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C'. Phsocfh (1C) OH US007087789B2 (12) United States Patent (10) Patent No.: US 7,087,789 B2 Prakash et al. (45) Date of Patent: Aug. 8, 2006 (54) METHODS FOR NUCLEOPHILC OTHER PUBLICATIONS FLUOROMETHYLATION Stahly, Nucleophilic Addition of Difluoromethyl Phenyl Sulfone to Aldehydes and Various Transformation of the (75) Inventors: issure Esthi, Resulting Alcohols, Journal of Fluorine Chemistry, 43, s s s 1989, 53-66.* E. i. 'S'srge A. Olah, Russell et al., Effective Nucleophilic Trifluoromethylation everly 1111s, with Fluoroform and Common Base, Tetrahedron, 54, 1998, Assignee: University of Southern California, 13771-13782.* - (73) Los Angeles, CA (US) Large et al., Nucleophilic Trifluoromethylation of Carbonyl s Compounds and Disulfides with Trifluoromethane and Sili (*) Notice: Subject to any disclaimer, the term of this con-Containing Bases with Fluoroform and Common Base, patent is extended or adjusted under 35 Snythesis, J. Org. Chem. 2000, 65, 8848-8856. U.S.C. 154(b) by 0 days. Prakash, G.K.S.; Krishnamurti, R.; Olah, G.A., J. Am. Chem. Soc. 1989, 111, 393-395. (21) Appl. No.: 10/755,902 (Continued) (22) Filed: Jan. 12, 2004 Primary Examiner Johann Richter O O Assistant Examiner Chukwuma Nwaonicha (65) P O PublicationDO Dat (74) Attorney, Agent, or Firm Winston & Strawn LLP US 2004/0230079 A1 Nov. 18, 2004 (57) ABSTRACT Related U.S. Application Data (60) Provisional application No. 60/440,011, filed on Jan. 13, 2003. A novel, convenient and efficient method for trifluoromethy s lation of substrate compounds is disclosed. Particularly, (51) Int. Cl. alkoxide and hydroxide induced nucleophilic trifluorom C07C 319/00 (2006.01) ethylation of carbonyl compounds, disulfides and other (52) U.S. Cl. ......................... 568/56, 568/323: 568/437 electrophiles, using phenyl trifluoromethyl Sulfone Field of Classification Search .................. Sosso, PhSOCF, (or sulfoxide PhSOCF) is disclosed Amethod of (58) 568/323. 437 both symmetrical and unsymmetrical anti-2,2-difluoropro See application file for complete search history pan-1,3-diols with high diastereoselectivity (up to 94% de) is disclosed using difluoromethyl phenyl sulfone. This References Cited unusual type of high diastereoselectivity was obtained via an (56) intramolecular charge-charge repulsion effect rather than the traditional steric control (based on the Cram's rule). Thus, U.S. PATENT DOCUMENTS difluoromethyl phenyl sulfone can be used as a novel difluoromethylene dianion species (“CF2'), which can 9. A E. See al. soil couple two electrophiles (such as diphenyl disulfide or Iw - - - - - - - - - - - - - - - - - - - non-enolizable aldehydes) to give new difluoromethylenated FOREIGN PATENT DOCUMENTS products. WO WO 98.22435 * 5/1998 WO WO9822435 5, 1998 26 Claims, 8 Drawing Sheets O C'. NaOH/H2O/CH2Cl2PhSOCFH (1c) ( ) OHl CF 2 8 -() 90% 17a OH H fBuOK (3 equiv.) 17a + CHK)-CHO DMF g2 C - 50 °C - RT (1 equiv.) (2 equiv.) 21 (SS-or RR-) 76% yield de = 92% US 7,087,789 B2 Page 2 OTHER PUBLICATIONS Jablonski, L.; Joubert, J.; Billard, T.; Langlois, B.R., Synlett, Prakash, G.K.S.; Yudin, A.K., Chem. Rev. 1997, 97, 757 2003, 230-232. 786. Inschauspe, D.; Sortais, J.P.: Billard, T.; Langlois, B.R., Prakash, G.K.S." Hu, J. Olah, G.A., J. Org. Chem. 2003, 68, Synlett, 2003, 233-235. 4457-4463. Jablonski, L.; Billard, T.; Langlois, B.R.: Tetrahedron Lett. Shono, T.: Ishifume, M.: Okada, T.: Kashimura, S., J. Org. 2003, 44, 1055-1057. Chem. 1991, 56, 2-4. Shein, S.M.; Krasnopolskaya, M.I.; Boiko, V.N., Zh. Barhdadi, R.; Troupel, M.; Perichon, J., Chem. Comm. Obshei Khim., 1966, 36, 2141. 1998, 1251-1252. Steensma, R.W.; Galabi, S.; Tagat, J.R.; McCombie, S.W., Folleas, B.; Marek, I., Normant, J.F.; Saint-Jalmes, L. Tet Tetrahedron Lett., 2001, 42, 2281-2282. rahedron Lett. 1998, 39, 2973-2976. Folleas, B.; Marek, I., Normant, J.F.; Saint-Jalmes, L. Tet Barrera, M.D.; Cheburkov, Y.; Lamanna, W.M., J. Fluorine rahedron 200, 56, 275-283. Chem., 2002, 117, 13-16. Russell, J.; Roques, N., Tetrahedron, 1998, 54, 13771 Yudin, A.K.; Prakash, G.K.S.; Deflieux, D.; Bradley, M.: 13782. Bau, R.; Olah, G.A., J. Am. Chem. Soc., 1997, 119, 1572 Large, S.; Roques, N.; Langlois, B.R., J. Org. Chem. 2000, 1581. 65, 8848-8856. Kuroboshi, M.: Ishihara, T.; Bull. Chem. Soc. Jpn., 1990, 63, Roques, N.; Mispelaere, C., Tetrahedron Lett. 1999, 40, 1185-1190. 64 11-6414. Hine, J.; Porter, J.J., J. Am... chem. Soc., 1960, 82, 6178 Billard, T.B.: Langlois, B.R., Org. Lett. 2000, 2, 2101-2103. 6181. Billard, T.; Langlois B.R.: Blond, G., Eur. J. Org. Chem. Stahly, P. J. Fluorine Chem., 1989, 43, 53-66. 2001, 1467-1471. Saikia et al., “Chemistry of Trichiorofluoromethane: Syn Billard, T.; Langlois, B.R., J. Org. Chem., 2002, 67, 997 thesis of Chiorofluoromethyl Phenyl Sulfone and 1OOO. Fluoromethyl Ohenyl Sulfone and Some of Their Reac Langlois, B.R.: Billard, T., Synthesis, 2003, 185-192. tions”, Journal of Organic Chemistry, vol. 66 (3), pp. 643 Ait-Mohand, S.; Takechi, N.; Medebielle, M.: Dolbier, W., 647 (2001). Jr., Org. Lett., 2001, 3, 4271-4273. Motherwell, W.B.: Storey, L.J., Synlett, 2002, 646-648. * cited by examiner U.S. Patent Aug. 8, 2006 Sheet 1 of 8 US 7,087,789 B2 FIGURE 1 O () fier,N-or ():ifor - CF3 U.S. Patent Aug. 8, 2006 Sheet 2 of 8 US 7,087,789 B2 FIGURE 2 O O O 1C 4. 5 OR ECFE E" CEE (R = H, alkyl group. E., E = electrophiles, such as disulfides, aldehydes) U.S. Patent Aug. 8, 2006 Sheet 3 of 8 US 7,087,789 B2 FIGURE 3 H PhSO2CF3 (1a)'BuOK CF3 DMF, -50 °C to RT U.S. Patent Aug. 8, 2006 Sheet 4 of 8 US 7,087,789 B2 FIGURE 4 Ph-S-S-Ph-S-S-Ph. -->PhSO2CF31'BuOK Ph-S-CF DMF, -30°C - rt. 3 10 U.S. Patent Aug. 8, 2006 Sheet S of 8 US 7,087,789 B2 FIGURES O fBuOK 9) Ph-S-CF.H Ph-s-CF, PhssPh Ph-SCFSPh O O O 2 6 12 fBuO PSSP r 5 CFSPh PhSCFSPh SSPhil PhscF, Ph-SS O OtBu 13 16 15 fEuOH fuok PhSCFH 14 Stepwise formation of 12 and 13. U.S. Patent Aug. 8, 2006 Sheet 6 of 8 US 7,087,789 B2 FIGURE 6 O pH pH C'. PhSOCF2H (1c) / fibuOK c1 DMF F O - 50 °C - RT 18 N ", /anti- (S,S- or RR-) Crict, Oin M = H (17a) = K (17b) (a) 'F NMR for antiisomer. -120.9 ppm (pseudot, JFH = 11.4 Hz, 2F). (b) 'F NMR: -104.4 ppm (dd, J = 238.0 Hz, 2.8 Hz, 1F); - 119.8 ppm (dd, J = 238.0 Hz, 21.0 Hz, 1F). U.S. Patent Aug. 8, 2006 Sheet 7 of 8 US 7,087,789 B2 FGURE F. O OH OH H PhSOCF2H (1c)/feuok c1 DMF F2 a 50 °C s- RT 18 (82% isolated) anti- (S,S- or R,R) 1cBuOK OK" O CFastPh8) as 17b fBuO anti- (SS-or R,R) U.S. Patent Aug. 8, 2006 Sheet 8 of 8 US 7,087,789 B2 FIGURE 8 O H PhSOCF2H (1c) pH 9. NaOH/H2O/CH2Cl2 ( ) H CF.--()5 90% 17a 9H gH fBuOK (3 equiv.) 17a + CH( )-CHO DMF g2 C o - 50 °C - RT (1 equiv.) (2 equiv.) 21 (SS- or R,R) 76% yield de E 92% US 7,087,789 B2 1. 2 METHODS FOR NUCLEOPHILC DMF. See, (a) Russell, J.; Roques, N. Tetrahedron 1998, 54, FLUOROMETHYLATION 13771. (b) Large, S.; Roques, N.; Langlois, B. R J. Org. Chem. 2000, 65,8848. (c) Roques, N.; Russell, J.; Langlois, This application claims the benefit of provisional appli B.; Saint-Jalmes, L.; Large, S. PCT Int. Appl. 1998, WO cation Ser. No. 60/440,011, filed on Jan. 13, 2003, the 5 9822435. (d) Roques, N.; Mispelaere, C. Tetrahedron Lett. entirety of which is incorporated herein by reference thereto. 1999, 40, 6411, each of which are incorporated herein by reference. TECHNICAL FIELD CF/N-formylmorpholine adduct was also developed as This invention relates to a novel synthetic method for the 10 a stable reagent for the trifluoromethylation of non-enoliz nucleophilic trifluoromethylation and difluoromethylenation able carbonyl compounds (Billard, T. B.; Langlois, B. R. of Substrate compounds. The invention more particularly Org. Lett. 2000, 2, 2101). Under similar consideration, relates to the alkoxide and hydroxide induced trifluorom piperazino hemiaminal of trifluoro-acetaldehyde was also ethylation and difluoromethylenation of Substrates using tri used as a trifluoromethylating agent (Billard, T., Langlois, B. and difluoromethyl sulfones and sulfoxides. 15 R.; Blond, G. Eur: J. Org. Chem. 2001, 1467: Billard, T.: Langlois, B. R. J. Org. Chem. 2002, 67.997: Langlois, B. BACKGROUND ART R.: Billard, T. Synthesis 2003, 185). Trifluoromethyl iodide (CFI) has also been successfully In the past two decades, organofluorine compounds have used as a nucleophilic trifluoromethylating agent under the attracted much attention due to their unique properties and 20 activation of electron-donating tetrakis-(dimethylamino)eth unusual reactivities. Among them, trifluoromethyl group (CF) containing compounds are of particular importance ylene (TDAE) (Ait-Mohand, S.; Takechi, N.; Medebielle, for different applications in the materials field, as well as in M.: Dolbier, W. Jr. Org. Lett. 2001, 3, 4271). Motherwell et the pharmaceutical and agrochemical industries. Although al. reported the nucleophilic trifluoromethylation using tri many trifluoromethylation methods are known, Such as 25 fluoromethyl-acetophenone-N,N-dimethyl-trimethylsily organometallic, nucleophilic, electrophilic and radical trif lamine adduct (Motherwell, W. B. Storey, L.J. Synlett 2002, luoromethylations, fluoride induced nucleophilic trifluorom 646). Langlois et al. also have reported nucleophilic trifluo ethylation with (trifluoromethyl)trimethylsilane (TMS-CF) romethylations of non-enolizable carbonyl compounds previously developed by the present inventors is considered using trifluoroacetic acid derivatives, trifluoromethane a straightforward, convenient and versatile method.
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