Concentration-Dependent Chemo- and Regioselective Metalation of 6,6′-Dibromo-2,2′-bipyridine

Abstract

A reliable and synthetically useful strategy for the selective single or double metalation of 6,6′-dibromo-2,2′-bipyridine via lithium-halogen exchange is discussed. Experimental conditions for the optimal formylation of the singly and doubly lithiated intermediates are outlined as well as unequivocal X-ray crystallographic evidence for the regiochemistry of a competing deprotonation pathway.

Key words

bipyridine ligands - lithium-halogen exchange - metalation - regiocontrol

References and Notes

• 1 Newkome GR. Patri AK. Holder E. Schuber US. Eur. J. Org. Chem.  2004,  235 
• 2 For example: Welter S. Brunner K. Hofstraat JW. De Cola L. Nature (London)  2003,  421:  54 
• 3 Chelucci G. Thummel RP. Chem. Rev.  2002,  102:  3129 
• 4 Murphy A. Pace A. Stack TDP. Org. Lett.  2004,  6:  3119 
• 5 Preparation of 6,6′-Diformyl-2,2′-bipyridyl ( 3). A warm solution (ca. 50 °C) of 6,6′-dibromo-2,2′-bipyridyl (1.0 g, 3.18 mmol) in THF (50 mL) was slowly added to a solution of 2.5 M n-BuLi (3.84 mL, 9.6 mmol, 3.0 equiv) in THF (60 mL) at -78 °C at such a rate that precipitation was avoided and the temperature did not increase above -70 °C. The resultant dark red solution was stirred below -75 °C for 45 min before quenching with DMF (0.74 mL, 9.6 mmol, 3.0 equiv). The solution was allowed to warm to -30 °C where upon aq HCl (4 M, 20 mL) was added. The reaction mixture was then allowed to reach r.t. and the aqueous layer was separated from the organic phase. The aqueous layer was basified to pH 14 with sat. KOH solution and washed with warm (ca. 40 °C) CHCl₃ (2 × 30 mL). The combined organic extracts were washed with brine (2 × 100 mL), dried over MgSO₄ and concentrated in vacuo. The resultant solid was triturated with MeOH (20 mL), the solid collected by filtration and recrystallised from toluene to give 3 (0.41 g, 70%). All analytical and spectroscopic data were consistent with those reported. See: Parks JE. Wagner BE. Holm RH. J. Organomet. Chem.  1973,  56:  53 
• 6 Tsuji J. In Palladium Reagents and Catalysts   Wiley; Chichester: 2004. 
• 7 Charbonnière LJ. Ziessel Z. Tetrahedron Lett.  2003,  44:  6305 
• 8 Cai D. Hughes DL. Verhoeven TR. Tetrahedron Lett.  1996,  37:  2537 
• 9 Mase T. Houpis IN. Akao A. Dorziotis I. Emerson K. Hoamg T. Iida T. Itoh T. Kamei K. Kato S. Kato Y. Kawasaki M. Lang F. Lee J. Lynch J. Maligres P. Molina A. Nemoto T. Okada S. Reamer R. Song JZ. Tschaen D. Wada T. Zewge D. Volante RP. Reider PJ. Tomimoto K. J. Org. Chem.  2001,  66:  6775 
• 10 Horiuchi Y. Taniguchi T. Oshima K. Utimoto K. Tetrahedron Lett.  1994,  35:  7977 
• 11 Preparation of 6-Bromo-6′-formyl-2,2′-bipyridyl ( 5). Although the stoichiometric ratio for optimal yield of the aldehyde as judged by ¹H NMR is as given in Table 1, it was found that the following procedure gave the highest isolated yield: n-BuLi (2.5 M, 0.14 mL, 0.35 mmol, 1.1 equiv) was added dropwise to a solution of 6,6′-dibromo-2,2′-bipyridyl (0.10 g, 0.32 mmol, 1.0 equiv) in dry THF (40 mL) at -90 °C. After the addition was complete the reaction was allowed to warm to -80 °C and was kept at this temperature for a further 15 min. During the addition the reaction became a clear red colour. Note: If precipitation occurs during this addition the yield is dramatically decreased. Dry DMF (0.030 mL, 0.38 mmol, 1.2 equiv) in Et₂O (10 mL) was then slowly added to the reaction mixture. After the addition was complete, the mixture was stirred until its temperature was -30 °C, at which point aq HCl (5%, 2.0 mL) was added and the mixture was allowed to reach r.t. THF was removed and the aqueous layer basified with KOH (pH ca. 14). The product was then extracted with EtOAc (3 × 30 mL). The organic extracts were combined, washed with brine (3 × 50 mL) and dried over MgSO₄. The solvent was removed in vacuo. This solid was purified by flash chromatography on silica gel eluting with light PE-EtOAc (99:1) to give 5 (0.030 g, 37%) as a white solid R _f = 0.16 (light PE-EtOAc, 99:1). All analytical and spectroscopic data were consistent with those previously reported by: El-ghayoury A. Ziessel R. J. Org. Chem.  2000,  65:  7757 

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Preparation of 6,6′-Dibromo-[2,2′]bipyridinyl-5-carbaldehyde ( 6).
Although the stoichiometric ratio for optimal yield of the aldehyde as judged by ¹H NMR is as given in Table 1, it was found that the following procedure gave the highest isolated yield: n-BuLi (2.5 M, 0.14 mL, 0.35 mmol, 1.1 equiv) was added dropwise to a solution of 6,6′-dibromo-2,2′-bipyridyl (0.10 g, 0.32 mmol, 1.0 equiv) in dry THF (40 mL) at
-90 °C. After the addition was complete the reaction was allowed to warm to -80 °C and the temperature was maintained for a further 15 min. Dry DMF (0.028 mL, 0.38 mmol, 1.2 equiv) in Et₂O (10 mL) was then slowly added to the reaction. After the addition was complete, the mixture was stirred until its temperature was -30 °C, at which point aq HCl (5%, 2.0 mL) was added to it and the reaction was allowed to warm to r.t. Then, THF was removed in vacuo and the resultant white solid was collected by filtration and dried in vacuo. This solid was purified by flash chromatography on silica gel eluting with light PE-EtOAc (99:1) to give the aldehyde 6 (14 mg, 26%) as a white solid; R _f = 0.24 (light PE-EtOAc 99:1); mp 188-189 °C. IR: 1682 (s, C=O), 1574 (m, arom. C=N), 1531 (m, arom. C=C). ¹H NMR (400 MHz): δ = 7.52 [dd, 1 H, J = 7.88, 0.77 Hz, N=C(Br)CH], 7.66 [t, 1 H, J = 7.80 Hz, N=C(Br)CHCH], 8.21 [d, 1 H, J = 8.01 Hz, C(CHO)CHCH], 8.40 (dd, 1 H, J = 7.70, 0.77 Hz, N=C(Br)CHCHCH], 8.46 [dd, 1 H, J = 7.95 0.60 Hz, C(CHO)CHCH], 10.31 (d, 1 H, J = 0.68 Hz). ¹³C NMR: δ = 120.7 (CH), 121.3 (CH), 129.7 (CH), 130.4 (i-C), 139.0 (CH), 139.4 (CH), 142.0 (i-C), 144.7 (i-C), 154.3 (i-C), 159.2, 190.8 (CHO). MS (EI): m/z (%) = 298 (5) [M - CHO]⁺, 262 (10) [M - Br]⁺, 234 (10) [M - CHO - Br]⁺, 181 (12) [M - 2Br]⁺, 105 (35), [C₅H₃NCHO]⁺, 76 (100) [C₅H₃N]⁺. HRMS (EI): m/z calcd for C₁₁H₆Br₂N₂O (⁷⁹Br): 339.8841; found: 339.8839.

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The X-ray data have been deposited at the Cambridge Crystallographic Database: CCDC 299072.