PAPER
A Practical Synthesis of para Di- and Mono-Substituted Benzhydrylamines from Benzhydrol Precursors
671
4,4’-Dichlorobenzhydrylamine (6e)21,43
Rf 0.29 (silica gel, CH2Cl2/EtOAc, 50:50).
tion of racemic 6i with D- or L-tartaric acid were, [a]D -10.9 and
+10.8 in EtOH, respectively.
IR (film): n = 3384, 3029, 2909, 1661, 1488, 1089, 1014 cm-1.
1H NMR: d = 1.80 (br s, 2 H), 5.16 (s, 1 H), 7.28 (s, 8 H).
13C NMR: d = 58.5, 128.2, 128.7, 132.8, 143.6.
4-Methoxybenzhydrylamine (6f)24,44
Rf 0.15 (silica gel, CH2Cl2/EtOAc, 75:25).
References
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889.
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Cossement, E. Synthesis 1995, 766.
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3293.
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J. R. Bioorg. Med. Chem. Lett. 1999, 9, 1329.
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S. Tetrahedron 1989, 45, 5767.
IR (film): n = 3369, 3026, 3834, 1610, 1516, 1454, 1247, 1175,
1032 cm-1.
1H NMR: d = 1.82 (br s, 2 H), 3.77 (s, 3 H), 5.17 (s, 1 H), 6.84 (d, 2
H, J = 8.8 Hz), 7.2-7.40 (m, 7 H).
13C NMR: d = 55.7, 59.6, 114.3, 127.2, 128.4, 128.9, 138.3, 146.3,
159.0.
4-Methylbenzhydrylamine (6g)19,21,45,46
Rf 0.29 (silica gel, CH2Cl2/EtOAc, 75:25).
IR (film): n = 3371, 3024, 3920, 1601, 1512, 1492, 1452 cm-1.
1H NMR: d = 1.84 (br s, 2 H), 2.31 (s, 3 H), 5.17 (s, 1 H), 7.1-7.4
(m, 9 H).
13C NMR: d = 21.6, 60.0, 127.3, 127.4, 129.0, 129.7, 137.0, 143.2,
146.3.
(11) Henneuse, C.; Boxus, T.; Tesolin, L.; Pantano, G.; Marchand-
Brynaert, J. Synthesis 1996, 495.
4-Fluorobenzhydrylamine (6h)21,42
Rf = 0.24 (silica gel, CH2Cl2/EtOAc, 75:25).
(12) Petasis, N.A.; Goodman, A.; Zavialov, I.A. Tetrahedron
1997, 53, 16463.
(13) Sawada, S.; Yasui, K.; Takahashi, S. Biosci. Biotech.
Biochem. 1992, 56, 1506.
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(15) Wakamiya, T.; Kamata, M.; Kusumoto, S.; Kobayashi, H.;
Sai, Y.; Tamai, I.; Tsuji, A. Bull. Chem. Soc. Jpn. 1998, 71,
699.
(16) Feuer, H.; Braunstein, D. M. J. Org. Chem. 1969, 34, 1817.
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16B, 432.
IR (film): n = 3375, 3028, 2852, 1891, 1602, 1508, 1222, 1156, 910,
841, 699 cm-1.
1H NMR: d = 1.78 (br s, 2 H), 5.20 (s, 1 H), 6.99 (dd, 2 H, JHH = 8.7,
JHF = 8.7 Hz), 7.2-7.4 (m, 7 H).
13C NMR: d = 59.0, 115.0 (d, JC-F = 21.3 Hz), 126.6, 126.9, 128.2,
128.4, 141.3 (d, JC-F = 2.9 Hz), 145.4, 161.7 (d, JC-F = 243.6 Hz).
4-Chlorobenzhydrylamine (6i)25,47,48
Rf 0.32 (silica gel, CH2Cl2/EtOAc, 75:25).
IR (film): n = 3376, 3025, 2851, 1655, 1488, 1089, 1014, 754 cm-1.
1H NMR: d = 1.76 (br s, 2 H), 5.16 (s, 1 H), 7.2-7.4 (m, 9 H).
13C NMR: d = 59.0, 126.6, 127.0, 128.1, 128.3, 132.4, 144.0, 145.1.
(19) Hoffman, R. V.; Poelker, D. J. J. Org. Chem. 1979, 44, 2364.
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Essenburg, A. D.; Stanfield, R. L.; Bousley, R. F.; Krause, B.
R.; Roth, B. D. Bioorg. Med. Chem. 1995, 3, 29.
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38, 7011.
A part of the racemic mixture (0.2 g) was derivatized with trifluoro-
acetic anhydride (0.25 mL) in CH2Cl2 (20 mL) at 0°C, for 3 h, under
argon. After purification by flash column chromatography (silica
gel, CH2Cl2/hexane, 50:50), the resulting N-(trifluoroacetyl)-4-
chlorobenzhydrylamine was analyzed by gas chromatography on a
capillary CP-chirasil-Dex CB column. The retention times (R ) of
t
(26) Marchand-Brynaert, J. Recent Res. Develop. in Polymer Sci.
1998, 2, 335.
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38, 1387.
the enantiomers were 57.70 min and 58.18 min at 90 kPa and
155°C; 74.40 min and 75.02 min at 70 kPa and 155°C; 44.60 min
and 44.91 min at 90 kPa and 160°C, respectively.
(28) Henneuse, C.; Goret, B.; Marchand-Brynaert, J. Polymer
1998, 39, 835.
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Tesolin, L.; Adriaensen, Y.; Marchand-Brynaert, J. Polymer
1998, 39, 5359.
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Lett. 1993, 3, 681.
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Tetrahedron :Asymmetry 1995, 6, 183.
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Tetrahedron :Asymmetry 1998, 9, 3963.
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Ed. Engl. 1995, 34, 490.
Preparative Chromatographic Resolution of 3i
Home-made MPLC equipment (medium pressure liquid chroma-
tography, similar to the Prochrom system) equipped with an auto-
matic injection system, and a AD4 (20 µm) column of 25 cm length
and 50 mm of internal diameter was used. The elution was done
with hexane/i-PrOH (92: 8) at 100 mL/min, and the UV detector
was set at 231 nm. Portions of 20 mg of racemic 3i could be injected
every 17 min : (+)-(S)-3i: R = 14.9 min; [a]D +19.0 (±0.5) (CH2Cl2,
t
c = 0.476%); (-)-(R)-3i: R = 17.9 min; [a]D -19.0 (±0.5) (CH2Cl2,
t
c = 0.418%); % ee from analytical HPLC >99%.
After basic hydrolysis as described above, and purification by flash
column chromatography (silica gel, CH2Cl2/EtOAc, 75:25), (-)-3i
gave (+)-6i: [a]D +15.6 (±0.5) (EtOH, c = 1.1%), and (+)-3i gave
(-)-6i: [a]D -15.6 (±0.5) (EtOH, c = 0.56%); [a]D -25.7 (±0.5)
(CH2Cl2, c = 0.51%). The literature values31 mentioned after resolu-
Synthesis 2000, No. 5, 667–672 ISSN 0039-7881 © Thieme Stuttgart · New York