Microwave Assisted One Pot, One Step Synthesis of Substituted-2-Aminothiophenes through the Gewald Reaction & Study of its Antibacterial, Antifungal Activities

Microwave Assisted One Pot, One Step Synthesis of Substituted-2-Aminothiophenes through the Gewald Reaction & Study of its Antibacterial, Antifungal Activities

D M Mamatha*, T H Suresha Kumara

Department of Chemistry Department of Chemistry UBDT College of Engineering UBDT College of Engineering Davanagere India Davanagere, India

Abstract: A Series of 5 novel substituted 2-aminothiophenes (3C, NR2, NR3, NR4, NR6) were synthesized under microwave accelerated synthetic method by a 3-component one pot Gewald reaction. Which gives the products in short time and the synthesized compounds were characterized by the spectroscopic method, physicochemical and analytical data. By using Agar diffusion method Antibacterial and Antifungal activities were tested.

Key words: Substituted 2-aminothiophenes, Microwave accelerated organic synthesis, Gewald reaction.

1. INTRODUCTION

   Derivatives of Thiophenes having different uses in the field of Industrial and Medicinal Chemistry. Substituted thiophenes exhibit important applications in the Medicinal Chemistry, acts as building blocks in the Dye and other Industries. Amongst the various methods of synthesis reported for thiophenes, the Gewald reaction is an interesting one. It is an organic reaction involving the condensation of a ketone or an aldehyde with a -cyano ester in the presence of elemental sulphur & base to give a polysubstituted 2 aminothiophenes[1-3].

   O

   R2 OR3

   O

   Since this method is simple, quick and environmental friendly for the synthesis of substituted- 2-aminothiophene derivatives.

   In the present study we report the synthesis & antimicrobial, antifungal activities of 5 novel substituted 2-aminothiophenes using microwave accelerated synthesis carried out in good yield, short reaction time or mild conditions

2. EXPERIMENTAL SECTION

The IR spectra of synthesized compounds were characterized by FTIR & 1HNMR spectroscopy. The IR spectra of synthesized compounds were characterized by FTIR obtained on a Brucker infrared spectrometer and 1HNMR spectra from Jeol 400MHz spectrometer with Internal standard TMS.

Procedure for the synthesis of (3C) Ethyl-5-amino-4- cyano-3-methyl thiophene-2-carboxylate under microwave oven irradiation method.

A mixture of Ethyl Acetoacetate (0.1mole), Malononitrile (0.1mole), Elemental Sulphur (0.05mole) in Ethanol (15ml) were charged to a 250ml round bottom flask, kept in microwave oven maintain temperature 700C for 8 minutes. The reaction completion was monitored by TLC, filter the reaction

O N

+ C

R1

OR3

R2

S8

NH2

S

R1

mixture, wash with ethanol, to the filtrate check pH by using litmus paper then keep the filtrate in oven 5 minutes to remove excess ethanol, after attaining room

Figure 1: General example for Gewald reaction.

One of our research goal is focused on developing one pot, one step method using microwave oven by Gewald reaction method. This method has application in organic synthesis to improve yield and reduce time of reaction.

Draw backs of Conventional method in Gewald reaction.

1. Loss of catalyst during workup.

2. Duration of reaction was more.

3. Lengthy procedure for isolation of product.

4. Use of organic solvents having high boiling points and toxic. Ex: 1,4-dioxane, DMF.

5. Low yield and use of dangerous bases. Ex: Morphine.

temperature add ice cubes we get black coloured precipitate, workup using cold water, black amorphous precipitate was formed filter and washed with cold water, dried to afford corresponding substituted 2- aminothiophene, product weight 0.62 g.

Procedure for synthesis of (NR2) Ethyl-2-amino-4- (3-formylpropyl)thiophene-3-carboxylate under microwave oven irradiation method.

A mixture of Ethylcyanoacetate (0.1mole), Glutaraldehyde (0.1mole), elemental sulphur (0.05mole), DMF (0.1mole) in ethanol (15ml) were charged to a 250ml round bottom flask, kept in microwave oven maintain temperature 700C, Triethylamine (0.01mole) add two times with stirring for 1 hour, workup with methanol and water mixture,

dark brown colour shiny scalp like amorphous precipitate formed after dried, product weight 1.46g.

Procedure for the synthesis of (NR3) Ethyl-2-amino- 4-(2-Bromophenyl)thiophene-3-carboxylate.

A mixture of Ethylcyanoacetate (0.1mole), 2- Bromoacetophenone (0.1mole), elemental sulphur (0.05mole) in ethanol (15ml) were charged to a 250ml round bottom flask, kept in microwave oven maintain temperature 1200C for 21 minutes, workup by dissolving reaction mixture in DCM and water then shake well separate organic layer by using separating funnel, to the organic layer add brine solution to remove water, kept the organic layer for dry in beaker, get dark brown colour amorphous precipitate, product weight

0.35 g.

Procedure for the synthesis of (NR4) Ethyl-2-amino- 4-(4-nitrophenyl) thiophene-3-carboxylate under microwave oven irradiation method.

A mixture of Ethylcyanoacetate (0.1mole), 4- Nitroacetophenone (0.1mole), elemental sulphur (0.05mole) in ethanol (15ml) were charged to a 250ml round bottom flask, kept in microwave oven maintain temperature 1200C for 46 minutes. The reaction completion was monitored by TLC, after the completion of reaction workup by using ethanol : methanol = 2 : 1 ration, dark brown coloured amorphous precipitate settled at the bottom of beaker, filtered and kept it for dry. Product weight 0.72g.

Procedure for the synthesis of (NR6) Ethyl-2-amino- 4-(3,5-dichlorophenyl) thiophene-3- carboxylate under microwave oven irradiation method.

A mixture of Ethylcyanoacetate (0.01mole), 3- Hydroxyacetophenone (0.01mole), elemental sulphur (0.05mole) in ethanol (15ml) were charged to a 250ml round bottom flask, kept in microwave oven maintain temperature 1200C for 48 minutes. The reaction completion was monitored by TLC, after the completion of reaction workup by using ethanol : methanol = 2 : 1 ration, dark brown coloured amorphous precipitate settled at the bottom of beaker, filtered and kept it for dry. Product weight 0.45g.

III. RESULT AND DISCUSSION

This work consists of demonstrating the synthesis of substituted-2-aminothiophenes by using microwave oven. The reaction of different acetophenones with elemental sulphur either ethylcyanoacetate or malononitrile gave the substituted 2-aminothiophenes. The products were characterized by the spectral data of 1H NMR., FTIR, physicochemical & analytical data.

IR and 1H NMR Spectral data for selected synthesized compounds

Compound 3C: Ethyl-5-amino-4-cyano-3- methylthiophene-2carboxylate

Black precipitate, IR (KBr) (cm-1) : 3300 (N-H), 2222 (CN), 1650 (C-H), 1310 (C=O), 1030 (C-S) ; 1H

NMR (400MHz; CDCl3), (ppm) : 8.34 (m,

J=13.206Hz, 2H), 2.00 (d, J=5.008Hz, 3H), 3.35 (t, J=12.618Hz, 2H), 1.13 (s, J=5.126Hz, 3H).

Compound NR3 : Ethyl-2-amino-4-(2- bromophenyl)thiophene-3-carboxylate

Brown precipitate, , IR (KBr) (cm-1) : 2900 (C-H), 1506 (C-C), 1650 (C-H), 1342 (N-H), 1250 (C-O), 1030

(C-S), 690 (C-Br) ; 1H NMR (400MHz; CDCl3),

(ppm) : 5.92 (t, J=4.029Hz, 2H), 3.84 (q, J=17.124Hz, 2H), 3.00 (s, J=3.452Hz, 1H).

Compound NR4 : Ethyl-2-amino-4-(4- nitrophenyl)thiophene-3-carboxylate

Brown precipitate, , IR (KBr) (cm-1) : 2900 (C-H), 1674 (C=O), 1500 (N-O), 1342 (N-H), 1030 (C-S), 840 (C=C) ; 1H NMR (400MHz; CDCl3), (ppm) : 3.00 (t, J=3.993Hz, 2H), 1.07 (s, J=2.687Hz, 1H), 2.12 (q, J=17.124Hz, 2H).\

Compound NR6 : Ethyl-2-amino-4-(3,5- dichlorophenyl)thiophene-3-carboxylate

Brown precipitate, IR (KBr) (cm-1) : 3500 (N-H), 2222 (CN), 1650 (C-H), 1250 (C-N), 1030 (C-S), 790 (C-Cl), 665 (C=C) ; 1H NMR (400MHz; CDCl3), (ppm) : 2.09 (t, J=3.99Hz, 2H), 3.00 (s, J=2.646Hz,

3H), 1.28 (q, J=17.12Hz, 2H), 1.25 (s, J=3.452Hz,

1H).

S. N	Name of Compound	Molecula r formula & Molecula r mass	Structural formula	Yie ld	Colo ur
1	Ethyl-5-amino-4- cyano-3- methylthiophene- 2-carboxylate.	C9H10O2N 2S, 210.25g/m ole	CN N C2H5OOC S 3C	0.6 2g H2	Blac k colo ur
2	Ethyl-2-amino-4- (3- formylpropyl)thi ophene-3- carboxylate.	C11H15SO3 N, 241.31g/m ole	COOC2H5 OHC NH2 S NR2	1.4 6g	Dark shin y bro wn colo ur
3	Ethyl-2-amino-4- (2- bromophenyl)thi ophene-3- carboxylate.	C13H12O2 NSBr, 326.21g/m ole	Br COOC2H5 NH2 S NR3	0.3 5g	Bro wn colo ur
4	Ethyl-2-amino-4- (4- nitrophenyl)thiop hene-3- carboxylate.	C13H12N2S O4, 292.31g/m ole	O2N COOC2H5 NH2 S NR4	0.7 2g	Bro wn colo ur
5	Ethyl-2-amino-4- (3,5- dichlorophenyl)t hiophene-3- carboxylate.	C13H11Cl2 NSO2, 316.2g/mo le	COOC2H5 Cl NH2 S NR6	0.4 5g	Bro wn colo ur

Table 1. Chemical data of substituted 2- aminothiophenes.

Cl

S . N	Com poun d	Mole cular form ula	Mel ting poi nt (0C )	Yi el d ( % )	Analysis (calculated/found) (%)
					C	H	N	S
1	3C	C9H10 N2O2 S	294 – 295	25	51.41 /51.4 8	4.79 /5.1 1	13.32 /13.0 0	15.25 /15.4 3
2	NR2	C11H1 5N O3S	245 – 246	58	54.75 /54.4 5	6.27 /6.3 2	5.80/ 6.12	13.29 /13.3 4

Table 2. Analytical and Physicochemical data of the synthesized compounds.

3	NR3	C13H1 2BrN O2S	>30 0	45	47.86 /47.5 9	3.71 /4.1 0	4.29/ 4.33	9.83/ 9.78
4	NR4	C13H1 2N2 O4S	>30 0	12	53.42 /53.4 0	4.14 /4.2 1	9.58/ 9.31	10.97 /10.3 4
5	NR6	C13H1 1Cl2N O2S	>30 0	11	49.38 /49.4 0	3.51 /3.4 9	4.43/ 4.58	10.14 /10.2 0

Table 3. Antibacterial activity of substituted 2- aminothiophenes.

S.N	Organism: Bacillus cereus (Gram +ve), Control : 11mm (Ciprofoxacin)
	Compound	Conc.1 (50µl)	Conc.2 (150µl)	Conc.3 (200µl)
1	3C	6mm	9mm	10mm
2	NR2	4mm	6mm	9mm
3	NR3	3mm	5mm	10mm
4	NR4	6mm	10mm	12mm
5	NR6	3mm	8mm	11mm

Table 4. Antifungal activity of substituted 2- aminothiophenes.

S.N	Organism: Candida albicans, Control : 20mm (Itraconazole)
	Compound	Conc.1 (50µl)	Conc.2 (150µl)	Conc.3 (200µl)
1	3C	12mm	14mm	17mm
2	NR2	6mm	10mm	15mm
3	NR3	–	5mm	7mm
4	NR4	8mm	10mm	17mm
5	NR6	6mm	10mm	20mm

IV. CONCLUSION

In this work we described an efficient and suitable modification to the Gewald reaction carried in microwave oven gives moderate to excellent yields and 3C and NR6 compounds shows significant Antifungal activity.

ACKNOWLEDGEMENT

Dr. Ravishanakara Shastri P S and Smt.Rathnamma D, thanks for financial support & providing necessary facilities and thankful to Department of Chemistry, UBDT College of Engineering for support to carry out this research work.

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