FEATURE ARTICLE
Chiral Primary Amines
165
and the use of THF as a replacement solvent for Et2O are avail-
able.21
13C NMR (100 MHz, CDCl3): δ = 146.6, 128.2, 126.7, 126.6, 55.1,
52.4, 44.4, 34.8, 27.7, 24.9, 24.6, 23.5, 22.8, 22.6, 14.0.
MS (EI): m/z (%) = 247 (2) [M+], 232 (4), 190 (100), 106 (10), 105
(82), 86 (48).
HRMS (70 eV): m/z [M+] calcd for C17H29N: 247.2300; found:
247.2295.
(3S)-N-[(S)-1-Phenylethyl]nonan-3-amine (3t)
Following general procedure E using heptanal (0.67 mL, 5.0 mmol,
1.0 equiv), CuBr (2.15 g, 15.0 mmol, 3.0 equiv), 2.0 M EtMgCl in
THF (15.0 mL, 30.0 mmol, 6.0 equiv), BF3·OEt2 (1.91 mL, 15.0
mmol, 3.0 equiv), Et2O (44.0 mL, 0.08 M). Crude product: 81% de.
Purification by flash chromatography (silica gel, hexanes–EtOAc–
NH4OH, 92:6:2) gave the mixture of diastereomers as a colorless
viscous liquid, which was then treated with ethereal HCl to obtain
the hydrochloride salt; yield: 1.14 g (81%).
Acknowledgment
We are grateful for financial support from Jacobs University
Bremen. This work has been performed within the graduate pro-
gram of Nanomolecular Science.
(S,S)-3t
Free base; Rf = 0.48 (hexanes–EtOAc–NH4OH, 84:14:2).
IR (KBr): 3425, 3025, 2959, 2856, 1453, 1368, 1210, 1119, 1028,
700, 553 cm–1.
References
1H NMR (400 MHz, CDCl3): δ = 7.31–7.19 (m, 5 H), 3.86 (q, J =
6.8 Hz, 1 H), 2.29–2.23 (m, 1 H), 1.43–1.17 (m, 16 H), 0.88 (t, J =
6.8 Hz, 3 H), 0.80 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 146.5, 128.2, 126.6, 55.5, 55.0,
33.1, 31.8, 29.6, 27.1, 25.1, 24.8, 22.6, 14.1, 10.1.
MS (EI): m/z (%) = 247 (2) [M+], 232 (7), 218 (45), 162 (58), 114
(30), 105 (100), 58 (28).
HRMS (70 eV): m/z [M]+ calcd for C17H29N; 247.2300; found:
247.2293.
(1) For very recent reviews, see: (a) Xie, J.-H.; Zhu, S.-F.; Zhou,
Q.-L. Chem. Soc. Rev. 2012, 41, 4126. (b) Jones, S.; Warner,
C. J. A. Org. Biomol. Chem. 2012, 10, 2189. (c) Mathew, S.;
Yun, H. ACS Catalysis 2012, 2, 993. (d) Xie, J.-H.; Zhu, S.-
F.; Zhou, Q.-L. Chem. Rev. 2011, 111, 1713. (e) Tufvesson,
P.; Lima-Ramos, J.; Jensen, J. S.; Al-Haque, N.; Neto, W.;
Woodley, J. M. Biotechnol. Bioeng. 2011, 108, 1479.
(f) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev.
2010, 110, 3600. (g) Fleury-Brégeot, N.; de La Fuente, V.;
Castillón, S.; Claver, C. ChemCatChem 2010, 2, 1346.
(h) Hesp, K. D.; Stradiotto, M. ChemCatChem 2010, 2,
1192. (i) Nugent, T. C.; El-Shazly, M. Adv. Synth. Catal.
2010, 352, 753. (j) Koszelewski, D.; Tauber, K.; Faber, K.;
Kroutil, W. Trends Biotechnol. 2010, 28, 324.
(2) We have demonstrated this for primary amines 4p and 4q,
i.e., Pd/C (6.0 mol%), AcOH, low hydrogen pressures (4
bar), r.t., allowed hydrogenolysis; see the procedure for 4p
(experimental section) for an example. Note that the
racemization of chiral amines is possible in the presence of
Pd, see ref. 3.
(5S)-N-[(S)-1-Phenylethyl]undecan-5-amine (3u)
Following general procedure E using heptanal (0.67 mL, 5.0 mmol,
1.00 equiv), CuBr (2.15 g, 15.0 mmol, 3.0 equiv), 2.0 M BuMgCl
in THF (15.0 mL, 30.0 mmol, 6.0 equiv), BF3·OEt2 (1.27 mL, 10.0
mmol, 2.0 equiv), Et2O (44.0 mL, 0.08 M). Crude product: 86% de.
Purification by flash chromatography (silica gel, hexanes–EtOAc–
NH4OH, 92:6:2) gave the mixture of diastereomers as a colorless
viscous liquid, which was then treated with ethereal HCl to obtain
the hydrochloride salt; yield: 1.32 g (85%).
(3) Parvulescu, A. N.; Jacobs, P. A.; De Vos, D. E. Chem.–Eur.
J. 2007, 13, 2034.
(S,S)-3u
Major product, the diastereomers were not separable via chroma-
tography (silica gel); the mixture was characterized as the free base;
Rf = 0.55 (hexanes–EtOAc–NH4OH, 84:14:2).
(4) For supportive examples, see: (a) Nugent, T. C.; Seemayer,
R. Org. Process Res. Dev. 2006, 10, 142. (b) Neidigh, K. A.;
Avery, M. A.; Williamson, J. S.; Bhattacharyya, S. J. Chem.
Soc., Perkin Trans. 1 1998, 2527. (c) Bhattacharyya, S.;
Chatterjee, A.; Williamson, J. S. Synlett 1995, 1079.
(d) Seebach, D.; Hungerbuehler, E.; Naef, R.;
IR (KBr): 3444, 3025, 2957, 2856, 1603, 1466, 1368, 1118, 909,
700, 556 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.33–7.20 (m, 5 H), 3.86 (q, J =
6.4 Hz, 1 H), 2.32–2.27 (m, 1 H), 1.34–1.12 (m, 20 H), 0.90–0.82
(m, 6 H).
Schnurrenberger, P.; Weidmann, B.; Zueger, M. Synthesis
1982, 138.
(5) For the reductive amination of keto esters, see: Nugent, T.
C.; Ghosh, A. Eur. J. Org. Chem. 2007, 3863.
13C NMR (100 MHz, CDCl3): δ = 146.4, 128.2, 126.6, 54.9, 53.9,
34.4, 33.6, 31.8, 29.6, 27.9, 25.1, 24.8, 22.8, 22.6, 14.1, 14.0.
(6) See the following reference which strongly implies that
chloro-, bromo-, and presumably iodoaromatic moieties
would be hydrogenolyzed when using our methods:
Bringmann, G.; Geisler, J.-P.; Geuder, T.; Künkel, G.;
Kinzinger, L. Liebigs Ann. Chem. 1990, 795.
(7) Nugent, T. C.; Negru, D. E.; El-Shazly, M.; Hu, D.; Sadiq,
A.; Bibi, A.; Umar, M. N. Adv. Synth. Catal. 2011, 353,
2085; and supporting information therein.
(8) See ref. 7, p 2087 for the text discussion of compound 2a.
(9) See ref. 7, compounds 2d and 3d (Tables 1 and 2).
(10) See ref. 6, p 797, in reference to aromatic halide removal:
‘This well-known hydro-dehalogenation can be prevented
only by application of a special catalyst mixture Rh2O3/PtO2
(3:2), which thus allows the preparation of the corresponding
secondary amine 9m with a still significant stereoselectivity
(see Table 1).’
(S)-2-Methyl-N-[(S)-1-phenylethyl]octan-4-amine (3v)
Following general procedure E using 3-methylbutanal (0.54 mL,
5.0 mmol, 1.0 equiv), CuBr (2.15 g, 15.0 mmol, 3.0 equiv), 2.0 M
BuMgCl in THF (15.0 mL, 30.0 mmol, 6.0 equiv), BF3·OEt2 (1.27
mL, 10.0 mmol, 2.0 equiv), Et2O (44.0 mL, 0.08 M). Crude product:
90% de. Purification by flash chromatography (silica gel, hexanes–
EtOAc–NH4OH, 93.5:3.5:3) gave the mixture of diastereomers as a
colorless viscous liquid, which was then treated with ethereal HCl
to obtain the hydrochloride salt; yield: 1.21 g (85%).
(S,S)-3v
Free base; Rf = 0.48 (hexanes–EtOAc–NH4OH, 83:15:2).
IR (KBr): 3441, 3026, 2956, 2930, 2628, 1467, 1367, 1154, 1118,
700, 558 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.33–7.19 (m, 5 H), 3.86 (q, J =
6.4 Hz, 1 H), 2.38–2.32 (m, 1 H), 1.63–1.55 (m, 1 H), 1.33–1.12 (m,
12 H), 0.89 (d, J = 6.8 Hz, 3 H), 0.84 (t, J = 6.8 Hz, 3 H), 0.77 (d,
J = 6.8 Hz, 3 H).
(11) Process for the preparation of (S,S)-cis-2-benzhydryl-3-
benzylaminoquinuclidine: Nugent, T. C.; Seemayer, R. WO
2004035575, 2004.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 153–166