Synthesis of Enantiopure 1-Benzyl-2,3-disubstituted Piperazines from Enantiopure p-Toluenesulfinimines

Abstract

The treatment of enantiopure N-sulfinyl-N′-benzyldiaminoalcohols with diethyl oxalate and sodium methoxide followed by reduction with BH₃ affords enantiopure 1-benzyl-2,3-disubstituted piperazines. A related sequence produces substituted monoketopiperazines in good yields.

Key words

piperazines - amino alcohols - sulfinimines - chiral auxiliaries - asymmetric synthesis

References

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• 15b

  Synthesis of (+)-(5R,6S)-1-benzyl-5-ethyl-6-hydroxymethylpiperazin-2,3-dione, 2a. From 1a (416 mg, 1.20 mmol) in anhyd CH₂Cl₂ (6 mL/mmol) at r.t., with diethyl oxalate (0.98 mL, 7.20 mmol, 6 equiv) and 0.5 equiv of a solution of NaOMe in MeOH (0.3 M, 2 mL, 0.60 mmol) a crude product was obtained after standard extractive isolation. Purification by washing thoroughly the crude product with 90% Et₂O-hexane and chromatography (5% MeOH-CH₂Cl₂) of the mother liquor afforded 250 mg (0.95 mmol, 79%) of 2a as a white solid. Data of 2a: mp: 90-92 °C. R_f = 0.25 (12:1 CH₂Cl₂-MeOH). [α]²⁰ _D +166.5 (c 1.19, MeOH). ¹H NMR (CD₃OD, 400 MHz): δ = 0.75 (t, 3 H, J = 7.5 H), 1.33 (m, 1 H), 1.55 (m, 1 H), 3.52 (m, 1 H), 3.61 (ddd, 1 H, J = 7.6, 5.0, 1.1 Hz), 3.87 (dd, 1 H, J = 11.2, 7.6 Hz), 3.96 (dd, 1 H, J = 11.2, 5.0 Hz), 4.25 (d, 1 H, J = 14.2 Hz), 5.53 (d, 1 H, J = 14.2 Hz), 7.57 (m, 5 H). ¹³C NMR (DMSO-d₆, 50 MHz): δ = 10.4, 28.2, 49.2, 50.6, 58.0, 61.0, 128.5, 129.3 (2 C), 129.6 (2 C), 137.5, 157.4, 157.8. IR(film): 3413, 2928, 1665, 1454, 1117, 1052, 757, 705 cm^-1. MS (ES): 297 [M + Cl]⁺ (100%). Anal. Calcd for C₁₄H₁₈N₂O₃: C, 64.10; H, 6.92; N, 10.68. Found: C, 63.85; H, 7.04; N, 10.49.

• 16 Initial attempts performed with LiAlH₄ as reducing agent gave the expected piperazines in poor yields, see: Falorni M. Lardicci L. Giacomelli G. Marchetti M. Tetrahedron Lett.  1989,  30:  3551 
• 18 Dinsmore CJ. Bergman JM. Bogusky MJ. Culberson JC. Hamilton KA. Graham SL. Org. Lett.  2001,  3:  865 

14

The preparation of 1a-c and 1f was carried out following the procedures described in ref. [12b] ; details will be published soon in a full account on this chemistry.

17

Synthesis of (-)-(2S,3R)-1-benzyl-3-ethyl-2-hydroxy-methylpiperazine, 4a. From 2a (188 mg, 0.713 mmol) in
anhyd THF (10 mL/mmol) with 9 equiv of BH₃·SMe₂ in THF (2 M, 3.21 mL, 6.417 mmol), after refluxing for 7 h, removal of the solvent and sequential treatment with 4 equiv of a 0.4 M HCl (30 min at 100 °C) and 6 equiv of a 0.4 M solution of NaOH (90 min at 0 ºC) a crude product was obtained after standard extractive isolation. Purification by chromatography (0-20% MeOH-Et₂O) afforded 123 mg (0.525 mmol, 75%) of 4a as a colorless oil. Data of 4a: R_f = 0.10 (40% MeOH-Et₂O). [α]²⁰ _D -14.1 (c 0.91, CHCl₃). ¹H NMR (CDCl₃, 300 MHz): δ = 0.92 (t, 3 H, J = 7.3 Hz), 1.48 (sept, 1 H, J = 7.6 Hz), 1.72 (m, 1 H), 2.19 (m, 1 H), 2.29 (dt, 1 H, J = 9.9, 3.0 Hz), 2.70 (m, 1 H), 2.78-2.96 (m, 3 H), 3.29 (d, 1 H, J = 13.3 Hz), 3.65 (dd, 1 H, J = 11.7, 1.6 Hz), 4.02 (d, 1 H, J = 13.3 Hz), 4.05 (dd, 1 H, J = 11.8, 3.2 Hz), 7.26 (m, 5 H). ¹³C NMR (CDCl₃, 50 MHz): δ = 10.3, 25.1, 43.1, 50.5, 58.3, 59.1, 63.3, 127.0, 128.3 (2 C), 128.7 (2 C), 138.4. IR(film): 3306, 3057, 3021, 2958, 1490, 1452, 1027, 739, 699 cm^-1. MS (ES): 235 [M + 1]⁺ (100%).

19

Synthesis of (+)-(5R,6S,S _S )-1-benzyl-6-[(t-butyldimethyl-silyloxy)methyl]-5-ethyl-4-(p-tolylsulfinyl)piperazin-2-one, 11. From 10 (315 mg, 0.59 mmol) in DMF (6 mL, 10 mL/mmol) at r.t., with 1.8 equiv of Cs₂CO₃ (340 mg, 1.04 mmol) at 65 °C (2 h) a crude product was obtained after standard extractive isolation. Purification by chromatography on silica gel (0-30% Et₂O-CH₂Cl₂) afforded 269 mg (0.54 mmol, 92%) of 11 as a white foam. Data of 11: R_f = 0.27 (10% Et₂O-CH₂Cl₂). [α]²⁰ _D +61.1 (c 1.10, CHCl₃). ¹H NMR (CDCl₃, 500 MHz): δ = 0.07 (s, 3 H), 0.10 (s, 3 H), 0.54 (t, 3 H, J = 7.5 Hz), 0.90 (s, 9 H), 1.33-1.42 (m, 1 H), 1.75-1.83 (m, 1 H), 2.39 (s, 3 H), 3.08 (d, 1 H, J = 17.7 Hz), 3.26 (ddd, 1 H, J = 8.3, 5.3, 1.5 Hz), 3.66 (dd, 1 H, J = 9.8, 8.5 Hz), 3.71 (dd, 1 H, J = 9.7, 5.3 Hz), 3.75 (ddd, 1 H, J = 10.2, 4.7, 1.5 Hz), 3.80 (d, 1 H, J = 17.7 Hz), 3.84 (d, 1 H, J = 14.3 Hz), 5.33 (d, 1 H, J = 14.3 Hz), 7.24-7.33 (m, 7 H), 7.47 (d, 2 H, J = 8.1 Hz). ¹³C NMR (CDCl₃, 50 MHz): δ = -5.3, -5.2, 10.3, 18.1, 21.3, 22.5, 25.8 (3 C), 39.7, 48.6, 57.8, 59.1, 62.4, 125.6 (2 C), 128.0, 128.8 (2 C), 128.9 (2 C), 129.8 (2 C), 136.6, 139.3, 141.8, 165.5. IR(film): 2963, 2855, 1732, 1646, 1435, 1260, 1090, 1018, 799 cm^-1. MS (ES): 501 [M + 1]⁺ (100%), 502 [M + 2]⁺, 503 [M + 3]⁺, 523 [M + Na]⁺.
Synthesis of (+)-(5R,6S)-1-benzyl-6-(t-butyldimethylsilyl-oxymethyl)-5-ethyl-5,6-dihydro-1H-pyrazin-2-one, 12. From a cold (0 °C) suspension of 4 equiv of NaH in anhyd THF (5 mL/mmol of NaH), with a solution of 11 (72 mg, 0.144 mmol) in THF (5 mL/mmol) after stirring at r.t. (1 h) and at reflux (1 h), a crude product was obtained after standard extractive isolation. Purification by chromato-graphy on silica gel (30-80% Et₂O-hexane) afforded 43 mg (0.119 mmol, 83%) of 12 as a colorless oil. Data of 12: R_f = 0.38 (80% Et₂O-hexane). [α]²⁰ _D +188.3 (c 1.23, CHCl₃). ¹H NMR (CDCl₃, 500 MHz): δ = 0.05 (s, 6 H), 0.54 (t, 3 H, J = 7.4 Hz), 0.86 (s, 9 H), 0.86-0.98 (m, 1 H), 1.40-1.49 (m, 1 H), 3.27 (ap t, 1 H, J = 6.5 Hz), 3.55 (dd, 1 H, J = 10.2, 6.9 Hz), 3.63 (dd, 1 H, J = 10.2, 5.8 Hz), 3.78 (dd, 1 H, J = 7.7, 5.5 Hz), 3.92 (d, 1 H, J = 14.3 Hz), 5.34 (d, 1 H, J = 14.3 Hz), 7.26-7.34 (m, 5 H), 7.70 (d, 1 H, J = 1.5 Hz). ¹³C NMR (CDCl₃, 50 MHz): δ = -5.6, -5.5, 10.2, 18.1, 25.8 (4 C), 48.4, 55.2, 59.4, 63.0, 128.1, 128.8 (2 C), 129.1 (2 C), 136.1, 155.1 (2 C). IR(film): 3400, 3030, 2929, 2857, 1674, 1632, 1454, 1361, 1258, 1101, 908, 838, 804, 779, 704 cm^-1. MS (ES): 361 [M + 1]⁺ (100%), 743 [2 M + Na]⁺.