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Der Pharmacia Sinica, 2012, 3 (1):156-159
ISSN: 0976-8688
CODEN (USA): PSHIBD
Synthesis of Novel N-acetyl-(3-substituted-1H-pyrazole-(4H)5-on)-yl-1,2,3,4-tetrahydrocarbazole and its antimicrobial studies
T. Surendiran
Research and Development Centre, Faculty of Chemistry, Chennai Institute of Technology,
Chennai, India
______________________________________________________________________________
ABSTRACT
A new family of Novel N-acetyl-(3- substituted-1H-pyrazole-(4H)-5-on)-yl-1,2,3,4-tetrahydrocarbazole 4(a-e) were
prepared by the cyclocondenstion of N-(hydrazino acetyl)-1,2,3,4-tetrahydrocarbazole 2 with series of substituted βketoesters3(a-e). The compound N-(hydrazino acetyl)-1, 2, 3, 4-tetrahydrocarbazole was prepared by the
condensation of N-(chloroacetyl)-1, 2, 3, 4-tetrahydrocarbazoles 1 with hydrazine hydrate. The titled compounds
have been characterized on the basis of analysis of IR, HNMR and MASS spectroscopy. All the titled compounds
4(a-e) were screened for antibacterial and antifungal activities
Keywords: N-acetyl-(3-substituted-1H-pyrazole-(4H)-5-on)-yl-1,2,3,4-tetrahydro carbazole, N-(hydrazino acetyl)1, 2, 3, 4-tetrahydrocarbazole, N-(chloroacetyl)-1, 2, 3, 4-tetrahydrocarbazoles, antibacterial and antifungal activities
_________________________________________________________________________________________
INTRODUCTION
Carbazole derivatives are important class of heterocyclic compounds possessing [1,2] variety of biological activity.
Carbazole skeleton bearing natural products fused with heterocyclic ring have drawn significant attention [3,4] due
to excellent pharmacological activities of their analogues. There are numerous evidences illustrating that the fused
ring of heterocycles at N th position have gained unique importance [5,6] on pharmacological studies. Recently, the
heterocyclic nitrogen ring system have reported been an excellent anti-microbial [7] activities. The pyrazole ring
system plays an important role in many biological processes [8, 9, 10] such as therapeutic agents, etc... As these two
heterocycles are potent as biologically active compound, in the present study we planned to prepare compounds
containing both 1,2,3,4-tetrahydrocarbazole and pyrazole structures in one compound. In view of these observation,
we report herein the reaction of substituted β-ketoesters with N-(hydrazino acetyl)-1, 2, 3, 4-tetrahydrocarbazole to
get N-acetyl-(3- substituted-1H-pyrazole-(4H)-5-on)-yl-1,2,3,4-tetrahydrocarbazole 3(a-e)
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NH2NH2.H2O
R-COCH2COOC2H5
O
CH2Cl
1
3(a-e)
N
N
O
CH2 NHNH2
2
N
O
R
3a/4a CH3
N
O
N
R
4(a-e)
3b/4b CH2 CH3
3c/4c
C6H5
3d/4d p-CH3 C6H5
3e/4e
p-Cl C6H5
Scheme-1 Synthesis of N-acetyl-(3-alkyl substituted-1H-pyrazole-(4H)-5-on)-yl-1,2,3,4-tetrahydrocarbazoles
MATERIALS AND METHODS
All the chemicals were purchased from Merk and used without purification. Melting points determined in open
capillaries on Thermonik melting point apparatus, Mumbai, India and are uncorrected. TLC analysis were done on
glass plates coated with silicagel-G and spotting was done using iodine. IR (KBr) spectra were recorded on Jasco
FT-IR 5300 spectrometer. 1H and 13C NMR spectra were in CDCl3 using jeol GSX 400 (400MHz) and Jeol ECA500
(500 MHz) NMR spectrometer. Mass spectra were recorded using Joel GC mate and MAL-DI-TOF LD
spectrometer. Column chromatography was performed using silica gel (100-200mesh).
2.1 Syntheses of N-(chloroacetyl)-1,2,3,4-tetrahydro-carbazoles
A mixture of appropriate 1,2,3,4-tetrahydrocarbazole (0.1 mole), chloroacetyl chloride (1.13g, 0.1 mole) and
anhydrous potassium carbonate (1.38 g, 0.01mole) in DMF (10 ml) was refluxed for 8 hours. The reaction mixture
was diluted with ice-cold water. The separated solid was filtered, washed with water and re-crystallized from
ethanol to give compounds 1
2.2 Syntheses of N-( hydrazino acetyl) -1,2,3,4-tetrahydrocarbazoles
The mixture of N-(chloroacetyl)-1,2,3,4-tetrahydrocarbazole 1 (2.33g, 0.1mole) and hydrazine hydrate (0.5g,
0.1mole) in DMF (10ml) was refluxed for 5 hours. The reaction was monitored by TLC for successful completion.
The reaction mixture was cooled and poured into crushed ice. Thus the solid was separated filtered, washed
thoroughly with water and re-crystallized from ethanol to furnish the compound 2.
2.3 Synthesis of N-acetyl-(3-alkyl substituted-1H-pyrazole-(4H)-5-on)-yl-1,2,3,4-tetrahydrocarbazoles
A mixture of N-(hydrazino acetyl)-1,2,3,4-tetrahydrocarbazole 3 (0.01 mole) and appropriate β-ketoesters 3a-e (0.01
mole) was refluxed in a water bath for 8 hr. The reaction was monitored by TLC for successful completion of
reaction. Then, the compound filtered off, washed with excess of water and re-crystallized from ethanol to obtained
N-acetyl-(3-alkyl substituted-1H-pyrazole-(4H)-5-on)-yl-1,2,3,4-tetrahydrocarbazole 4(a-e)
(4a) N-acetyl-(3-methyl-1H-pyrazole-(4H)-5-on)-yl-1,2,3,4-tetrahydrocarbazole
IR (KBr):1620, 1628, 1635 Cm-1; 1HNMR δ: 1.82-1.92(m,4H,2CH2), 2.40 (d,2H,CH2),2.71-2.78(m,4H,2CH2), (s,
2H,CH2-N) 4.48(s,2H,CH2-N) 5.56 (s, 1H, NH),7.08-7.10(m,4H,ArH). Melting point: 145oC; Yield 54%
Molecular
Formula: C17 H17 N3O2 (m/z) : 295.13 Elemental Analysis Calcd(Found):C: 69.14 (69.16); H:
5.80(5.82);N: 14.23 (14.26).
(4 b)N-acetyl-(3-ethyl-1H-pyrazole-(4H)-5-on)-yl-1,2,3,4- tetrahydrocarbazole
IR (KBr):1622, 1642 Cm-1; 1HNMR δ: 1.21(s,3H,CH2)1.80-1.91 (m,4H, 2CH2), 2.42(d,2H,CH2), 2.702.76(m,4H,2CH2), (s, 2H,CH2-N) 4.45(s,2H, CH2-N), 5.54 (s,1H, NH), 7.02 -7.08(m,4H,ArH) Melting point:
126oC; Yield 62%:Molecular Formula:C18 H19 N3O2 (m/z) 309.15 ;Elemental Analysis: Calcd.(Found) :C :
69.88(69.91) ; H: 6.19(6.23);N: 13.58 (13.60).
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(4c)N-acetyl-(3-phenyl-1H-pyrazole-(4H)-5-on)-yl-1,2,3,4-tetrahydrocarbazole
IR (KBr):1625, 1680, 1630 Cm-1; 1HNMR δ: 1.84-1.96(m,4H,2CH2), 2.45(d,2H,CH2), 2.72-2.79(m,4H,2CH2), 4.42
(s,2H,CH2-N) 4.48(s,2H,CH2-N) 5.56 (s,1H, NH),6.98-7.20(m,9H,ArH) Melting point: 145oC; Yield 55% ;MF C22
H19 N3O2:(m/z) 357.08;Elemental Analysis Calcd(Found) :C : 73.93(73.95);H: 5.36(5.38);N: 11.76 (11.78).
(4d) N-acetyl-(3-(p-methyl phenyl) -1H-pyrazole-(4H)-5-on)-yl-1,2,3,4- tetrahydrocarbazole
IR (KBr):1615, 1630, 1656 Cm-1; 1HNMR δ: 1.81-1.92(m,4H,2CH2), 2.32 (s, 3H, CH3), 2.43(d,2H,CH2), 2.732.78(m,4H,2CH2), 4.40 (s,2H,CH2-N) 4.42(s,2H,CH2-N) 5.50 (s,1H, NH),6.92-7.40(m,8H,ArH) . Melting
point:
156oC; Yield 65% Molecular Formula:C23 H21 N3O2 (m/z) :355.21; Elemental Analysis: Calcd.(Found) :C :
77.72(77.74);H: 5.96(5.98);N: 11.82 (11.84).
(4e) N-acetyl-(3-(p-chlorophenyl)-1H-pyrazole-(4H)-5-on)-yl-1,2,3,4-tetrahydrocarbazole
IR (KBr):1614, 1632, 1666 Cm-1; 1HNMR δ: 1.84-1.96(m,4H, 2CH2), 2.34(d, 2H, CH2), 2.70-2.76(m,4H,2CH2),
4.44 (s,2H,CH2-N) 4.34(s,2H,CH2-N) , 5.53 (s,1H, NH),6.90-7.44(m,8H,ArH):Melting point: 156oC; Yield 60%
Molecular Formula:C18 H19 N3O2 (m/z) : 391.20;Elemental Analysis: Calcd.(Found) : C : 67.43(67.45);H:
4.63(4.65);N: 10.76 (10.78).
2.4 Antimicrobial studies
Newly synthesized compounds 3(a-e) were screened for their in vitro antibacterial activity against Bacillus cereus,
Bacillus subtilis, Streptococci mutans, and Micrococcus luteus, at concentration of 25µg using ciprofloxacin as
standard and antifungal activity against Aspergillus niger, Candida albicans Altenaria macrospora and Fusarium
oxysporum at concentration of 25 µg using ketoconazole as standard . DMF was used as solvent control, nutrient
agar was used as culture medium and method employed was cup [11] plate method. The zones of inhibition formed
were measured in mm and are shown in Tables I and II respectively to antibacterial and antifungal activities
Table -I Antibacterial activity of compounds 3a-e (zone inhibition in mm)
Compound B.cereus B.subtilis S.aureus M.luteus
4a
18
18
17
19
4b
27
29
28
25
4c
23
22
24
25
4d
23
26
21
24
4e
25
27
24
26
DMF-negative control; Reference Standard ciprofloxacin
Table -II Antifungal activity of compounds 3(a-e) (zone inhibition in mm)
Compound A.nigar C.albicans F.oxysporum A.macrospora
4a
17
19
18
15
4b
27
26
28
26
4c
19
20
18
17
4d
24
23
21
23
4e
26
24
28
26
DMF-negative control; Reference Standard Ketoconazole
RESULTS AND DISCUSSION
The hydrazinolysis of compound 1[12] with hydrazine hydrate afforded N-(hydrazinoacetyl)-1,2,3,4tetrahydrocarbazole 2. The 1HNMR spectrum of hydrazide 2, showed a singlet for N-H at δ3.1 ppm and singlet for
NH2 δ 2.90 ppm. Its IR spectrum showed a band between 3094and 3316cm-1.The disappearance of the hydrazide
peaks and appearances of new absorption peaks at 1620cm-1 and 1628 cm-1 for carbonyl stretching for –CO-CH2-C
and –CO-CH2-N respectively has confirmed cyclization of the hydrazide to compound N-acetyl- (3-methyl-1Hpyrazole- (4H)-5-on)-yl-1,2,3,4-tetrahydrocarbazole 4a.
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In 1HNMR spectrum, appearance a new doublet at δ 2.40 ppm for methylene protons confirmed the hydrazide has
been converted to pyrazolinone. Further, a sharp singlet peak appeared at δ 3.0 indicates the presence of methyl
group in pyrazolinone .The remaining peaks, a multiplet at δ 7.08 integrating for four aromatic protons and a singlet
at δ 4.42 for methylene protons as in N-(hydrazinoacetyl)-1,2,3,4-tetrahydro carbazole confirms the structure of the
compound. The mass spectrum showed the molecular ion peak at 308.50(40%) and the major fragmentations are
appeared at 278.72(22%), 227.92(15%), 166.82 (35%) 148.80(80%) and 128.99(24%).
Antibacterial activities of all the newly prepared compounds against four bacteria are presented in Table –I .The
antibacterial activity of compounds 4b and 4e are respectively having ethyl and p-chloro phenyl groups in
heterocyclic moieties found to be excellent. The compounds 4a and 4d are having methyl and p-methyl phenyl
group exhibited better activity than compounds 4a. (Shown in Table –I)
Antifungal activities of all the newly prepared compounds against fungi are presented in Table –I. The antifungal
activity of compounds 4b and 4e are excellent activity towards Fusarium oxysporum and Altenaria macrospore
among the four organism. The compounds 4c and 4d are having moderate activity where as 4a having considerable
activities for the tested organisms (Shown in Table –II)
Acknowledgement
The authors are grateful to Dr.Ceeal Analytical Lab, Thorappakkam, Chennai for providing antimicrobial studies.
The authors are also grateful to SAIF, IIT, Chennai, providing spectral data for the derived compounds.
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