Efficient Entry to Diastereo- and Enantiomerically Pure α-Branched [2.2]Paracyclophanyl-alkylamines

Abstract

The preparation of diastereo- and enantiomerically pure α-branched [2.2]paracyclophanyl-alkylamines is reported. Key step is the nucleophilic 1,2-addition of various alkyllithium reagents to either enantiomer of 4-formyl[2.2]paracyclophane-N,N-dimethyl-hydrazone obtained by resolution (HPLC). The resulting hydrazines were converted to the corresponding amines by reductive N-N bond cleavage. Reaction with CbzCl gave both enantiomers of the N-Cbz-protected diastereo- and enantiomerically pure (de, ee ≥99%) title compounds in good yields, respectively.

cyclophanes - amines - hydrazones - nucleophilic addition - planar chirality

References

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For other hydrazones of 4-formyl[2.2]paracyclophane see:

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8

Conditions for HPLC: Chiralpak AD [(20 µm (250 × 50 mm)] mobile phase: n-hexane-EtOH = 95:5; flow rate: 30 mL/min; t _R = 17.4 min and 21.3 min.

9 For the resolution of rac-4-acetyl[2.2]paracyclophane via the corresponding SAMP-hydrazone, see: Minuti L. Taticchi A. Marrocchi A. Tetrahedron: Asymmetry  2000,  11:  4221 

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General Procedure for the Preparation of the Protected 1-([2.2]Paracyclophan-4-yl)-alkylamines 6. The hydrazone was dissolved in dry THF (10 mL/mmol) and cooled to -100 °C. After 30 min, 3 equiv of the organolithium reagent were added dropwise under argon. The solution was allowed to warm up to r.t. overnight and quenched with sat. NaHCO₃ solution. The aqueous portion was three times extracted with CH₂Cl₂ and the combined organic layers were washed with brine, dried over MgSO₄ and concentrated in vacuo. The crude hydrazine was dissolved in dry THF (10 mL/mmol). After subsequent addition of 10 equiv of BH₃·THF (1.0 M in THF), the reaction mixture was heated under reflux for 4 h. It was cooled to 0 °C and quenched with 1 M aq HCl. After refluxing for 4 min the THF was evaporated under reduced pressure and the aqueous solution was basified with a sat. aq NaHCO₃ solution. The amines were extracted with CH₂Cl₂, the solution was concentrated in vacuo and the residue converted to the corresponding benzylcarbamates. The crude products were dissolved in CH₂Cl₂-H₂O = 2:1 (10 mL/mmol) and treated with K₂CO₃ (2.7 equiv) and CbzCl (2.5 equiv). After 72 h reflux, the aqueous layer was extracted three times with CH₂Cl₂, and the combined organic layers were washed with brine, dried over MgSO₄, and concentrated in vacuo. The benzylcarbamates were obtained as colorless solids after flash column chromatography (SiO₂, n-pentane-Et₂O-CH₂Cl₂ = 10:1:2.2). Apart from the hydrazone resolution, our procedure can be carried out on gram scale.

11 Ethyllithium and n-propyllithium were easily prepared by halogen-metal exchange of the corresponding alkyl iodide with t-BuLi. See: Bailey WF. Punzalan ER. J. Org. Chem.  1990,  55:  5404 

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Representative Spectroscopic Data.
1-([2.2]Paracyclophan-4-yl)-hexylamine (6e): mp 112 °C. ¹H NMR (300 MHz, CDCl₃): δ = 0.85 (t, 3 H, J = 6.8 Hz, CH ₃), 1.22 [m, 9 H, (CH ₂)₅CH₃], 1.51 [m, 1 H, (CH ₂)₅CH₃], 3.02 (m, 7 H, CH ₂CH ₂,CH ₂CHH), 3.38 (m, 1 H, CH₂CHH), 4.96 [m, 2 H, NH, NCH(CH₂)₅CH₃], 5.21 (d, 1 H, J = 12.2 Hz, CHHC₆H₅), 5.32 (d, 1 H, J = 12.2 Hz, CHHC₆H₅), 6.16 (d, 1 H, J = 7.7 Hz, ArH), 6.21 (s, 1 H, ArH), 6.40 (s, 2 H, ArH), 6.50 (s, 2 H, ArH), 6.74 (d, 1 H, J = 7.7 Hz, ArH), 7.40 (m, 5 H, C₆ H ₅) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 14.05, 22.53, 25.98, 28.94, 31.68, 33.29, 34.65, 35.29, 35.32, 39.40, 52.36, 66.85, 127.89, 128.21, 128.61, 131.58, 131.79, 132.52, 132.76, 135.50, 136.24, 136.86, 139.05, 139.44, 140.04, 141.28, 156.01 ppm. IR (KBr): 3885 (s), 3821 (w), 3759 (s), 3726 (m), 3645 (m), 3608 (m), 3535 (m), 3505 (m), 3465 (s), 3430 (s), 3397 (m), 3276 (s), 2955 (s), 2927 (s), 2855 (s), 2370 (m), 2345 (m), 1685 (s), 1546 (s), 1497 (m), 1454 (s), 1425 (s), 1380 (m), 1330 (s), 1252 (s), 1161 (s), 1103 (s), 1055 (m), 1023 (s), 933 (m), 899 (m), 856 (s), 795 (w), 755 (s), 699 (s), 656 (m), 613 (s), 545 (s), 513 (s), 482 (s) cm^-1. MS (EI, 70 eV): m/z (%) = 457 (6) [M⁺ + 2], 456 (34) [M⁺ + 1], 455 (90) [M⁺], 372 (10), 371 (6), 370 (23), 364 (7), 328 (10), 327 (28), 326 (100), 321 (24), 320 (84), 306 (7), 304 (8), 303 (14), 236 (6), 222 (5), 216 (9), 199 (18), 193 (12), 131 (9), 130 (10), 119 (11), 105 (9), 104 (10), 92 (7), 91 (89). Anal. Calcd for C₃₁H₃₇NO₂ (455.63): C, 81.72; H, 8.19; N, 3.07. Found: C, 81.91; H, 8.56; N, 3.02.

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CCDC-281111 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: [phone]; email: [e-mail]].

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Noll, S. planned dissertation, RWTH Aachen, 2006.