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Synlett 2002(5): 0808-0810
DOI: 10.1055/s-2002-25342
LETTER
© Georg Thieme Verlag Stuttgart · New York

Directed Deprotonation-Transmetallation of 4-Bromopyridine: Flexible Routes to Substituted Pyridines

Gunter Kariga, Nopporn Thasanaa,b,c, Timothy Gallagher*a
a School of Chemistry, University of Bristol, Bristol BS8 1TS, UK
Fax: +44(117)9298611; e-Mail: T.Gallagher@bristol.ac.uk;
b Chulabhorn Research Institute, Bangkok 10210, Thailand
c Department of Chemistry, Mahidol University, Bangkok 10400, Thailand
Further Information

Publication History

Received 8 March 2002
Publication Date:
07 February 2007 (online)

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Abstract

Halide-directed deprotonation and Li-Zn exchange of 4-bromopyridine 4 provides organozinc 6, which undergoes Pd-mediated coupling to give the 3-aryl-4-bromopyridines 7. Further substitution is achieved to provide the 3,4-disubstituted pyridines 8 and 9, and the 3,4,5-trisubstituted variants 10.

Key words

directed lithiation - transmetallation - cross-coupling - zinc - pyridine

5

All new compounds have been fully characterized by IR, 1H and 13C NMR, and HRMS. Selected data are presented below. It is noteworthy that the bromo moiety of 6 does not participate in a ‘homocoupling’ process [i.e. a Pd(0)-mediated dimerization of 6], and only the cross coupled product 7 is observed. Furthermore, in addition to aryl iodides, organozinc 6 has also been coupled successfully to vinyl triflates.

6

We used an excess (2.5 equiv as compared to the aryl iodide) of 4-bromopyridine and yields are based on the aryl iodide component. A solution of LDA [from diisopropylamine (1.4 mL, 10 mmol), n-BuLi (4 mL, 2.5 M in hexanes, 10 mmol) in THF (5 mL)] was transferred to a solution of 4-bromo-pyridine hydrochloride (970 mg, 5 mmol) in THF (5 mL) at -78 °C and stirred for 30 min. Dry ZnCl2 (700 mg, 5 mmol) in THF (5 mL) was added. A precipitate was formed and the mixture was allowed to warm to room temperature. Aryl iodide (2 mmol) and Pd(PPh3)4 (0.06 g, 0.05 mmol) were added and the reaction mixture was heated to reflux for 3 hours. After cooling, sat. aq NH4Cl was added, and the product was extracted with EtOAc, the extracts were washed with water, dried (MgSO4), and evaporated under reduced pressure. Purification by silica gel flash chromato-graphy gave the 3-aryl-4-bromopyridines 7.
Selected data for 3-aryl-4-bromopyridines: 7a: mp 169 °C (EtOAc-hexane); 1H NMR (300 MHz, CDCl3) δ 7.63 (2 H, d, J = 8.8 Hz, CH2′,6′), 7.68 (1 H, d, J = 5.3 Hz, CH5), 8.36 (2 H, d, J = 8.9 Hz, CH3′,5′), 8.46 (1 H, d, J = 5.3 Hz, CH6), 8.53 (1 H, s, CH2). 7b: mp 60-62 °C (EtOAc-hexane); 1H NMR (300 MHz, CDCl3) δ 3.87 (3 H, s, OCH 3), 7.01 (2 H, d, J = 8.8 Hz, CH3′,5′), 7.37 (2 H, d, J = 8.8 Hz, CH2′,6′), 7.61 (1 H, dd, J = 0.4, 5.3 Hz, CH5), 8.33 (1 H, d, J = 5.3 Hz, CH6), 8.50 (1 H, s, CH2). 7c: mp 69-70 °C (EtOAc:hexane); 1H NMR (300 MHz, CDCl3) δ 7.43 (1 H, dd, J = 5.1, 7.9, Hz, CH5′), 7.67 (1 H, d, J = 5.3 Hz, CH5), 7.79 (1 H, d, J = 7.9 Hz, CH4′), 8.44 (1 H, d, J = 5.2 Hz, CH6), 8.53 (1 H, s, CH2), 8.70 (2 H, s, CH2′,6′). 7d: oil 1H NMR (300 MHz, CDCl3) δ 7.44 (5 H, m, PhH), 7.61 (1 H, dd, J = 0.5, 5.3 Hz, CH5), 8.33 (1 H, d, J = 5.3 Hz, CH6), 8.51 (1 H, s, CH2).

8

General procedure for Suzuki coupling of 7 to give 8: To the 4-bromo-3-arylpyridines 7 (0.2 mmol) in toluene (9 mL) and EtOH (1 mL) were added aryl boronic acid (0.25 mmol), Pd(PPh3)4 (0.02 g, 0.017 mmol) and 10% aq Na2CO3
(3 mL). The mixture was heated at reflux for 3 hours, then cooled, filtered, and extracted with EtOAc. The extracts were washed with water, dried (MgSO4), concentrated and the product was isolated following flash chromatography.
Selected data for 3,4-diarylbromopyridines: 8a mp 124-125 °C (EtOAc-hexane); 1H NMR (300 MHz, CDCl3) δ 7.13 (2 H, m, CH3′′,5′′), 7.31 (3 H, m, CH2′′,4′′,6′′), 7.33 (2 H, d, J = 8.9 Hz, CH2′,6′), 7.40 (1 H, d, J = 4.9 Hz, CH5), 8.15 (2 H, d, J = 8.9 Hz, CH3′,5′), 8.66 (1 H, s, CH2); 8.71 (1 H, br.d, J = 4.0 Hz, CH6). 8b mp 110-111 °C (EtOAc-hexane); 1H NMR (300 MHz, CDCl3) δ 3.80 (3 H, s, OCH 3), 6.81 (2 H, d, J = 8.6 Hz, CH3′,5′), 7.07 (2 H, d, J = 8.6 Hz, CH2′,6′), 7.17 (2 H, m, CH3′′,5′′), 7.28 (3 H, m, CH2′′,4′′,6′′), 7.33 (1 H, d, J = 5.1 Hz, CH5), 8.60 (1 H, br.d, CH6); 8.62 (1 H, br.s, CH2). 8c mp 133-134 °C (EtOAc-hexane); 1H NMR (300 MHz, CDCl3) δ 7.21-7.25 (2 H, m, CH5′,5′′), 7.41 (1 H, dd, J = 0.7, 4.6 Hz, CH5), 7.44 (2 H, m, CH4′,4′′), 8.46 (2 H, m, CH2′,2′′), 8.57 (2 H, m, CH6′,6′′), 8.70 (1 H, br.s, CH2); 8.75 (1 H, d, J = 4.6 Hz, CH6).

9

A solution of LDA [from diisopropylamine (0.35 mL, 2 mmol), n-BuLi (1 mL, 2.0 M in hexanes, 2 mmol) in THF (2 mL)] was transferred to a solution of 7d (250 mg, 1 mmol) in THF (2 mL) at -78 °C and stirred for 30 min. ZnCl2
(138 mg, 1 mmol) in THF (2 mL) was added. A precipitate was formed and the mixture was allowed to warm to room temperature. 1-Iodo-4-nitrobenzene (or iodobenzene)
(1 mmol) and Pd(PPh3)4 (0.015 g, 0.01 mmol) were added and the reaction mixture was heated at reflux for 3 hours. After cooling, saturated aqueous NH4Cl was added, and the product was extracted with EtOAc, the extracts were washed with water, dried (MgSO4), and evaporated under reduced pressure. Purification by silica gel flash chromatography gave the 3,5-diaryl-4-bromopyridines 10.
Selected data for 3,5-diaryl-4-bromopyridines: 10a mp 153-154 °C (EtOAc-hexane); 1H NMR (300 MHz, CDCl3) δ 7.48 (5 H, m, PhH), 7.53 (2 H, d, J = 9.0 Hz, CH3′,5′), 8.36 (2 H, d, J = 9.0 Hz, CH2′,6′), 8.45 (1 H, s, CH2); 8.53 (1 H, s, CH6); 13C NMR (75 MHz, CDCl3) δ 123.6 (CH), 128.4 (CH), 128.6 (CH), 129.5 (CH), 130.8 (CH), 133.0 (C), 137.2 (C), 137.3 (C), 139.4 (C), 144.3 (C), 147.8 (C),148.8 (CH), 150.5 (CH). 10b mp 116-117 °C (EtOAc-hexane); 1H NMR (300 MHz, CDCl3) δ 7.48 (10 H, m, PhH), 8.45 (2 H, s, CH2, 6); 13C NMR (75 MHz, CDCl3) δ 128.3 (CH), 128.4 (CH), 129.6 (CH), 133.4 (C), 137.9 (C), 139.1 (C), 149.4 (CH).