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Synlett 2005(17): 2679-2681  
DOI: 10.1055/s-2005-917095
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Dieter Enders*a, Stephan Nolla, Jan W. Batsb
a Institut für Organische Chemie, RWTH Aachen, Landoltweg 1, 52074 Aachen, Germany
Fax: +49(241)8092127; e-Mail: enders@rwth-aachen.de;
b Institut für Organische Chemie, Universität Frankfurt, Marie-Curie-Strasse 11, 60439 Frankfurt am Main, Germany
Further Information

Publication History

Received 15 August 2005
Publication Date:
05 October 2005 (online)

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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.

Key words

cyclophanes - amines - hydrazones - nucleophilic addition - planar chirality

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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.

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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.

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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: +44(1223)336033; email: deposit@ccdc.cam.ac.uk].

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