PAPER
Formation of Secondary Amines by Reductive Mono-N-Alkylation of Primary Amines
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Entry 7
Anal. Calcd for C9H12N2O3: C, 55.09; H, 6.16; N, 14.28. Found: C,
54.81; H, 6.43; N, 14.42.
1H NMR: = 1.05–1.25 (2 H, m), 1.30–1.45 (2 H, m), 1.47–1.6 (2
H, m), 1.62–1.78 (2 H, m), 1.9 (1 H, br s), 2.28 (3 H, t, J = 4.6 Hz),
2.32 (3 H, t, J = 6.2 Hz), 2.54 (2 H, t, J = 6.0 Hz), 2.88 (1 H, quint,
J = 6.7 Hz), 3.52 (4 H, t, J = 4.7 Hz).
Entry 3
1H NMR: = 2.30 (3 H, s), 3.75 (2 H, s), 3.90 (2 H, s), 7.06–7.32 (6
H, m), 7.56-7.64 (1 H, m), 8.50 (1 H, d, J = 8 Hz).
Anal. Calcd for C11H22N2O: C, 66.62; H, 11.18; N, 14.13. Found: C,
66.34; H, 11.29; N, 14.65.
Anal. Calcd for C14H16N2: C, 79.21; H, 7.60; N, 13.20. Found: C,
79.05; H, 7.73; N, 13.51.
Entry 8
1H NMR: = 1.15–1.30 (2 H, m), 1.38–1.48 (2 H, m), 1.52–1.70 (3
H, m), 1.70–1.84 (2 H, m), 1.97 (4 H, quintet, J = 4.0 Hz), 2.30 (2
H, t, J = 4.2 Hz), 2.50 (2 H, t, J = 7.0 Hz), 2.95 (1 H, quint, J = 6.9
Hz), 3.28 (4 H, quintet, J = 6.0 Hz).
Entry 4
1H NMR: = 1.75 (2 H, quintet, J = 6.1 Hz), 2.23 (1 H, br s), 2.65
(2 H, t, J = 6.1 Hz), 2.89 (1 H, br s), 3.50 (2 H, s), 3.78 (2 H, t,
J = 6.0 Hz), 7.15–7.25 (4 H, m).
Anal. Calcd for C12H22N2O: C, 68.53; H, 10.54; N, 13.32. Found: C,
68.63; H, 10.85; N, 13.15.
Anal. Calcd for C10H14ClNO: C, 60.15; H, 7.07; N, 7.01. Found: C,
60.35; H, 7.13; N, 7.03.
Entry 9
Entry 5
1H NMR: = 1.12 (3 H, d, J = 3.4 Hz), 1.58–1.65 (2 H, m), 1.88–
1.96 (2 H, m), 2.22 (2 H, t, J = 4.4 Hz), 2.50 (2 H, t, J = 6.9 Hz),
3.16–3.26 (4 H, m), 3.90 (1 H, q, J = 3.4 Hz), 6.00 (1 H, d, J = 3.1
Hz), 6.30 (1 H, d, J = 3.1 Hz), 7.20 (1 H, d, J = 1.8 Hz).
1H NMR: = 2.29 (2 H, s), 2.75 (2 H, t, J = 5.0 Hz), 3.50 (2 H, t,
J = 5.0 Hz), 3.76 (2 H, s), 6.18 (1 H, d, J = 3.2 Hz), 6.23 (1 H, d,
J = 3.2 Hz).
Anal. Calcd for C7H10BrNO2: C, 38.20; H, 4.58; N, 6.36. Found: C,
37.92; H, 4.71; N, 6.36.
Anal. Calcd for C13H20N2O2: C, 66.07; H, 8.53; N, 11.85. Found: C,
66.03; H, 8.85; N, 11.68.
Entry 6
Entry 10
1H NMR: = 0.90 (t, 3 H, J = 7.2 Hz), 1.50 (q, 2 H, J = 7.2 Hz), 2.10
(1 H, br s), 2.30–2.80 (m, 10 H), 3.50–3.80 (m, 4 H).
1H NMR: = 1.41 (3 H, d, J = 4.2 Hz), 1.62–1.73 (2 H, m), 2.70 (2
H, t, J = 6.8 Hz), 2.78 (2 H, br s), 3.70 (1 H, t, J = 4.2 Hz), 3.88 (2
H, q, J = 6.8 Hz), 6.30 (1 H, d, J = 3.1 Hz), 6.40 (1 H, dd, J = 1.8,
3.1 Hz), 7.60 (1 H, d, J = 1.8 Hz).
Anal. Calcd for C9H20N2O: C, 62.75; H, 11.70; N, 16.26. Found: C,
62.39; H, 11.43; N, 16.42.
Anal. Calcd for C9H15NO2: C, 63.88; H, 8.93; N, 8.28. Found: C,
63.73; H, 8.95; N, 8.26.
Entry 7
1H NMR: = 0.72–0.95 (2 H, m), 1.04–1.28 (3 H, m), 1.32–1.48 (1
H, m), 1.54–1.76 (7 H, m), 2.24–2.46 (8 H, m), 2.58 (2 H, t, J = 7.0
Hz), 3.62 (4 H, t, J = 6.0 Hz).
Entry 11
1H NMR: = 1.19 (3 H, d, J = 6.6 Hz), 1.49 (2 H, quintet, J = 6.3
Hz), 2.40–2.60 (2 H, m), 3.10 (2 H, br s), 3.52–3.62 (2 H, m), 3.68
(1 H, q, J = 6.6 Hz), 6.98 (1 H, ddd, J = 8.4, 4.5, 0.9 Hz), 7.08 (1 H,
d, J = 8.0 Hz), 7.47 (1 H, dd, J = 7.9, 1.8 Hz), 8.36 (1 H, d, J = 4.5
Hz).
Anal. Calcd for C14H28N2O: C, 69.95; H, 11.74; N, 11.65. Found: C,
69.61; H, 11.93; N, 11.32.
Acknowledgment
Anal. Calcd for C10H16N2O: C, 66.63; H, 8.95; N, 15.54. Found: C,
66.51; H, 8.99; N, 15.27.
H. J. K. thanks the Department of Chemistry, University of Wis-
consin at Milwaukee for allowing her to use their NMR facility.
Secondary Amines from Aldehydes and Primary Amines; Gen-
eral Procedure
References
A mixture of the aldehyde (5.5 mmol), Ti(i-PrO)4 (3.0 mL, 10
mmol) and the primary amine (5 mmol) in anhyd THF (15 mL) was
allowed to stir for 8 h at r.t. under N2. NaBH4 (0.57 g, 15 mmol) and
absolute EtOH (5 mL) were then added, and the resulting mixture
was stirred for an additional 7 h at r.t. The reaction mixture was
then quenched and worked up as described above for the reductive
amination of ketones. For the reaction involving aminoacetalde-
hyde diethyl acetal (Table 2, entry 1), the work-up and purification
procedures were same as described above in the case of entry 3,
Table 1. The data below correspond to the entries in Table 2.
(1) (a) Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. J.
Comb. Chem. 1999, 1, 55. (b) Henkel, T.; Brunne, R. M.;
Mueller, H.; Reichel, F. Angew. Chem. Int. Ed. 1999, 38,
643.
(2) Insaf, S. S.; Witiak, D. T. Synthesis 1999, 435; and
references therein.
(3) See, for example: (a) Swamura, M.; Ito, Y. Chem. Rev.
1992, 92, 857. (b) Togni, A.; Venanzi, L. M. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 497. (c) Hoog, P. D.; Gamez, P.;
Driessen, W. L.; Reedijk, J. Tetrahedron Lett. 2002, 43,
6783. (d) Joensson, D.; Unden, A. Tetrahedron Lett. 2002,
43, 3125.
(4) See, for example: (a) Jensen, K. J.; Alsina, J.; Songster, M.
F.; Vagner, J.; Albericio, F.; Barany, G. J. Am. Chem. Soc.
1998, 120, 5441. (b) Bhattacharyya, S.; Fan, L.; Vo, L.;
Labadie, J. Comb. Chem. High Throughput Screening 2000,
3, 117. (c) Krueger, E. B.; Hopkins, T. P.; Keaney, M. T.;
Walters, M. A.; Boldi, A. M. J. Comb. Chem. 2002, 4, 229.
(5) For a recent overview on the methods for secondary amine
synthesis, see: Salvatore, R. N.; Yoon, C. H.; Jung, K. W.
Tetrahedron 2001, 57, 7785.
Entry 1
1H NMR: = 0.93 (3 H, t, J = 7.2 Hz), 1.21 (6 H, t, J = 7.0 Hz),
1.42–1.65 (2 H, m), 2.04 (2 H, q, J = 7.3 Hz), 2.57–2.75 (2 H, m),
3.13 (1 H, br s) 3.67 (4 H, q, J = 7.0 Hz), 4.60 (1 H, t, J = 5.6 Hz).
Anal. Calcd for C9H21NO2: C, 61.67; H, 12.08; N, 7.99. Found: C,
61.41; H, 11.95; N, 7.72.
Entry 2
1H NMR: = 2.19 (2 H, br s), 2.80 (2 H, t, J = 5.1 Hz), 3.60 (2 H, t,
J = 5.1 Hz), 3.90 (2 H, s), 7.50 (2 H, d, J = 8 Hz), 8.26 (2 H, d, J = 8
Hz).
Synthesis 2003, No. 14, 2206–2210 © Thieme Stuttgart · New York