Csp^³-Csp^² Palladium-Catalyzed Cross-Coupling Reaction of Trialkylbismuth Reagents with Aryl, Heteroaryl, and Vinyl Halides and Triflates

Abstract

The palladium-catalyzed cross-coupling reaction of trialkylbismuth reagents with aryl and heteroaryl halides and triflates is reported. Moderate to good yields were obtained for the transfer of primary alkyl groups. The reaction tolerates numerous functional groups on the electrophilic and nucleophilic partners. The cross-coupling of α-bromostyrene with tris(1,3-dioxan-2-ylethyl)bismuth is also reported.

Key words

cross-coupling - organometallic reagents - palladium - halides - catalysis

References

• For an excellent review on molecular interactions in medicinal chemistry, see:
• 2a Bissantz C. Kuhn BK. Stahl M. J. Med. Chem.  2010,  53:  5061 
• 2b See also: Gagnon A. Duplessis M. Fader L. Org. Prep. Proced. Int.  2010,  42:  1 
• 3 See: Han C. Buchwald SL. J. Am. Chem. Soc.  2009,  131:  7532 ; and references cited therein
• 4a Luo X. Zhang H. Duan H. Liu Q. Zhu L. Zhang T. Lei A. Org. Lett.  2007,  9:  4571 
• 4b Zhang H. Lu X. Wongkhan K. Duan H. Li Q. Zhu L. Wang J. Batsanov AS. Howard JAK. Marder TB. Lei A. Chem. Eur. J.  2009,  15:  3823 
• 5a Luh T.-Y. Leung M.-K. Wong K.-T. Chem. Rev.  2000,  100:  3187 
• 5b Frisch AC. Beller M. Angew. Chem. Int. Ed.  2005,  44:  674 
• 6a Kondolff I. Doucet H. Santelli M. Tetrahedron  2004,  60:  3813 
• 6b Wang B. Sun H.-X. Sun Z.-H. Lin G.-Q. Adv. Synth. Catal.  2009,  351:  415 
• 6c Wang B. Sun H.-X. Sun Z.-H. Eur. J. Org. Chem.  2009,  3688 
• 6d Chemler SR. Trauner D. Danishefsky SJ. Angew. Chem. Int. Ed.  2001,  40:  4544 
• 7a Manolikakes G. Muñoz Hernandez C. Schade MA. Metzger A. Knochel P. J. Org. Chem.  2008,  73:  8422 
• 7b Liu J. Deng Y. Wang H. Zhang H. Yu G. Wu B. Zhang H. Li Q. Marder TB. Yang Z. Lei A. Org. Lett.  2008,  10:  2661 
• 7c Liu Q. Duan H. Luo X. Tang Y. Li G. Huang R. Lei A. Adv. Synth. Catal.  2008,  350:  1349 
• 7d Wang H. Liu J. Deng Y. Min T. Yu G. Wu X. Yang Z. Lei A. Chem. Eur. J.  2009,  15:  1499 
• 8a Kondolff I. Feuerstein M. Doucet H. Santellli M. Tetrahedron  2007,  63:  9514 
• 8b Hamaguchi H. Uemura M. Yasui H. Yorimitsu H. Oshima K. Chem. Lett.  2008,  37:  1178 
• 9a Shenglof M. Gelman D. Heymer B. Schumann H. Molander GA. Blum J. Synthesis  2003,  302 
• 9b Pena MA. Pérez Sestelo J. Sarandeses LA. Synthesis  2005,  485 
• 9c Chupak LS. Wolkowski JP. Chantigny YA. J. Org. Chem.  2009,  74:  1388 
• For reviews on bismuth chemistry, see:
• 10a Finet J.-P. Chem. Rev.  1989,  89:  1487 
• 10b Suzuki H. Ikegami T. Matano Y. Synthesis  1997,  249 
• 11a Barton DHR. Ozbalik N. Ramesh M. Tetrahedron  1988,  44:  5661 
• 11b Rao MLN. Yamazaki O. Shimada S. Tanaka T. Suzuki Y. Tanaka M. Org. Lett.  2001,  3:  4103 
• 11c Shimada S. Yamazaki O. Tanaka T. Rao MLN. Suzuki Y. Tanaka M. Angew. Chem. Int. Ed.  2003,  42:  1845 
• 11d Kang S.-K. Ryu H.-C. Kim JW. Synth. Commun.  2001,  31:  1021 
• 11e Kang S.-K. Ryu H.-C. Hong Y.-T. Kim M.-S. Lee S.-W. Jung J.-H. Synth. Commun.  2001,  31:  2365 
• 11f Moiseev DV. Malysheva YB. Shavyrin AS. Kurskii YA. Gushchin AV. J. Organomet. Chem.  2005,  690:  3652 
• 11g Rao MLN. Banerjee D. Jadhav DN. Tetrahedron Lett.  2007,  48:  2707 
• 11h Rao MLN. Banerjee D. Jadhav DN. Tetrahedron Lett.  2007,  48:  6644 
• For the coupling of methyl groups using dialkoxymethylbismuth and diarylmethylbismuth species, see:
• 12a Rao MLN. Shimada S. Tanaka M. Org. Lett.  1999,  1:  1271 
• 12b Rao MLN. Shimada S. Yamazaki O. Tanaka M. J. Organomet. Chem.  2002,  659:  117 
• 12c Yamazaki O. Tanaka T. Shimada S. Suzuki Y. Tanaka M. Synlett  2004,  1921 
• 13 Gagnon A. St-Onge M. Little K. Duplessis M. Barabé F. J. Am. Chem. Soc.  2007,  129:  44 
• 14 Gagnon A. Duplessis M. Alsabeh P. Barabé F. J. Org. Chem.  2008,  73:  3604 
• 15 The organomagnesium reagents were titrated before use using diphenylditelluride: Aso Y. Yamashita H. Otsubo T. Ogura F. J. Org. Chem.  1989,  54:  5627 

1

Current address: Constellation Pharmaceuticals, Cambridge, MA, USA; [e-mail].

16

General Procedure for the Preparation of 4, 6a-o, and 8 In a round-bottom flask equiped with a condenser and sparged with argon, BiCl₃ (173 mg, 0.55 mmol) was suspended in anhydrous THF (3 mL) and cooled to 0 ˚C. The organomagnesium reagent (1.705 mmol, THF or Et₂O solution) was slowly added dropwise, and the solution was stirred at 0 ˚C for 30 min, warmed to r.t., and then heated at 65 ˚C for an additional 30 min. The reaction mixture was cooled to r.t. and diluted with DMF (1 mL). A DMF solution of the aryl or heteroaryl halide or pseudo halide (0.500 mmol in 4 mL) was then added, followed by K₂CO₃ or Cs₂CO₃ (1.00 mmol) and Pd(PPh₃)₄ (28 mg, 0.025 mmol). The solution was degassed by bubbling argon during 15 min, and then stirred at 110 ˚C for 18 h. The reaction mixture was cooled to r.t., diluted with sat. aq NaHCO₃ (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic phases were washed with brine (3 × 10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (1% to 15% EtOAc-hexanes or Et₂O-hexanes) to afford the desired products 4, 6a-o, and 8.
Spectral Data for 6n R _f = 0.41 (20% EtOAc-hexanes). ^¹H NMR (400 MHz, CDCl₃): δ = 8.81 (d, J = 1.8 Hz, 1 H), 8.08 (d, J = 8.4 Hz, 1 H), 7.94 (s, 1 H), 7.76 (d, J = 8.1 Hz, 1 H), 7.66 (t, J = 8.2 Hz, 1 H), 7.53 (t, J = 7.0 Hz, 1 H), 4.56 (t, J = 5.1 Hz, 1 H), 4.12 (dd, J = 10.0, 5.0 Hz, 2 H), 3.76 (dt, J = 12.5, 2.4 Hz, 2 H), 2.93 (t, J = 7.8 Hz, 2 H), 2.13-2.04 (m, 1 H), 2.02-1.99 (m, 2 H), 1.35 (d, J = 13 Hz, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 152.5, 147.2, 134.8, 134.7, 129.6, 129.0, 128.6, 127.8, 127.0, 101.4, 67.3, 36.6, 27.7, 26.2. IR (neat): 2959, 2850, 1494, 1378, 1240, 1138, 1082, 1043, 1002 cm^-¹. HRMS (EI): m/z calcd for C₁₅H₁₇NO₂ [M]: 243.1259; found: 244.1328 [M + H].