Rapid and Efficient Synthesis of Functionalized Bipyridines

Abstract

The Negishi reaction affords a mild and efficient method to convert chloro- and bromo-pyridines into functionalized 2,2′-bipyridines using commercially available starting materials. This method also extends to the conversion of dibromopyridines to 5- and 6-bromobipyridines, which are powerful synthons for incorporation into larger supramolecular systems.

palladium - catalysis - organometallic reagents - cross-coupling - bipyridines

References

<A NAME="RS04002ST-1A">1a</A> Kaes C. Katz A. Hosseini MW. Chem. Rev.  2000,  100:  3553 

<A NAME="RS04002ST-1B">1b</A> Constable EC. Adv. Inorg. Chem.  1989,  34:  1 

<A NAME="RS04002ST-2">2</A> Ward MD. J. Chem. Soc., Dalton Trans.  1994,  3095 

<A NAME="RS04002ST-3">3</A> Ward MD. McCleverty JA. Jeffery JC. Coord. Chem. Rev.  2001,  222:  251 

<A NAME="RS04002ST-4">4</A> Newkome GR. Hager DC. J. Org. Chem.  1982,  47:  599 

<A NAME="RS04002ST-5">5</A> Hanan GS. Lehn J.-M. Kyritsakas N. Fischer J. J. Chem. Soc., Chem. Commun.  1995,  765 

<A NAME="RS04002ST-6">6</A> Hanan GS. Schubert US. Volkmer D. Riviere E. Lehn J.-M. Kyritsakas N. Fischer J. Can. J. Chem.  1997,  75:  169 

<A NAME="RS04002ST-7">7</A> Bolm C. Ewald M. Felder M. Schlingloff G. Chem. Ber.  1992,  125:  1169 

<A NAME="RS04002ST-8">8</A> Deshayes K. Broene RD. Chao I. Knobler CB. Diederich F. J. Org. Chem.  1991,  56:  6787 

<A NAME="RS04002ST-9">9</A> Rottlander M. Boymond L. Berillon L. Lepretre A. Varchi G. Avolio S. Laaziri H. Queguiner G. Ricci A. Cahiez G. Knochel P. Chem.-Eur. J.  2000,  6:  767 

<A NAME="RS04002ST-10">10</A> Berillon L. Lepretre A. Turck A. Ple N. Queguiner G. Cahiez G. Knochel P. Synlett  1998,  1359 

<A NAME="RS04002ST-11">11</A> Bonnet V. Mongin F. Trecourt F. Queguiner G. Knochel P. Tetrahedron Lett.  2001,  42:  5717 

<A NAME="RS04002ST-12">12</A> Trecourt F. Gervais B. Mallet M. Queguiner G. J. Org. Chem.  1996,  61:  1673 

<A NAME="RS04002ST-13">13</A> Knochel P. Almena Perea JJ. Jones P. Tetrahedron  1998,  54:  8275 

<A NAME="RS04002ST-14">14</A> Zhu L. Wehmeyer RM. Rieke RD. J. Org. Chem.  1991,  56:  1445 

<A NAME="RS04002ST-15">15</A> Turck A. Ple N. Lepretre-Gaquere A. Queguiner G. Heterocycles  1998,  49:  205 

<A NAME="RS04002ST-16">16</A> Gros P. Fort Y. Synthesis  1999,  754 

<A NAME="RS04002ST-17">17</A> Savage SA. Smith AP. Fraser CL. J. Org. Chem.  1998,  63:  10048 

<A NAME="RS04002ST-18">18</A> Khan MA. Tuck DG. Acta Cryst., Sect. C: Cryst. Struct. Commun.  1984,  40:  60 

<A NAME="RS04002ST-19">19</A>

General Procedure: A flame-dried Schlenk tube was charged with Pd(PPh₃)₄ and 2-halopyridine under argon. 2-Pyridylzinc bromide (THF solution) was then added by syringe. The mixture was stirred at r.t. for several hours, and was poured into an aq EDTA/Na₂CO₃ solution. After the precipitate had dissolved, the mixture was extracted with Et₂O (3 ¥ 50 mL), and dried over Na₂SO₄. The solvent was evaporated and the residue was chromatographed on an alumina column (neutral, Brockmann I) with 10:1 hexane:EtOAc.

<A NAME="RS04002ST-20">20</A>

Compound 3c: 1: 4.5 mmol; 2c: 2.91 mmol; Pd(PPh₃)₄: 0.06 mmol. Chromatographed with 10:1 hexane:EtOAc as eluent to yield a colorless liquid. ¹H NMR (300 MHz, CDCl₃): δ = 8.64 (d, J = 4.8 Hz, 1 H, H_{6 ′}), 8.49 (d, J = 4.4 Hz, 1 H, H₆), 7.80-7.73 (m, 2 H, H_{3 ′ ,4 ′}), 7.56 (d, J = 7.7 Hz, 1 H, H ₄), 7.27-2.22 (m, 1 H, H_{5 ′}), 7.18 (d, J = 7.8, 4.7 Hz, 1 H, H_{5 ′}), 2.46 (s, 3 H, Me). ¹³C NMR (75 MHz, CDCl₃): δ = 159.0, 156.4, 148.6, 146.8, 139.2, 136.6, 132.3, 124.2, 123.1, 122.7, 20.0. FAB/NBA: 171.1 [MH⁺]. Compounds 3d-f: 3.0 mmol scale with 2 mol% Pd(PPh₃)₄, chromatographed with 10:1 hexane:EtOAc. NMR spectra are identical to those previously reported. [30]

<A NAME="RS04002ST-21">21</A>

Pd₂(dba)₃ and P(o-tolyl)₃ or P(2-furyl)₃ were tested as catalysts giving conversions of less than 20% with the same reaction conditions. Although recent results showed that Pd[P(t-Bu)₃]₂ is a powerful catalyst for coupling a broad range of aryl chlorides and organozinc halides, [22] the cost and the availability of the catalyst are a concern.

<A NAME="RS04002ST-22">22</A> Dai C. Fu GC. J. Am. Chem. Soc.  2001,  123:  2719 

<A NAME="RS04002ST-23">23</A>

Compound 3g: 4.3 mmol scale with 3 mol% Pd(PPh₃)₄, chromatographed with a hexane:EtOAc solvent gradient (10:1 to 3:1). ¹H NMR (500 MHz, CDCl₃): δ = 8.80 (d, J = 4.9 Hz, 1 H), 8.68 (br, 2 H), 8.40 (d, J = 7.9 Hz, 1 H), 7.83 (td, J ^t = 7.7 Hz, J ^d = 1.5 Hz, 1 H), 7.49 (dd, J = 4.9, 1.2 Hz, 1 H), 7.35 (dd, J = 7.3, 4.9 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 157.6, 154.1, 150.1, 149.5, 137.3, 124.9, 124.8, 123.0, 121.4. 121.3, 116.8. Compound 3h: 1.0 mmol scale with 3 mol% Pd(PPh₃)₄. Extracted with CH₂Cl₂ and chromatographed with a hexane:EtOAc solvent gradient (10:1 to 3:1 to 1:1). Mp: 174-175 °C (EtOH). ¹H NMR (300 MHz, CDCl₃): δ = 9.42 (s, 1 H), 9.08 (s, 2 H), 8.84 (d, J = 5.0 Hz, 1 H), 8.75 (d, J = 4.6 Hz, 1 H), 8.43 (d, J = 7.9 Hz, 1 H), 8.33 (d, J = 4.1 Hz, 1 H), 7.83 (t, J = 7.7 Hz, 1 H), 7.64 (d, J = 7.7 Hz, 2 H, Ph), 7.56-7.45 (m, 3 H, Ph), 7.32 (dd, J = 7.4, 4.8 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 161.7, 157.2, 156.1, 155.4, 150.1, 149.5, 145.7, 137.0, 134.2, 133.2, 129.6, 129.2, 127.0, 123.9, 121.9, 121.2, 119.7. FAB/NBA: 311.1 [MH⁺]. Compound 3i: 3.0 mmol scale with 2 mol% Pd(PPh₃)₄, chromatographed with 13:1 hexane:EtOAc. NMR spectra are identical to those previously reported.²⁴

<A NAME="RS04002ST-24">24</A> Wakabayashi S. Tanaka T. Kubo Y. Uenishi J. Oae S. Bull. Chem. Soc. Jpn.  1989,  62:  3848 

<A NAME="RS04002ST-25">25</A> Fang Y.-Q. Taylor NJ. Hanan GS. Loiseau F. Passalaqua R. Campagna S. J. Am. Chem. Soc.  2002,  124:  7912 

<A NAME="RS04002ST-26">26</A>

Compound 5: 3.0 mmol scale with 2 mol% Pd(PPh₃)₄, chromatographed with 10:1 hexane:EtOAc. NMR spectra are identical to those previously reported.⁶

<A NAME="RS04002ST-27">27</A>

Compound 8: 2.0 mmol scale with 3 mol% Pd(PPh₃)₄, chromatographed with 10:1 hexane:EtOAc. NMR spectra are identical to those previously reported.²⁸

<A NAME="RS04002ST-28">28</A> Romero FM. Ziessel R. Tetrahedron Lett.  1995,  36:  6471 

<A NAME="RS04002ST-29A">29a</A> Hanan GS. Volkmer D. Schubert US. Lehn J.-M. Baum G. Fenske D. Angew. Chem., Int. Ed. Engl.  1997,  36:  1842 

<A NAME="RS04002ST-29B">29b</A> Hanan GS. Arana CR. Lehn J.-M. Fenske D. Angew. Chem., Int. Ed. Engl.  1995,  34:  1122 

<A NAME="RS04002ST-29C">29c</A> Ceroni P. Credi A. Balzani V. Campagna S. Hanan GS. Arana CR. Lehn J.-M. Eur. J. Inorg. Chem.  1999,  1409 

<A NAME="RS04002ST-29D">29d</A> Baxter PNW. Compr. Supramol. Chem.  1996,  9:  165 

<A NAME="RS04002ST-30">30</A> Schubert US. Eschbaumer C. Heller M. Org. Lett.  2000,  3373