8586
K. M. Amore et al. / Tetrahedron Letters 47 (2006) 8583–8586
Boruah, R. C.; Sandhu, J. S. Tetrahedron Lett. 2002, 43,
Acknowledgments
143.
18. Zhan, Z. P.; Lang, K. Synlett 2005, 1551.
The University of Connecticut and the NSF REU
program (CHE-0354012) are thanked for the funding.
19. Reactions were conducted using a commercially available
monomode microwave unit (CEM DiscoverTM). The
machine consists of a continuous focused microwave
power delivery system with operator selectable power
output from 0 to 300 W. Syntheses of the Michael adducts
were performed in glass vessels (capacity 10 mL) sealed
with a septum. The pressure was controlled by a load cell
connected to the vessel. The temperature of the contents of
the vessel was monitored using a calibrated infrared
temperature control mounted under the reaction vessel.
Hydrolysis reactions were performed in a 100 mL round-
bottom flask. The apparatus was equipped with an
opening in the top (attenuator) through which a glass
tube could be placed connecting the flask in the microwave
cavity with a reflux condenser located outside the cavity.
All reactions were stirred by means of a rotating magnetic
plate located below the floor of the microwave cavity and
a Teflon-coated magnetic stir bar in the vessel.
20. Typical procedure for the Michael addition reaction: Prep-
aration of 3-phenylaminopropanoate (2). In a 10 mL glass
tube were placed aniline (1.395 g, 1.36 mL, 15.0 mmol),
methyl acrylate (1.2915 g, 1.35 mL, 15.0 mmol), acetic acid
(0.090 g, 0.086 mL, 1.5 mmol), and a magnetic stir bar. The
vessel was sealed with a septum and placed into the
microwave cavity where it was sealed with a pressure lock.
Using an initial microwave power of 300, the reaction
mixture was heated from rt to 200 °C where it was held by
modulating microwave power for a total reaction time of
20 min. Upon completion, the reaction mixture was cooled
to room temperature, the tube opened and the crude
product characterized by comparison of NMR data with
that in the literature. 1H NMR (CDCl3): d 7.18 (t, 2H,
J = 7.5 Hz), d 6.70 (t, 1H, J = 7.3 Hz), d 6.62 (d, 2H,
J = 7.7 Hz), d 4.00 (br, 1H), d 3.70 (s, 3H), d 3.46 (t,
2H, J = 6.4 Hz), d 2.63 (t, 2H, J = 6.4 Hz).
References and notes
1. Enantioselective Synthesis of b-Amino Acids; Juaristi, E.,
Soloshonok, V. A., Eds.; Wiley-Interscience: New York,
2005.
2. For examples see: (a) Fulo¨p, F. Chem. Rev. 2001, 101,
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3. For a recent review see: Liljeblad, A.; Kanerva, L. T.
Tetrahedron 2006, 62, 5831.
4. For examples see: (a) Varala, R.; Alam, M. M.; Adapa, S.
R. Synlett 2003, 720; (b) Bartoli, G.; Bosco, M.; Marcan-
toni, E.; Petrini, M.; Sambri, L.; Torregiani, E. J. Org.
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71, 2532.
6. Werbel, L. M.; Kesten, S. J.; Turner, W. R. Eur. J. Med.
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8. Basu, B.; Das, P.; Hoassain, I. Synlett 2004, 2630.
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Organomet. Chem. 2003, 665, 250; (b) Li, K.; Phua, P. H.;
Hii, K. K. Tetrahedron 2005, 61, 6237.
21. Typical procedure for the hydrolysis of the Michael adduct:
Preparation of 3-phenylaminopropanoic acid (3). In a
100 mL round-bottom flask were placed methanol
(30 mL), water (30 mL), potassium hydroxide (4.489 g,
80.0 mmol), and the entire contents of the reaction
mixture from the synthesis of 2. Using an initial micro-
wave power of 200 W, the reaction mixture was heated
from rt to reflux (87 °C), where it was held by modulating
microwave power for a total reaction time of 30 min.
Upon completion, the solution was allowed to cool,
poured into a separatory funnel, and the pH adjusted to
6.0 using HCl and NaHCO3. The aqueous phase was
extracted with four 20 mL portions of diethyl ether. The
organic extracts were combined, washed with brine, dried
over MgSO4, whereupon the solvent was removed in
vacuo, leaving the crude product. This product (500 mg)
was purified using flash chromatography, an 80:20:0.1
DCM/MeOH/Et3N mixture used as the eluent. The white
solid recovered was characterized as 3 by the comparison
of NMR data with that in the literature (379 mg,
2.31 mmol; 74% overall yield for the two steps). 1H
NMR (d6-DMSO): d 7.22 (t, 2H, J = 7.4 Hz), d 6.77 (t,
1H, J = 7.4 Hz), d 6.67 (d, 2H, J = 7.6 Hz), d 3.50 (t, 2H,
J = 6.3 Hz), d 2.70 (t, 2H, J = 6.3 Hz).
13. Lu, Z.; Twieg, R. J. Tetrahedron Lett. B 2005, 46, 2997.
14. A number of books on microwave-promoted synthesis
have been published recently: (a) Kappe, C. O.; Stadler, A.
Microwaves in Organic and Medicinal Chemistry; Wiley-
VCH: Weinhiem, 2005; (b) Microwave-Assisted Organic
Synthesis; Lidstro¨m, P., Tierney, J. P., Eds.; Blackwell:
Oxford, 2005; (c) Microwaves in Organic Synthesis; Loupy,
A., Ed.; Wiley-VCH: Weinheim, 2002; (d) Hayes, B. L.
Microwave Synthesis: Chemistry at the Speed of Light;
CEM Publishing: Matthews NC, 2002.
15. For a recent review see: Kappe, C. O. Angew. Chem., Int.
Ed. 2004, 43, 6250.
16. For other reviews on the general area of microwave-
promoted organic synthesis see: (a) Larhed, M.; Moberg,
C.; Hallberg, A. Acc. Chem. Res. 2002, 35, 717; (b) Lew,
A.; Krutzik, P. O.; Hart, M. E.; Chamberlain, A. R. J.
Comb. Chem. 2002, 4, 95; (c) Lidstro¨m, P.; Tierney, J. P.;
Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225.
17. For examples see: (a) Monfray, J. K.; Koskinen, A. M. P.
Lett. Org. Chem. 2006, 3, 324; (b) Zhan, Z. P.; Yang, W.
Z.; Yang, R. F. Synlett 2005, 2425; (c) Rao, H. S. P.;
Jothilingam, S. J. Chem. Sci. 2005, 117, 323; (d) Khalafi-
Nezhad, A.; Zarea, A.; Rad, M. N. S.; Mokhtari, B.;
Parhami, A. Synthesis 2005, 419; (e) Sharma, U.; Bora, U.;