научная статья по теме SYNTHESIS AND REACTIONS OF SOME NEW PYRROLYLTHIENO[2,3-D]QUINOXALINE AND PYRROLOPYRAZINOTHIENOQUINOXALINES Химия

SYNTHESIS AND REACTIONS OF SOME NEW PYRROLYLTfflENO[2,3-D]QUINOXALINE AND PYRROLOPYRAZINOTHIENOQUINOXALINES

© 2012 Ahmed A. Geies, Yasser A. Elossaily#, and Osama Sh. Moustafa

Chemistry Department, Faculty of Science, Assiut University, Assiut, 71516 Egypt Received August 1, 2011; in final form, August 15, 2011

The synthesis of 3-pyrrolyl-2-substituted thieno[2,3-b]quinoxalines from the precursor 3-amino derivatives are described. Synthesized compounds were subjected to reactions with other reagents to synthesize poly-fused heterocyclic incorporated thienoquinoxaline moiety. Some of the synthesized compounds were screened for their antibacterial and antifungal activities.

Keywords: pyrrolylthienoquinoxaline, pyrrolopyrazinothienoquinoxalines, pyrrolyl triazolylthienoquinoxaline, synthesis, antimicrobial activity.

INTRODUCTION

During the last few years, quinoxalines have been of special interest due to their biological activity. This has led to the development of a new class of structural elements for mycobacteriostatic drugs [1—3] based quinoxaline derivatives that have been explored for developing pharmaceutically important molecules for examples, imidazoquinoxalines ribonucleosides as linear of antivira [4], pyrazoloquinoxaline showed a relatively high antibacterial activity wherein MIC value was 25 mg/mL against Bacillus licheniformis and Cellulomonas sp. [5], quinoxaline-1,4-di-^-oxides for treatment of tuberculosis [6], pyrimido[4,5-b]quinox-aline used as anti-hypertensive and blood platelet ant aggregating agents [7], also some quinoxaline derivatives have a cytotoxic effects on human cancer cell lines [8, 9], commercially impotent as agrochemicals [10], herbicides [11], hypoxic-cytoxic agents [12], antivirus [13] (Hepatitis B), antimicrobial [14], and amebicides [15].

On the other hand, several series of heterocyclic compounds possessing a bridgehead pyrrolyl moiety play a vital role in many biological activities [10—12].

Thus, as part of an ongoing program for the synthesis ofpoly fused heterocyclic systems with expected biological activity [13—18], in the present report, we present the full experimental details and biological evaluation of novel pyrrolyfuro[2,3-d] pyrimidine series.

RESULTS AND DISCUSSION

The starting compounds ethyl 3-aminothieno[2,3-b]quinoxaline-2-carboxylate (Ia) and 3-acetyl-3-aminothieno[2,3-b]quinoxaline (Ib) were synthesized

# Corresponding author: e-mail: yasserabdelmoez@yahoo.com.

from the reaction of 2-mercaptoquinoxaline-3-carbo-nitrile with ethyl chloroacetate and chloroacetone according our previous procedure. The amino group of (Ia,b) was converted to the 1-pyrrolyl moiety via the interaction with 2,5-dimethoxytetrahydrfuran in boiling acetic acid to afford 3-pyrrolyl-2-substitut-edthieno[2,3-b]quinoxalines (IIa,b) in good yield. IR spectra of the pyrrolyl derivatives represent the disappearance of the bands corresponding the amino group and show high value for the carbonyl group as a result of cancel the effect of the amino group. On the other hand 1H NMR spectra of compounds (IIa,b) showed bands characteristic for two sets of pyrrole CH protons.

Compounds (IIa,b) were used as key intermediates in the synthesis of other substituted thieno[2,3-b]qui-noxalines. Thus, reaction of ethyl 3-pyrrolylth-ieno[2,3-b]quinoxaline-2-carboxylate (IIa) with hydrazine hydrate leads to the formation of the corresponding carbohydrazide derivative (III) (Scheme 1). Several pyrrolythieno quinoxaline substituted at posi-tion-2 with different heterocyclic residues were obtained via treatment of compound (IV) with different reagents. Thus, the mercaptoxadiazolyl derivative (IV) was synthesized from the reaction of (III) with carbon disulfide in pyridine. The mercapto compound (IV) was easily converted into the corresponding S-alkylat-ed products (V&,b) upon treatment with ethyl chloro-acetate or phenacyl bromide respectively. Also, interaction of compound (III) with acetyl acetone afforded the dimethylpyrazolyl derivative (VI). The carbohy-drazide added easily phenyl isocyanate in absolute etha-nol to afford the thiosemicarbazide derivative (VII) which upon treatment with alcoholic potassium hydroxide result in the triazolethione derivative (VIII).

Diazotization of the carbohydrazide (III) leads to the formation of the carboazide derivative (IX). The reaction of (IX) with aromatic amines gave urea derivatives (Xa,b). Furthermore refluxing of the azide derivative in an inert high boiling point solvent such as xylene, led to the formation of pyrro-lo[1",2":1',6']pyrazino[2',3':4,5]thieno[2,3-^]quinox-

alin-2-(1H)-ne (XI) through a Curitus rearrangement. The pyrazinone derivative was subjected to thionation by reacting with phosphorus pentasulfide in dry pyri-dine to give the corresponding pyrazinthione (XII). S-Methylation of (XII) using methyl iodide in ethanol in the presence of anhydrous potassium carbonate as basic catalyst afforded (XIII) in good yield.

N S T T

N-N

a, R = OEt

b, R = Ph xch2cor X = Br or Cl AcONa/EtOH

N S CO CH3

NA

CH3

CONHNHCSNHPh

KOH/EtOH

N X

a, R = C6H5

b, R = C6H4-OCH3p

"S' XIII

K2CO3/EtOH

"N' ^SCH3

N S XII Scheme 1

N S 1

H

On the other hand, 2-acetyl-3-pyrrolyl derivative (IIb) was allowed to react with thiosemicarbazide in glacial acetic acid to give the corresponding thiosemicarba-zone (XIV), which was further reacted with ethyl chloro-acetate and phenacyl bromide in boiling ethanol in the

presence of anhydrous potassium carbonate to afford compounds (XVa,b) in a considerable yield (Scheme 2). The thiazolidinone derivative (XVa) was condensed with anisaldehyde in ethanol in presence ofpiperidine as basic catalyst to afford the anisylidene derivative (XVI).

..XX

N S COCH3 IIb

nh2nhcsnh2

AcOH "

N S XIV

NNHCSNH CH3

2

ClCH2COOEt /EtOH EtO^. PhCOCH3Br K2CO3 K2CO^

N.

N S

CH3

XVa

OHCC6H5 ■ OCH3P

O

CH XVb

N-N

3

Ph

.S. ^CHC3H6OCH3O N-N^ ^ 36 3

CH3 N-L

3 u O

H

XVI

Scheme 2

Biological activity. Five compounds were selected and screened in vitro for their antimicrobial activity against four strains of bacteria (Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus albus) and six fungal species (Aspergillusflavus, Aspergillus niger, Candida albicans, Geotrichum candi-dum, Scopulariopsis brevicaulis and Trichophyton rubrum) using the filter paper disc method [17]. The biological activity, as expressed by the growth of the inhibition zones of the tested microorganism are summarized in Table 1 and Table 2. From Table 1, it is

obvious that, as bactericides there is no activity for the tested compounds against except for compound (V) and (Via). As for fungicides in Table 2, moderate activity was shown against A. flavus, A. niger, C. albican-sand, G. candidum, S. brevicaulis and T. rubrum.

EXPERIMENTAL

Melting points are uncorrected and were measured on a Gallenkamp apparatus. IR spectra were recorded on a Pye-Unicam SP3-100 spectrophotometer using

Table 1. Antibactertial activity (Inhibition Zone in mm)

Table 2. Antifungal activity (Inhibition Zone mm)

Organisms Chloramphenicol* (IIIa) (IIIc) (V) (VIa) (XIIIb)

B. cereus 25 - - 17 8 -

E. coli 25 - - - - -

P. aeruginosa 25 - - - - -

S. albus 25 - - - - -

Organisms Derma-tine* (IIIa) (IIIc) (V) (VIa) (XIIIb)

A. flavus 28 8 8 8 - -

A. niger 35 15 10 8 - -

C. albicans 22 10 - - - -

G. candidum 35 10 7 7 - -

S. brevicaulis 25 - - - - -

T. rubrum 25 - - - - -

* Chloramphenicol as antibacterial standard.

* Dermatine as antifungal standard.

KBr discs. 1H NMR spectra were obtained with a Joel LA 400 MHz FT.NMR spectrometer (S in ppm, J in Hz). MS — on a Joel JMS-600 mass spectrometer. Elemental analyses were determined using a Perkin-Elmer 240C microanalyzer and all compounds gave results in acceptable range.

Ethyl 3-aminothieno[2,3-b]qumoxaline-2-carbox-ylate (Ia) and 3-acetyl-3-aminothieno[2,3-A]quinoxa-line(Ib). These compounds were synthesized according to our previous reports [18].

3-Pyrrolyl-2-substitutedthieno[2,3-A]qumoxalines (IIa,b). A mixture of compound (Ia) or (Ib) (0.01 mol) and 2,5-dimethoxytetrahydrofuran (0.01 mol) in glacial acetic acid (30 mL) was refluxed for 2 h, the solvent was reduced to one third ofvolume under reduced pressure and then cool. The brown precipitate was extracted several times on cold with ethanol; the extracts were combined together and evaporated under reduced pressure. The pyrrolyl derivatives (IIa,b) were collected by filtration.

Ethyl 3-Pyrrolylthieno[2,3-b]quinoxalme2-carboxy-late (IIa) was separated from ethanol as yellow crystals, m.p.160°C, yield 58%. Found, %: C 57.33; H 4.02; N 15.60; S 11.70. C17H13N3O2S. Anal. calcd., %: C 57.13; H 4.06 ; N 15.37; S 11.73. IR (v, cm-1): 1720 (C=O), 1620 (C=N). 1H NMR (CDCl3): 1.36-1.39 (3 H, t, J 7.2, CH3), 4.39-44.44 (2 H, q, J 8, CH2), 6.47-6.49 (2 H, t, J 2, 2 CHpyrrolyl), 7.23-7.24 (2 H, t, J 2.4, 2 CHpyrrolyl), 7.81-7.91 (2 H, m, Ar-H), 8.168.28 (2 H, m, Ar-H). MS: m/z 323.3 (M+).

2-Acetyl-3-pyrrolylthieno[2,3-b]quinoxaline (IIb) was separated from ethanol as yellow crystals, m.p. 210°C, yield 62%. Found, %: C 59.49; H 3.51; N 17.03; S 13.36. C16H11N3OS. Anal. calcd., %: C 59.24; H 3.73; N 17.27; S 13.18. IR (v, cm-1): 1680 (C=O), 1610 (C=N). 1H NMR (CDCl3): S 2.23 (3 H, s, CH3), 6.51-6.52 (2 H, t, J 2.4, 2 CHpyrrolyl), 7.05-7.06 (2 H, t, J 2, 2 CHpyrrolyl), 7.75-7.86 (2 H, m, Ar-H), 8.138.20 (2 H, m, Ar-H).

3-Pyrrolylthieno[2,3-b]quinoxalme2-carbohydrazide (III). A mixture of compound (IIa) (0.01 mol) and hydrazine hydrate (3 mL) was refluxed in absolute ethanol (30 mL) for 4 h. The solid product separated from the hot mixture was filtered off and recrystallized from dioxane to give pale yellow crystals of the carbohy-drayide derivative (III), m.p. 192-193°C, yield 71%. Found, %: C 58.48; H 3.52; N 22.90; S 10.43. C15H11N5OS. Anal. calcd., %: C 58.24; H 3.58; N 22.64; S 10.36. IR (v, cm-1): 3400-3250 (NHNH2), 1660 (C=O), 1610 (C=N). 1H NMR(DMSO-

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