Indian Journal of Chemistry Vol. 38B, February 1999, Pi> 192 - 196 Synthesis, separation of E, Z isomers, their configuration by IH NMR spectra and antifungal activity of new substituted 1 ,3-diphenyl-2- (1,2,4-triazol-I-yl)- prop-2-en-I-ones Vinod Rama Uchil & Vidya Joshi* C C Shroff Research Institute, Excel Estate, S V Road, Goregaon (W), Mumbai,400062, India Received 22 september 1998; accepted (revised) 28 December 1998 00- (I ,2,4-Triazol-l-yl)-4-chloroacetophenone 2 on condensation with substituted aryl ald ehydes 3a-i in presence of piperidine (catalytic amount) and toluene gave new substituted triazolylpropenones (E) 4a-i and (Z) Sa-c isomers respectivel y. Their configuration has been determined by IH NMR spectra. Compounds 4a, 4c, 4d, 4e and Sa have been fo un d to have fungicidal activity against Trichophyton mentagrophytes. and Tricho phyton rubrum. 4d is active even again st Candida albicans. Azole substituted 2-propen-l-ones are reported to ' £1 1 1 - 14 h b' 'd 114 I h possess antI unga er ICI a , pant growt antiallergic l6 , antibac- , 1171 7 , .. 18 .. I ' f h tena .. , antlmlcotlc , actJvliy. n vIew 0 t ese reports we have synthesised some new . substituted triazolyl-2-propen-l-ones (E) 4a-i and (Z) 5a-c, w- (1 ,2,4-Triazol-I -yl)-4-chloroacetophenone 2 was pre- pared by literature method I3 . 19 . Condensation of2 and substituted aldehydes 3a-i in presence of piperidine (catalytic amount) in dry toluene afforded E isomers 4a-i, and Z isomers, 5a-c out of which compounds (E) 4a-i and (Z) 5a-c were separated by column chromatography and crystallized as needles in pure condition (Table I), while compounds (Z) 5d-i could not be isolated. The structure of all the compounds (Scheme I) were confirmed by elemental analyses , UV, IR and IH NMR spectra. E and Z isomers were distinguished by TLC , melting points, IH NMR spectra and GCMS . Fungicidal activity The fungicidal activiiy of the compounds 4a-i and 5a was determined against Candida albicans, Tri chophyton mentagrophytes and Tricophyton rub rum. Dimethyl formam ide (DMF) which was used as a control solvent did not show any fungicidal activiiy. Compounds 4a and 4c were found to be active against T mentagrophytes and T rubrum at a minimum inhibitory concentration (MIC) of 25 l-l g/mL. Compound 4b was active against T rub rum at a MIC of 25 l-lg/mL and 4e was active against T mentagrophyte at a MIC of 25 l-lg/mL and against T rubrurn at a MIC of 200 l-lg/mL , Compound 4d was active against all three organisms at a MIC of 25 l-lg/mL. The Z isomer, 5a was active against T mentagrophytes and T rubrum at a MIC of 2 00 l-lg/mL Compounds 4e, 41', 4g and 4h were inactive at all concentrations , Table II. Methodology-Fungicidal activiiy of the test compound was determined by using Schraufstatter dilution technique 20 , According to the techniqu e, Schrauf statter medium was prepared and its dilution was carried out in a test tube , the tota l volume of which was kept at 5 mL with differing concentrati on (200 I-lg-25 I-lg) . Depending on the conc entration required the amount of the me dium wa s adjusted w ith respect to the test compound and 0.1 mL of the culture , Before the introduction of the test co mpound and the culture the med ium was sterilized in autoclave for 15 min at a pressure of IS Ib s . Th e incubation took place in dark at room temp. The incubation period for C. albicans was 7 da ys and for T mentagrophytes and T rub rum was 1 1- 12 days. The greatest dilution where no growth whatsoever would be observed with the naked eye, was given th e lowest fungistatic concentration and was the MIC for that compound . The antifungal acti viiy of th e compounds is given in Table II . Results and Discussion of E (4a) & Z (5a). The E and Z configuration was assigned to 4a and 5a re spec ti ve ly ,.. .
Transcript
Indian Journal of Chemistry Vol. 38B, February 1999, Pi> 192 - 196
Synthesis, separation of E, Z isomers, their configuration by IH NMR spectra and antifungal activity of new substituted 1 ,3-diphenyl-2- (1,2,4-triazol-I-yl)
prop-2-en-I-ones
Vinod Rama Uchil & Vidya Joshi*
C C Shroff Research Institute, Excel Estate, S V Road, Goregaon (W), Mumbai, 400062, India
Received 22 september 1998; accepted (revised) 28 December 1998
00- (I ,2,4-Triazol-l-yl)-4-chloroacetophenone 2 on condensation with substituted aryl aldehydes 3a-i in presence of piperidine (catalytic amount) and toluene gave new substituted triazolylpropenones (E) 4a-i and (Z) Sa-c isomers respectively. Their configuration has been determined by IH NMR spectra. Compounds 4a, 4c, 4d, 4e and Sa have been found to have fungicidal activity against Trichophyton mentagrophytes. and Trichophyton rubrum. 4d is active even against Candida albicans.
Azole substituted 2-propen-l-ones are reported to ' £1 11-14 h b ' 'd 114 I h possess antI unga er ICI a , pant growt
, 1171 7 , .. 18 .. I ' f h tena .. , antlmlcotlc , actJvliy. n vIew 0 t ese reports we have synthesised some new . substituted triazolyl-2-propen-l-ones (E) 4a-i and (Z) 5a-c, w(1 ,2,4-Triazol-I -yl)-4-chloroacetophenone 2 was prepared by literature method I3.19. Condensation of2 and substituted aldehydes 3a-i in presence of piperidine (catalytic amount) in dry toluene afforded E isomers 4a-i, and Z isomers, 5a-c out of which compounds (E) 4a-i and (Z) 5a-c were separated by column chromatography and crystallized as needles in pure condition (Table I), while compounds (Z) 5d-i could not be isolated . The structure of all the compounds (Scheme I) were confirmed by elemental analyses, UV, IR and IH NMR spectra . E and Z isomers were distinguished by TLC, melting points, IH NMR spectra and GCMS.
Fungicidal activity The fungicidal activiiy of the compounds 4a-i and
5a was determined against Candida albicans, Trichophyton mentagrophytes and Tricophyton rub rum. Dimethyl formam ide (DMF) which was used as a control solvent did not show any fungicidal activiiy. Compounds 4a and 4c were found to be active against T mentagrophytes and T rubrum at a minimum inhibitory concentration (MIC) of 25 l-lg/mL. Compound 4b was active against T rub rum at a MIC of 25 l-lg/mL and 4e was active against
T mentagrophyte at a MIC of 25 l-lg/mL and against
T rubrurn at a MIC of 200 l-lg/mL , Compound 4d was active against all three organisms at a MIC of 25
l-lg/mL. The Z isomer, 5a was active against T mentagrophytes and T rubrum at a MIC of 200
l-lg/mL Compounds 4e, 41', 4g and 4h were inactive at all concentrations, Table II.
Methodology-Fungicidal activiiy of the test compound was determined by using Schraufstatter dilution technique20
, According to the technique, Schraufstatter medium was prepared and its dilution was carried out in a test tube, the total volume of which was kept at 5 mL with differing concentration
(200 I-lg-25 I-lg) . Depending on the concentrati on required the amount of the medium was adjusted with respect to the test compound and 0 .1 mL of the culture , Before the introduction of the test compound and the culture the med ium was sterilized in autoclave for 15 min at a pressure of IS Ibs . The incubation took place in dark at room temp. The incubation period for C. albicans was 7 days and for T mentagrophytes and T rub rum was 11- 12 days . The greatest dilution where no growth whatsoever would be observed with the naked eye, was given the lowest fungistatic concentration and was the MIC for that compound. The antifungal acti viiy of the compounds is given in Table II.
Results and Discussion Confi~:uration of E (4a) & Z (5a). The E and Z
configuration was assigned to 4a and 5a respecti ve ly
,.. .
t
.--,
;
UCHIL et al. : SYNTIIESIS OF r,3-DIPHENYL-2-( I ,2,4-TRIAZOL- I-YL}-PROP-2-EN-I-ONES 193
Table I-Physical data of substituted 1,3-diphenyl-2- (I ,2,4-triazol-l-yl)-2-propen-I-ones, 4a-i (E) and 5a-c (Z)
Compdt m p (0C) Rfvalue Yield Mol formula Elemental analysis Cal cd / Found (%) Solvent· Eluent! (%) C H N CI S
All compounds 4a-i and 5a-c crystallized in need les. ·Solvents for crystallization : (I) benzene (2) methanol (3) benzene-pet. ether (60-80°) tEluents for TLC : chloroform-ethyl acetate (7:3) for 4b,5b,4g,4h and 4i ; (6:4) for 4a,4c,4d,4e,4f,5b and 5c tEluents for colurun chromatography : chloroform- ethyl acetate (9: I) for 4a,4b, and 4e; (8 :2) for 4c,4g,4i and 5b; (4 :6) for 4d, 4h, Sa, 5c; p :8} for 4f.
Table II--Antifungal activity of diphenyl-triazolylpropenones 4a-i (E) and Sa (Z)
Minimum inhibitory concentration (MIC) against
Compd C. albican T. mentagrophyres T. rubrum 25 200 25 200 25 200
~glmL ~glmL ~glmL ~glmL ~glmL ~glmL
4a + + + +
4b + + 4c + + + +
4d + + + + + +
4e + + + 4f 4g 4h 4i Sa + +
Active (+); Inactive (-)
on the basis of lH NMR studies. In 4a the olefinic proton was observed at 8 7.50 whereas in Sa it was observed at 8 7.55. This down field shift of the olefinic proton in Sa is due to the C=O group which being on the same side of the double bond, exerts
deshielding effect on olefinic proton23 (Scheme I).Taking into consideration Cahn- Ingold Prelog convention of priorities of groups24-26 and the
'H NMR spectra, 4a and Sa are designated as E and Z isomers respectively. Similar deshielding effect on o lefinic proton is observed in Z isomers Sb, and Sc. (Table III). 1M IR spectra it is observed that in Z isomers Sa-c the keto group absorbs at a higher frequency than the corresponding E isomers 4a-c. (Table-III). This change in (C=O) frequency is in conformity with the observations of earlier authors27
.
The configuration of 4a-c (E) and Sa-c (Z) is therefore supported even by IR data27.
Deshielding effect on triazolyl proton Cs-H. Also in the isomer 4a the triazole protons appear at 8 8.19 (Cs-H) and 8. 15 (C3-H) while in Sa they appear at 8 8.30 (Cs -H) and 8.05 (C3-H) respectively, i. e. there is appreciable deshielding by a difference of 8 0.1 I in the chemical shift of Cs-H of triazole in Z isomer Sa as compared witli that of Cs-H of triazole in E isomer 4a. (Table III). From the ball and stick
194 INDIAN J CHEM, SEC B, FEBRUARY 1999
model it was observed that C=O group can exert deshielding effect on Cs-H of triazole in Sa, whereas the deshielding effect of C=O group on C}-H of triazole in Sa is ruled out as the configuration of the
RI=R.J=H; Rz=O RI = Dr; ~ = R.J = H RI = ~ = R.J = - OCllJ RJ = R.J = H; Rz = - S - CH~ RI = - Q4Hs; ~ = R.J = H RJ = - 0CIlJ; ~ = OH; R.J = H RI = R.J = H; ~ = OR R.J~=-O-CHz-O-; R.J=H RJ =~=H; ~&-N(CHJh
Scheme I
triazole ring favoring the deshielding effect on C3-H is not possible due to the possible repulsive force between the oxygen of C=O group and the second nitrogen atom of the triazole ring. Similar deshielding effect on Cs-H of triazole is observed in Z isomers 5b and 5c. The average difference between the chemical shifts of triazolyl protons Cs-H illld CrH in E isomers 4a-c is 8 0.046 'while that in Z isomers 5a-c is 80.255. The average difference between the chemical shifts of triazolyl protons Cs-H and C3-H in co mpounds 4d-i is found to be 0.055 which agrees \ve ll wi th that of E isomers 4a-c. Configuration E is therefore assigned to compounds 4d-i.
Experimental Section The general procedures adopted for the preparation
of different compounds are described below: Preparation of CD -(t, 2, 4-triazol-l-yl)-4-chloro
acetophenone 2. A mixture of 1,2,4··triazole (1.84 g, 0.02 mole), triethylamine (3.325 g, 3.2 mL, 0.032 mole) and acetonitrile (40 mL) was stirred vigorously in a 250 mL round bottomed flask equipped with a reflux condenser and a mechanical stirrer. To the above mixture was added co-bromo-4-chloro: acetophenone (prepared by bromination of 4-
. chloroacetophenonei l (5 g, 0.021 mole} in acetonitrile (40 mL) by a dropping funnel at a fast rate (5 min). About 50 mL of acetonitrile was distilled off and the residue was decomposed by adding 150 mL of cold water. Yellow coloured crystals were separated,which were filtered, dried and crystallized from m'~thanol to yield fine colourless needles,m.p.
I
147°, yield 3.4 g (73'1'0 theory). Rr value 0.233 ,
Table III-E & Z Configuratiqn of compounds 4a-i and 5a-c by difference in spectral data
Compd Chemical shift values in 0 e .e .m. IR (KBr) Mass Olefinic H Triazolyl protons v in cm· l
Preparation of l,3-bis (4-chlorophenyl)-2-(l,2,4-triazol-l-yl) prop-2-en-l-one, 4a (E) & 5a (Z) In a 250 mL round bottomed three necked flask placed in an oil bath and equipped with a reflux condenser and a mechanical stirrer, was placed 00-
(I, 2, 4-triazol-I-yl)-4:.chloroacetophenone 2 (2 g, 0.009 mole) in dry toluene (75 mL) and the solution stirred. To this was added 4-chlorobenzaldehyde, 3a (1.3 g, 0.009 mole) and piperidine (2 drops) and refluxed for 16 hr. The oil bath-temp wa~ maintained at 160° The reaction mixture was transferred to a separating funnel , washed with water several times to remove traces of piperidine and was made neutral to pH by water washings. Toluene was distilled off under reduced pressure to give brownish red gummy residue which on TLC showed two spqts having Rf values 0.8 and 0.63 corresponding to E and Z isomers respectively [Eluent: chloroform-ethyl acetate (6 : 4)] .
Separation of E and Z isomers. The above gummy oil was subjected to column chromatography on silica gel (60-100 mesh) using solvents of increasing polarity. On elution with chloroform-ethyl acetate (9 : I) a gummy residue was obtained which on crystallization from benzene-pet. ether (60-80°) gave colourless crystals of 4a (E isomer), m p 102°, yield 0.6 g (19.31 % theory).;Rf value 0.80 [CHCI3-
EtOAc (9: I)]. On further elution with chloroformethyl acetate (4 : 6) a solid was obtained which on crystallization with benzene gave fluffy white crystals of 5a (Z isomer), m.p. 189°, yield 1:2 g (38.6% theory). Rf value 0.63 [Eluent: CHCI3-.EtOAc ·(6:4)]. By similar method Z isomers 5b and 5c were separated from the corresponding E isomers 4b and 4c respectively. Attempts were made to isolate 5d-i
but they could not be isolated in pure condition even by preparative TLC. However their presence was detected by GCMS in the worked up reaction mixture. Isomer 4a gave the following spectra : UV (MeOH): 225 (log E=3.8660), 306 (log E=3 .9744) nm; IR (KBr): 1665 (C=0),1650 (strong) (C=C), 1595
- H ofB ring, .1=8.604 Hz), 7.27 & 7.30 (2H, d, C3-H & Cs-H of Bring, .1=8.607 Hz), 7.50 (IH, s, olefinic proton), 7.46 & 7.49 (2H, d, C3·-H & Cs·-H from A ring, .1=8.607 Hz), 7.73 & 7.76 (2 H, d, CrH & C6·-H from A ring, .1=8.607 Hz), 8.15 (IH, s, C3-H of triazole), 8.19 (IH, s, Cs -H of triazolei2
•
Isomer 5a gave the following spectral values : UV (MeOH): 212 (log £ =4.1278), 267 (log E=4.3085) nm, IR (KBr):1670 (C=O), 1640 (weak) (C=C), 1595 (C=N), 840 (substituted phenyl) cm'l. IH NMR (CDCh) (300 MHz): 87.18 -7.19 (4H,s, CrH, C3-H, & Cs-H & C6-H of Bring), 7.34 & 7.37 (2H,d, C3·-H & Cy-H from A ring J=8.973 Hz), 7.55 (IH,s, olefinic proton), 7.84 & 7.87 (2 H,d, C2·-H & C6·-H from A ring, J=8.973 Hz), 8.05 (lH, s, C3-H oftriazole), 8.30 (I H, s, Cs-H of triazole).
Acknowledgement We are thankful to Mr Chiplunkar, U D C T,
Mumbai, for elemental analyses, Head, R SIC, Powai, Mumbai, for I H NMR spectra, and Director Dr B G Khadase, Haffkine Institute, Parel, Mumbai, for fungicidal activity.
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