An Unexpected C–C Bond Cleavage of Acetophenones: Synthesis of Bis(heteroaryl)arylmethanes and Triarylmethanes via SeO₂/Lanthanide Chloride Catalyzed Friedel–Crafts Arylation

Abstract

A novel synthesis of bisheteroarylaryl methanes and triarylmethanes is described by the selective C–C bond cleavage of acetophenones in the presence of SeO₂/lanthanide chlorides. The present strategy provides an in situ generation of aldehydes from acetophenones followed by a double Friedel–Crafts reaction of electron-rich arenes. Natural product 1,1,1-tris(3-indolyl)methane is synthesized in a single step following the same protocol.

Key words

acetophenones - C–C bond cleavage - double Friedel–Crafts reaction

• References and Notes

• 1a Agh-Atabay NM, Dulger B, Gucin F. Eur. J. Med. Chem. 2003; 38: 875
• 1b Mann J, Baron A, Opoku-Boahen Y, Johansson E, Parkinson G, Kelland LR, Neidle S. J. Med. Chem. 2001; 44: 138
• 1c Yeung KS, Meanwell A, Qiu Z, Hernandez D, Zhang S, McPhee F, Weinheimer S, Clark JM, Janc JW. Bioorg. Med. Chem. Lett. 2001; 11: 2355
• 1d Mibu N, Yokomizo K, Uyeda M, Sumoto K. Chem. Pharm. Bull. 2005; 53: 1171
• 1e Mibu N, Yokomizo K, Uyeda M, Sumoto K. Chem. Pharm. Bull. 2003; 51: 1325
• 1f Lewis MR, Goland PP. Cancer Res. 1952; 12: 130
• 1g Parai MK, Panda G, Chaturvedi V, Manju YK, Sinha S. Bioorg. Med. Chem. Lett. 2008; 18: 289
• 1h Panda G, Shagufta Mishra JK, Chaturvedi V, Srivastava AK, Srivastava R, Srivastava BS. Bioorg. Med. Chem. 2004; 12: 5269
• 1i Mibu N, Sumoto K. Chem. Pharm. Bull. 2000; 48: 1810
• 2 Fukuda M, Fukunishi A, Mori M. JP 06171214, 1994
• 3 Nakanishi M, Mukai T, Inamasu S. JP 44027990, 1969
• 4 Stoll M, Winter M, Gautschi F, Flament I, Willhalm B. Helv. Chim. Acta 1967; 50: 628
• 5a Nair V, Thomas S, Mathew SC, Abhilash KG. Tetrahedron 2006; 62: 6731
• 5b Walsh CT, Garneau-Tsodikova S, Howard-Jones AR. Nat. Prod. Rep. 2006; 23: 517
• 5c Butin AV, Stroganova TA, Kul’nevich VG. Chem. Heterocycl. Compd. 1999; 35: 757
• 5d Shchepinov MS, Korshun VA. Chem. Soc. Rev. 2003; 32: 170
• 5e Irie M. J. Am. Chem. Soc. 1983; 105: 2078
• 6 Pajewski R, Ostaszewski R, Ziach K, Kulesza A, Jurczak J. Synthesis 2004; 865
• 7a Hall JE. US 4429090, 1984
• 7b Gandini A. EP 0379250, 1990
• 7c Musau RM, Whiting A. J. Chem. Soc., Perkin Trans. 1 1994; 2881
• 7d He Y, Chen Z, Wu C. Chin. J. Synth. Chem. 1993; 1: 123
• 8 Genovese S, Epifana F, Pelucchini C, Curini M. Eur. J. Org. Chem. 2009; 1132
• 9a Nair V, Abhilash KG, Vidya N. Org. Lett. 2005; 7: 5857
• 9b Nair V, Vidya N, Abhilash KG. Synthesis 2006; 21: 3647
• 10 Jaratjaroonphong J, Tuengpanya S, Saeeng R, Udompong S, Srisook K. Eur. J. Med. Chem. 2014; 83: 561
• 11 Gagieva SC, Sukhova TA, Savinov DV, Tuskaev VA, Lyssenko KA, Bravaya NM, Belokon YuN, Bulychev BM. Russ. Chem. Bull. 2006; 55: 1794
• 12 Thirupathi P, Kim SS. J. Org. Chem. 2010; 75: 5240
• 13a Alonso N, Esquivias J, Omez-Array RG, Carretero JC. J. Org. Chem. 2008; 73: 6401
• 13b Temelli B, Unaleroglu C. Tetrahedron 2006; 62: 10130
• 13c Esquivias J, Gomez-Array RG, Carretero JC. Angew. Chem. Int. Ed. 2006; 45: 629
• 14 Ohishi T, Kojima T, Matsuoka T, Shiro M, Kotsuki H. Tetrahedron Lett. 2001; 42: 2493
• 15 Mibu N, Yokomizo K, Miyata T, Sumoto K. J. Heterocycl. Chem. 2010; 47: 1434
• 16 Roberts BA, Cave GW. V, Raston CL, Scott JL. Green Chem. 2001; 3: 280
• 17 Prakash GK. S, Panja C, Shakhmin A, Shah E, Mathew T, Olah GA. J. Org. Chem. 2009; 74: 8659
• 18 Barbero M, Cadamuro S, Dughera S, Rucci M, Spano G, Venturello P. Tetrahedron 2014; 70: 1818
• 19 An LT, Ding FQ, Zou JP. Dyes Pigm. 2008; 77: 478
• 20 Leng Y, Chen F, Zuo L, Duan W. Tetrahedron Lett. 2010; 51: 2370
• 21 Zolfigol MA, Salehi P, Shiri M, Sayadi A, Abdoli A, Keypur H, Rezaeivala K, Niknam M, Kolvari E. Mol. Diversity 2008; 12: 203
• 22 Prakash SG. K, Fogassy G, Olah GA. Catal. Lett. 2010; 138: 155
• 23a Rad-Moghadam K, Sharifi-Kiasaraie M. Tetrahedron 2009; 65: 8816
• 23b Wang A, Zheng X, Zhao Z, Li C, Cui Y, Zheng X, Yin J, Yang G. Appl. Catal., A 2014; 482: 198

For reviews and some recent reports on C–C bond cleavage, see:
• 24a Cai S, Zhao X, Wang X, Liu Q, Li Z, Wang DZ. Angew. Chem. Int. Ed. 2012; 51: 8050
• 24b Liu H, Dong C, Zhang Z, Wu P, Jiang X. Angew. Chem. Int. Ed. 2012; 51: 12570
• 24c Qin C, Zhou W, Chen F, Ou Y, Jiao N. Angew. Chem. Int. Ed. 2011; 50: 12595
• 24d Murakami M, Matsuda T. Chem. Commun. 2011; 47: 1100
• 24e Bonesi SM, Fagnoni M. Chem. Eur. J. 2010; 16: 13572
• 24f Winter C, Krause N. Angew. Chem. Int. Ed. 2009; 48: 2460 ; Angew. Chem. 2009, 121, 6457
• 24g Park YJ, Park J.-W, Jun CH. Acc. Chem. Res. 2008; 41: 222
• 24h Seiser T, Cramer N. Org. Biomol. Chem. 2009; 7: 2835
• 25a Zhang C, Feng P, Jiao N. J. Am. Chem. Soc. 2013; 135: 15257
• 25b Zhou W, Yang Y, Liu Y, Deng GJ. Green Chem. 2013; 15: 76
• 25c Bowring MA, Bergman RG, Tilley TD. J. Am. Chem. Soc. 2013; 135: 13121
• 25d Souillart L, Cramer N. Chem. Sci. 2014; 5: 837
• 25e Ogata K, Shimada D, Furuya S, Fukuzawa SI. Org. Lett. 2013; 15: 1182
• 25f Zhu Y, Yan H, Lu L, Liu D, Rong G, Mao J. J. Org. Chem. 2013; 78: 9898
• 25g Bour JR, Green JC, Winton VJ, Johnson JB. J. Org. Chem. 2013; 78: 1665
• 25h Xu F, Tao T, Zhang K, Wang X.-X, Huang W, You X.-Z. Dalton Trans. 2013; 42: 3631
• 25i Ziadi A, Correa A, Martin R. Chem. Commun. 2013; 49: 4286
• 25j Chen F, Wang T, Jiao N. Chem. Rev. 2014; 114: 8613
• 25k Grenning AJ, Tunge JA. J. Am. Chem. Soc. 2011; 133: 14785
• 25l Allpress CJ, Miłaczewska A, Borowski T, Bennett JR, Tierney DL, Arif AM, Berreau LM. J. Am. Chem. Soc. 2014; 136: 7821
• 25m Huang X, Li X, Zou M, Song S, Tang C, Yuan Y, Jiao N. J. Am. Chem. Soc. 2014; 136: 14858
• 25n Li H, Li W, Liu W, He Z, Li Z. Angew. Chem. Int. Ed. 2011; 50: 2975
• 25o Tang C, Jiao N. Angew. Chem. Int. Ed. 2014; 53: 6528
• 25p Zhou W, Fan W, Jiang Q, Liang Y, Jiao N. Org. Lett. 2015; 17: 2542
• 25q Zhang C, Xu Z, Shen T, Wu G, Zhang L, Jiao N. Org. Lett. 2012; 14: 2362
• 26a Friedel–Crafts and Related Reactions. Vol. 1–4. Olah GA. Wiley-Interscience; New York: 1963
• 26b Olah GA, Krishnamurti R, Prakash GK. S In Comprehensive Organic Synthesis. Vol. 3. Trost BM, Fleming I. Pergamon Press; Oxford: 1991: 293
• 26c Jorgensen KA. Synthesis 2003; 1117
• 26d Bandini M, Melloni A, Umani-Ronchi A. Angew. Chem. Int. Ed. 2004; 43: 550
• 26e Bandini M, Melloni A, Tommasi S, Umani-Ronchi A. Synlett 2005; 1199
• 26f Poulsen TB, Jorgensen KA. Chem. Rev. 2008; 108: 2903
• 26g Bandini M, Umani-Ronchi A. Catalytic Asymmetric Friedel–Crafts Alkylations . Wiley-VCH; Weinheim: 2009
• 27 Kobayashi S, Sugiura M, Kitagawa H, Lam WW. L. Chem. Rev. 2002; 102: 2227
• 28 Xu F, Luo Y, Wu J, Shen Q, Chen H. Heteroat. Chem. 2006; 17: 389
• 29a Santosh Kumar G, Pushpa Ragini S, Sanjeeva Kumar S, Meshram HM. RSC Adv. 2015; 5: 51576
• 29b Madhu Babu B, Santosh Kumar G, Thakur PB, Bangade VM. Tetrahedron Lett. 2014; 55: 3473
• 29c Santosh Kumar G, Pushpa Ragini S, Meshram HM. Tetrahedron Lett. 2013; 54: 5974
• 29d Meshram HM, Ramesh P, Santosh Kumar G, Reddy BC. K. Tetrahedron Lett. 2010; 51: 4313
• 29e Raghavender Reddy M, Nageswara Rao N, Ramakrishna K, Meshram HM. Tetrahedron Lett. 2014; 55: 1898
• 29f Nageswara Rao N, Raghavende Reddy M, Ramakrishna K, Meshram HM. Helv. Chim. Acta 2014; 97: 744
• 29g Swetha A, Kumar GS, Kumar AS, Meshram HM. Tetrahedron Lett. 2014; 55: 4705
• 29h Madhu Babu B, Thakur PB, Rao NN, Kumar GS, Meshram HM. Tetrahedron Lett. 2014; 55: 1868
• 29i Madhu Babu B, Thakur PB, Bangade VM. Tetrahedron Lett. 2014; 55: 766
• 30 Ravikanth V, Imelda O, Irene W, Hartmut L. J. Nat. Prod. 2003; 66: 1520
• 31 General Procedure for the Synthesis of Compounds 4 or 5 A solution of acetophenone 1 (1 mmol), SeO₂ (2 mmol), and YbCl₃ (0.3 mmol) in DMSO–H₂O (9:1, 3 mL) was well stirred at 110 °C for 15 h. Then the 2-methylfuran (2) or 2-methylthiophene (3) was added to the reaction mixture at r.t. and stirred again for 10 min at 70 °C. After completion of the reaction, the reaction mixture brought to r.t., and it was filtered through a short pad of Celite, excess SeO₂, and other selenium-containing byproducts were removed by adsorption on Celite. Water was added to the filtrate, and the mixture was extracted with CH₂Cl₂. The combined organic layers were dried over anhydrous Na₂SO₄, concentrated in vacuo, and purified by chromatography on silica gel to afford required products 4 or 5. The recovered catalyst was obtained from the aqueous layer after removing water. ¹H NMR, ¹³C NMR, MS, and IR spectral data for the new products are given below. 2-[Bis(5-methylfuran-2-yl)methyl]-6-methoxyphenol (4c, Scheme 3) Dark-brown viscous oil. ¹H NMR (300 MHz, CDCl₃): δ = 2.23 (s, 6 H), 3.86 (s, 3 H), 4.01 (s, 1 H), 5.86 (s, 4 H), 6.73–6.83 (m, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 13.6, 37.6, 55.9, 105.9, 107.9, 109.1, 119.2, 121.3, 123.3, 125.6, 142.9, 146.3, 151.1, 152.4, ppm. IR (KBr): ν = 731, 790, 1023, 1232 1290, 1481, 1608, 3521 cm^–1. ESI-MS: m/z = 321 [M + Na]⁺. ESI-HRMS: m/z calcd for C₁₈H₁₈O₄Na [M + Na]⁺: 321.1098; found: 321.1092. 4-[Bis(5-methylfuran-2-yl)methyl]benzene-1,2-diol (4d, Scheme 3) Dark-brown viscous oil. ¹H NMR (300 MHz, CDCl₃): δ = 2.24 (s, 6 H), 5.21 (s, 1 H), 5.83–5.88 (m, 4 H), 6.68 (dd, J = 1.88, 8.12 Hz, 1 H), 6.75 (d, J = 1.88 Hz, 1 H), 6.80 (d, J = 8.30 Hz, 1 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 13.5, 44.3, 106.0, 107.9, 115.2, 115.4, 120.9, 132.9, 142.5, 143.3, 151.3, 152.9 ppm. IR (KBr): ν = 750, 801, 1107, 1269, 1519, 1603, 3387cm^–1. ESI-MS: m/z = 307 [M + Na]⁺. ESI-HRMS: m/z calcd for C₁₇H₁₆O₄Na [M + Na]⁺: 307.0945; found: 307.0939. 2-[Bis(5-methylfuran-2-yl)methyl]-4,6-dichlorophenol (4e, Scheme 3) Dark-brown viscous oil. ¹H NMR (300 MHz, CDCl₃): δ = 2.24 (s, 6 H), 5.73–5.76 (m, 1 H), 5.87–5.93 (m, 4 H), 7.01–7.04 (m, 1 H), 7.22 (d, J = 2.13 Hz, 1 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 13.5, 38.4, 106.1, 108.6, 120.4, 125.2, 127.1, 128.3, 128.9, 147.6, 150.8, 151.7 ppm. IR (KBr): ν = 735, 811, 1051, 1182, 1240, 1321, 1465, 1679, 3509 cm^–1. ESI-MS: m/z = 360 [M + Na]⁺. ESI-HRMS: m/z calcd for C₁₇H₁₄Cl₂O₃Na [M + Na]⁺: 360.0214; found: 360.0210. 2-[Bis(5-methylthiophen-2-yl)methyl]phenol (5a, Scheme 3) Dark-brown viscous oil. ¹H NMR (300 MHz, CDCl₃): δ = 2.40 (s, 6 H), 5.94 (s, 1 H), 6.56–6.58 (m, 2 H), 6.63 (d, J = 3.35 Hz, 2 H), 6.77 (dd, J = 1.22, 8.54 Hz, 1 H), 6.88 (td, J = 1.22, 7.47 Hz, 1 H), 7.12–7.16 (m, 2 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 15.3, 41.6, 116.2, 120.8, 124.6, 125.8, 128.3, 129.3, 130.1, 139.3, 143.7, 153.0 ppm. IR (KBr): ν = 754, 810, 1042, 1227, 1270, 1455, 1593, 3504 cm^–1. ESI-MS: m/z = 301 [M + H]⁺. ESI-HRMS: m/z calcd for C₁₇H₁₇OS₂ [M + H]⁺: 301.0719; found: 301.0714. 2-[Bis(5-methylthiophen-2-yl)methyl]-4-nitrophenol (5b, Scheme 3) White solid; mp 196–198 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.44 (s, 6 H), 5.94 (s, 1 H), 6.61 (dd, J = 0.94, 3.39 Hz, 2 H), 6.65 (d, J = 3.39 Hz, 2 H), 6.90 (q, J = 6.04 Hz, 1 H), 8.07–8.12 (m, 2 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 15.3, 41.6, 116.5, 124.7, 124.9, 125.5, 126.4, 131.0, 140.2, 141.7, 158.8 ppm. IR (KBr): ν = 639, 1071, 1278, 1327, 1486, 1588, 3317 cm^–1. ESI-MS: m/z = 368 [M + Na]⁺. ESI-HRMS: m/z calcd for C₁₇H₁₆NO₃S₂ [M + Na]⁺: 368.0390; found: 368.0387. 4-[Bis(5-methylthiophen-2-yl)methyl]benzene-1,2-diol (5c, Scheme 3) Dark-brown viscous oil. ¹H NMR (300 MHz, CDCl₃): δ = 2.40 (s, 6 H), 5.55 (s, 1 H), 6.53–6.60 (m, 4 H), 6.72–6.82 (m, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 15.3, 47.0, 115.1, 115.4, 120.9, 124.4, 125.5, 136.9, 138.9, 142.4, 143.2, 145.3 ppm. IR (KBr): ν = 765, 806, 1111, 1282, 1518, 1607, 3392 cm^–1. ESI-MS: m/z = 317 [M + H]⁺. ESI-HRMS: m/z calcd for C₁₇H₁₇O₂S₂ [M + H]⁺: 317.0668; found: 317.0666. 2-[Bis(5-methylthiophen-2-yl)methyl]-4,6-dichlorophenol (5d, Scheme 3) Dark-brown viscous oil. ¹H NMR (300 MHz, CDCl₃): δ = 2.42 (s, 6 H), 5.71 (s, 1 H), 6.04 (br s, 1 H), 6.57 (s, 4 H), 7.09 (d, J = 2.45 Hz, 1 H), 7.24 (d, J = 2.45 Hz, 1 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 15.3, 40.7, 120.4, 124.6, 125.2, 126.0, 127.1, 128.0, 133.0, 139.3, 142.9, 147.2 ppm. IR (KBr): ν = 757, 800, 1039, 1161, 1227, 1321, 1460, 1667, 3521 cm^–1. ESI-MS: m/z = 370 [M + H]⁺. ESI-HRMS: m/z calcd for C₁₇H₁₈Cl₂OS₂ [M + H]⁺: 370.3362; found: 370.3358. 5,5′-[(3-Nitrophenyl)methylene]bis(2-methylthiophene) (5e, Scheme 3) Dark-brown viscous oil. ¹H NMR (300 MHz, CDCl₃): δ = 2.40 (s, 6 H), 5.77 (s, 1 H), 6.54–6.62 (m, 4 H), 7.44 (t, J = 8.30 Hz, 1 H), 7.64 (d, J = 7.55 Hz, 1 H), 8.08 (d, J = 8.30 Hz, 1 H), 8.16 (s, 1 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 15.1, 47.0, 121.9, 123.0, 124.6, 126.0, 129.1, 134.2, 139.6, 143.2, 145.7, 148.1 ppm. IR (KBr): ν = 730, 800, 1229, 1350, 1530 cm^–1. ESI-MS: m/z = 352 [M + Na]⁺. ESI-HRMS: m/z calcd for C₁₇H₁₅NO₂S₂Na [M + Na]⁺: 352.0347; found: 352.0342. 3-[Bis(5-methylthiophen-2-yl)methyl]phenol (5f, Scheme 3) Dark-brown viscous oil. ¹H NMR (300 MHz, CDCl₃): δ = 2.39 (s, 6 H), 5.25 (br s, 1 H), 5.60 (s, 1 H), 6.49–6.61 (m, 4 H), 6.63–6.77 (m, 2 H), 6.82–6.89 (m, 1 H), 7.09–7.18 (m, 1 H) ppm. IR (KBr): ν = 703, 754, 803, 1040, 1227, 1263, 1451, 1598, 3393 cm^–1. ESI-MS: m/z = 301 [M + H]⁺. ESI-HRMS: m/z calcd for C₁₇H₁₇O₂S₂ [M + H]⁺: 301.0717; found: 301.0712. 5,5′-[(4-Fluorophenyl)methylene]bis(2-methylthiophene) (5h, Scheme 3) Dark-brown viscous oil. ¹H NMR (300 MHz, CDCl₃): δ = 2.40 (s, 6 H), 5.64 (s, 1 H), 6.56 (s, 4 H), 6.97 (t, J = 3.50 Hz, 2 H), 7.22–7.28 (m, 2 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 15.0, 46.8, 115.1, 124.4, 125.5, 129.6, 138.9, 144.8, 159.9, 163.1 ppm. IR (KBr): ν = 537, 803, 842, 1158, 1227, 1505, 1603 cm^–1. ESI-MS: m/z = 303 [M + H]⁺. ESI-HRMS: m/z calcd for C₁₇H₁₆FS₂ [M + H]⁺: 303.0673; found: 303.0670. 5,5′-[(3,4-Dimethoxyphenyl)methylene]bis(2-methylthiophene) (5j, Scheme 3) Brown solid; mp 112–114 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.40 (s, 6 H), 3.81 (s, 3 H), 3.84 (s, 3 H), 5.61 (s, 1 H), 6.55 (dd, J = 0.94, 3.39 Hz, 2 H), 6.59 (d, J = 3.21 Hz, 2 H), 6.80–6.86 (m, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 15.2, 47.3, 55.7, 110.8, 111.6, 120.2, 124.3, 125.4, 136.3, 138.8, 145.4, 147.9, 148.7 ppm. IR (KBr): ν = 721, 759, 1038, 1251, 1302, 1491, 1572, 1692 cm^–1. ESI-MS: m/z = 367 [M + Na]⁺. ESI-HRMS: m/z calcd for C₁₉H₂₀O₂S₂Na [M + H]⁺: 367.0899; found: 367.0894.
• 32a Zhang L, Bi X, Guan X, Li X, Liu Q, Barry BD, Liao P. Angew. Chem. Int. Ed. 2013; 52: 11303
• 32b Koito Y, Nakajima K, Kitano M, Hara M. Chem. Lett. 2013; 42: 873
• 33a Assary RS, Curtiss LA. J. Phys. Chem. A 2011; 115: 8754
• 33b Sugimura T, Futagawa T, Mori A, Ryu I, Sonoda N, Tai A. J. Org. Chem. 1996; 61: 6100