O. O. Fadeyi, C. O. Okoro / Tetrahedron Letters 49 (2008) 4725–4727
4727
Table 1
2. Park, B. K.; Kitterringham, N. R.; O’Neill, P. M. Annu. Rev. Pharmacol. Toxicol.
2001, 41, 443–470.
Formation of desired cyclohexandione 10 and by-product pentanedioate 1
3. Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56, 7613–7632.
4. Lin, P.; Jiang, J. Tetrahedron 2000, 56, 3635–3671.
Keto-ester
Base (equiv)
Solvent
Yieldb (%)
5. Andrew, R. J.; Mellor, J. M.; Reid, G. Tetrahedron 2000, 56, 7255–7260.
6. Andrew, R. J.; Mellor, J. M. Tetrahedron 2000, 56, 7261–7266.
7. Andrew, R. J.; Mellor, J. M. Tetrahedron 2000, 56, 7262–7272.
8. Tyvorskii, V. I.; Bobrov, D. N.; Kulinkovich, O. G.; Aelterman, W.; De Kimpe, N.
Tetrahedron 2000, 56, 7313–7318.
9. Bohacek, R. S.; McMartin, C.; Guida, C. W. Med. Res. Rev. 1996, 16, 3–50.
10. Grunewald, G. L.; Lu, J.; Criscione, K. R.; Okoro, C. O. Bioorg. Med. Chem. Lett.
2005, 15, 5319–5323.
11. Christophe, C.; Billard, T.; Langlois, B. R. Eur. J. Org. Chem. 2005, 3745–3748.
12. Lopez, S. E.; Rebollo, O.; Salazar, J.; Charris, E. J.; Yanez, C. J. Fluorine Chem. 2003,
120, 71–75.
13. Okoro, C. O.; Fadeyi, O. O.; Jackson, P. L.; Richmond, R. L.; Farmer, T. Tetrahedron
Lett. 2006, 47, 7451–7454.
1
10
1a
1b
1a
1a
1a
1a
MeONa (1.0 equiv)
EtONa (1.0 equiv)
t-BuONa (1.0 equiv)
NaH (1.2 equiv)
DBU (10%)
MeOH
EtOH
28a 1a
39 1b
0
0
0
0
20
26
45
5.6
9.2
12
t-BuOH
THF
CH2Cl2
Toluene
DBU (10%)
a
Due to transesterification caused by ethoxide ion, 1b was formed in 7% yield.
b
Isolated yields.
14. Procedure for 5-(trifluoromethyl)cyclohexane-1,3-dione 10: Keto-ester
3
(1 mmol) was added to a mixture of sodium alkoxide freshly prepared from
sodium metal (1 mmol) in 3 ml of absolute dry alcohol. The mixture was
CF3
O
O
stirred for 40 min; 4,4,4-trifluoromethyl crotonate
4 (1 mmol) was added
dropwise, and the mixture was stirred for additional 15 min at room
temperature. The mixture was refluxed for 6–8 h. The mixture was
evaporated and the sodium salt was dissolved in 10 ml of water, which was
extracted with CH2Cl2 (5 Â 10 ml). Into the aqueous layer was added 2 ml of
5 M NaOH. The mixture was refluxed for 1 h and allowed to cool to room
temperature. The cooled mixture was acidified with 2 M H2SO4 and then
extracted with EtOAc, the combined organic layer was dried over anhydrous
MgSO4 and solvent removed under reduced pressure to give white solid, which
was recrystallized from EtOAc/Hexane to give 10 as white solid. Mp: 140–
δ
O
+
RO
O
6
R= Me, Et
Figure 1. Possible activation by the CF3 moiety.
142 °C; IR (nujol): 2922, 2720, 1716, 1622 cmÀ1 1H NMR (CDCl3, 300 MHz): d
;
2.25 (m, 1H), 2.36–2.391 (d, 4H), 3.42 (s, 2H), 5.23 (s, 1H). EIMS m/z; 42 (100%),
69 (40%), 123 (20%), 152 (90%), 180 (12.5%), (M+). Elemental analysis
(C7H7F3O2), Mw: 180.12; calcd: C (46.68), H (3.92). Found: C (46.86), H (3.96).
Spectral analysis of by-products: Compound 1a, 1-Ethyl-5-methyl 3-(trifluoro-
methyl)-pentanedioate: Colorless oil. Bp: 88.7 °C; IR (nujol): 2957.56, 2925.18,
en-1-oate, followed by heating in water gave moderate yield of 5-
(trifluoromethyl)cyclohexane-1,3-dione 10 as stable white solids
(Scheme 1).14
2853.77, 1748.53, 1440.22 cmÀ1 lH NMR (CDCl3, 300 MHz): d 1.20 (3H, t,
.
We note that attempted hydrolysis and decarboxylation under
strong acid or strong base conditions, including the use of
lithium hydroxide in tetrahydrofuran, led to ring-opened product.
The resulting 5-(trifluoromethyl)cyclohexane-1,3-dione was easily
converted to 3-amino-5-trifluoromethyl)cyclohex-2-en-1-one via
azeotropic removal of water using a dean Stark trap (Scheme 1),
as reported by Manfredini and co-workers.15,16
In summary, two six-membered trifluoromethyl building blocks
have been prepared as novel synthetically useful intermediates.
The use of these compounds for the synthesis of various hetero-
cycles, including anticancer and anticonvulsant agents is in
progress and will be reported in specialized journals.
J = 7.01 Hz), 2.45 (2H, dd, J = 16.2, 7.49 Hz), 2.57 (2H, dd, J = 16.2, 5.79 Hz), 3.20
(1H, m), 3.6 (3H, s), 4.01 (2H, q, J = 7.01 Hz). EIMS m/z; 42 (17%), 123 (19%), 169
(68%), 197 (100%), 211 (30%) 242 (60%) (M+). Elemental analysis (C9H13F3O4),
Mw: 242.19; calcd: C (44.63), H (5.41). Found: C (45.11), H (5.77).
Compound 1b, Diethyl-3-(trifluoromethyl)-pentanedioate: Colorless oil. Bp:
95.1 °C; IR (nujol): 2970.22, 2949.35, 2922.06, 2862.71 1745.39,
l
1451.13 cmÀ1. H NMR (CDCl3, 300 MHz): d 1.24 (3H, t, J = 7.12 Hz), 2.50 (2H,
dd, J = 16.3, 7.52 Hz), 2.62 (2H, dd, J = 16.3, 5.8 Hz), 3.30 (1H, m), 4.12 (4H, q,
J = 7.11 Hz). EIMS m/z; 42 (10%), 115 (9%), 182 (22%), 210 (9%), 211 (100%), 256
(12%) (M+). Mw: 256.22. HRMS17
Compound 8, Ethyl-3-(cyanomethyl)-4,4,4-trifluorobutanoate: Yellow oil; IR
(nujol): 2957.56, 2925.18, 2853.77, 1748.53,1440.22 cmÀl lH NMR (CDCl3,
.
300 MHz): d 1.24 (3H, t, J = 7.9 Hz) 2.5 (2H, dd, J = 16.8, 8.1 Hz), 2.7 (2H, dd,
J = 16.8, 6.2 Hz), 3.4 (1H, m), 4.14 (2H, q, J = 7.9 Hz). EIMS m/z; 42 (7%), 123
(20%), 169 (18%), 209 (100%) (M+).
Elemental analysis (C8H10F3NO2), Mw: 209.16; calcd: C (45.94), H (4.82), N
(6.70). Found: C (46.33), H (4.75), N (6.49).
Acknowledgments
15. Procedure for 3-amino-5-(trifluoromethyl)cyclohex-2-en-1-one11: 5-trifluoro-
methyl-cyclohex-1,3-dione 10 (1 mmol) and ammonium acetate (1 mmol) in
10 ml of xylene was refluxed with the separation of water using a Dean Stark
trap. After about 3 h the reaction was cooled and evaporated to give yellow oil.
Recrystallizations with xylene afforded 11 in 89% yield as yellow solid. Mp:
We gratefully acknowledge the US Department of Education
and Title III Tennessee State University for financial support.
160–162 °C; IR (nujol) 3289, 3195, 1659, 1459 cmÀ1
;
1H NMR (CDCl3,
300 MHz): d 2.27 (m, 1H), 2.36–2.391 (d, 4H), 5.01 (s, 1H), 6.9 (br s, 2H).
EIMS m/z; 42 (27%), 82 (100%), 162 (12.5%), 178 (85%), 179 (27%), (M+).
Elemental analysis (C7H8F3NO), Mw: 179.14; calcd: C (46.93), H (4.50), N
(7.82). Found: C (47.40), H (4.45), N (7.41).
References and notes
1. (a) Schlosser, M. In Enantiocontrolled Synthesis of Fluoroorganic Compounds:
Stereochemical Challenges and Biomedical Targets; Soloshonok, V. A., Ed.; Wiley:
Chichester, 1999; pp 613–659; (b) Michel, D.; Schlosser, M. Tetrahedron 2000,
56, 4253–4260.
16. Baraldi, P. G.; Simoni, D.; Manfredini, S. Synthesis 1983, 902–903.
17. Shinohara, N.; Haga, J.; Yamazaki, T.; Kitazume, T.; Nakamura, S. J. Org. Chem.
1995, 60, 4363–4374.