Synthesis, Inhaltsverzeichnis Synthesis 2014; 46(11): 1475-1480DOI: 10.1055/s-0033-1340955 paper © Georg Thieme Verlag Stuttgart · New YorkSolvent-Free Synthesis of a Secondary N-Benzhydrylamine as a Chiral Reagent for Asymmetric Deprotonation of Bicyclic N-Benzylamino Ketones Autoren Institutsangaben 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 Artikel empfehlen Abstract Artikel einzeln kaufen(opens in new window) Alle Artikel dieser Rubrik(opens in new window) 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 Key wordsaldol reaction - N-alkylation - asymmetric synthesis - amines - enantioselectivity Volltext Referenzen 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 2a Majewski M, Nowak P. J. Org. Chem. 2000; 65: 5152 2b Inoue M, Lee N, Kasuya S, Sato T, Hirama M, Moriyama M, Fukuyama Y. J. Org. 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Bull. 1983; 31: 2329 18 Selim KB, Matsumoto Y, Yamada K.-I, Tomioka K. Angew. Chem. Int. Ed. 2009; 48: 8733 19 Sciebura J, Gawronski J. Tetrahedron: Asymmetry 2013; 24: 683 20 Majewski M, Wang F. Tetrahedron 2002; 58: 4567 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)}. 22a Brzezinski K, Lazny R, Sienkiewicz M, Wojtulewski S, Dauter Z. Acta Crystallogr., Sect. E 2012; 68: o149 22b Lazny R, Wolosewicz K, Dauter Z, Brzezinski K. Acta Crystallogr., Sect. E 2012; 68: o1367 23a Lazny R, Nodzewska A, Sidorowicz K, Kalicki P. Beilstein J. Org. Chem. 2012; 8: 1877 23b Lazny R, Wolosewicz K. Tetrahedron Lett. 2013; 54: 1103 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 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 28 Nanda KK, Trotter BW. Tetrahedron Lett. 2005; 46: 2025 Zusatzmaterial Zusatzmaterial Supporting Information (PDF) (opens in new window)
