The Journal of Organic Chemistry
ARTICLE
The reaction was initiated with 220 μL of a stock solution
containing 3-phenylpropionaldehyde (0.11 mmol, 220 μL, 0.05
M, 1 equiv) and mesitylene as an internal standard (0.011 mmol,
220 μL, 0.05 M, 0.10 equiv). The reactions were stirred at room
temperature and directly sampled by GC for reaction progress.
Products and starting materials are referenced to mesitylene.
Large-Scale Aldol Reaction. Proline derivative 2a (35 mg,
0.094 mmol, 0.10 equiv) and urea 1a (81 mg, 0.235 mmol, 0.25
equiv) were placed into a flask. Acetonitrile (1.9 mL) was added
followed by acetone (11.2 mL, 153 mmol, 163 equiv). The
reaction was initiated with 3-phenylpropionaldehyde (0.125 mL,
0.941 mmol, 1 equiv). The reaction was stirred at room tempe-
rature for 16 h. The reaction was then concentrated with silica gel
and directly chromatographed using 2% diethyl ether/hexanes to
afford the two observed products as light yellow oils.
(4) (a) Pihko, P. M.; Laurikainen, K. M.; Usano, A.; Nyberg, A. I.;
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(7) The term urea will be used as a broad category to include
thioureas as well as ureas unless explicitly examining the difference between
the two.
€
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(10) The reaction between the prolyl-iminium and an enol has been
referred to as the Mannich Pathway by both List and Wang. See refs 9a
and 9b.
Data for R,β Product 3. (37.5 mg, 92% purity assuming t-
butyldiphenylsilanol as an impurity based upon comparison to
1
previously reported spectrum,34 21% yield). H NMR: (600
MHz, CDCl3) δ7.31ꢀ7.27 (m, 2H), 7.22ꢀ7.16 (m, 3H), 6.81
(dt, J = 6.81, 15.96 Hz, 1H), 6.09 (dt, J = 1.50, 15.96 Hz, 1H),
2.79 (t, J = 7.74 Hz, 2H), 2.58ꢀ2.51 (m, 2H), 2.22 (s, 3H) ppm.
13C NMR (150 MHz, CDCl3) δ198.5, 147.0, 140.7, 131.7, 128.5,
128.3, 126.2, 34.4, 34.1, 26.9 ppm. The proton and carbon data
are in accordance with that reported in the literature.35
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(13) Reaction was run in dioxane.
Data for β,γ Product 4. (36.4 mg, 22% yield). Exists as a
∼1:4.3 (cis:trans) mixture as judged by the peaks at 3.15 and 3.29
1
ppm. NMR data for the trans isomer are as follows. H NMR:
(600 MHz, CDCl3) δ7.31ꢀ7.26 (m, 2H), 7.22ꢀ7.15 (m, 3H),
5.74ꢀ5.67 (m, 1H), 5.65ꢀ5.60 (m, 1H), 3.38 (d, J = 6.78, 2H),
3.15 (d, J = 6.66, 2H), 2.14 (s, 3H) ppm. 13C NMR: (150 MHz,
CDCl3) δ 207.1, 140.1, 133.7, 128.52, 128.48, 126.1, 123.4, 47.4,
39.0, 29.44 ppm. The proton data are in accordance with that
reported in the literature.36
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M. B.; Zeitler, K.; Gschwind, R. M. J. Org. Chem. 2011, 76, 3005.
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131, 17060. (b) Zhang, Z.; Schreiner, P. R. Chem. Soc. Rev. 2009,
38, 1187.
’ ASSOCIATED CONTENT
S
Supporting Information. Copies of GC/HPLC chroma-
b
tograms and corresponding chiral methods as well as 1H and 13
C
(18) (a) Hong, B.-C.; Wu, M.-F.; Tseng, H.-C.; Liao, J.-H. Org. Lett.
2006, 8, 2217. (b) Guidi, V.; Sandoval, S.; McGregor, M. A.; Rosen, W.
Tetrahedron Lett. 2010, 51, 5086.
NMR spectra. This material is available free of charge via the
(19) Massi, A.; Nuzzi, A.; Dondoni, A. J. Org. Chem. 2007, 72,
10279.
’ AUTHOR INFORMATION
(20) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J. Organometallics 1996, 15, 1518.
(21) Saito, T.; Nishimoto, Y.; Yasuda, M.; Baba, A. J. Org. Chem.
2006, 71, 8516.
Corresponding Author
*mcquade@chem.fsu.edu
(22) Pratt, R. C.; Lohmeijer, B. G. G.; Long, D. A.; Lundberg,
P. N. P.; Dove, A. P.; Li, H. B.; Wade, C. G.; Waymouth, R. M.; Hedrick,
J. L. Macromolecules 2006, 39, 7863.
(23) Scates, B. A.; Lashbrook, B. L.; Chastain, B. C.; Tominaga, K.;
Elliott, B. T.; Theising, N. J.; Baker, T. A.; Fitch, R. W. Bioorg. Med. Chem.
2008, 16, 10295.
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(28) Tajuddin, H.; Shukla, L.; Maxwell, A. C.; Marder, T. B.; Steel,
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’ ACKNOWLEDGMENT
The authors thank NSF (CHE-0809261), NDSEG (SMO),
and FSU for startup support. Additionally, we thank the FSU
Vice-President of Research and the Dean of Arts and Sciences for
upgrading the NMR facility.
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dx.doi.org/10.1021/jo200838v |J. Org. Chem. 2011, 76, 6503–6517