Regioselective Pd(0)-Catalyzed Hiyama Cross-Coupling Reactions at Dihalo-Substituted Heterocycles

Abstract

The regioselectivity of the Hiyama cross-coupling reaction at various dihalo-substituted heterocycles has been studied. Methyl 2,3-dibromo-5-furancarboxylate and n-octyltrifluorosilane were employed to find optimum reaction conditions [CsF; Pd₂dba₃/P(2-furyl)₃ as catalyst, 80-150 ˚C in toluene or benzene] for the desired transformation. Subsequent experiments with the title compounds and with different primary alkyltrifluorosilanes illustrate the generality of this regiochemical process.

Key words

catalysis - cross-coupling - heterocycles - palladium - ­regioselectivity - silane

References and Notes

• 1a Joule JA. Mills K. Heterocyclic Chemistry   4th ed.:  Blackwell; Oxford: 2000. 
• 1b Gilchrist TL. Heterocyclic Chemistry   3rd ed.:  Longman; Harlow: 1997. 
• 1c Eicher T. Hauptmann S. The Chemistry of Heterocycles   2nd ed.:  Wiley-VCH; Weinheim: 2003. 
• 1d Li JJ. Gribble GW. Palladium in Heterocyclic Chemistry   Pergamon Press; Oxford: 2000. 
• For reviews, see:
• 2a Schröter S. Stock C. Bach T. Tetrahedron  2005,  61:  2245 
• 2b Fairlamb IJS. Chem. Soc. Rev.  2007,  36:  1036 
• 3 Bach T. Bartels M. Synthesis  2003,  925 
• 4a Matsuhashi H. Kuroboshi M. Hatanaka Y. Hiyama T. Tetrahedron Lett.  1994,  35:  6507 
• 4b Matsuhashi H. Asai S. Hirabayashi K. Hatanaka Y. Mori A. Hiyama T. Bull. Chem. Soc. Jpn.  1997,  70:  437 
• For reviews, see:
• 5a Hiyama T. in Metal-Catalyzed Cross-Coupling Reactions   Diederich F. Stang PJ. Wiley-VCH; Weinheim: 1998.  p.421-453  
• 5b Denmark SE. Sweis RF. in Metal-Catalyzed Cross-Coupling Reactions   2nd ed., Vol. 1:  de Meijere A. Diederich F. Wiley-VCH; Weinheim: 2004.  p.163-216  
• 6a Strotman NA. Sommer S. Fu GC. Angew. Chem. Int. Ed.  2007,  46:  3556 
• 6b Dai X. Strotman NA. Fu GC. J. Am. Chem. Soc.  2008,  130:  3302 
• 7a Denmark SE. Choi JY. J. Am. Chem. Soc.  1999,  121:  5821 
• 7b Denmark SE. Wu Z. Org. Lett.  1999,  1:  1495 
• 7c Denmark SE. Sweis RF. Chem. Pharm. Bull.  2002,  50:  1531 
• 7d Denmark SE. Ober MH. Adv. Synth. Catal.  2004,  346:  1703 
• 7e Denmark SE. Regens CS. Acc. Chem. Res.  2008,  41:  1486 
• 7f Denmark SE. Werner NS. J. Am. Chem. Soc.  2008,  130:  16382 
• 7g Denmark SE. Smith RC. Chang W.-TT. Muhui JM. J. Am. Chem. Soc.  2009,  131:  3104 
• 8 Bury P. Hareau G. Kocieński P. Dhanak D. Tetrahedron  1994,  50:  8793 
• 9 Hatanaka Y. Hiyama T. Tetrahedron Lett.  1990,  31:  2719 
• 11a Bach T. Krüger L. Tetrahedron Lett.  1998,  39:  1729 
• 11b Bach T. Krüger L. Synlett  1998,  1185 
• 11c Bach T. Krüger L. Eur. J. Org. Chem.  1999,  2045 
• 13a Farina V. Krishnan B. J. Am. Chem. Soc.  1991,  113:  9585 
• 13b Amatore C. Jutand A. Meyer G. Atmani H. Khalil F. Chahdi FO. Organometallics  1998,  17:  2958 
• 13c For a review, see: Andersen NG. Keay BA. Chem. Rev.  2001,  101:  997 
• 15 A guide for predicting regioselectivity in cross-coupling reactions has been suggested, see: Handy ST. Zhang Y. Chem. Commun.  2006,  299 
• For Suzuki cross-coupling of 2,4-dibromopyridine, see:
• 16a Sicre C. Alonso-Gómez J.-L. Cid MM. Tetrahedron  2006,  62:  11063 
• 16b Voisin-Chiret AS. Bouillon A. Burzicki G. Célant M. Legay R. El-Kashef H. Rault S. Tetrahedron  2009,  65:  607 
• 17 For Pd-catalyzed amination of 2,4-dibromopyridine, see: Denhart DJ. Purandare AV. Catt JD. King HD. Gao A. Deskus JA. Poss MA. Stark AD. Torrente JR. Johnson G. Mattson RJ. Bioorg. Med. Chem. Lett.  2004,  14:  4249 
• 18a Damrauer R. Danahey SE. Organometallics  1986,  5:  1490 
• 18b Schraml J. Chvalovsk V. Mägi M. Lippmaa E. J. Organomet. Chem.  1973,  51:  C5 

10

Activating reagents were screened in the reaction of substrate 3 with n-octyltrifluorosilane in THF at 100 ˚C, employing Pd₂dba₃/P(2-furyl)₃ as the catalyst. Almost no conversion was achieved with the given activating reagents, while anhydrous CsF delivered a significant conversion after 18 h (26% 4a, 34% 5).

12

Other ligands that have been tested include tri-tert-butyl-phosphonium tetrafluoroborate (PtBu₃˙HBF₄), tricyclo-hexylphosphane (PCy₃), 1,2-bis(diphenylphosphino)ethane (dppe), 1,2-bis(di-2-furylphosphino)ethane (dfpe), and 1,4-bis(diphenylphosphino)butane (dppb).

14

Typical procedure: A flame-dried Schlenk tube was charged with Pd₂dba₃ (9.2 mg, 0.01 mmol), P(2-furyl)₃ (18.6 mg, 0.08 mmol) and benzene (2 mL) under an atmosphere of argon. The solution was stirred at r.t. for 15 min then n-octyltrifluorosilane (74 µL, 0.40 mmol) and CsF (122 mg, 0.80 mmol, which was stored and weighed in a glove box) were added, followed by dibromofuran 3 (56.8 mg, 0.20 mmol). The tube was closed with a Teflon screw plug, situated behind an explosion shield (CAUTION!), heated to 80 ˚C and stirred for 15 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (5 mL) and H₂O (5 mL). After separation of the layers, the aqueous phase was extracted with EtOAc (3 × 5 mL) and the combined organic layers were dried over Na₂SO₄ and concentrated in vacuo. Purification of the crude product by flash column chromatography (silica gel; pentane-Et₂O, 99:1) yielded compound 4a (45.6 mg, 0.14 mmol, 72%) as a colorless liquid. ^¹H NMR (500 MHz, CDCl₃): δ = 0.88 (t, ^³ J = 7.0 Hz, 3 H), 1.20-1.36 (m, 10 H), 1.68 (quint, ^³ J = 7.5 Hz, 2 H), 2.70 (t, ^³ J = 7.5 Hz, 2 H), 3.88 (s, 3 H), 7.11 (s, 1 H); ^¹³C NMR (90.6 MHz, CDCl₃): δ = 14.1, 22.6, 26.5, 27.5, 29.0, 29.1, 29.1, 31.8, 52.0, 97.9, 121.2, 142.6, 158.3, 158.5; HRMS: m/z calcd for C₁₄H₂₁BrO₃: 316.0674; found: 316.0673.