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Synlett 2006(1): 0053-0056  
DOI: 10.1055/s-2005-922772
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of ortho-Cyanopyridylboronic Acids and Esters toward Cyano-Functionalized Bipyridines

Thomas Cailly, Frédéric Fabis, Alexandre Bouillon, Stéphane Lemaître, Jana Sopkova, Olivieira de Santos, Sylvain Rault*
UPRES-EA 3915: Centre d’Etudes et de Recherche sur le Médicament de Normandie, U.F.R. des Sciences Pharmaceutiques, Université de Caen Basse-Normandie, 5 Rue Vaubénard, 14032 Caen Cedex, France
Fax: +33(2)31931159; e-Mail: sylvain.rault@unicaen.fr;
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Publication History

Received 17 October 2005
Publication Date:
16 December 2005 (online)

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Abstract

This work describes the synthesis of ortho-cyanopyridylboronic acids and esters. Their reactivity with pyridine halides in the Suzuki cross-coupling reaction is evaluated and shows that the cyanopyridyl boronic esters appear to be more stable than their corresponding acids. These esters allowed us to synthesize new ­cyanobipyridine systems.

Key words

cross-coupling - lithiation - nitriles - boronic acids - bi­pyridines

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Typical Procedure for Obtention of ortho -Cyano-pyridylboronic Acids 1a-d.
To a stirred solution under N2 of 2,2,6,6-tetramethyl-piperidine (20.2 mmol, 3.4 mL) in THF (40 mL) was added at -30 °C 2.5 M n-BuLi (19.2 mmol, 7.7 mL). The solution was allowed to reach 0 °C, kept under stirring during 15 min and cooled to -80 °C. 2-Cyanopyridine (9.6 mmol, 1 g) in THF (20 mL) was slowly added to the mixture over 15 min. After 30 min of stirring at -80 °C, a solution of triisopropyl-borate (20.2 mmol, 4.66 mL) in THF (10 mL) was slowly added over 15 min and the resulting mixture stirred for 30 min. The solution was then allowed to warm slowly to r.t. The mixture was quenched with 40 mL of H2O and washed 3 times with Et2O (75 mL). The aqueous layer was then acidified to pH 6 by addition of 3 M HCl, extracted with EtOAc (5 × 100 mL), and the organic layer was evaporated to give the 2-cyano-3-pyridylboronic acid (1c) as a white powder (yield 65%); mp >220 °C. 1H NMR (400 MHz, CD3OD): δ = 7.62 (dd, ³ J = 4.8 Hz, ³ J = 7.7 Hz, 1 H), 8.09 (dd, ³ J = 7.7 Hz, 4 J = 1.7 Hz, 1 H), 8.67 (dd, ³ J = 4.7 Hz, 4 J = 1.7 Hz, 1 H), 8.82 (br s, 2 H). IR (KBr): 3225, 2260 (CN), 1581, 1563, 1451, 1332, 1195, 1157, 1080, 1038, 772, 637, 559 cm-1.

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Typical Procedure for Suzuki Cross-Coupling 2, 3, 5a-d.
A three-necked flask, equipped with a septum inlet, a reflux condenser and a thermometer, was degassed with argon and charged with 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)nicotinonitrile (4b, 1.6 mmol, 0.36 g), K2CO3 (3.3 mmol, 0.46 g) and Pd(PPh3)4 (0.08 mmol, 91 mg). A degassed solution of 3-bromopyridine (1.5 mmol, 0.15 mL) in a toluene-EtOH mixture (10 mL, 1 mL) was added rapidly through the septum inlet with a syringe. The mixture was heated to 100 °C for 24 h (TLC monitoring) under stirring. The flask was poured in H2O (30 mL), and extracted with EtOAc (3 × 50 mL). The organic layer was then washed with brine, dried with MgSO4, filtered, and evaporated. [3,4′]Bipyridinyl-3′-carbonitrile was isolated as a white powder 5b (yield 58%) by column chromatography using EtOAc-cyclohexane (1:1) and EtOAc as eluants; mp 180 °C. 1H NMR (400 MHz, CDCl3): δ = 7.49-7.53 (m, 2 H), 8.01 (ddd, ³ J = 8.0 Hz 4 J = 2.4 Hz 4 J = 1.7 Hz, 1 H), 8.79 (dd, ³ J = 4.8 Hz 4 J = 1.7 Hz, 1 H), 8.83 (d, 4 J = 2.4 Hz, 1 H), 8.89 (d, ³ J = 5.1 Hz, 1 H), 9.02 (s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 108.69, 116.05, 123.51, 123.55, 123.67, 131.57, 135.73, 148.85, 151.24, 153.20, 154.06. IR (KBr): 3429, 3093, 3015, 2228 (CN), 1721, 1593, 1585, 1471, 1418, 1400, 1195, 1013, 864, 809, 745, 711, 643, 543 cm-1. HRMS: m/z calcd: 182.0718; found: 182.0719.

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Typical Procedure for the Synthesis of ortho -Cyano-pyridylboronic Esters 4a-d.
A solution of the 2-cyano-3-pyridylboronic acid (1c, 4.3 mmol, 1 g), pinacol (4.3 mmol, 0.52 g) and MgSO4 (3 g) in toluene (25 mL) was stirred overnight (TLC monitoring). The suspension was filtered and the resulting solution washed with brine (3 × 15 mL). Evaporation of the organic layer gave the pure product 4c as yellow crystals (yield 82%); mp 66 °C. 1H NMR (400 MHz, CDCl3): δ = 1.39 (s, 12 H), 7.48 (dd, ³ J = 4.8 Hz, ³ J = 7.8 Hz, 1 H), 8.18 (dd, ³ J = 7.8 Hz, 4 J = 1.7 Hz, 1 H), 8.75 (dd, ³ J = 4.7 Hz, 4 J = 1.7 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 24.80, 85.33, 117.19, 125.71, 143.41, 152.31. IR (KBr): 3053, 2979, 2238 (CN), 1582, 1557, 1458, 1361, 1145, 1130, 1074, 1041, 962, 837, 778, 662, 561 cm-1. Anal. Calcd for C12H15BN2O2 (%): C, 62.65; H, 6.57; N, 12.18. Found: C, 62.41; H, 6.88; N, 11.74.

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Crystallographic data for the structural analysis have been deposited with the Cambridge Crystallographic Data Centre, publication number: CCDC 288826.