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Synlett 2006(9): 1379-1383  
DOI: 10.1055/s-2006-939714
LETTER
© Georg Thieme Verlag Stuttgart · New York

Metallation versus Heteroatom Lithium Complexation: Mono- and ­Dilithiation of Dipyridylpiperazines

Frédéric Louërat, Philippe C. Gros*, Yves Fort*
Synthèse Organique et Réactivité, UMR 7565, Faculté des Sciences, Université Henri Poincaré, Nancy, Boulevard des Aiguillettes, BP 239, 54506 Vandoeuvre-lès-Nancy, France
Fax: +33(3)83684320; e-Mail: Philippe.Gros@sor.uhp-nancy.fr; e-Mail: Yves.Fort@sor.uhp-nancy.fr;
Further Information

Publication History

Received 16 January 2006
Publication Date:
22 May 2006 (online)

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Abstract

BuLi-LiDMAE induced the efficient lithiation of di­pyridylpiperazines despite strong competing lithium coordination by several nitrogen atoms. Symmetrical substrates led to a one-pot dilithiation while dissymmetrical species gave mono- or dilithiation under temperature control.

Key words

aggregation - lithiation - regioselectivity - heterocycles - pyridine

    References and Notes

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11

General Procedure for Bisfunctionalization of 1, 2 and 3.
Under N2, n-BuLi (6.40 mL, 16 mmol) was added dropwise to a solution of 2-(dimethylaminoethanol) (0.80 mL, 8 mmol) in toluene (10 mL) at 0 °C. After 15 min of stirring, 1, 2 or 3 (0.24 g, 1 mmol) was added at 0 °C, the mixture was then allowed to warm to 25 °C for isomer 1 or maintained at 0 °C for isomer 2 and 3 and stirred for 3 h. The suspension was then cooled to -78 °C and was treated with a solution of the appropriate electrophile (10 mmol) in THF (10 mL). The temperature was then maintained at -78 °C for 1 h and allowed to warm to r.t. At 0 °C the suspension was then hydrolyzed with H2O (3 mL). The reaction medium was then evaporated under vacuum and the crude product was purified by chromatography on silica gel (pretreated with Et3N) using EtOAc-hexane mixtures as eluent. Selected Spectroscopic Data. Compound 1a: 1H NMR (CDCl3): δ = 2.49 (s, 6 H), 3.64 (s, 8 H), 6.29 (d, J = 8.3 Hz, 2 H), 6.51 (d, J = 7.6 Hz, 2 H), 7.27 (t, J = 8.3 Hz, 2 H) ppm. 13C NMR (CDCl3): δ = 13.0, 44.4, 101.5, 110.2, 137.3, 157.4, 158.5 ppm. MS (EI): m/z (rel. int.) = 332 (13) [M+], 192 (38), 179 (32), 165 (39), 153 (100), 79 (26). Anal. Calcd for C16H20N4S2: C, 57.80; H, 6.06; N, 16.85. Found: C, 57.61; H, 6.13; N, 17.02.
Compound 1c: 1H NMR (CDCl3): δ = 3.66 (s, 8 H), 6.54 (d, J = 8.3 Hz, 2 H), 6.78 (d, J = 7.1 Hz, 2 H), 7.31 (t, J = 7.6 Hz, 2 H) ppm. 13C NMR (CDCl3): δ = 44.4, 104.9, 116.4, 139.7, 140.3, 159.0 ppm. MS (EI): m/z (rel. int.) = 400 (3), 398 (5) [M+], 396 (3), 197 (77), 185 (62), 163 (89), 80 (100), 58 (62). Anal. Calcd for C14H14Br2N4: C, 42.24; H, 3.54; N, 14.07. Found: C, 42.38; H, 3.22; N, 13.82.
Compound 2a: 1H NMR (CDCl3): δ = 2.53 (s, 6 H), 3.45 (s, 8 H), 6.42 (d, J = 6.3 Hz, 2 H), 6.54 (s, 2 H), 8.15 (d, J = 5.9 Hz, 2 H) ppm. 13C NMR (CDCl3): δ = 12.3, 49.4, 105.1, 117.2, 141.1, 155.1, 158.3 ppm. MS (EI): m/z (rel. int.) = 332 (35) [M+], 193 (30), 179 (93), 165 (45), 153 (100), 79 (73). Anal. Calcd for C16H20N4S2: C, 57.80; H, 6.06; N, 16.85. Found: C, 57.92; H, 5.87; N, 16.72.
Compound 2c: 1H NMR (CDCl3): δ = 3.54 (s, 8 H), 6.61 (d, J = 6.1 Hz, 2 H), 6.86 (s, 2 H), 8.01 (d, J = 6.2 Hz, 2 H) ppm. 13C NMR (CDCl3): δ = 49.5, 106.8, 110.4, 137.7, 140.5, 158.3 ppm. MS (EI): m/z (rel. int.) = 400(7), 398 (12) [M+], 396 (6), 332 (42), 120 (41), 105 (92), 80 (100), 58 (92). Anal. Calcd for C14H14Br2N4: C, 42.24; H, 3.54; N, 14.07. Found: C, 41.98; H, 3.75; N, 14.22.
Compound 6a: 1H NMR (CDCl3): δ = 3.48 (t, J = 4.3 Hz, 4 H), 3.71 (t, J = 4.3 Hz, 4 H), 6.44-6.68 (m, 4 H), 7.42 (t, J = 6.2 Hz, 1 H), 8.02 (d, J = 4.1 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = 44.1, 45.5, 104.4, 107.2, 112.9, 119.6, 127.9, 140.2, 149.7, 152.8, 156.5 ppm. MS (EI): m/z (rel. int.) = 308 (10) [M+], 168 (29), 143 (30), 141 (100), 113 (40). Anal. Calcd for C14H14Cl2N4: C, 54.38; H, 4.56; N, 18.12. Found: C, 54.49; H, 4.71; N, 18.33.
Compound 6b: 1H NMR (CDCl3): δ = 3.47 (t, J = 5.2 Hz, 4 H), 3.71 (t, J = 5.2 Hz, 4 H), 6.53 (d, J = 8.2 Hz, 1 H), 6.62 (dd, J = 5.9, 2.3 Hz, 1 H), 6.65-6.68 (m, 2 H), 7.45 (t, J = 8.0 Hz, 1 H), 8.05 (d, J = 6.1 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = 44.0, 45.4, 104.9, 107.7, 111.1, 138.8, 140.4, 143.6, 148.1, 150.0, 156.1, 158.6 ppm. MS (EI): m/z (rel. int.) = 398 (54) [M+], 185 (100). Anal. Calcd for C14H14Br2N4: C, 42.24; H, 3.54; N, 14.07. Found: C, 42.44; H, 3.36; N, 14.23.
Compound 6c: 1H NMR (CDCl3): δ = 2.51 (s, 3 H), 2.55 (s, 3 H), 3.42 (t, J = 5.1 Hz, 4 H), 3.69 (t, J = 5.2 Hz, 4 H), 6.31 (d, J = 8.2 Hz, 1 H), 6.46 (dd, J = 6.1, 2.3 Hz, 1 H), 6.54-6.57 (m, 2 H), 7.33 (t, J = 7.9 Hz, 1 H), 8.14 (d, J = 5.8 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = 13.3, 13.5, 44.3, 45.7, 101.7, 104.9, 105.6, 110.7, 137.7, 149.6, 154.7, 157.8, 158.4, 160.4 ppm. MS (EI): m/z (rel. int.) = 332 (17) [M+], 180 (35), 153 (100), 79 (17). Anal. Calcd for C16H20N4S2: C, 57.80; H, 6.06; N, 16.85. Found: C, 58.04; H, 6.21; N, 16.62.

12

Monolithiation of 3.
The above procedure was repeated except that BuLi-LiDMAE was reacted for 3 h at -40 °C.
Spectroscopic Data.
Compound 5a: 1H NMR (CDCl3): δ = 3.49 (t, J = 4.3 Hz, 4 H), 3.69 (t, J = 4.3 Hz, 4 H), 6.57-6.68 (m, 4 H), 7.53 (t, J = 6.1 Hz, 1 H), 8.03 (d, J = 4.3 Hz, 1 H), 8.21 (d, J = 6.1 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = 44.4, 45.7, 107.1, 107.3, 113.9, 137.4, 140.0, 148.1, 149.6, 152.8, 156.6, 158.9 ppm. MS (EI): m/z (rel. int.) = 274 (9) [M+], 168 (22), 107 (100), 79 (40), 78 (29). Anal. Calcd for C14H15ClN4: C, 61.20; H, 5.50; N, 20.39. Found: C, 61.34; H, 5.43; N, 20.12.
Compound 5b: 1H NMR (CDCl3): δ = 3.49 (t, J = 4.7 Hz, 4 H), 3.72 (t, J = 5.1 Hz, 4 H), 6.62-6.72 (m, 3 H), 6.83-6.85 (m, 1 H), 7.53 (t, J = 8.4 Hz, 1 H), 8.02 (d, J = 6.2 Hz, 1 H), 8.22 (d, J = 4.4 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = 44.3, 45.5, 107.0, 110.5, 110.8, 116.7, 137.7, 147.9, 148.9, 149.9: 156.1, 153.8 ppm. MS (EI): m/z (rel. int.) = 398 (24) [M+], 320 (32), 318 (35), 107 (100), 79(38), 78 (47). Anal. Calcd for C14H15BrN4: C, 52.68; H, 4.74; N, 17.55. Found: C, 52.51; H, 4.53; N, 17.72.
Compound 5c: 1H NMR (CDCl3): δ = 2.56 (s, 3 H), 3.46 (t, J = 5.2 Hz, 4 H), 3.69 (t, J = 5.3 Hz, 4 H), 6.48 (d, J = 8.3 Hz, 1 H), 6.59 (s, 1 H), 6.64-6.69 (m, 2 H), 7.52 (t, J = 8.0 Hz, 1 H), 8.15 (d, J = 5.8 Hz, 1 H), 8.22 (d, J = 4.3 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = 13.4, 44.5, 45.7, 104.9, 105.6, 107.1, 113.8, 137.7, 148.1, 149.5, 150.4, 145.6, 160.0 ppm. MS (EI): m/z (rel. int.) = 286 (19) [M+], 180 (46), 107 (100), 79 (91), 78 (60). Anal. Calcd for C15H18N4S: C, 62.91; H, 6.33; N, 19.56. Found: C, 62.67; H, 6.58; N, 19.27.