42(t, 2H); 3.24(t, 2H); 3.10 (s, 2H); 2.38-
2.32 (m, 4H); 2.06 (s, 1H); 13 C-NMR in CDCl3 : 26.34, 45.78, 49.65,
57.66, 69.86, 77.22, 117.11, 128.36, 133.46, 147.08; m/z: 239 (M-H)-.

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 Devender Mandala et al. / Journal of Pharmacy Research 2012,5(7),3848-3854
Table 3: Anti-Fungal Activity of N-alkyl derivatives of - 1-piperidin-4-yl-1H-benzotriazole:
Name of the compound Conc. Zone of inhibition (in mm)
cg/ml Candida Fusarium Dreschleria Colletotrichum
albucance oxysporium halides falcatum

1-(1-Methyl-piperdin-4-yl)-1H-benzotriazole (6a) 600 5.52 4.54 5.82 3.45

900 10.25 9.25 11.25 6.42
1-(1-propyl-piperidin-4-yl)-1H-benzotriazole (6d) 600 NA 7.62 7.82 6.05
900 NA 14.25 14.54 11.90
(4-benzotriazol-1-yl-piperidin-1-yl)-oxo-acetic acid ethyl ester (6h) 600 NA 5.59 8.56 5.62
900 NA 10.25 16.39 10.28
1-(1-Allyl-piperidin-4-yl)-1H-benzotriazole (6i) 600 5.52 4.26 4.21 2.35
900 11.06 8.28 8.24 4.49
1-(1-Prop-2-ynyl-piperidin-4-yl)-2H-benzotriazole (6j) 600 5.52 2.45 5.26 2.32
900 10.25 4.85 10.28 4.60
4-(4-Benzotriazol-1yl-piperidin-1-yl)-butan-2-ol (6k) 600 5.59 3.32 3.26 3.49
900 12.50 6.25 6.25 7.25
2-(-4-Benzotriazol-1-yl piperidin-1-yl)-ethanesulfonyl chloride (6l) 600 5.36 5.92 4.52 2.25
900 11.25 11.25 8.65 4.28
1-(-4-Benzotriazol-1-yl piperidin-1-yl)-3-dimethylamino-propan-1-one (6m) 600 6.05 5.59 3.82 5.59
900 12.49 10.25 6.59 10.62
1-[1-(4-Nitro-benzyl)-piperidin-4-yl]-1H-benzotriazole (6o) 600 4.52 5.52 7.45 6.92
900 8.42 10.25 14.82 13.24
3-(4-benzotriazol-1-yl-piperidin-1-yl)-propionic acid ethyl ester (6q) 600 5.25 4.82 8.52 5.26
900 10.05 8.50 16.25 10.05
Standard: Itrazole 600 5.35 10.80 7.56 9.34
900 12.01 20.03 14.76 18.26

O
S
OH O O
(a ) (b ) N N O
N + N N
N N N O
76 % , 24 h N 7 3% , 1 8h
O O O O (3 )
N (4 b-3 5 % )
( 4 a -6 5 % )
(1 ) (2 ) O
O

R e a g e n t s & C o n d it i o n s : ( a ) M e s y l c h l o r id e , E t 3 N / A C N ; (b ) B e n z o t r ia z o l e ( 3 ) , K 2 C O 3 /D M F
Scheme 01:
N N
(d ) N
N (c ) N N
N N
4 5 -9 8 % , 2 - 2 4 h
N
9 5 % ,1 8 h

N N N
4a O (5 ) H
O R
( 6a - 6 q )

R e a g e n t s & C o n d i o ti o n s : (c ) M e t h a n o l ic H C l, ( d ) H a l o a n d o th e r c o m p o u n d s ( 6 a - 6 q ) .
Scheme 02:
Analysis of 4-(4-Benzotriazol-1yl-piperidin-1-yl)-butan-2-ol(6k): 7.40 (t, 1H); 7.38 (t, 1H); 5.04-4.98 (m, 1H); 3.68 (t, 2H); 3.16(t, 2H);
1
HNMR-(400MHz) in CDCl3 : 8.08 (d, 1H); 7.62 (d, 1H); 7.40 (t, 1H); 3.32(t, 2H); 2.98 (t, 2H); 2.38-2.32 (m, 4H); MS-m/z: 329 (M+1) +.
7.38 (t, 1H); 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): 1.36 (d, 3H); 13 C-NMR in Analysis of 1-(-4-Benzotriazol-1-yl piperidin-1-yl)-3-dimethylamino-
CDCl 3 : 24.12, 27.76, 40.78, 45.50, 49.65, 56.16, 65.14, 119.10, 127.66, propan-1-one(6m): 1 HNMR-(400MHz) in DMSO-d6 : 8.08 (d, 1H); 7.62
133.46, 146.88; MS-m/z: 275 (M+H), ESI-HRMS: m/z Calcd. For (d, 1H); 7.40 (t, 1H); 7.38 (t, 1H) 5.02-4.91 (m, 1H); 3.46(t, 2H); 3.32(t,
C15 H22 N4 O [M+H] + 275.1798: Found: 275.1754. 2H); 2.72-2.65 (m, 4H); 2.43-2.35 (m, 4H); 2.34 (s, 6H); MS-m/z: 302
(M+H) +, ESI-HRMS: m/z Calcd. For C 16 H23 N5 O [M+H] + 302.1704: Found:
Analysis of 2-(-4-Benzotriazol-1-yl piperidin-1-yl)-ethanesulfonyl 302.1721.
chloride(6l): 1 HNMR-(400MHz) in CDCl3 : 8.09 (d, 1H); 7.82 (d, 1H);

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 Devender Mandala et al. / Journal of Pharmacy Research 2012,5(7),3848-3854
Analysis of 1-[1-(4-Methoxy-benzyl)-piperidin-4-yl]-1H-benzotriazole
(6n):1 HNMR-(400MHz) in CDCl3 : 8.12 (d, 1H); 7.86 (d, 1H); 7.40 (t,
1H); 7.38 (t, 1H); 7.18 (d, 2H); 6.90 (d, 2H); 5.01-4.96 (m, 1H); 3.88 (s,
3H); 3.72 (s, 2H); 3.36(t, 2H); 3.22(t, 2 H); 2.43-2.35 (m, 4H); 13 C-NMR in
DMSO-d6 : 28.22, 49.62, 55.66, 56.80, 59.32, 114.50, 119.55, 124.36,
126.76, 131.22, 133.46, 137.24, 146.98, 160.56; MS-m/z: 323 (M+H) +,
ESI-HRMS: m/z Calcd. For C19 H23 N4 O [M+H] + 323.2010: Found: 323.2019.
Analysis of 1-[1-(4-Nitro-benzyl)-piperidin-4-yl]-1H-benzotriazole
(6o):1 HNMR-(400MHz) in CDCl3 : 8.00 (d, 1H); 7.66 (d, 1H); 7.47 (t,
1H); 7.28 (t, 1H); 7.18 (d, 2H); 6.98 (d, 2H); 5.02-4.94 (m, 1H); 4.06 (s, 2H);
3.36(t, 2H); 3.12(t, 2H); 2.43-2.35 (m, 4H); 13 C-NMR in CDCl3 : d 27.12,
38..62, 45.56, 63.40, 117.50, 122.36, 127.42, 130.22, 135.12, 142.28, 145.76,
150.30; MS- m/z: 338 (M+H)+; ESI-HRMS: m/z Calcd. For C18 H19 N5 O2
[M+H] + 338.3578: Found: 338.3555.
Analysis of 1-[1-(3-Nitro-benzyl)-piperidin-4-yl]-1H-benzotriazole
(6p):1 HNMR-(400MHz) in CDCl3 : 8.06 (d, 1H); 7.76 (d, 1H); 7.45 (t,
1H); 7.28 (t, 1H); 7.18 (d, 1H); 6.88 (s, 1H); 6.82 (d, 1H); 6.65 (d, 1H);
4.98-4.92 (m, 1H); 4.38 (s, 2H); 3.32(t, 2H); 3.20(t, 2H); 2.43-2.35 (m, 4H);
FT-IR in cm-1 : 3050, 2935, 1512, 1456, 1351, 1176; m/z: 338 (M+1)
+
.Analysis of 3-(4-benzotriazol-1-yl-piperidin-1-yl)-propionic acid ethyl
ester(6q):1 HNMR-(400MHz) in CDCl3 : 8.07 (d, 1H); 7.58 (d, 1H); 7.46
(t, 1H); 7.36 (t, 1H); 4.78-4.66 (m, 1H); 4.16(q, 2H); 3.12(d, 2H); 2.81(t,
2H); 2.58 (t, 2H); 2.45-2.35 (m, 4H); 2.30 (t, 2H); 2.26 (t, 2H); 1.28 (t, 3H);
13
C-NMR in CDCl3 : 14.64, 28.42, 36.01, 39.80, 42.21, 55.56, 62.55,
117.30, 127.62, 135.22, 145.76, 172.98; FT-IR in cm-1 : 2950, 1732, 1445,
1165, 1058; MS: m/z: 303 (M+H) +; ESI-HRMS: m/z Calcd. For C 16 H22 N4 O2
[M+H] + 303.1812; Found: 303.1816.
CONCLUSION:
As per the literature survey it is observed that N-substituted-1-(piperidin-4-
yl)-1H-benzotriazole have been showing pharmacological activities keeping
this in view about 17 related compounds have been prepared and their
spectral analysis and biological screening have been made from these studies.
It is that these compounds are highly effective for invitro biological action.
Further work in this area of investigation is in progress.
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