Synthesis and Characterization of Some New Imidazo [2,1-A] Pyrazolo [3,4-D] Thiazoles as Potentials Fungicide

Introduction

Many imidazoles have been reported to exhibit antibacterials¹, herbicidal^2,3,  insecticidal⁴, fungicidal activity^5-7. The importance of some thiazoles prompted us to synthesized some novel imidazo [2,1-a] pyrazolo [3,4-d] thiazoles derivatives with a view to studying their antifungal activity. 2-Mercapto imidazoline was prepared following the method⁸ which well agreed with their analytical data already reported in the literature⁸. 2-[p-Ethoxy arylididene]-5,6-dihydroimidazo [2,1-a] thiazolidine-3-ones  (IIa–f) was synthesized by a mixture of 2-mercapto imidazoline, pyridine and ethyl chloroacetate in dry ethanol. The reaction of (IIa–f) with hydrazine hydrate or 2,4-dinirophenyl hydrazine and anhydrous sodium acetate in glacial acetic acid to give 3-(p-Ethoxy aryl)-cis-3,3a, imidazo [2,1-a] pyrazolo [3,4-d] thiazoles (IIIa–l). All the prepared (IIa–f) and (IIIa–l) compounds were characterized with their m.p., yield, molecular formula and elemental analysis, I.R. and ¹HNMR spectral data of the representative compounds are also given as footnote in the Table-1.

Fungicidal Activity

The compounds (IIa–f) and (IIIa–l) were screened for their antifungal activity against Alternaria solanai and Puccina recondita at 1000, 100 and 10 ppm concentration following the agar plate technique⁹. It is appeared from the screening data that all the compounds were more active against Alternaria solanai as compared with Puccinia recondita but their difference was marginal most of the compound showed the significant anti-fungal activity at 1000 ppm against both the fungal species but their toxicity decreased markedly at lower concentration (100 & 10 ppm). The compounds (IIIc & IIIi) exhibited fungitoxicity of the order of Dithane M-45 at 1000 ppm against both the test fungi. However, their activity decreased markedly at lower concentration (100 ppm & 10 ppm) except in the case of the compounds IIIc & IIIi which inhibited 50-53% growth of the both the fungi species even at 10 ppm.

It is however, noteworthy that the introduction of chloro and methoxy group in the aryl moiety of these compounds tend to enhance the fungitoxicity, and that the introduction of chloro group at ortho position is more effective than that of para position, likewise, the introduction of methoxy group that at ortho position is more also noted that the compounds bearing 2,4-dinetro phenyl moiety are more active. The overall results are not so encouraging as one would expert from combined performance of the two biolabile nuclei viz. imidazole and thiazole. the fungicidal activity of (IIIa–l) compounds were screened and the fungicidal data are recorded in table-2.

Scheme 1 Click here to View scheme

 

Experimental

Melting points were determined in open capillaries and are uncorrected. The IR spectra in KBr were recorded on a Jasco FT/IR-460 plus Fourier Transform infrared specro photometer. ¹HNMR spectra were scanned on a bruker ultraspec 500 MHz/ AMX spectrometer using Dinso as solvent chemical shifts are expressed in d ppm spectra were recorded on JEO2 SX 102/DA-6000 mass spectrophotometer using argon/Xenon (6KV, 10mA) as the FAB gas with m-nitrobenzylalcohol as the matrix.

Synthesis of 2-(p-Ethoxy arylidine)-5,6-dihydro imidazo [2,1-a]-thiazolidine-3-ones (IIa–f)

The corresponding 2-(p-Ethoxy arylidene)-5,6-hydroimidazol [2,1-a] thiazolidine -3-ones were synthesized by condensation of 2-mercapto imidazolene. Pyridine and ethyl chloroacetate in dry ethanol was refluxed on a stem bath for 4 hrs. there after suitable ethoxy aromatic aldehyde and piperidine was added and the reaction mixture was refluxed further for 1 hr. cooled, filtered, washed well with water and the product was recrystallized from glacial acetic to give cream colour crystals. The structure was assigned on the basis of analytical data and spectral data which are given in the table-1.

Synthesis of 3-(p-ethoxyaryl)-cis-3,3a,6,7-tetrahydro-2H-Imidazo[2,1-a] pyrazolo 

[3,4-d]-thiazoles (IIIa–l).

A mixture of 2-(p-ethoxy arylidene-5,6-dihydro imidazo [2,1-a]-thiazoledine-3-ones (0.0025 mol), hydrazine hydrate (0.0025 mol) or 2,4-di-nitro phenyl hydrazine (0.0025 mol) and anhydrous sodium acetate (0.0025 mol) in glacial acetic acid (50 ml) was heated under refluxes for 6 hrs., cooled to room temperature, filtered, washed will with water and recrystallized from acetic acid as light yellow crystals. All the prepared title compounds with their characterization data m.p., yield, molecular formula, elemental analysis and spectral data as footnote are recorded in table-1.

Table 1: Characterization data of 2-(p-Ethoxy arylidene-5,6-dihydro imidazo [2,1-a] thiazolidine –3-ones (IIa–f) and 3-(p-ethoxy aryl) cis–3,3a, 6,7-tetrahydro-2H-imidazo [2,1-a] pyrazolo [3,4-d] thiazoles (IIIa–l)

Compd. No.	R	Ar	Molecular formulae	M.P. (0C)	Yield (%)	Analysis, Found (Calculated)
						C	N	S
IIa*		C6H5	C14H15N2O2S	245	62	61.20 (61.09)	10.28 (10.18)	11.72 (11.63)
b		m-NO2C6H4	C14H14N3O4S	255	35	52.62 (52.50)	13.22 (13.12)	10.10 (10.00)
c		o-ClC6H4	C14H14N2O2SCl	196	49	54.17 (54.28)	09.15 (09.04)	10.44 (10.33)
d		p-ClC6H4	C14H14N2O2SCl	201	52	54.25 (54.28)	09.02 (09.18)	10.35 (10.33)
e		o-H3COC6H4	C15H17N2O3S	198	56	59.10 (59.01)	09.28 (09.18)	10.50 (10.49)
f		p-H3COC6H4	C15H17N2O3S	203	58	59.25 (59.01)	09.25 (09.18)	10.48 (10.49)
IIIa*0	H	C6H5	C14H17N4OS	245	58	58.25 (58.13)	19.28 (19.26)	11.20 (11.07)
b	H	m-NO2C6H4	C14H16N5OS	250	35	50.30 (50.29)	21.00 (20.95)	09.49 (09.45)
c	H	o-ClC6H4	C14H16N4OSCl	215	49	52.00 (51.93)	17.40 (17.20)	09.45 (09.43)
d	H	p-ClC6H4	C14H16N4OSCl	230	52	52.10 (52.08)	17.40 (17.31)	09.91 (09.88)
e**	H	o-H3COC6H4	C15H19N4O2S	248	56	56.54 (56.42)	17.60 (17.55)	9.98 (10.03)
f	H	p-H3COC5H4	C15H19N4O2S	251	60	56.38 (56.42)	17.52 (17.55)	10.21 (10.03)
g	2,4-di-nitro- phenyl	C6H5	C20H19N6O6S	246	70	51.02 (50.94)	17.79 (17.83)	06.58 (06.79)
h	2,4-di-nitro- phenyl	m-NO2C6H4	C20H18N7O7S	252	45	48.15 (48.00)	19.55 (19.60)	06.52 (06.40)
i	2,4-di-nitro- phenyl	o-ClC6H4	C20H18N6O5SCl	245	48	49.17 (49.02)	17.25 (17.16)	06.48 (06.53)
j	2,4-di-nitro- phenyl	p-ClC6H4	C20H18N6O5SCl	230	42	49.18 (49.02)	17.30 (17.16)	06.55 (06.53)
k	2,4-di-nitro- phenyl	o-H3COC6H4	C21H21N6O6S	242	41	52.02 (51.95)	17.28 (17.31)	06.46 (06.59)
l	2,4-di-nitro- phenyl	p-H3COC5H4	C21H21N6O6S	247	46	52.05 (51.95)	17.41 (17.31)	06.60 (06.59)

*IIa.  IR (KBr); 840 (1,4-disubstituted benzene ring) 1520 (C-N-Stretching),

1590 (>C=C<), 1610  (>C=N), 1680 (>C=O),

3050 (Ar-C-H Stretching) cm^–1

¹HNMR (DMSOd₆) d : 3.4 (2H, t, C₅ Methylene proton),

3.8 (2H, t, C₆ methylene proton) 1.4 (3H, t, CH₃ proton),

3.8 (3H, s, OCH₃),  7.0-8.1 (7H, m, Ar-H)

*IIIa    IR(KBr) : 820 (1,4-disubstituted benzene ring,

1510 (C-N-Stretching), 1600 (>C=C<). 1620 (>C=N),

3040 (Ar C-H) Stretching), 3280 (N-H Stretching) cm^–1

¹HNMR (CDCl₃) d : 1.35 (2H, t, CH₃),

2.5 (1H, s, NH Exchangeable with D₂O),

3.38 (2H, t, C₇ methylene proton),

3.7 (2H, t, C₆ methylene proton),

4.1 (2H, q, CH₂ protons of ethoxy group),

7.57 (1H, d, J = 8.48, Hz, C_3a-H),

7.80 (H, d, J = 8.49 Hz, H-3 & H-5′),

7.88 (2H, d, J = 8.48, Hz, H-2′, & H-6′)

**IIIe   IR (KBr) : 825 (1,4-disubstituted benzene ring), 1520 (C-N stretching),

1610 (>C=C>), 1625 (>C=N), 3030 (Ar C-H) stretching),

3260 (N-H Stretching) cm^–1

¹HNMR (CDCl₃) d : 1.28 (3H, t, CH₃); 2.4 (1H, s, NH);

3.28 (2H, t, C₇ methylene proton)

3.7 (2H, q, t, C₆ methylene proton)

4.2 (2H, q, CH₂, Proton of ethoxy group)

7.48 (1H, d, J = 8.49 H_Z, C3a-H),

7.80 (H, d, J = 8.50 H_Z, H-3′ & H-5′)

7.85 (2H, d, J = 8.48, H_Z, H-2′ & H-6′)

Table 2: Fungicidal screening data of 3-(p-ethoxy)-cis-3.3a, 6.7-tetrahydro-2H-Imidazo[2,1-a] pyrazolo [3,4-d] thiazoles (IIIa–l)

Compd. No.	Average (%) inhibition against
	Alternaria solanai at			Puccinia recondita at
	1000 ppm	100 ppm	10 ppm	1000 ppm	100 ppm	10 ppm
IIIa	62	35	15	60	63	13
b	74	40	20	72	38	18
c	98	64	51	97	63	50
d	78	42	22	76	41	20
e	72	38	20	70	36	18
f	71	36	19	71	34	17
g	74	37	17	71	36	15
i	99	66	53	98	64	51
j	92	48	25	90	46	24
k	85	42	22	83	40	20
l	83	41	21	81	39	19
Dithane M-45	100	85	65	100	82	64

Acknoweldgements

The author express their deep gratitude to the Principal and Head, Department of chemistry, of the respective institutions for the their constant research encouragement and for providing necessary research facilities and also to CDRI, Lucknow for recording spectral data.

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