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.

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

References

1

DRL Publication No. 251

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 

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.

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 

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⁺].

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