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

doi:10.1055/s-2005-922772

LETTER

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;

Abstract

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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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Referenzen

References and Notes

1a Webb KS. Levy D. Tetrahedron Lett. 1995, 36: 5117

1b Voisin AS. Bouillon A. Lancelot JC. Rault S. Tetrahedron 2005, 61: 1427

1c Brown Ripin DH. Cai W. Brenek SJ. Tetrahedron Lett. 2000, 41: 5817

2 Thiebes C. Prakash GHS. Petasis NA. Olah GA. Synlett 1998, 141

3a Prakash GKS. Panja C. Mathew T. Surampundi V. Petasis NA. Olah GA. Org. Lett. 2004, 6: 2205

3b Salzbrunn S. Simon J. Prakash GKS. Petasis NA. Olah GA. Synlett 2000, 1485

4a Miyaura N. Suzuki A. Chem. Rev. 1995, 95: 2457

4b Tyrrell E. Brookes P. Synthesis 2003, 469

5a Chan DMT. Monaco KL. Wang RP. Winters MP. Tetrahedron Lett. 1998, 39: 2933

5b Lam PYS. Clark CG. Saubern S. Adams J. Chan DMT. Combs A. Tetrahedron Lett. 1998, 39: 2941

5c Lam PYS. Vincent G. Clark CG. Deudon D. Jadhav PK. Tetrahedron Lett. 2001, 42: 3415

5d Herradura PS. Pendola KA. Guy RK. Org. Lett. 2000, 2: 2019

6a Parry PR. Wang C. Batsanov AS. Bryce MR. Tarbit B. J. Org. Chem. 2002, 67: 7541

6b Sutherland S. Gallagher T. J. Org. Chem. 2003, 68: 3352

6c Thompson AE. Hughes G. Batsanev AS. Bryce MR. Parry PR. Tarbit B. J. Org. Chem. 2005, 70: 388

6d Cioffi CL. Spencer WT. Richards JJ. Herr RJ. J. Org. Chem. 2004, 69: 2210

7 Cai D. Larsen RD. Reider PJ. Tetrahedron Lett. 2002, 43: 4285

8a Bouillon A. Lancelot JC. Collot V. Bovy PR. Rault S. Tetrahedron 2002, 58: 2885

8b Bouillon A. Lancelot JC. Collot V. Bovy PR. Rault S. Tetrahedron 2002, 58: 3323

8c Bouillon A. Lancelot JC. Collot V. Bovy PR. Rault S. Tetrahedron 2002, 58: 4369

9 Bouillon A. Voisin AS. Robic A. Lancelot JC. Collot V. Rault S. J. Org. Chem. 2003, 68: 10178

10 Cailly T. Fabis F. Lemaître S. Bouillon A. Rault S. Tetrahedron Lett. 2005, 46: 135

11 Hansen HM. Lysén M. Begtrup M. Kristensen J. Tetrahedron 2005, 61: 9955

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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.

13a Fischer FC. Havinga E. Recl. Trav. Chim. Pays-Bas 1974, 93: 21

13b Fuller AA. Hester HR. Salo EV. Stevens EP. Tetrahedron Lett. 2003, 44: 2935

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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.

15 Watanabe T. Miyaura N. Suzuki A. Synlett 1991, 207

16a Mattesson DS. J. Organomet. Chem. 1999, 581: 51

16b Urawa Y. Naka H. Miyazawa M. Souda S. Ogura K. J. Organomet. Chem. 2002, 653: 269

17a Wong KT. Chien YY. Liao YL. Lin CC. Chou MY. Leung MK. J. Org. Chem. 2002, 67: 1041

17b Chan DMT. Monaco KL. Li R. Bonne D. Clark CG. Lam PYS. Tetrahedron Lett. 2003, 44: 3863

17c Kristensen J. Lysén M. Vedso P. Begtrup M. Org. Lett. 2001, 3: 1435

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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.