Synthesis and Characterization of Perfluoromethyl-1,3-dicarbonyl Derivatives of the potent phototoxin α-Terthiophene and α-Bithiophene.

Samir A. AL-Taweel* Salah AL-Trawneh

Department of Chemistry, Mu,tah University; Karak-Jordan.

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Abstract :

5-Acetyl-2,2′:5′,2″-Terthiophene (5) and 5-Acetyl-2,2′-Bithiophene (7) were treated with ethyl trifluoroacetate in the presence of potassium t-butoxide to afford 1-(5-α-terthienyl)-4,4,4-trifluoro-1,3-butanedione (4) and 1-(5-α-bithienyl)-4,4,4-trifluoro-1,3-butanedione (6), in good yields, respectively. Under similar conditions 3-acetyl-2,5-dichlorothiophene (9) affords 1-(2,5-dichloro-3-thienyl)-4,4,4-trifluoro-1,3-butanedione (8) .

The structures of the new compounds were confirmed by elemental analysis, mass spectrometry, 1H-NMR, and 13C-NMR spectral data.

Introduction

2,2′:5′,2″-Terthiophene (1) , 2,2´-bithiophene (2) , and several of their derivatives are biologically active natural products [1-4]. 2,2′:5′,2″-Terthiophene, the best known of this series was found in plants of the family compositae (Asteraceae). It shows nematicidal and fungicidal activity, which is enhanced by near ultraviolet radiation. It was found that thiophene and its higher α-oligomers are of interest as repeating units for the construction of electroconductive polymers. Much of the research has been focused on the modification of the base monomer units, specifically the 3-alkyl derivatives which yield soluble polymers with improved coductivity. The synthesis, functionalization and application of conjugated polythiophenes have been recently reviewed [5]. Several drugs derived from 3-substituted thiophene are in use, for example, cetiedil an efficient vaso-dilator, ticarcilline, semi-synthetic β-lactam antibiotics with thiophene-3-malonic acid unit [6]. Various synthetic methods for the preparation of 3-Substituted thiophenes have been reviewed [7].

Trifluoromethyl substituted heterocycles are of interest since they show a unique and significant changes in their chemical and physiological properties [8]. Perfluoromethyl-1,3-dicarbonyl compounds are useful synthetic intermediates for the preparation of five-membered and six-membered heterocycles [9]. The commerically available 1-(2-thienyl)-4,4,4-trifluoro-1,3-butanedione (3) has proved to be very versatile and powerful chelating agent for the extraction of radioactive metal ions from acidic solutions [10]. Perfluoro-1,3-dicarbonyl derivatives of 2,2′:5′,2″-terthiophene (1), and 2,2′-bithiophene (2) are desirable for the exploration of the chemistry of oligothiophenes via chemical transformation of 1,3-dicarbonyl moiety to various five-membered and six-membered heterocyclic compounds. To the best of our knowledge, Perfluoromethyl-1,3-dicarbonyl derivatives of 2,2′:5′,2″-terthiophene (1), 2,2′-bithiophene (2), and 2,5-dichlorothiophene hitherto are unreported. Accordingly, the present work aims at describing the synthesis and characterization of (4), (6), (8) as shown in schemes (1-3).

Scheme 1

i) 2-Thienylmagnesium bromide, [NiCl2.( dppp)], Et2O/rt .

ii) CH3COCl, AlCl3, CS2/rt .

iii) potassium t-butoxide, C6H6/rt .

Scheme 2

i) 2-Thienylmagnesium bromide, [NiCl2.( dppp)], Et2O/rt .

ii) CH3COCl, AlCl3, CS2/rt .

iii) potassium t-butoxide, C6H6/rt .

Scheme 3

i) CH3COCl, AlCl3, CS2/rt .ii) potassium t-butoxide, C6H6/rt .

Result and Discussion

Synthesis :

The synthesis of (4) was started from acylation of 2,2′:5′,2″-terthiophene (1). The Friedel-Crafts reaction of (1) with acetyl chloride catalyzed by anhydrous aluminum chloride in carbon disulfide at room temperature afforded mixture of the desired 5-acetyl-α-terthiophene (5) in 30 % yield with m.p 173-176C° ( Lit [11] 176C° ) a long with expected 5,5′–bis(acetyl)-α -terthiophene (10) in 30 % yield , 5-acetyl-α-terthiophene (5) can be separated from the mixture based on solubility difference between (5) and (10), since (5) is hexane-soluble while (10) is hexane insoluble. Dropwise addition of ethyl trifluoroacetate to a suspension of potassium t-butoxide and (5) in benzene at room temperature afford the desired 1,3-diketone (4) in 73 % (Scheme 1). 1-(5-α-Bithienyl)-4,4,4-trifluoro-1,3-butanedione (6) was prepared in a similar strategy. The Friedel- Crafts acylation of (2) afforded 5-acetyl-α-bithiophene (7) in 35 % yield with m.p 105-106 ºC ( Lit [12] m.p 110 °°C° ) , which reacted with ethyl trifluoroacetate in the presence of potassium t-butoxide to give the 1,3-diketone (6) in 70 % yield (Scheme 2). Similarly, (8) was obtained in 75 % yield starting from 3-acetyl-2,5-dichlorothiophene[13] as shown in Scheme (3).

Spectral Data :

The spectral (ms, nmr) and microanalytical data of compound (4), (6), (8) are in agreement with assigned structures and are given in the experimental section. Assigments of 1H nmr are straight forward, and carbon-13-assignments are based on chemical shifts and on the coupling constants between carbon atoms and fluorine atoms. The 1H-nmr spectral analysis of (4), (6), (8) showed the presence of the enol tautomer in more than 97%, the enol tautomer percentage concentration was calculated from the area of vinylic protons which occur between 6.40-6.65 ppm and the area of the the methylene protons which occur between 3.30-3.35 ppm. This predominance of the enol tautomer can be explained due to the presence of intramolecular hydrogen bonding between the enolic hydrogen and the adjacent fluorine atom, as shown in the figure below for compound (8).

The enolic proton for (8) appears at 14.6 ppm in 1H-nmr as broad singlet, which disappears immediately upon the addition of D2O, while the vinylic proton for (8) appears at 6.65 ppm and exchanges deuterium more slowly (78 % after 20 hrs at room temperature). Analysis of 13C nmr spectra of (8) shows the carbon of trifluoromethyl group as quartet at 117.0 ppm with 1J coupling constant of 283 Hz, while the carbonyl carbon adjacent to the trifluoromethyl appears as quartet at 177.1 ppm with 2J of 37.4 Hz and the vinylic carbon appears at 94.9 ppm as quartet with 3J of 2.3 Hz, the coupling constants are consistant with assigned structure and the fact, that the magnitude of the coupling constants decrease with the increase of the number of intervening bonds[17].

Uv-visible spectra of (4) shows λmax at 445 nm, which is red-shifted in comparison with λmax of α-terthiophene which has λmax at 355nm[15], this red shift can be explained due to the presence of trifluoromethyl diketone moiety as an electron-withdrawing group.Work is underway to investigate (8), (6) and (4) as chelating agents for the extraction of radioactive metal ions like Th+4 and UO2+2 from aqueous acidic solutions.

Experimental

2,5-Dibromothiophene,2-bromothiophene, 2,5-dichlorothiophene and 1,3-bis(diphenylphosphino)propane nickel (II) chloride NiCl2 (dppp) were purchased from Acros. The acetyl chloride, potassium t-butoxide and 1-(2-thienyl)-4,4,4-trifluoro-1,3-butanedione were purchased from Aldrich. Ethyl trifluoroacetate [16 ], 3-acetyl-2,5-dichlorothiophene [13], 2,2′–bithiophene and 2,2′:5′,2′-terthiophene [14], were prepared according to the literature procedures. Solvents were dried by using standard procedures.Melting points were determined on Electrothermal melting point apparatus and are uncorrected. 1H nmr and 13C nmr were obtained with Bruker AC-200 spectrometer for solutions in CDCl3 or DMSO-d6. The nmr spectra were calibrated by using signals from the solvent referenced to tetramethylsilane (Me)4Si. The elemental analysis were determined by M.H.W laboratories Phoenix, Arizona, U.S.A. Mass spectra were determined by using a finnigan MAT 731 spectrometer at 70 eV and VG-70s spectrometer. Uv-visible spectra were recorded on GENEYS 2.

General Procedure for the Preparation of Trifluoromethyl-Substituted-1,3-diketones(4),(6) and (8).

A flame–dried round bottomed flask (250 ml), equipped with magnetic stirrer, N2-inlet and rubber septa was charged with a particular methyl ketone (30mmole), dry benzene (50 ml), potassium t-butoxide (33mmole) under nitrogen atmosphere, Ethyl trifluoroacetate (33 mmole) was added dropwise over 15 minutes at 10 ºC, and the reaction mixture was stirred at r.t for 36h. Solution of H2SO4 (5 %) was added dropwise to adjust the pH to a value between 6-7, the solution was extracted with Et2O (2x50 ml). The organic layer was dried over anhydrous (Na2SO4) and evaporated. The residue was purfied by column chromatography on silica gel with CH2Cl2 followed by crystallization from CH2Cl2-hexane for (4) and (6) and vacuum distillation for (8).

Yields and ,physical and spectroscopic data of (4), (6) and (8) are shown below :

1-(5-α-terthienyl)-4,4,4-trifluoro-1,3-butanedione (4).

Yield : 73%, m.p 170-171ºC, 1H nmr (deuteriochloroform) δ: 7.72 (d, J=3.91Hz, 1H), 7.25 (m,H), 7.14 (d, J=3.91Hz, 1H), 7.05 (dd, J=3.91Hz, 3.41Hz, 1H ), 6.42 (s, 1H); 13C nmr (deuteriochloroform) δ: 182.0 (s), 170.5 (q, 2JCF=38.1Hz), 147.2 (s), 139.5 (s), 137.0 (s), 136.3 (s), 134.2 (s), 133.8 (s), 127.1 (s), 128.2 (s), 118.0 (q, 1JCF=282.0Hz), 93.3 (q, 3JCF=3.05Hz); ir (potassium bromide) : [3580, 3479, 3416] (OH), 1639, 1618, 1458, 1284, 1190, 1149, 1111, 792 cm-1, ms : m/z (% rel. int.) : 386(M+,13 ), 317(4), 290(7.5) , 275(7), 248(5), 203(9), 78(19) ; uv (CHCl3) : λmax = 445nm. Anal. Calcd. For C16H9F3O2S3 : C, 49.73 ; H, 2.35 .Found : C, 50.20 ; H,2.43 .

1-(5-α-bithienyl)-4,4,4-trifluoro-1,3-butanedione (6)

Yield : 70 %, m.p 107-108 ºC, 1H nmr (deuteriochloroform) δ 14.6(br s exchangeable with deuterium oxide, 1H), 7.72 (d, JHH=4.0Hz, 1H), 7.35 (m, 2H), 7.23 (d, JHH=4.0Hz, 1H), 7.08 (dd, J=5.0Hz, 4.0Hz, 1H), 6.40 (s, 1H); 13C nmr (deuteriochloroform) δ: 182.0(s),170.5 (q, 2JCF=37.3Hz), 147.6 (s), 137.0 (s), 135.8 (s), 127.4 (s), 126.2 (s), 124.8 (s), 128.5 (s), 133.5 (s), 117.9 (q, 1JCF=279.6Hz), 93.3 (q, 3JCF=3.30Hz); ir (potassium bromide) : [3580, 3500, 3414] (OH), 1650 (C=O), 1618 (C=COH), 1454, 1296, 1147, 800 cm-1; uv (CHCl3) : λmax = 400nm; ms : m/z ( % rel. int.) : 304 (M+, 97), 235 (95), 193 (88), 167 (43), 121 (81), 69 (100), 28 (87).

Anal. Calcd. for C12H7F3O2S2 : C, 47.36; H, 2.32. Found : C, 47.50; H, 2.29.

1-[2,5-dichloro-3-thienyl]-4,4,4-trifluoro-1,3-butanedione (8).

Yield : 75 %, m.p 38-39ºC, b.p 96ºC/4mmHg , 1H nmr (deuteriochloroform) δ:14.5 (br s, exchangeable with deuterium oxide, 1H), 7.20 (s, 1H), 6.65 (s, 1H); 13C nmr (deuteriochloroform)δ: 178.7 (s), 177.3 (q, 2JCF=37.4Hz, 131.6 (s), 130.2 (s), 127.9 (s), 125.9 (s), 116.9 (q ,1JCF=283.1Hz), 94.9 (q, 3JCF=2.3Hz); ir (potassium bromide) : 3415 (weak, OH), 1640 (C=O), 1595 (C=C-OH), 1450, 1278, 1205, 1157, 1097, 1041, 802 cm-1; ms : m/z ( % rel. int.) : 290 (M+, 6), 255 (74), 221 (13), 179 (36), 69 (82), 28 (100). Anal. Calcd. for C8H3Cl2F3O2S : C, 33.01; H, 1.04.Found : C, 33.12; H, 1.06.

REFERENCES AND NOTES

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