Domino reactions with 5-azido- and 5-amino-4- trifluoromethyl-1,3-azoles.
Klaus Burger1; Eva Höß; Lothar Hennig and Lothar Beyer2
1 Department of Organic Chemistry, University of Leipzig, Johannisallee 29, D-04103 Leipzig, Germany
Reacciones dominó con 5-azido- y 5-amino-4-trifluorometil-1,3 azoles.
Palabras clave: 5-Fluoro-4-trifluormetil-1,3-azoles; 5-azido-4-trifluormetil-1,3-azoles; 5-amino-4-trifluor-metil-1,3-azoles, reacciones tipo dominó; [1.4] eliminación HF; adición Michael.
Compounds with substructures like CF 3 -C=C-NH-R are remarkable reactive towards primary amines. They behave like “ortho-fluorides” and are readily susceptible to elimination / addition sequences which can be linked together and performed as domino reactions.
Keywords: 5-Fluoro-4-trifluoromethyl-1,3-azoles, 5-azido-4-trifluoromethyl-1,3-azoles, 5-amino-4-trifluoromethyl-1,3-azoles, domino reaction, [1.4] HF-elimination, Michael addition
Domino reactions offer preparatively simple and elegant solutions of complex synthetic problems.1 The efficiency of this concept relies on linking together single reaction steps, thus avoiding separation and purification procedures after each step. When certain structural requirements are met, perfluoroalkyl substituted compounds readily undergo domino reactions.2
RESULTS AND DISCUSSION
Although the trifluoromethyl group is often considered to be chemically inert,3,4 it is known to undergo a variety of reactions. The hydrolytic behavior of a trifluoromethyl group is very much dependent on its position in a molecule.
Undersurprisinglymild conditionsacompleteF/H-exchangeofatrifluoromethyl group can be achieved when compounds 2b and 5b are treated with LiAlH 4 in diethyl ether at room temperature. Starting from 5b, three cycles, each consisting of twosteps,namely [ 1.4 ] -eliminationfollowed byadditionofa hydrideion,arelinked together to give a six-step domino reaction (5 → 6 → 7 → 8 → 9 → 10 → 11).
Thisreactionsequencecan beappliedfora concisedecorationofheterocyclic systems bearing subunits like CF 3 CH=CHNH- with interesting substituent patterns.
The first step of the domino reaction is a nucleophilic displacement reaction of the single fluorine bound to C-(5) (1 → 12). The subunit CF 3 C=C-NH-C 6 H 5 is capable for a 1.4-HF-elimination to give a highly reactive Michael system (13), since the consecutive addition is driven by rearomatization (13 → 14). The newly formedsubunitH 5 C 6 NH-CF 2 C=C-NH-C 6 H 5 againundergoesa1.4-HF-elimination (14 → 15) followed by a Michael addition (15 → 16). The final step of the sequence is a HF-elimination (16 → 17) to form an amidine moiety. When the core unit CF 3 C=C-NH-R is present twice in a molecule, it should be possible to run two domino reactions – with six steps each – parallel in a one-pot procedure.12
Solvents were purified and dried prior to use. Reagents were used as purchased. Flash chromatography was performed using silica gel (32-63 ìm) with solvent systems given in the text. Melting points (uncorrected) were determined with a Tottoli apparatus (Fa. Büchi). 1 H (200 MHz, 360 MHz), 13 C (50 MHz, 75 MHz) and 19 F (188 MHz, 282 MHz) NMR spectra were recorded on Bruker WP 200, Bruker AM 360, Jeol C 60 HL and Jeol FX 90 Q spectrometers. TMS was used as reference for 1 H and 13 C NMR spectra (internal), and CF 3 COOH for 19 F NMR spectra (external). IR spectra were obtained on Perkin Elmer 157 G and 257 spectrometers. Mass spectra were recorded on a Varian MAT CH 5 spectrometer at 70 eV.
We thank Deutsche Forschungsgemeinschaft and Fonds der Chemischen Industrie for financial support.
1. a) Tietze LF., Beifuss U. Angew. Chem.. 1993, 105, 137; b) Tietze LF. Chem. Rev. 1996, 96, 115.
2. a) Knunyants IL., Bargamova MD. Izv. Akad. Nauk SSSR, Ser. Khim. (Engl. Transl.) 1977, 1776; b) Bargamova MD., Motsishkite SM., Knunyants IL. Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.) 1990, 39, 2338.
3. Mc Bee ET., Pierce OR., Kilbourne HW. J. Am. Chem. Soc. 1953, 75, 4091.
4. Haszeldine RN. J. Chem. Soc. 1953, 922.
5. Kitazume T., Ohuogi T. Synthesis 1988, 614.
6. a) Weygand F., Steglich W., Lengyel I., Fraunberger F., Maierhofer H, Oettmeier W. Chem. Ber. 1966, 99, 1944; b) Burger K., Mütze K., Hollweck W., Koksch B., Kuhl P., Jakubke H-D., Riede J., Schier A. J. prakt. Chem. / Chem. Ztg.1993, 335, 321.
7. a) Kimoto H., Cohen LA. J. Org. Chem. 1979, 44, 2902; b) Kimoto H., Cohen LA. J. Org. Chem.1980, 45, 3831.
8. a) Burger K., Höß E., Chem. Ztg. 1989, 113, 385; b) Burger K., Höß E., Geith K. Synthesis 1990, 360.
9. a) Burger K., Ottlinger R., Goth H., Firl J., Chem. Ber. 1982, 115, 2494; b) Burger K., Geith K., Sewald N. J. Fluorine Chem. 1990, 46, 105; c) Burger K., Helmreich B. J. prakt. Chem. / Chem. Ztg. 1992, 334, 311.
10. a) Burger K., Höß E., Sewald N., Geith K., Riede J., Bissinger P., Z. Naturforsch. 1990, 45b, 1695; b) Burger K., Geith K., Höß E. Synthesis 1990, 352.
11. Höß E. PhD, Techn. University Munich, 1990.
12. work in progress.
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