Regioselective Synthesis of 4-Substituted-1-Aryl-1-butanones Using a Sonogashira-Hydration Strategy: Copper-Free Palladium-Catalyzed Reaction of Terminal Alkynes with Aryl Bromides [1]

Abstract

A simple one-pot procedure has been developed for the synthesis of 4-substituted-1-aryl-1-butanones through copper-free Sonogashira reaction of aryl bromides with terminal alkynes in DMF under inert atmosphere, followed by the treatment with acid in the presence of oxygen. A variety of aryl bromides was reacted with 3-butyn-1-ol according to this procedure to give the expected compounds in good yield. The mechanism of the reaction and applications of the methodology are discussed.

Key words

1-aryl-1-butanones - aryl bromide - 3-butyn-1-ol - palladium catalyst - hydration

1

DRL Publication No. 251

References

• 2a Fuji K, Noide M, Usami Y, and Takigawa T. inventors; Jpn. Kokai Tokkyo Koho JP 62209073  A2.  ; Chem. Abstr. 1987, 110, 135247
• 2b Saladino R. Crestini C. Palamara AT. Danti MC. Manetti F. Corelli F. Garaci E. Botta M. J. Med. Chem.  2001,  44:  4554 
• 2c De Kimpe N. Tehrani KA. Stevens C. De Cooman P. Tetrahedron  1997,  53:  3693 
• 3 Scott WJ, Popp MA, and Hartsough DS. inventors; WO 9743240  A1.  ; Chem. Abstr. 1997, 128, 22719
• 4 Geronikaki AA. Hadjipavlou-Litina DJ. Arzneim.-Forsch.  1998,  48:  263 
• 5 Matuz J, Csehi A, Bihari M, Barta S, Gizella SI, Szporny L, Ezer E, Saghy K, Domany G, and Hajos G. inventors; Hung. Teljes HU 67625  A2.  ; Chem. Abstr. 1995, 124, 55943
• 6 Giardina GAM, Grugni M, Graziani D, and Raveglia LF. inventors; WO 9852942  A1.  ; Chem. Abstr.1998, 130, 24978
• For synthesis via Friedel-Crafts reaction see:
• 7a Niu Z. Liu C. Shi L. Huaxue Shiji  1995,  17:  317 ; Chem. Abstr. 1995, 124, 231951
• 7b Seko S, and Furuya A. inventors; Jpn. Kokai Tokkyo Koho JP 11292808  A2.  ; Chem. Abstr. 1999, 131, 311907
• 7c Miyai T. Onishi Y. Baba A. Tetrahedron  1999,  55:  1017 
• 7d Kimura N. Tukamuku S. Bull. Chem. Soc. Jpn.  1991,  64:  2433 
• For synthesis via chemoselective oxidation of alcohols see:
• 8a Singh J. Sharma M. Chhibber M. Kaur J. Kad GL. Synth. Commun.  2000,  30:  3941 
• 8b Zhang G. Li W. Cai K. Li Z. Huaxue Tongbao  1992,  4:  34 ; Chem. Abstr. 1992, 118, 123774
• 8c Muzart J. Ajjou AN. Synth. Commun.  1992,  22:  1993 
• For synthesis via chemoselective reduction see:
• 9a Barrero AF. Alvarez-Manzaneda EJ. Chahboun R. Meneses R. Synlett  2000,  197 
• 9b Isobe K. Mohri K. Sano H. Taga J. Tsuda Y. Chem. Pharm. Bull.  1986,  34:  3029 
• For synthesis via acyl transfer reactions with phosphine oxides see:
• 10a Wallace P. Warren S. J. Chem. Soc., Perkin Trans. 1  1988,  2971 
• 10b Wallace P. Warren S. Tetrahedron Lett.  1985,  26:  5713 
• For other methods see:
• 11a Fuji K. Node M. Usami Y. Chem. Lett.  1986,  6:  961 
• 11b Fuji K. Usami Y. Kiryu Y. Node M. Synthesis  1992,  852 
• 11c Bretsch W. Reissig HU. Liebigs Ann. Chem.  1987,  3:  175 
• 12a Niita M. Yi A. Kobayashi T. Bull. Chem. Soc. Jpn.  1985,  58:  991 
• 12b Echavarren AM. Perez M. Castano AM. Cuerva JM. J. Org. Chem.  1994,  59:  4179 
• 13a Taura Y. Tanaka M. Wu XM. Funakoshi K. Sakai K. Tetrahedron  1991,  47:  4879 
• 13b O’Connor JM. Pu L. Rheingold AL. J. Am. Chem. Soc.  1990,  112:  6232 
• 14a Pal M, Rao YK, Rajagopalan R, Misra P, Kumar PM, and Rao CS. inventors; World Patent WO  01/90097.  ; Chem. Abstr. 2002, 136, 5893
• 14b Pattabiraman VR. Padakanti PS. Veeramaneni VR. Pal M. Yeleswarapu KR. Synlett  2002,  947 
• 14c For a brief overview see: Scrip  2002,  112:  43 
• 15 For a recent example, see: Shuki A. Keiko K. Jiro T. Tsunehisa H. Hatsuo Y. Masao K. J. Org. Chem.  2001,  66:  7919 
• 16a Sonogashira K. Tohda Y. Hagihara N. Tetrahedron  1975,  16:  4467 
• 16b Sonogashira K. In Comprehensive Organic Synthesis   Vol. 3:  Trost BM. Fleming I. Pergamon Press; New York: 1991.  p.521 
• 16c Pal M. Kundu NG. J. Chem. Soc., Perkin Trans. 1  1996,  449 
• For earlier reports on the occasional use of aryl bromide, see:
• 17a Dieck HA. Heck RF. J. Organomet. Chem.  1975,  93:  259 
• 17b Takahashi S. Kuroyama Y. Sonogashira K. Hagihara N. Synthesis  1980,  627 
• 17c Austin WB. Bilow N. Kelleghan WJ. Lau KSY. J. Org. Chem.  1981,  46:  2280 
• 17d Nguefack J.-F. Bolitt V. Sinou D. Tetrahedron Lett.  1996,  37:  5527 
• 17e Villemin D. Goussu D. Heterocycles  1989,  29:  1255 
• 17f De la Rosa MA. Velarde E. Guzman A. Synth. Commun.  1990,  20:  2059 
• 17g Bleicher L. Cosford DP. Synlett  1995,  1115 
• 17h Tischler A. Lanza TJ. Tetrahedron Lett.  1986,  27:  1653 
• 17i Sakamoto T. Kondo Y. Yamanaka H. Heterocycles  1986,  24:  31 
• 18a Krause N. Thorand S. J. Org. Chem.  1998,  63:  8551 
• 18b Rosenblum SB. Huynh T. Afonso A. Davis HR. Tetrahedron  2000,  56:  5735 
• 18c Brimble MA. Pavia GS. Stevenson RJ. Tetrahedron Lett.  2002,  43:  1735 
• 19 Hundertmark T. Littke AF. Buchwald SL. Fu GC. Org. Lett.  2000,  2:  1729 
• 21a Rossi R. Carpita A. Bigelli C. Tetrahedron Lett.  1985,  26:  523 
• 21b Kundu NG. Pal M. Chowdhury C. J. Chem. Res., Synop.  1993,  432 
• 21c Lei A. Srivastava M. Zhang X. J. Org. Chem.  2002,  67:  1969  and references therein.
• 22a Fukuyama T. Shinmen M. Nishitani S. Sato M. Ryu I. Org. Lett.  2002,  4:  1691 
• 22b Wu M.-J. Wei L.-M. Lin C.-F. Leou S.-P. Wei L.-L. Tetrahedron  2001,  57:  7839 
• 24a

  Palladium metal deposited on the wall of the reaction flask perhaps did not participate in the hydration step.

• 24b

  The alkyne was purified carefully using column chromatography in order to ensure the removal of the traces amount of Pd-catalyst.

• 25a Tsuchimoto T. Joya T. Shirakawa E. Kawakami Y. Synlett  2000,  1777 ; and references therein
• 25b Olah GA. Meidar D. Synthesis  1978,  671 
• 25c Noyce DS. Matesich AM. Peterson E. J. Am. Chem. Soc.  1967,  89:  6225 
• 25d Bosch E. Jeffries L. Tetrahedron Lett.  2001,  42:  8141 
• 25e Yamanaka H. Shiraiwa M. Sakamoto T. Konno S. Chem. Pharm. Bull.  1981,  29:  3548 
• 26 Imi K. Imai K. Utimoto K. Tetrahedron Lett.  1987,  28:  3127 
• 27a For a discussion on generation of Pd(0) from Pd(II) salts in Et₃N, see: Hegedus LS. Angew. Chem., Int. Ed. Engl.  1988,  27:  1113 
• 27b See also: Jeevanandam A. Narkunan K. Ling Y.-C. J. Org. Chem.  2001,  66:  6014 
• 27c For oxidation of Pd(0) to Pd(II) in the presence of oxygen, see: Kataoka H. Watanabe K. Miyazaki K. Tahara S. Ogu K. Matsuoka R. Goto K. Chem. Lett.  1990,  1705 
• 27d See also: Kataoka H. Watanabe K. Goto K. Tetrahedron Lett.  1990,  31:  4181 
• For hydration of alkynes controlled by neighboring group participation, see:
• 28a Stork G. Borch R. J. Am. Chem. Soc.  1964,  86:  935 
• 28b Hooz J. Layton RB. Can. J. Chem.  1970,  50:  1105 ; See also ref. 26
• O-Formylation of alcohols using DMF in the presence of other reagents has been reported, see for example:
• 29a Barluenga J. Campos PJ. Gonzalez-Nunez E. Asensio G. Synthesis  1985,  426 
• 29b Luca LD. Giacomelli G. Porcheddu A. J. Org. Chem.  2002,  67:  5152 
• 30a Commons TJ, Musial CL, and Christman S. inventors; WO 9857928  A1.  ; Chem. Abstr. 1998, 130, 81279
• 30b Commons TJ, and Christman S. inventors; US 5977170  A.  ; Chem. Abstr. 1999, 131, 310456
• 30c Tomita Y. Kabashima S. Okawara T. Yamasaki T. Furukawa M.
  J. Heterocycl. Chem.  1990,  27:  707 
• 31a Miller NE. Hammett F. Saltissi S. Rao S. Van Zeller H. Coltart J. Lewis B. Br. Med. J.  1981,  282:  1741 
• 31b Picardo M. Massey JB. Kuhn DE. Gotto AM. Gianturco SH. Pownall HJ. Arteriosclerosis  1986,  6:  434 ; Chem. Abstr. 1986, 105 188171
• 32 Mewshaw RE. Silverman LS. Mathew RM. Kaiser C. Sherrill RG. Cheng M. Tiffany CW. Karbon EW. Bailey MA. Borosky SA. Ferkany JW. Abreu ME. J. Med. Chem.  1993,  36:  1488 

1

DRL Publication No. 251

20

Dimerization of terminal alkyne in the presence of copper(I) salt and amine base is a required process for
the in situ conversion of Pd(II) to the active catalyst Pd(0), see ref. 16a.

23

Typical procedure for the synthesis of 4-substituted 1-aryl-1-butanones: Preparation of Ia: To a solution of 4-bromoacetophenone (1 g, 5.03 mmol) in DMF (10mL) was added PdCl₂(PPh₃)₂ (0.10 g, 0.15 mmol)and Et₃N (4.06 g, 40.20 mmol) under nitrogen atmosphere. The mixture was stirred for 15 min at 25 C and then 3-butyn-1-ol (0.71 g, 10.05 mmol) was added very slowly via syringe to the stirred reaction mixture. The temperature of the mixture was increased slowly to 80 °C and stirring continued for 8 h. During the reaction, which was followed by TLC, precipitation of Et₃N·HBr as crystalline solid was observed. After the complete consumption of the aryl bromide, the reaction mixture was cooled to r.t. and 20% HCl solution (100 mL) was added to it with vigorous stirring. After stirring for 8 h the mixture was diluted with water and EtOAc (150 mL), filtered through a small pad of celite (EtOAc). The organic layer was collected, washed with H₂O (2 × 100 mL), dried over anhyd Na₂SO₄, filtered and concentrated under low vacuum. The residue thus obtained was purified by flash chromatography to afford the desired compound. Compound Ia was isolated in 59% yield as light yellow solid, mp 91-92 °C (hexane); IR (KBr): 3342 (br, OH), 1678 (C=O), 1502 cm^-1; ¹H NMR (200 MHz, CDCl₃): δ = 8.04 (m, 4 H, ArH), 3.76 (t, J = 5.91 Hz, 2 H, CH ₂OH), 3.16 (t, J = 6.98 Hz, 2 H, CH₂CO), 2.65 (s, 3 H, CH₃), 2.09-1.97 (m, 2 H, CH₂), 1.65 (br s, D₂O exchangeable, 1 H, OH); M (CI, I-butane): m/z (%) = 207 (100) [MH⁺]; ¹³C NMR: 199.89, 197.61, 139.94, 139.87, 128.37 (2 C), 128.13 (2 C), 61.71, 35.42, 26.74, 26.62.
Spectral data for 1d: pale yellow oil; IR (KBr): 3420 (br, OH), 1679 (C=O), 1607 cm^-1; ¹H NMR (200 MHz, CDCl₃): δ = 7.90 (d, J = 7.81 Hz, 2 H, ArH), 7.29 (d, J = 7.80 Hz,
2 H, ArH), 3.76 (t, J = 5.86 Hz, 2 H, CH ₂OH), 3.13 (t, J = 6.84 Hz, 2 H, CH₂CO), 2.43 (s, 3 H, CH₃), 2.09-1.97
(m, 2 H, CH₂), 1.80 (br s, D₂O exchangeable, 1 H, OH); MS (CI, I-butane): m/z (%) = 179 (100) [MH⁺]; ¹³C NMR: 199.12, 143.87, 134.27, 129.20 (2 C), 128.15 (2 C), 62.28, 35.21, 27.00, 21.64.
Spectral data for 1ff: IR (KBr): 1719 (OCHO), 1665 (C=O), 1588 cm^-1; ¹H NMR (200 MHz, CDCl₃): δ = 8.07 (s, 1 H, CHO), 7.88 (d, J = 8.33 Hz, 2 H, ArH), 7.27 (d, J = 8.30 Hz, 2 H, ArH), 4.28 (t, J = 6.31 Hz, 2 H, CH₂O), 3.05 (t, J = 7.13 Hz, 2 H, CH₂CO), 2.53 (s, 3 H, SCH₃), 2.16-2.09 (m, 2 H, CH₂); MS (CI, I-butane): m/z (%) = 239 (100) [MH⁺].