Cross-coupling between 3-Pyridylmagnesium Chlorides and Heteroaromatic Halides

Abstract

Phenyl- and thienylpyridines were prepared by Pd(0)-catalyzed cross-coupling of 3-pyridylmagnesium chlorides with iodobenzene or iodothiophene at room temperature. Starting from bromo and chloro azines and diazines, the Ni(0)-catalyzed reaction proved more suitable to allow the synthesis of pyridylpyridines, pyridylquinolines and pyridyldiazines.

cross-coupling - heterocycles - magnesium - organometallic reagent - transition metals

References

<A NAME="RG07402ST-1A">1a</A>

According to the MDL Drug Data Report, the most widespread heterocycles in pharmaceutically active compounds are pyridine (out of 15000 structures), imidazole (out of 11000), indole (out of 6700) and pyrimidine (out of 4500).

<A NAME="RG07402ST-1B">1b</A> Quéguiner G. Marsais F. Snieckus V. Epsztajn J. Adv. Heterocycl. Chem.  1991,  52:  187 

<A NAME="RG07402ST-2">2</A> Lehn JM. Supramolecular Chemistry   VCH Verlasgesellschaft; Weinheim: 1995. 

<A NAME="RG07402ST-3">3</A> Katritzky AR. Rees CW. Comprehensive Heterocyclic Chemistry   Vol. 2:  Pergamon Press; New York: 1984. 

<A NAME="RG07402ST-4">4</A> Stanforth SP. Tetrahedron  1998,  54:  263 ; and references cited therein

<A NAME="RG07402ST-5A">5a</A> Tamao K. Sumitani K. Kumada M. J. Am. Chem. Soc.  1972,  94:  4374 

<A NAME="RG07402ST-5B">5b</A> Corriu RPJ. Masse JP. J. Chem. Soc., Chem. Commun.  1972,  144 

<A NAME="RG07402ST-5C">5c</A> Pridgen LN. J. Heterocycl. Chem.  1975,  12:  443 

<A NAME="RG07402ST-5D">5d</A> Albers WM. Canters GW. Reedijk J. Tetrahedron  1995,  51:  3897 

<A NAME="RG07402ST-5E">5e</A> Böhm VPW. Weskamp T. Gstôttmayr CWK. Herrmann WA. Angew. Chem. Int. Ed.  2000,  39:  1602 

<A NAME="RG07402ST-5F">5f</A> Diederich F. Stang PJ. Metal-Catalyzed Cross-Coupling Reactions   Wiley-VCH; Weinheim: 1998. 

<A NAME="RG07402ST-6A">6a</A> Negishi E.-I. King AO. Okukado NJ. J. Org. Chem.  1977,  42:  1821 

<A NAME="RG07402ST-6B">6b</A> Sakamoto T. Kondo Y. Murata Y. Yamanata H. Tetrahedron  1993,  43:  9713 

<A NAME="RG07402ST-6C">6c</A> Trécourt F. Gervais B. Mallet M. Quéguiner G. J. Org. Chem.  1996,  61:  1673 

<A NAME="RG07402ST-6D">6d</A> Trécourt F. Gervais B. Mongin O. Le Gal C. Mongin F. Quéguiner G. J. Org. Chem.  1998,  63:  2892 

<A NAME="RG07402ST-6E">6e</A> Hargreaves SL. Pilkington BL. Russel SE. Worthington PA. Tetrahedron Lett.  2000,  41:  1653 

<A NAME="RG07402ST-6F">6f</A> Karig G. Spencer JA. Gallagher T. Org. Lett.  2001,  3:  835 

<A NAME="RG07402ST-6G">6g</A> Loren JC. Siegel JS. Angew. Chem. Int. Ed.  2001,  40:  754 

<A NAME="RG07402ST-7A">7a</A> Miyaura N. Suzuki A. Chem. Rev.  1995,  95:  2457 

<A NAME="RG07402ST-7B">7b</A> Suzuki A. J. Organomet. Chem.  1999,  576:  147 

<A NAME="RG07402ST-7C">7c</A> Godard A. Turck A. Plé N. Marsais F. Quéguiner G. Trends Heterocycl. Chem.  1993,  3:  19 

<A NAME="RG07402ST-7D">7d</A> Godard A. Marsais F. Plé N. Trécourt F. Turck A. Quéguiner G. Heterocycles  1995,  40:  1055 

<A NAME="RG07402ST-7E">7e</A> Ishikura M. Kamada M. Terashima M. Synthesis  1984,  936 

<A NAME="RG07402ST-7F">7f</A> Schomaker JM. Thomas TJ. J. Org. Chem.  2001,  66:  7125 

<A NAME="RG07402ST-8A">8a</A> Stille JK. Angew. Chem. Int. Ed.  1986,  25:  508 

<A NAME="RG07402ST-8B">8b</A> Mathieu J. Gros P. Fort Y. Tetrahedron Lett.  2001,  42:  1879 

To our knowledge, only one example concerns the use of a pyridylmagnesium halide in a metal transition-catalyzed cross-coupling reaction:

<A NAME="RG07402ST-9A">9a</A> Tamao K. Komada S. Nakajima I. Kumada M. Tetrahedron  1982,  38:  3347 ; where nickel-catalyzed reaction of 2-pyridylmagnesium chloride and 2-bromopyridine proceeds in 13% yield

<A NAME="RG07402ST-9B">9b</A> Besides, 2-, 3- and 4-pyridylmagnesium bromides have been used to react with phenyl pyridine-2-sulfoxides: Furukawa N. Shibutani T. Fujihara H. Tetrahedron Lett.  1987,  28:  5845 

<A NAME="RG07402ST-9C">9c</A> Also see: Furukawa N. Shibutani T. Fujihara H. Tetrahedron Lett.  1989,  30:  7091 

<A NAME="RG07402ST-10A">10a</A> Mongin F. Quéguiner G. Tetrahedron  2001,  57:  4059 

<A NAME="RG07402ST-10B">10b</A> Turck A. Plé N. Mongin F. Quéguiner G. Tetrahedron  2001,  57:  4489 

<A NAME="RG07402ST-11A">11a</A> Trécourt F. Breton G. Bonnet V. Mongin F. Marsais F. Quéguiner G. Tetrahedron Lett.  1999,  40:  4339 

<A NAME="RG07402ST-11B">11b</A> Trécourt F. Breton G. Bonnet V. Mongin F. Marsais F. Quéguiner G. Tetrahedron  2000,  56:  1349 

<A NAME="RG07402ST-12">12</A>

In a general procedure, the required 3-bromopyridine (1.2 mmol) was dissolved in THF (5 mL) and a solution of i-PrMgCl (1.4 mmol) in THF (0.70 mL) was added dropwise at r.t. to the mixture. After 1 h at the same temperature, the iodo derivative (1.0 mmol) and Pd(PPh₃)₄ (12 mg, 10 µmol) were introduced; the mixture was stirred for 17 h and quenched with an aqueous saturated NH₄Cl solution (5 mL). The aqueous solution was extracted several times with CH₂Cl₂. The organic layer was dried over MgSO₄, the solvents were evaporated under reduced pressure and the crude compound was chromatographed on a silica gel column. 3-Phenylpyridine(2a) starting from 3-bromopyridine and using iodobenzene (eluent: CH₂Cl₂-Et₂O, 90:10). Yield: 60%. The physical and spectral data are analogous to those obtained for a commercial sample. 3-Bromo-5-phenylpyridine(2b) starting from 3,5-dibromopyridine and using iodobenzene (eluent: CH₂Cl₂). Yield: 52%; the ¹H NMR data are in accordance with those of the literature; [19] ¹³C NMR (CDCl₃) δ 120.7, 126.9 (2C), 128.4, 128.9 (2C), 135.9, 136.4, 137.7, 146.1, 149.1; IR (KBr): 3019, 1890, 1580, 1542, 1430, 1404, 1317, 1282, 1170, 1106, 1007, 880, 795, 763, 702, 670 cm^-1. Anal. Calcd for C₁₁H₈BrN (234.10): C, 56.44; H, 3.44; N, 5.98. Found: C, 56.60; H, 3.51; N, 6.17%. 5-Bromo-2-fluoro-3-phenylpyridine(2c) starting from 3,5-dibromo-2-fluoropyridine and using iodobenzene (eluent: CH₂Cl₂). Yield: 58%; ¹H NMR (CDCl₃) δ 7.4 (m, 5 H, Ph), 7.9 (ddd, 1 H, J = 8.4, 2.5, 0.5 Hz, H₄), 8.15 (d, 1 H, J = 2.5 Hz, H₆); ¹³C NMR (CDCl₃) δ 116.5, 125.5, 128.5 (2C), 128.7 (2C), 128.9, 132.0, 142.5, 146.5, 159.0; IR (KBr): 3063, 1588, 1556, 1455, 1417, 1284, 1243, 1199, 1108, 1041, 1016, 901, 775, 731, 697, 636 cm^-1. Anal. Calcd for C₁₁H₇BrFN (252.09): C, 52.41; H, 2.80; N, 5.56. Found: C, 52.19; H, 2.65; N, 5.48%.

<A NAME="RG07402ST-13">13</A>

The toxicity of nickel salts led us to turn first to palladium-catalyzed cross-coupling reactions.

<A NAME="RG07402ST-14">14</A>

3-(2-Thienyl)pyridine(3) [20] using the general procedure,¹² starting from 3-bromopyridine and 2-iodothiophene (eluent: Et₂O-petroleum ether, 50:50). Yield: 54%; the ¹H NMR data are in accordance with those of the literature. [21]

<A NAME="RG07402ST-15">15</A>

2,3′-Bipyridine(4): Pd(dba)₂ (29 mg, 0.050 mmol), dppf (28 mg, 0.050 mmol) and, 10 min later, 2-bromopyridine (96 µL, 1.0 mmol) were added to THF (3 mL). After stirring for 30 min at r.t., this solution was transferred at r.t. to a freshly prepared (see general procedure 1) solution of 3-pyridylmagnesium chloride (1.2 mmol) in THF (5-6 mL). After 4 h at reflux, the mixture was quenched with an aqueous saturated NH₄Cl solution (5 mL) to give 4 (eluent: CH₂Cl₂-Et₂O, 90:10). Yield: 64%; the physical and spectral data are analogous to those obtained for a commercial sample.

Concerning the use of this catalyst, see:

<A NAME="RG07402ST-16A">16a</A> Hayashi T. Konishi M. Kobori Y. Kumada M. Higuchi T. Hirotsu K. J. Am. Chem. Soc.  1984,  106:  158 

<A NAME="RG07402ST-16B">16b</A> Amatore C. Jutand A. J. Organomet. Chem.  1999,  576:  254 

<A NAME="RG07402ST-16C">16c</A> Sato F. Urabe H. Okamoto S. Chem. Rev.  2000,  100:  2757 

<A NAME="RG07402ST-16D">16d</A> Bonnet V. Mongin F. Trécourt F. Quéguiner G. Knochel P. Tetrahedron Lett.  2001,  42:  5717 

<A NAME="RG07402ST-17">17</A> Fleming I. Frontier Orbitals and Organic Chemical Reactions   John Wiley and Sons; Chichester: 1978. 

<A NAME="RG07402ST-18">18</A>

In a general procedure, Ni(acac)₂ (13 mg, 0.050 mmol), dppe (20 mg, 0.050 mmol) and, 10 min later, the required 2-halo substrate (1.0 mmol) were added to THF (3 mL). After stirring for 30 min at r.t., this solution was transferred at r.t. to a freshly prepared (see general procedure 1) solution of 3-pyridylmagnesium chloride (1.2 mmol) in THF (5-6 mL). After 18 h at r.t., the mixture was quenched with an aqueous saturated NH₄Cl solution (5 mL). 6-Bromo-2-(3-pyridyl)pyridine(5a) starting from 2,6-dibromopyridine (eluent: CH₂Cl₂-Et₂O, 90:10). Yield: 34%; mp 82-84 °C (lit. [22] mp 73-74 °C). 5-Bromo-2-(3-pyridyl)pyridine (5b) starting from 2,5-dibromopyridine (eluent: CH₂Cl₂-Et₂O, 90:10). Yield: 61%; mp 72-74 °C (lit. [22] mp 75-77 °C); ¹³C NMR (CDCl₃) δ 120.6, 121.9, 121.9, 124.3, 134.4, 139.1, 148.2, 150.4, 151.5, 153.6. Anal. Calcd for C₁₀H₇BrN₂ (235.08): C, 51.09; H, 3.00; N, 11.92. Found: C, 51.14; H, 3.06; N, 11.79%. 2-(3-Pyridyl)quinoline (5c) starting from 2-chloroquinoline (eluent: CH₂Cl₂-Et₂O, 90:10). Yield: 76%; mp 72 °C; the ¹H NMR data are in accordance with those of the literature; [6b] ¹³C NMR (CDCl₃) δ 117.4, 122.6, 125.7, 126.3, 126.5, 128.7, 128.9, 133.9, 134.1, 136.1, 147.3, 147.7, 149.1, 153.5; IR (KBr): 2925, 2855, 1577, 1304, 1129, 1020, 811, 786, 755, 710 cm^-1. Anal. Calcd for C₁₄H₁₀N₂ (206.25): C, 81.53; H, 4.89; N, 13.58. Found: C, 81.27; H, 5.02; N, 13.29%. 2-(3-Pyridyl)pyrimidine (5d) starting from 2-chloropyrimidine (eluent: CH₂Cl₂-Et₂O, 90:10). Yield: 69%; mp 52 °C (lit. [23] mp 48-49 °C); ¹³C NMR (CDCl₃) δ 118.7, 122.3, 132.1, 134.4, 148.8, 150.3, 156.3 (2C), 161.9; IR (KBr): 3044, 2963, 2928, 2854, 1582, 1567, 1408, 1261, 1083, 1021, 787, 708 cm^-1. Anal. Calcd for C₉H₇N₃ (157.18): C, 68.78; H, 4.49; N, 26.73. Found: C, 68.54; H, 4.18; N, 26.42%. 2-(3-Pyridyl)pyrazine (5e) [24] starting from 2-chloropyrazine (eluent: CH₂Cl₂-Et₂O, 90:10). Yield: 69%; mp 92-94 °C; ¹H NMR (CDCl₃) δ 7.38 (dd, 1 H, J = 7.9, 4.5 Hz, H_{5 ′}), 8.27 (dt, 1 H, J = 7.9, 1.9 Hz, H_{4 ′}), 8.51 (d, 1 H, J = 1.5 Hz, H₅), 8.61 (d, 1 H, J = 1.5 Hz, H₆), 8.65 (dd, 4 H, J = 4.5, 1.9 Hz, H_{6 ′}), 9.00 (s, 1 H, H₃), 9.18 (d, 1 H, J = 1.5 Hz, H_{2 ′}); ¹³C NMR (CDCl₃) δ 124.3, 130.1, 134.8, 142.4, 144.2, 144.9, 148.4, 150.8, 151.1; IR (KBr): 2925, 2854, 1416, 1082, 1013, 815, 702 cm^-1. Anal. Calcd for C₉H₇N₃ (157.18): C, 68.78; H, 4.49; N, 26.73. Found: C, 68.48; H, 4.19; N, 26.47%.

<A NAME="RG07402ST-19">19</A> Nielsen SF. Nielsen EO. Olsen GM. Liljefors T. Peters D. J. Med. Chem.  2000,  43:  2217 

<A NAME="RG07402ST-20">20</A> Wynberg H. Van Bergen TJ. Kellogg RM. J. Org. Chem.  1969,  34:  3175 

<A NAME="RG07402ST-21">21</A> Novak I. Ng S.-C. Mok C.-Y. Huang H.-H. Fang J. Wang KK.-T. J. Chem. Soc., Perkin Trans. 2  1994,  1771 

<A NAME="RG07402ST-22">22</A> Ishikura M. Ohta T. Terashima M. Chem. Pharm. Bull.  1985,  33:  4755 

<A NAME="RG07402ST-23">23</A> Van Der Stoel RE. Van Der Plas HC. J. Chem. Soc., Perkin Trans. 1  1979,  2393 

<A NAME="RG07402ST-24">24</A> Hasebe M. Kogawa K. Tsuchiya T. Tetrahedron Lett.  1984,  25:  3887