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Synthesis 2014; 46(11): 1475-1480
DOI: 10.1055/s-0033-1340955
paper
© Georg Thieme Verlag Stuttgart · New York

Solvent-Free Synthesis of a Secondary N-Benzhydrylamine as a Chiral Reagent for Asymmetric Deprotonation of Bicyclic N-Benzylamino Ketones

Aneta Nodzewska*
Institute of Chemistry, University of Bialystok, Hurtowa 1, 15-399 Bialystok, Poland   Fax: +48(85)7470113   Email: annodz@uwb.edu.pl
,
Katarzyna Sidorowicz
Institute of Chemistry, University of Bialystok, Hurtowa 1, 15-399 Bialystok, Poland   Fax: +48(85)7470113   Email: annodz@uwb.edu.pl
,
Michal Sienkiewicz
Institute of Chemistry, University of Bialystok, Hurtowa 1, 15-399 Bialystok, Poland   Fax: +48(85)7470113   Email: annodz@uwb.edu.pl
› Author Affiliations
Further Information

Publication History

Received: 20 December 2013

Accepted after revision: 17 February 2014

Publication Date:
24 March 2014 (online)

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Abstract

Several chiral secondary N-benzhydrylamines were synthesized in good yields (68–92%) without racemization by the direct alkylation of amines with benzhydryl chloride under solvent-free conditions. Using the solvent-free conditions (R)-N-benzhydryl-1-phenylethylamine was obtained with the highest yield (92%), purified on ion-exchange resin, and converted to its hydrochloride salt. The resulting chiral amine hydrochloride was transformed into lithium amide/lithium chloride mixture used in asymmetric deprotonations of N-benzyl analogues of tropinone and granatanone followed by aldol reactions giving products in high ­diastereomeric purities (up to 96%) and enantiomeric excesses of 77 to 96%.

Key words

aldol reaction - N-alkylation - asymmetric synthesis - amines - enantioselectivity

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    for this article is available online at http://www.thieme-connect.com/ejournals/toc/synthesis.
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  • References

    • 1a O’Brien P. J. Chem. Soc., Perkin Trans. 1 1998; 1439
    • 1b Simpkins NS, Weller MD. Asymmetric Deprotonations using Chiral Lithium Amide Bases. In Topics in Current Stereochemistry. Vol. 26. Gawley RE. Wiley-VCH; Weinheim: 2010
      Search in Google Scholar
  • 3 Shirai R, Aoki K, Sato D, Kim H.-D, Murakata M, Yasukata T, Koga K. Chem. Pharm. Bull. 1994; 42: 690
    CrossrefSearch in Google Scholar
  • 4 Cain CM, Cousins RP. C, Coumbarides G, Simpkins NS. Tetrahedron 1990; 46: 523
    CrossrefSearch in Google Scholar
    • 5a Pollini GP, Benetti S, De Risi C, Zanirato V. Chem. Rev. 2006; 106: 2434
      CrossrefSearch in Google Scholar
    • 5b Bunn BJ, Simpkins NS, Spavold Z, Crimmin MJ. J. Chem. Soc., Perkin Trans. 1 1993; 3113
    • 5c Majewski M, Lazny R, Nowak P. Tetrahedron Lett. 1995; 36: 5465
      CrossrefSearch in Google Scholar
    • 5d Newcombe NJ, Simpkins NS. J. Chem. Soc., Chem. Commun. 1995; 831
  • 6 Lazny R, Wolosewicz K, Zielinska P, Urbanczyk-Lipkowska Z, Kalicki P. Tetrahedron 2011; 67: 9433
    CrossrefSearch in Google Scholar
  • 8 Lazny R, Nodzewska A, Sienkiewicz M. Lett. Org. Chem. 2010; 7: 21
    CrossrefSearch in Google Scholar
  • 9 Kusano G, Orihara S, Tsukamoto D, Shibano M, Coskun M, Guvenc A, Erdurak CS. Chem. Pharm. Bull. 2002; 50: 185
    CrossrefSearch in Google Scholar
  • 10 Duhamel L, Ravard A, Plaquevent JC, Ple G, Davoust D. Bull. Soc. Chim. Fr. 1990; 787
  • 11 Nowak P. Ph.D. Disssertation . University of Saskatchewan; Canada: 1998. http://library.usask.ca/theses/available/etd-10212004-001009/unrestricted/NQ32795.pdf (30.08.2012)
    Search in Google Scholar
  • 12 Enders D, Rembiak A, Seppelt M. Tetrahedron Lett. 2013; 54: 470
    CrossrefSearch in Google Scholar
  • 13 Juaristi E, Murer P, Seebach D. Synthesis 1993; 1243
    Thieme Connect
  • 14 Lovick HM, An DK, Livinghouse TS. Dalton Trans. 2011; 40: 7697
    CrossrefSearch in Google Scholar
  • 15 Kirincich SJ, Xiang J, Green N, Tam S, Yang HY, Shim J, Shen MW. H, Clark JD, McKew JC. Bioorg. Med. Chem. 2009; 17: 4383
    CrossrefSearch in Google Scholar
  • 16 Page PC. B, Allin SM, Dilly SJ, Buckley BR. Synth. Commun. 2007; 37: 2019
    CrossrefSearch in Google Scholar
  • 17 Miyake A, Itoh K, Tada N, Tanabe M, Hirata M, Oka Y. Chem. Pharm. Bull. 1983; 31: 2329
    CrossrefSearch in Google Scholar
  • 18 Selim KB, Matsumoto Y, Yamada K.-I, Tomioka K. Angew. Chem. Int. Ed. 2009; 48: 8733
    Search in Google Scholar
  • 19 Sciebura J, Gawronski J. Tetrahedron: Asymmetry 2013; 24: 683
    CrossrefSearch in Google Scholar
  • 20 Majewski M, Wang F. Tetrahedron 2002; 58: 4567
    CrossrefSearch in Google Scholar
  • 21 In the reaction of N-benzhydrylamine with n-BuLi, the secondary amine hydrogen is removed, not the benzhydryl proton. Although the pK a of diphenylmethane (PhCH2Ph) is lower than that of the secondary amine, the rate of abstraction of the CH proton by n-BuLi is much slower than the rate of abstraction of proton from the heteroatom, that is, the kinetic acidity, not the thermodynamic acidity determines the deprotonation selectivity. The faster rate of proton abstraction can be observed experimentally. In the presence of deuterated solvent, for example, MeOD, only the NH hydrogen is substituted by deuterium and is invisible in the NMR spectrum in contrast to Ph2CH {1H NMR (400 MHz, MeOD): δ = 7.45–7.08 (m, 15 H, ArH), 4.56 [s, 1 H, CH(Ph)2], 3.64 (q, J = 6.7 Hz, 1 H, CHMe), 1.36 (d, J = 6.7 Hz, 3 H, CH3)}. Signal from Ph2CH is observed in the NMR spectrum of Li-3, obtained in the reaction of amine 3 with n-BuLi in THF-d 8 under typical reaction condition (0 °C, 30 min) in NMR tube {1H NMR (400 MHz, THF-d 8): δ = 7.38–6.92 (m, 15 H, ArH), 4.81 [s, 1 H, CH(Ph)2], 3.74 (q, J = 6.4 Hz, 1 H, CHMe), 0.95 (d, J = 6.6 Hz, 3 H, CH3)}.
  • 24 In many cases, heating during crystallization caused the anti-syn isomerization and the formation of exo,syn-products. The characteristic doublet of the carbinol hydrogen in the exo,syn-isomer was shifted upfield (about 0.1–0.2 ppm) and had a lower coupling constant (up to 2.2 Hz).
  • 25 Brzezinski K, Lazny R, Nodzewska A, Sidorowicz K. Acta Crystallogr., Sect. C 2013; 69: 303
    CrossrefSearch in Google Scholar
  • 26 Momose T, Toshima M, Toyooka N, Hirai Y, Hans Eugster C. J. Chem. Soc., Perkin Trans. 1 1997; 1307
  • 27 Collino F. Boll. Chim. Farm. 1969; 108: 355 ; Chem. Abstr. 1969, 71, 101431
    Search in Google Scholar
  • 28 Nanda KK, Trotter BW. Tetrahedron Lett. 2005; 46: 2025
    CrossrefSearch in Google Scholar