4-Aryl- and 4-Vinyl-2,2-Dialkyl-3-chromenes from Tertiary 3-(o-Bromophenyl)propynols via a Palladium-Catalyzed Hydroarylation/Hydrovinylation-Cyclization Sequence

Abstract

4-Aryl- and 4-vinyl-2,2-dialkyl-3-chromenes were prepared from tertiary 3-(o-bromophenyl)propynols and aryl iodides or vinyl triflates through a one-pot process, which involves the addition of t-BuONa, dppf and, where appropriate, fresh Pd(OAc)₂ to the crude mixture resulting from the hydroarylation or hydrovinylation step [Pd(OAc)₂, Et₃N, HCOOH, Bu₄NCl, toluene]. In general, 4-aryl- and 4-vinyl-2,2-dialkyl-3-chromenes are obtained with high regioselectivity and overall yields range from satisfactory to high. Vinyl triflates tend to give higher yields than aryl iodides.

Key words

chromenes - palladium catalysis - cyclization - hydro­vinylation - hydroarylation

References and Notes

• 1 Cacchi S. Fabrizi G. In Handbook of Organopalladium Chemistry for Organic Synthesis   Vol. 1:  Negishi E. John Wiley & Sons; New York: 2002.  p.1335-1360  
• 2 Cacchi S. Fabrizi G. Goggiamani A. J. Mol. Catal. A: Chem.  2004,  214:  57 
• 3a Arcadi A. Bernocchi E. Burini A. Cacchi S. Marinelli F. Pietroni B. Tetrahedron  1988,  44:  481 
• 3b Arcadi A. Cacchi S. Fabrizi G. Marinelli F. Pace P. Eur. J. Org. Chem.  1999,  3305 
• 3c Arcadi A. Bernocchi E. Burini A. Cacchi S. Marinelli F. Pietroni B. Tetrahedron Lett.  1989,  30:  3465 
• 4a Cacchi S. Fabrizi G. Marinelli F. Moro L. Pace P. Tetrahedron  1996,  52:  10225 
• 4b Cacchi S. Fabrizi G. Goggiamani A. Moreno-Mañas M. Vallribera A. Tetrahedron Lett.  2002,  43:  5537 
• 5 Cacchi S. Fabrizi G. Moro L. Pace P. Synlett  1997,  1367 
• 6 Arcadi A. Cacchi S. Fabrizi G. Marinelli F. Pace P. Eur. J. Org. Chem.  2000,  4099 
• For some recent references, see:
• 7a Goujon J.-Y. Zammatio F. Chrétien J.-M. Beaudet I. Tetrahedron  2004,  60:  4037 
• 7b Kidwai M. Saxena S. Khan MKR. Thukral SS. Bioorg. Med. Chem. Lett.  2005,  15:  4295 
• 7c Youn SW. Eom JI. Org. Lett.  2005,  7:  3355 
• 7d Shi YL. Shi M. Org. Lett.  2005,  7:  3057 
• 7e Nevado C. Echavarren AM. Chem. Eur. J.  2005,  11:  3155 
• 7f Lee YR. Choi JH. Yoon SH. Tetrahedron Lett.  2005,  46:  7539 
• 7g van Otterlo W. Ngidi EL. Kuzvidza S. Morgans GL. Moleele SS. de Koning CB. Tetrahedron  2005,  61:  9996 
• 7h Zhao GL. Shi YL. Shi M. Org. Lett.  2005,  7:  4527 
• 8 Evans JM. Stemp G. Chem. Ber.  1991,  27:  439 
• 9a Attwood MR. Jones PS. Paciorek PB. Redshaw S. Life Sci.  1991,  48:  803 
• 9b Attwood MR. Churcher I. Dunsdon RM. Hurst DN. Jones PS. Tetrahedron Lett.  1991,  32:  811 
• See, for example:
• 10a Buckle DR. Arch JRS. Fenwick AE. Houge-Frydrych CSV. Pinto IL. Smith DG. Taylor SG. Tedder JM. J. Med. Chem.  1990,  33:  3028 
• 10b Bergmann R. Eiermann V. Gericke R. J. Med. Chem.  1990,  33:  2759 
• 10c Bergmann R. Gericke R. J. Med: Chem.  1990,  33:  492 
• 10d Gericke R. Harting G. Lues I. Shittenhelm C. J. Med. Chem.  1991,  34:  3074 
• 10e Cassidy F. Evans JM. Hadley MS. Haladij AH. Leach PE. Stemp G. J. Med. Chem.  1992,  35:  1623 
• 10f Satoh Y. Stanton JL. Hutchison AJ. Libby AH. Kowalsky TJ. Lee WH. White DH. Kimble EF. J. Med. Chem.  1993,  36:  3580 
• 10g Atwal KS. Grover GJ. Ahmed SZ. Ferrara FN. Harper TW. Kim KS. Sleph PG. Dzwonczyk S. Russel AD. Moreland S. McCullough JR. Normandin DE. J. Med. Chem.  1993,  36:  3971 
• 11 Akritopoulou-Zanze I. Patel JR. Hartandi K. Brenneman J. Winn M. Pratt JK. Grynfarb M. Goos-Nisson A. Von Geldern TW. Kym PR. Bioorg. Med. Chem. Lett.  2004,  14:  2079 
• 12 Teng M. Duong TT. Johnson AT. Klein ES. Wang L. Khalifa B. Chandraratna RAS. J. Med. Chem.  1997,  40:  2445 
• 13a Kemnitzer W. Drewe J. Jiang S. Zhang H. Wang Y. Zhao J. Jia S. Herich J. Labreque D. Storer R. Meerovitch K. Bouffard D. Rej R. Denis R. Blais C. Lamothe S. Attardo G. Gourdeau H. Tseng B. Kasibhatla S. Xiong Cai S. J. Med. Chem.  2004,  47:  6299 
• 13b Kasibhatla S. Gourdeau H. Meerovitch K. Drewe J. Reddy S. Qiu L. Zhang H. Bergeron F. Bouffard D. Yang O. Herich J. Lamothe S. Xiong Cai S. Tseng B. Mol. Cancer Ther.  2004,  11:  1365 
• 13c Gordeau H. Leblond L. Hamelin B. Desputeau C. Dong K. Kianicka I. Custeau D. Boudreau C. Geerts L. Xiong Cai S. Drewe J. Labreque D. Kasibhatla S. Tseng B. Mol. Cancer Ther.  2004,  11:  1375 
• 13d Kemnitzer W. Kasibhatla S. Songchun Jiang S. Zhang H. Zhao J. Jia S. Xu L. Crogan-Grundy C. Denis R. Barriault N. Vaillancourt L. Charron S. Dodd J. Attardo G. Labrecque D. Lamothe S. Gourdeau H. Tseng B. Drewea J. Caia SX. Bioorg. Med. Chem. Lett.  2005,  15:  4745 
• 14a Palucki M. Wolfe JP. Buchwald SL. J. Am. Chem. Soc.  1996,  118:  10333 
• 14b Kuwabe S.-i. Torraca KE. Buchwald SL. J. Am. Chem. Soc.  2001,  123:  12202 
• 17 Poli G. Giambastiani G. J. Org. Chem.  2002,  67:  9456 
• 18 Carpita A. Lessi A. Rossi R. Synthesis  1984,  571 
• 19 Ahlquist M. Fabrizi G. Cacchi S. Norrby P.-O. Chem. Commun.  2005,  4196 
• 20 Fagnou K. Lautens M. Angew. Chem. Int. Ed.  2002,  41:  26 
• 21 Amatore C. Jutand A. Acc. Chem. Res.  2000,  33:  314 

15

Hydroarylation/Hydrovinylation-Cyclization of 1; Procedure A To a stirred solution of 1a (0.160 g, 0.67 mmol) and 2b (0.395 g, 1.61 mmol) in THF (5 mL) were added Bu₃N (0.572 mL, 2.41 mmol), BuN₄Cl (0.198 g, 0.67 mmol), and Pd(OAc)₂ (0.008 g, 0.035 mmol). The solution was stirred under nitrogen for 3 min. Then, HCOOH (0.066 mL, 1.74 mmol) was added. The reaction mixture was stirred at 60 °C under nitrogen for 24 h, then cooled, and extracted with 0.1 M HCl (100 mL) and Et₂O (3 × 50 mL). The combined organic layers were washed with 5% NaHCO₃ (30 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was dissolved in toluene (5 mL), Pd(OAc)₂ (0.008 g, 0.035 mmol), dppf (0.019 g, 0.035 mmol), and t-BuONa (0.129 g, 1.34 mmol) were added and the reaction mixture was stirred at 110 °C under nitrogen for 16 h. After cooling, the mixture was extracted with 0.5 M NH₄Cl (100 mL) and EtOAc (3 × 50 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by chromatography (silica gel; n-hexane-EtOAc, 98:2) to give 4b (0.117 g, 61%); mp 113-115 °C. IR (KBr): 1690, 1610, 1270 cm^-1. ¹H NMR (CDCl₃): δ = 7.99 (d, J = 8.4 Hz, 2 H), 7.45 (d, J = 8.4 Hz, 2 H), 7.21-7.13 (m, 1 H), 6.97-6.78 (m, 3 H), 5.67 (s, 1 H), 2.63 (s, 3 H), 1.50 (s, 6 H). ¹³C NMR (CDCl₃): δ = 197.7, 153.3, 143.3, 136.3, 134.1, 130.0, 129.5, 128.9, 128.4, 128.3, 125.3, 120.7, 117.1, 75.7, 27.5, 26.7. EI-MS: m/z (%) = 263 (100) [M⁺ - CH₃].

16

One-Pot Hydroarylation/Hydrovinylation-Cyclization of 1; Procedure B To a stirred solution of 1a (0.143 g, 0.60 mmol) and 2d (0.153 g, 0.50 mmol) in DMF (2 mL) were added Pd(OAc)₂ (0.006 g, 0.026 mmol) and HCOOK (0.084 g, 1.00 mmol). The reaction mixture was stirred at 40 °C under nitrogen for 17 h, then cooled, and extracted with 5% NaHCO₃ (100 mL) and Et₂O (3 × 50 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was dissolved in toluene (5 mL), Pd(OAc)₂ (0.006 g, 0.026 mmol), dppf (0.014 g, 0.026 mmol), and
t-BuONa (0.096 g, 1.00 mmol) were added and the reaction mixture was stirred at 110 °C under nitrogen for 5 h. After cooling, the mixture was extracted with 0.5 M NH₄Cl (100 mL) and EtOAc (3 × 50 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by chromatography (silica gel; n-hexane-EtOAc, 99:1) to give 4d (0.063 g, 40%); mp 55-57 °C. IR (KBr): 1610, 1480, 1450, 1260 cm^-1. ¹H NMR (CDCl₃): δ = 7.32-7.07 (m, 7 H), 6.90-6.81 (m, 2 H), 5.83 (br s, 1 H), 5.47 (s, 1 H), 2.95-2.80 (m, 1 H), 2.38-1.80 (m, 6 H), 1.42 (s, 3 H), 1.40 (s, 3 H). ¹³C NMR (CDCl₃): δ = 153.3, 146.8, 136.3, 135.5, 128.8, 128.4, 126.8, 126.5, 126.3, 126.1, 125.2, 121.9, 120.5, 116.9, 75.5, 39.8, 33.6, 30.0, 29.2, 27.6, 27.5. EI-MS: m/z (%) = 316 (2) [M⁺], 301 (100) [M⁺ - CH₃].

22

One-Pot Synthesis of Chromenes without Work-up after Hydroarylation/Hydrovinylation
To a stirred solution of 1a (0.161 g, 0.67 mmol) and 2j (0.145 g, 0.56 mmol) in toluene (3 mL) were added Et₃N (0.234 mL, 1.68 mmol), BuN₄Cl (0.166 g, 0.56 mmol), and Pd(OAc)₂ (0.003 g, 0.014 mmol). The solution was stirred under nitrogen for 5 min and then HCOOH (0.042 mL, 1.12 mmol) was added. The reaction mixture was stirred at 50 °C under nitrogen for 7 h, then Pd(OAc)₂ (0.003 g, 0.014 mmol), dppf (0.016 g, 0.029 mmol), and NaOt-Bu (0.216 g, 2.25 mmol) were added, the temperature was raised to 110 °C and the reaction mixture was stirred under nitrogen for 16 h. After cooling, the mixture was extracted with 0.5 M NH₄Cl (100 mL) and EtOAc (3 × 50 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by chromatography (silica gel; n-hexane-EtOAc, 99:1) to give 4j (0.124 g, 82%) as an oil. IR: 1630, 1500, 1470, 1280 cm^-1. ¹H NMR (CDCl₃): δ = 7.08-7.01 (m, 2 H), 6.85-6.78 (m, 2 H), 5.68 (t, J = 8.2 Hz, 1 H), 5.39 (s, 1 H), 2.34-2.21 (m, 4 H), 1.60-1.44 (m, 8 H), 1.41 (s, 6 H). ¹³C NMR (CDCl₃): δ = 153.3, 139.0, 136.6, 129.5, 128.7, 127.0, 126.9, 125.4, 120.4, 116.7, 75.6, 29.9, 28.6, 28.4, 27.8, 26.6, 26.3. EI-MS: m/z (%) = 268 (7) [M⁺], 253 (100) [M⁺ - CH₃].