Acta Chim. Slov. 2004, 51, 537-544. 537 Short Communication CYCLOHEXENONES THROUGH ADDITION OF ETHYL ACETOACETATE TO CHALCONES DERIVED FROM 2-ACETYLTHIOPHENE Gheorghe Roman Department of Chemistry, Transilvania University, 29 Eroilor Blvd, 500036 Braşov, Romania Received 16-03-2004 Abstract Nine new ethyl 6-aiyl-4-(2-thienyl)cyclohex-3-en-2-one-l-carboxylates, valuable intermediates in the synthesis of fused heterocycles, have been prepared through NaOH-catalyzed cyclocondensation of 3-aiyl-l-(2-thienyl)prop-2-en-l-ones with ethyl acetoacetate. Key words: chalcone, Michael addition, cyclocondensation, cyclohexenones Introduction Chalcones and the corresponding heterocyclic analogs are valuable intermediates in organic synthesis1 and exhibit a multitude of biological activities.2 From a chemical point of view, an important feature of chalcones and their heteroanalogs is the ability to act as activated unsaturated systems in conjugated addition reactions of carbanions in the presence of basic catalysts.3'4 This type of reaction may be exploited with the view of obtaining highly functionalized cyclohexene derivatives,5 but is more commonly used for the preparation of 3,5-diaryl-6-carbethoxycyclohexenones via Michael addition of ethyl acetoacetate. The mentioned cyclohexenones are efficient synthons in building spiranic compounds6 or intermediates in the synthesis of fused heterocycles such as benzoselenadiazoles and benzothiadiazoles,7 benzopyrazoles and benzisoxazoles8'9 or carbazole derivatives.10 The synthesis of 6-acetyl-5-aryl-2-cyclohexenones or 5-aryl-6-carbethoxy-2-cyclohexenones substituted in position 4 with a 2-thienyl moiety through the Michael addition of acetylacetone and ethyl acetoacetate respectively to 3-aryl-l-(2-thienyl)-2-propenones, as well as these cyclohexenones’ involvement in various reactions have been already briefly described.11 Further on our studies on the preparation12 and reactivity13'14 of heterochalcones derived from 2-acetylthiophene, this paper presents the G. Roman: Cyclohexenones Through Addition of Ethyl Acetoacetate to Chalcones Derived from... 538 Acta Chim. Slov. 2004, 51, 537-544. synthesis of some new 5-aryl-6-carbethoxy-3-(2-thienyl)-2-cyclohexenones, whose various chemical functions commend them as valuable intermediates in subsequent reactions. Results and discussion The reaction of chalcones and their heterocyclic analogs with ethyl acetoacetate is known to lead to three structurally diverse types of compounds, depending on the experimental conditions employed: pyrylium salts,15 Michael addition products16 and cyclohexenone derivatives.17 The catalyst plays a key role in directing the reaction to different end products. A strong Lewis acid such as boron trifluoride etherate generates pyrylium cations from the reaction of chalcones and acetoacetic acid esters, but basic catalysts would turn the intermediate Michael addition product into cyclohexenones through the intramolecular cyclocondensation of the methyl group originating from acetoacetic acid ester and the ketone function of the initial chalcone. Thus, in the presence of a base, thienyl-containing chalcone analogs 1 and ethyl acetoacetate 2 produce cyclohexenones 3 by means of an intermediate Michael adduct, as outlined in Scheme 1. O 1a-i O vAr + H3C COOC2H5 base H3C-O O COOC2H5 Ar O Compound Ar 3a-i COOC2H5 3a 3b 3-methoxyphenyl 3,4-dimethoxyphenyl Ar 3c 3d 3,4-methylenedioxyphenyl 3,4,5-trimethoxyphenyl 3e 5-bromo-2-methoxyphenyl 3f 3-bromo-4-methoxyphenyl 3g 4-benzyloxyphenyl 3h 4-benzyloxy-3-methoxyphenyl 3i 2-benzyloxy-5-bromophenyl Scheme 1. Cyclohexenones 3 through cyclocondensation of chalcone analogs 1 derived from 2-acetylthiophene with ethyl acetoacetate. S 2 G. Roman: Cyclohexenones Through Addition of Ethyl Acetoacetate to Chalcones Derived from... Acta Chim. Slov. 2004, 51, 537-544. 539 The cyclocondensation of ethyl acetoacetate with chalcones 1 leads to the generation of two chiral centers at C1 and C6 in the structure of cyclohexenones 3. As the explored reaction is not stereoselective, both configuration of the chiral carbon atoms are expected to be noticed in the synthesized cyclohexenones 3, which would result in a mixture of diastereomers. No attempt to separate the diastereomeric cyclohexenones 3 has been undertaken, and the cyclocondensation products have been characterized in the form of the mixture originated from the synthesis. Literature reveals the involvement of both organic (sodium ethoxide, piperidine, diethylamine) and inorganic (alkaline hydroxides) basic catalysts in this sort of synthesis. In our hands, the use of sodium hydroxide as a catalyst, as described by Hanson,18 provided the desired cyclohexenones 3 in good yield. The organic compounds were separated out by pouring the reaction mixture in water. Compound 3b precipitated as a solid while the other cyclohexenones were initially oily compounds that after being kept for several days turned into solid materials as well. Compound 3g did not separate as a solid even after three weeks, and the organics were isolated in this čase by extracting them in diethyl ether. The slow removal of the solvent at room temperature fmally led to a solid material that was recrystallized. The yields of the cyclocondensation are good, varying form 43 to 79%. Structural analysis of the newly synthesized cyclohexenones 3 comprised IR and NMR investigations. The IR spectra of these compounds revealed a sharp strong absorption band above 1700 cm"1 that can be correlated with the presence of the ester function in the structure of cyclohexenones 3. Furthermore, another sharp strong absorption band was noticed at approximately 1660 cm"1 and was assigned to the carbonyl group conjugated with a carbon-carbon double bond. No other absorption band could be evidenced in the region of the IR spectrum associated with the stretching vibrations of the carbonyl group, thus excluding the intermediate Michael adduct having an extra carbonyl group. The ^-NMR spectra substantiated the results of the IR analysis. The characteristic signals of an ethyl ester moiety (a triplet at chemical shift values of about 1 ppm and a quartet at ? values above 4 ppm) confirmed the presence of the ester group in the structure of cyclohexenones 3. The proton at C6 of the cyclohexenone skeleton usually appears as a multiplet immediately below 3 ppm, excepting the čase of or^o-alkoxyaryl-substituted compounds 3e and 3i, when the G. Roman: Cyclohexenones Through Addition of Ethyl Acetoacetate to Chalcones Derived from... 540 Acta Chim. Slov. 2004, 51, 537-544. signals due to this proton shift to higher ? values and mingle with the peaks attributed to the proton at C1. The latter proton’s signals at about 3.15 ppm turn up as two pairs of doublets, on one hand as a result of the splitting due to the neighbouring C6 proton and owing to the possible cis-trans geometry on the other hand. The two diastereotopic protons at C5 of the cyclohexenone ring are represented in the lH NMR spectra of compounds 3 as a multiplet at 3.6-3.8 ppm, again with the exception of 3e and 3i whose bulky or^o-alkoxyaryl substituent at C6 causes a change of the typical chemical shift value and leads to the superimposition of these protons’ signals over the quartet recorded for the methylene group in the ester function. The characteristic signal in the lH NMR spectra of compounds 3 is however the singlet of the vinylic proton in the position 3 of the cyclohexenone ring, that occurs at approximately 6.5 ppm and confirms that the intramolecular cyclocondensation subsequent to the Michael addition actually took plače. As for the protons in the aromatic region, a similar pattern throughout the lH NMR spectra of ali compounds 3 allowed the assignment of the protons in the thiophene ring at approximately 7.10, 7.40 and 7.48 ppm. The number of the other aromatic protons of the aryl substituent in the position 6 of the cyclohexenone ring that was integrated in the lH NMR spectra of compounds 3 was always in good agreement with the factual one. Conclusions The reaction of several chalcone analogs containing a thiophene ring with ethyl acetoacetate in the presence of catalytic amounts of NaOH has been shown to afford, via a Michael addition followed by an intramolecular cyclocondensation, cyclohexenone derivatives which are useful intermediates in the synthesis of structurally diverse heterocycles. Experimental Elemental analysis was performed on a Carlo Erba 1106 analyzer. Melting points were taken on a Boëtius melting point microscope and are uncorrected. IR spectra were recorded on a SPECORD M80 spectrometer in KBr pellets. NMR analysis was conducted on a Bruker DXR-500 (500 MHz) instrument in CDC13. Ali chemical shifts G. Roman: Cyclohexenones Through Addition of Ethyl Acetoacetate to Chalcones Derived from... Acta Chim. Slov. 2004, 51, 537-544. 541 are reported in ppm downfield from tetramethylsilane; the coupling constants (J) are given in Hz. The synthesis of chalcones 1 having a 2-thienyl moiety was performed as reported.12'19"21 Ali other reagents are commercially available compounds and have been used without prior purification. General procedure for the synthesis of ethyl esters of 6-aryl-4-(2-thienyl)cyclohex-3-en-2-one-l-carboxylic acids through NaOH-catalyzed cyclocondensation of 3-aryl-l-(2-thienyl)prop-2-enones with ethyl acetoacetate Thienyl-containing chalcone analog 1 (3 mmol) and ethyl acetoacetate 2 (0.39 g, 0.40 mL, 3 mmol) were refluxed for 2 h in 10-15 mL ethanol in the presence of 0.5 mL 10% NaOH. The reaction mixture was then poured with good stirring into 200 mL ice-cold water and kept at room temperature until the reaction product separated as a solid, which was filtered off and recrystallized from ethanol. Alternatively, compound 3g was isolated by extracting the emulsion with diethyl ether. The ether phase was separated and dried over anhydrous Na2S04 prior to be subjected to solvent removal. The solid residue obtained was also recrystallized from ethanol. Ethyl 6-(3-methoxyphenyl)-4-(2-thienyl)cyclohex-3-en-2-one-l-carboxylate (3a) Yellow crystals, (0.65 g, 61%), mp 90-91 °C. Anal. Calcd for C20H2o04S: C 67.39, H 5.66. Found: C 67.52, H 5.51. IR (KBr, cm"1): 1660 (vc=o ketone), 1740 (vc=o ester). lH NMR (500 MHz, CDC13): 5 1.07 (3H, t, J 6.8 Hz, -CH2CH3), 2.92-2.98 (1H, m, >CHAr), 3.15 (1H, dd, Jtra„s 2.9 Hz, Jck 17.4 Hz, >CHCOOC2H5), 3.73-3.79 (2H, m, -CH2CHAr-), 3.82 (3H, s, -OCH3), 4.08 (2H, q, J 6.8 Hz, -CH2CH3), 6.55 (1H, s, =CH-CO-), 6.83 (1H, d, Jh2 7.7 Hz, Ar-H), 6.67 (1H, s, Ar-H), 6.91 (1H, d, Jh2 7.2 Hz), 7.11 (1H, s), 7.28 (1H, t, Jl2 7.2 Hz, Jia 7.7 Hz, Ar-H), 7.39 (1H, s), 7.48 (1H, d, Jl2 4 Hz). Ethyl 6-(3,4-dimethoxyphenyl)-4-(2-thienyl)cyclohex-3-en-2-one-l-carboxylate (3b). Yellow crystals, (0.60 g, 52%), mp 126-127 °C. Anal. Calcd for C2iH2205S: C 65.27, H 5.74. Found: C 65.08, H 5.79. IR (KBr, cm"1): 1660 (vc=o ketone), 1745 (vc=o ester). lH NMR (500 MHz, CDC13): 5 1.08 (3H, t, J 6.9 Hz, -CH2CH3), 2.9-2.98 (1H, m, >CHAr), 3.15 (1H, dd, Jtra„s 3 Hz, Jck 17.6 Hz, >CHCOOC2H5), 3.7-3.77 (2H, m, -CI^CHAr-), G. Roman: Cyclohexenones Through Addition of Ethyl Acetoacetate to Chalcones Derived from... 542 Acta Chim. Slov. 2004, 51, 537-544. 3.88 and 3.89 (3H, s, -OCH3), 4.07 (2H, q, J 6.9 Hz, -CH2CH3), 6.54 (1H, s, =CH-CO-), 6.82 (1H, s, Ar-H), 6.85 (1H, d, Jia 7.9 Hz, Ar-H), 6.88 (1H, d, Jia 7.9 Hz, Ar-H), 7.11 (1H, t, 7U4 Hz), 7.39 (1H, s), 7.49 (1H, d, 7U4.7 Hz). Ethyl 6-(3,4-methylenedioxyphenyl)-4-(2-thienyl)cyclohex-3-en-2-one-l-carboxylate (3c). Yellow crystals, (0.48 g, 43%), mp 123-124 °C. Anal. Calcd for C20H18O6S: C 64.85, H 4.90. Found: C 64.98, H 4.84. IR (KBr, cm"1): 1660 (vc=o ketone), 1740 (vc=o ester). 'H NMR (500 MHz, CDC13): 8 1.11 (3H, t, JI Hz, -CH2CH3), 2.84-2.93 (1H, m, >CHAr), 3.12 (1H, dd, Jtra„s 3.8 Hz, Jcm 17.8 Hz, >CHCOOC2H5), 3.61-3.74 (2H, m, -CH2CHAr-), 4.09 (2H, q, JI Hz, -CH2CH3), 5.96 (2H, s, -OCH20-), 6.53 (1H, s, =CH-CO-), 6.78 (2H, s, Ar-H), 6.81 (1H, d, Ar-H), 7.10 (1H, t, Jh2 4 Hz), 7.38 (1H, s), 7.48 (1H, d, Jl2 4.7 Hz). Ethyl 4-(2-thienyl)-6-(3,4,5-trimethoxyphenyl)cyclohex-3-en-2-one-l-carboxylate (3d). Yellow crystals, (0.99 g, 79%), mp 164-165 °C. Anal. Calcd for C22H2406S: C 63.44, H 5.81. Found: C 63.33, H 5.87. IR (KBr, cm"1): 1660 (vc=o ketone), 1740 (vc=o ester). lH NMR (500 MHz, CDC13): 5 1.10 (3H, t, J 6.7 Hz, -CH2CH3), 2.89-2.99 (1H, m, >CHAr), 3.17 (1H, dd, Jtra„s 3.5 Hz, Jds 17.7 Hz, >CHCOOC2H5), 3.71-3.79 (2H, m, -CH2CHAr-), 3.84 and 3.86 (3H, s, -OCH3), 4.10 (2H, q, J 6.7 Hz, -CH2CH3), 6.52 (2H, s, Ar-H), 6.55 (1H, s, =CH-CO-), 7.10 (1H, t, Jh2 4 Hz), 7.41 (1H, s); 7.49 (1H, d, Jh2 4.7 Hz). Ethyl 6-(5-bromo-2-methoxyphenyl)-4-(2-thienyl)cyclohex-3-en-2-one-l-carboxylate (3e). Yellow crystals, (0.89 g, 68%), mp 155-156 °C. Anal. Calcd for C20Hi9BrO4S: C 55.18, H 4.40. Found: C 55.32, H 4.28. IR (KBr, cm"1): 1670 (vc=o ketone), 1730 (vc=o ester). 'H NMR (500 MHz, CDC13): 5 1.08 (3H, t, JI Hz, -CH2CH3), 3.06-3.13 (2H, m, >CHAr and >CHCOOC2H5), 3.85 (3H, s, -OCH3), 3.96-4.04 (2H, m, -CH2CHAr-), 4.09 (2H, q, J Hz, -CH2CH3), 6.53 (1H, s, =CH-CO-), 6.79 (1H, d, Jh2 9 Hz, Ar-H), 7.10 (1H, br s), 7.32 (1H, d, Jh3 2.2 Hz, Ar-H), 7.35 (1H, d, Jh3 2.2 Hz, Ar-H), 7.37-7.40 (2H, m), 7.48 (1H, d, Ju 5.1 Hz). G. Roman: Cyclohexenones Through Addition of Ethyl Acetoacetate to Chalcones Derived from... Acta Chim. Slov. 2004, 51, 537-544. 543 Ethyl 6-(3-bromo-4-methoxyphenyl)-4-(2-thienyl)cyclohex-3-en-2-one-l-carboxylate (3f). Yellow crystals, (0.96 g, 74%), mp 130-131 °C. Anal. Calcd for C20H19BrO4S: C 55.18, H 4.40. Found: C 55.03, H 4.46. IR (KBr, cm"1): 1660 (vc=o ketone), 1745 (vc=o ester). lH NMR (500 MHz, CDC13): 5 1.11 (3H, t, J 6.9 Hz, -CH2CH3), 2.87-2.97 (1H, m, >CHAr), 3.13 (1H, dd, Jtra„s 3.3 Hz, Jds 16.2 Hz, >CHCOOC2H5), 3.63-3.78 (2H, m, -CH2CHAr-), 3.91 (3H, s, -OCH3), 4.10 (2H, q, J 6.9 Hz, -CH2CH3), 6.55 (1H, s, =CH-CO-), 6.89 (1H, d, Jh2 8.1 Hz, Ar-H), 7.12 (1H, br s), 7.25 (1H, d, Jl2 8.1 Hz, Ar-H), 7.40 (1H, s), 7.50 (1H, d, Jl2 4.7 Hz), 7.53 (1H, s). Ethyl 6-(4-benzyloxyphenyl)-4-(2-thienyl)cyclohex-3-en-2-one-l-carboxylate (3g). Yellow crystals, (0.60 g, 46%), mp 144-145 °C. Anal. Calcd for C26H2404S: C 72.22, H 5.55. Found: C 71.97, H 5.46. IR (KBr, cm"1): 1660 (vc=o ketone), 1745 (vc=o ester). lH NMR (500 MHz, CDC13): 5 1.05 (3H, t, J 6.8 Hz, -CH2CH3), 2.86-2.96 (1H, m, >CHAr), 3.13 (1H, dd, Jtnns 3.3 Hz, Jcis 16.3 Hz, >CHCOOC2H5), 3.64-3.79 (2H, m, -CH2CHAr-), 4.05 (2H, q, J 6.8 Hz, -CH^CHa), 5.06 (2H, s, -OCH2C6H5), 6.54 (1H, s, =CH-CO-), 6.96 (1H, d, Jl2 8 Hz, Ar-H), 7.10 (1H, s), 7.24 (1H, d, Jh2 8 Hz, Ar-H), 7.32-7.45 (6H, m), 7.48 (1H, d, Jh2 4.4 Hz). Ethyl 6-(4-benzyloxy-3-methoxyphenyl)-4-(2-thienyl)cyclohex-3-en-2-one-l- carboxylate (3h). Yellow crystals, (0.86 g, 62%), mp 139-140 °C. Anal. Calcd for C27H2605S: C 70.11, H 5.67. Found: C 70.23, H 5.59. IR (KBr, cm"1): 1650 (vc=o ketone), 1730 (vc=o ester). lH NMR (500 MHz, CDC13): 5 1.06 (3H, t, J 6.9 Hz, -CH2CH3), 2.86-2.97 (1H, m, >CHAr), 3.14 (1H, dd, Jtra„s 3 Hz, Jck 17.6 Hz, >CHCOOC2H5), 3.64-3.78 (2H, m, -CH^CHAr-), 3.90 (3H, s, -OCH3), 4.06 (2H, q, J 6.9 Hz, -CH2CH3), 5.15 (2H, s, -OCH2C6H5), 6.54 (1H, s, =CH-CO-), 6.80 (1H, d, Jh2 7.9 Hz), 6.82-6.89 (2H, m, Ar-H), 7.10 (1H, br s), 7.28-7.33 (1H, m), 7.34-7.41 (3H, m), 7.42-7.46 (2H, m), 7.48 (1H, d, Jh2 4.4 Hz). Ethyl 6-(2-benzyloxy-5-bromophenyl)-4-(2-thienyl)cyclohex-3-en-2-one-l-carboxylate (3i). Yellow crystals, (1.03 g, 67%), mp 134-135 °C. Anal. Calcd for C26H23Br04S: C 61.06, H 4.53. Found: C 60.90, H 4.59. IR (KBr, cm"1): 1660 (vc=o ketone), 1740 (vc=o ester). lH NMR (500 MHz, CDC13): 5 1.10 (3H, t, J 6.9 Hz, -CH2CH3), 3.01-3.15 (2H, G. Roman: Cyclohexenones Through Addition of Ethyl Acetoacetate to Chalcones Derived from... 544 Acta Chim. Slov. 2004, 51, 537-544. m, >CHAr and >CHCOOC2H5), 4.01-4.17 (4H, m, -CH2CHAr- and -CH2CH3), 5.13 (2H, s, -OCH2C6H5), 6.50 (1H, s, =CH-CO-), 6.84 (1H, d, J1,2 8.6 Hz, Ar-H), 7.09 (1H, br s), 7.28-7.36 (6H, m), 7.38-7.43 (2H, m), 7.47 (1H, d, J1,2 4.2 Hz). References 1. D. N. Dhar, The Chemistry of Chalcones and Related Compounds, Wiley-Interscience, New York, 1981. 2. J. R Dimmock, D. W. Elias, M. A. Beazely, N. M. Kandepu, Curr. Med. Chem. 1999, 6, 1125-1150. 3. H. O House, Modem Synthetic Reactions, 2nd edition, W.A. Benjamin, Menlo Park, California, 1972, p. 595. 4. M. E. Jung, Comprehensive Organic Synthesis, vol. 4, Eds. B. M. Trost, I. Fleming, Pergamon Press, Oxford, 1991, p. 1. 5. H. D. Tabba, N. M. Yousef, M. M. Al-Arab, Coll. Czech. Chem. Commun. 1995, 60, 594-604. 6. V. Padmavathi, K. Sharmila, A. Somasekhar Reddy, D. Bhaskar Reddy, Indian J. Chem., Sect. B, 2001, 40, 11-14. 7. D. Bhaskar Reddy, A. Somasekhar Reddy, V. Padmavathi, J. Chem. Research (S) 1998, 784-785. 8. V. Padmavathi, B. J. Mohan Reddy, A. Balaiah, K. Venugopal Reddy, D. Bhaskar Reddy, Molecules 2000, 5, 1281-1286. 9. V. Padmavathi, K. Sharmila, A. Balaiah, A. Somasekhar Reddy, D. Bhaskar Reddy, Synth. Commun. 2001, 37, 2119-2126. 10. V. Padmavathi, K. Sharmila, A. Padmaja, D. Bhaskar Reddy, Heterocycl. Commun. 1999, 5, 451-156. 11. K. M. Ghoneim, M. M. Badran, M. A. Shaaban, S. El-Meligie, Egypt. J. Pharm. Sci. 1989, 30, 369-377. 12. G. Roman, An. Şt. Univ. “Al. I. Cuza” laşi 2000, VIII, 181-184; Chem. Abstr. 2001, 134, 198180. 13. G. Roman, Buli. Transih. Univ. Bras., Series B 2000, 7(42), 69-74; Chem. Abstr. 2002, 136, 167317. 14. G. Roman, M. Andrei, Bul. Inst. Politehn. laşi 2002, XLVIII (Lil), 51-56. 15. W. Davey, J. R. Gwilt, J. Chem. Soc. 1957, 1015-1017. 16. J. A. VanAllan, G. A. Reynolds, J. Org. Chem. 1968, 33, 1102-1105. 17. A. Sammour, M. T. Elzimaity, A. Abdel-Maksoud, J. Chem. U.A.R. 1969, 12, 481-192. 18. G. A. Hanson, Buli. Soc. Chim. Belges 1958, 67, 712-716. 19. Ng. Ph. Buu-Hoi, Ng. Dat Xuong, M. Sy, Buli. Soc. Chim. France 1956, 1646-1650. 20. S. C. Kushwaha, J. Indian Chem. Soc. 1968, 45, 752-754. 21. V. I. Savin, Yu. P. Kitaev, Zh. Org. Khim. 1973, 9, 1101-1110. Povzetek S pomočjo NaOH katalizirane ciklokondenzacije 3-aril-1-(2-tienil)prop-2-en-1-onov z etil acetoacetatom smo pripravili devet novih 6-aril-4-(2-tienil)cikloheks-3-en-2-on-1-karboksilatov, uporabnih intermediatov v sintezi prikondenziranih heterociklov. G. Roman: Cyclohexenones Through Addition of Ethyl Acetoacetate to Chalcones Derived from...