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

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.

aggregation - lithiation - regioselectivity - heterocycles - pyridine

References and Notes

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α,α′-Disubstituted pyridines were formed in some cases upon electrophile addition (especially when MeSSMe was used) in the 4-aminopyridine series. See:

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<A NAME="RD01206ST-11">11</A>

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 C₁₄H₁₄Br₂N_4: 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.

<A NAME="RD01206ST-12">12</A>

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.