First Example of s-BuLi/(-)-Sparteine-Mediated Chiral Deprotonation of a Piperazine and Proof of the Sense of Induction

Abstract

This paper describes the first known example of a (-)-sparteine-mediated asymmetric deprotonation of a piperazine. Reaction of tert-butyl 4-tert-butylpiperazine-1-carboxylate with s-BuLi in the presence of (-)-sparteine at -78 °C and quenching with carbon dioxide proceeded in good yield and with a high degree of selectivity (er = 89:11). X-ray crystal structure analysis on a chiral derivative confirmed the R-enantiomer was the major product. This methodology was employed as a route to an advanced chiral intermediate that was used in parallel synthesis of a range of molecules of medicinal interest. Optimisation of the chemistry used to introduce a tert-butyl group onto a piperazine nitrogen is also described.

Key words

asymmetric deprotonation - piperazines - lithiation - (-)-sparteine - N-tert-butylpiperazine synthesis

References and Notes

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N-(tert-Butyl)piperazine is advertised as a commercially available compound. A sample ordered and received by us was, in fact, identified as N-(n-butyl)piperazine. Another company advertising the compound has now discontinued this product.

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( R )- tert -Butyl 2-(4-Benzylpiperazine-1-carbonyl)-4- tert -butylpiperazine-1-carboxylate (11)
To a solution of tert-butyl 4-tert-butylpiperazine-1-carb-
oxylate (500 mg, 2.1 mmol) and (-)-sparteine (0.62 mL, 2.7 mmol) in Et₂O (20 mL) at -78 °C under argon was added s-BuLi (1.92 mL, 2.7 mmol) dropwise. The resulting suspension was stirred at -78 °C for 5 h and then CO₂ was bubbled through the mixture via syringe for 30 min. After the addition of one pellet of CO₂ the reaction was allowed to warm to 0 °C and then quenched with H₂O (0.5 mL). The mixture was diluted with CH₂Cl₂ and Na₂SO₄ was added. The mixture was stirred for 5 min then filtered and concentrated at reduced pressure to give a light yellow oil. To a solution of this material in DMF (15 mL) at r.t. was added benzylpiperazine (0.30 mL, 1.7 mmol), DIPEA (0.58 mL, 3.3 mmol), and finally HATU [O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 627 mg, 1.7 mmol]. After 2 h H₂O (50 mL) was added and the mixture was stirred for 2 h. The mixture was then extracted with EtOAc (150 mL) and the organic layer washed with brine (3 × 50 mL), dried (Na₂SO₄), and concentrated at reduced pressure. The residue was purified via silica column chromatography (40 g silica) eluting with 0-10% MeOH in CH₂Cl₂ to give (R)-tert-butyl 2-(4-benzylpiperazine-1-carbonyl)-4-tert-butylpiperazine-1-carboxylate as a white solid (442 mg, 48% over two steps); mp 105 °C; [α]_D ²⁰ +12.8 (c 1.00, EtOH). ¹H NMR (500 MHz, DMSO, 373 K): δ = 0.98 (s, 9 H), 1.37 (s, 9 H), 2.09 (td, J = 11.6, 3.7 Hz, 1 H), 2.34-2.44 (m, 5 H), 2.84-2.92 (m, 1 H), 3.05-3.10 (m, 1 H), 3.39-3.53 (m, 5 H), 3.52 (s, 2 H), 3.60 (dt, J = 12.2, 3.1 Hz, 1 H), 4.68-4.71 (m, 1 H), 7.22-7.27 (m, 1 H), 7.29-7.33 (m, 4 H). ¹³C NMR (126 MHz, DMSO, 373 K): δ = 25.09, 27.55, 42.08, 42.91, 44.52, 46.70, 51.99, 52.37, 52.60, 61.31, 78.21, 126.22, 127.41, 128.16, 137.22, 154.41, 168.54. ESI-HRMS: m/z calcd for C₂₅H₄₁N₄O₃: 445.31732; found: 445.31726 [M + H]⁺. Chiral HPLC conditions: er = 89:11; Instrument: HP1100 System 2; column: 5 µm Chiralpak AD-H (250 mm × 4.6 mm) No. FE168; eluent: i-hexane-EtOH (50:50); ambient temperature; flow 1 mL/min; wavelength 210 nm; t _R (R) = 3.25 min; t _R (S) = 6.52 min.

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Selected Analytical Data
Compound 1: white solid; mp 89 °C; [α]_D ²⁰ +9.5 (c 1.00, EtOH). ¹H NMR (500 MHz, DMSO, 373 K): δ = 1.00 (s, 9 H), 1.38 (s, 9 H), 2.11 (td, J = 11.4, 4.2 Hz, 1 H), 2.38 (dd, J = 12.0, 4.8 Hz, 1 H), 2.68-2.76 (m, 4 H), 3.08 (dt, J = 12.2, 2.5 Hz, 1 H), 3.33-3.51 (m, 6 H), 3.61 (dt, J = 12.3, 3.1 Hz, 1 H), 4.67-4.70 (m, 1 H). ¹³C NMR (126 MHz, DMSO): δ = 18.49, 25.58, 27.98, 42.34, 45.01, 45.64, 47.05, 53.00, 55.98, 78.58, 155.11, 169.06. ESI-HRMS: m/z calcd for C₂₅H₄₁N₄O₃: 355.27037; found: 355.27036 [M + H]⁺.
Compound 12: white solid; mp 165 °C; [α]_D ²⁰ +11.0 (c 1.00, EtOH). ¹H NMR (400 MHz, CDCl₃): δ = 1.07 (s, 9 H), 2.01-2.18 (m, 2 H), 2.22 (s, 3 H), 2.83-3.13 (m, 4 H), 3.35-3.89 (m, 10 H). ¹³C NMR (101 MHz, CDCl₃): δ = 13.90, 25.44, 41.53, 43.62, 44.00, 44.67, 45.08, 46.78, 49.32, 113.18, 140.17, 154.54, 158.18, 170.07. ESI-HRMS: m/z calcd for C₂₅H₄₁N₄O₃: 429.18340; found: 429.18344 [M + H]⁺.
Compound 13: white solid; mp 208 °C; [α]_D ²⁰ +31.0 (c = 1.00, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 0.79-0.90 (m, 1 H), 1.04 (s, 9 H), 1.21-1.32 (m, 1 H), 1.45 (s, 9 H), 1.72-1.82 (m, 1 H), 1.88-2.28 (m, 4 H), 2.41-2.54 (m, 1 H), 2.43 (s, 3 H), 2.85-3.19 (m, 2 H), 3.35-3.87 (m, 10 H), 4.63-4.91 (m, 2 H), 7.31 (d, J = 8.2 Hz, 2 H), 7.75 (d, J = 8.2 Hz, 2 H). ¹³C NMR (176 MHz, CDCl₃): δ = 21.48, 24.81, 25.76, 28.34, 30.63, 38.55, 42.23, 43.16, 45.38, 45.72, 47.53, 48.31, 53.67, 57.88, 80.19, 127.47, 129.59, 135.67, 143.57, 155.57, 169.94, 170.13. ESI-HRMS: m/z calcd for C₂₅H₄₁N₄O₃: 606.33198; found: 606.33167 [M + H]⁺.

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C₃₀H₄₇N₅O₆S.C₂H₄Cl₂, M _r = 704.75, colourless block. Crystal dimensions: 0.20 × 0.15 × 0.03 mm, monoclinic, space group P2₁, a = 6.0241(3) Å, b = 19.1591(7) Å, c = 15.9244(8) Å, β = 99.631(2)°, V = 1812.03(14) ų, Z = 2, D _x = 1.292 Mg m^-3. Reflections collected: 25197; independent reflections: 8012 (R _int = 0.042), final R[F ² > 2σ (F ²)] = 0.052, R (all data) = 0.1249, wR(F ²) = 0.137. Flack parameter: -0.01 (7). Crystallographic data for this structure has been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 668196. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road Cambridge, CB2 1EZ, UK [fax: [phone]; e-mail: [e-mail]].