9290
Q. Chu et al. / Tetrahedron Letters 47 (2006) 9287–9290
extracted with AcOEt. The organic layer was washed with
Acknowledgement
aqueous NaHCO3 and concentrated to give 4.5 g (98%
yield) of 3. This product was analyzed by LCMS:
m/z = 923 [M+H]+. (2) Fmoc deprotection: Compound
3 (2.3 g, 2.5 mmol) in 20 mL of 1:4 piperidine/DMF was
stirred at 25 °C for 1 h. The concentrated reaction mixture
was mixed with 50 mL of H2O, extracted with ether.
Concentrated organic residue was triturated with hexanes
to give desired product 4 as a white solid (1.4 g, 80%).
This product was analyzed by GC; LCMS: m/z = 701
This work was supported by the National Institute
of General Medical Sciences SBIR Grants
(2R44GM062717-02 and 2R44GM067326-02).
References and notes
1
[M+H]+; H NMR (270 MHz, CDCl3): d = 7.63 (m, 1H),
1. Berkessel, A.; Gro¨ger, H. Asymmetric Organocatalysis—
From Biomimetic Concepts to Applications in Asymmetric
Synthesis; Wiley-VCH: Weinheim, 2005.
2. Selected reviews on organocatalysis: (a) Dalko, P.;
Moisoan, L. Angew. Chem., Int. Ed. 2004, 43, 5138; (b)
Houk, K. N.; List, B. Acc. Chem. Res. 2004, 37, 487; (c)
Lelais, G.; MacMillan, D. W. C. Aldrichim. Acta 2006, 39,
79; (d) Kocˇvsky´, P.; Malkov, A. Tetrahedron 2006, 62,
255.
7.25 (m, 8H), 4.45 (d, 2H), 3.67 (dd, 1H), 3.32 (dd, 1H),
2.91 (m, 2H), 2.75 (m, 1H), 2.32 (m, 2H) and 1.50 (br, 3H);
13C NMR: (270 MHz, CDCl3): d = 26.13, 32.99, 41.58,
42.81, 56.51, 102–125 (m, CF2, CF3) 126.91, 128.27,
128.65, 128.80, 129.41, 136.98, 137.91, 138.35, 174.20. (3)
Cycloaddition: Compound 4 (0.5 g, 0.7 mmol) and 1.0 mL
of acetone in 1.5 mL of DMF was irradiated under a
single-mode microwave reactor at 250 w, 150 °C for
30 min. The reaction mixture was concentrated under
vacuum. The residue was purified by flash column
chromatography with hex:EtOAc (1:1) and then 100%
EtOAc to give 0.44 g (85% yield) of 2 as a white solid. The
product 2 was analyzed by GC; LCMS and HRMS: m/z =
741.1710 [M+H]+ (100%, calcd mass 741.1774), 594.1
[C8F17CH2CH2C6H5CH2N@C(CH3)2]+ (24%); 1H NMR
(270 MHz, CDCl3): d = 7.30 (m, 5H), 7.12 (m, 4H), 4.65
(d, 1H), 4.08 (d, 1H), 3.89 (t, 1H), 3.17 (m, 2H), 2.88 (m,
2H), 2.34 (m, 2H) 1.71 (br, 1H) 1.22 (s, 3H) and 1.00 (s,
3H); 13C NMR (270 MHz, CDCl3): d = 26.09, 27.91,
32.85, 36.48, 43.24, 58.82, 104–125 (m, CF2, CF3) 126.91,
127.80, 128.29, 128.59, 129.90, 136.46, 136.64, 138.05,
174.16.
3. Selected papers in this field: (a) Enders, D.; Huttl, M. R.
¨
M.; Grondal, C.; Raabe, G. Nature 2006, 441, 861; (b)
Mitsumori, S.; Zhang, H.; Cheong, P. H.-Y.; Houk, K. N.;
Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006,
128, 1040.
4. Baker, R. T.; Kobayshi, S.; Leitner, W. Adv. Synth. Catal.
2006, 348, 1337.
5. Rousseau, R. W. Handbook of Separation Process Tech-
nology; Wiley: New York, 1987.
6. General reviews on fluorous chemistry: (a) Handbook of
Fluorous Chemistry; Gladysz, J. A., Curran, D. P.,
´
Horvath, I. T., Eds.; Wiley-VCH: Weinheim, 2004; (b)
Gladysz, J. A.; Curran, D. P. Tetrahedron 2002, 58, 3823;
(c) Curran, D. P. Angew. Chem., Int. Ed. 1998, 7, 1175; (d)
Zhang, W. Tetrahedron 2003, 59, 4475; (e) Zhang, W.;
Curran, D. P. Tetrahedron, in press.
15. General procedure for the control experiments and the
acid–base extraction: To a solution of 1ÆHCl salt (14 mg,
0.05 mmol) with 2 mL CH3CN–H2O (95:5, v:v), acrolein
(100 lL, 1.5 mmol) and cyclohexadiene (48 lL, 0.5 mmol)
were added. The solution was stirred for 40 h at 25 °C.
Then, 5 mL 0.05 M HCl aqueous solution was added to
the reaction mixture. The solution was extracted with
4 mL diethyl ether three times. The organic phases were
combined, washed with aqueous NaHCO3, dried over
Na2SO4 and concentrated to give the product. The acidic
phase was neutralized with aqueous NaHCO3 and
extracted with 4 mL diethyl ether three times. The
combined ethyl ester layer was dried over Na2SO4. Free
catalyst 1 (7.8 mg, 65%) was obtained from concentration
of the ester layer with a purity of 74%.
´
7. Selected papers on fluorous synthesis: (a) Horvath, I. T.;
´
Rabai, J. Science 1994, 266, 72–76; (b) Luo, Z. Y.; Zhang,
Q. S.; Oderaotoshi, Y.; Curran, D. P. Science 2001, 291,
1766; (c) Villard, A.-L.; Warrington, B. H.; Ladlow, M. J.
Comb. Chem. 2004, 6, 611; (d) Hein, J. E.; Geary, L. M.;
Jaworski, A. A.; Hultin, P. G. J. Org. Chem. 2005, 70,
9940–9946; (e) Kaleta, Z.; Makowski, B. T.; Soos, T.;
Dembinski, R. Org. Lett. 2006, 8, 1625–1628; (f) Zhang,
W.; Lu, Y.; Chen, C. H.-T.; Curran, D. P.; Geib, S. Eur. J.
Org. Chem. 2006, 2055.
8. (a) Zu, L.; Li, H.; Wang, J.; Yu, X.; Wang, W.
Tetrahedron Lett. 2006, 47, 5131; (b) Zu, L.; Wang, J.;
Li, Hao; Wang, W. Org. Lett. 2006, 8, 3077.
16. General procedure for imidazolidinone-catalyzed Diels–
Alder reaction: To a solution of 2 (37 mg, 0.05 mmol) and
HCl (0.05 mmol) in 2 mL CH3CN–H2O (95:5, v:v),
acrolein (100 lL, 1.5 mmol) and cyclohexadiene (48 lL,
0.5 mmol) were added. The solution was stirred for 40 h at
25 °C. Then, 0.1 g of MP-carbonate was added and the
mixture was shaken for 0.5 h to free the amine 2. After
filtration, the solution was concentrated and then loaded
onto a 0.5 g FluoroFlashÒ silica gel cartridge for F-SPE.
It was first eluted with 4 mL CH3CN–H2O (65:35, v:v) to
get the product 5. After that, 4 mL THF with 1% Et3N
was used to elute the fluorous catalyst 2 out of the
cartridge. The concentrated THF fraction gave the fluor-
ous catalyst 2 (31 mg) as a white solid in good recovery
(84%) and excellent purity (99%). In case of the reactions
with cyclopentdiene, 1.5 mmol diene and 0.5 mmol acro-
lein derivative were used. For the gram scale reaction,
555 mg (0.75 mmol) 1, 1.5 mL acrolein (22 mmol) and
0.75 mL cyclohexadiene (7.5 mmol) were used, and the
F-SPE was conducted on a 10 g endcapped FluoroFlashÒ
silica gel cartridge.
9. (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2000, 122, 4243; (b) Wilson, R. M.; Jen,
W. S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127,
11616.
10. (a) Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2003, 125, 1192; (b) Jen, W. S.; Wiener, J.
J. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122,
9874; (c) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2001, 123, 4370.
11. Benaglia, M.; Celentano, G.; Cinquini, M.; Puglisi, A.;
Cozzi, F. Adv. Synth. Catal. 2002, 344, 149.
12. Selka¨la¨, S. A.; Tois, J.; Pihko, P. M.; Koskinen, A. M. P.
Adv. Synth. Catal. 2002, 344, 941.
equity interest in Fluorous Technologies, Inc.
14. General procedure for the synthesis of fluorous chiral
imidazolidinone 2: (1) Amide coupling: A mixture of F-
benzylamine (2.9 g, 5 mmol), Fmoc-amino acid (2.1 g, 5.5
mmol), HOBT (0.7 g, 5.5 mmol), DIC (0.65 g, 5.5 mmol)
in 15 mL of CH2Cl2 was stirred at 25 °C for 1 h. The
reaction mixture was concentrated, mixed with H2O, and