Recent Development In Direct Methods For .
Recent development in directmethods fortrifluoromethylthiolationOrganic SeminarZeren ZhangDec 4th, 20131
Outline1. Introduction2. Direct trifluoromethylthiolation Electrophilic trifluoromethylthiolation Transition metal-catalyzed nucleophilictrifluoromethylthiolation3. Summary2
IntroductionCoccidiosis3
4Boiko, V. N., Beilstein. J Org Chem, 2010, 6, 880-921.
IntroductionPotential Inhibitor ofCholesteryl Ester Transfer ProteinInhibitorRIC50 (μM) in buffer1OMe152OEt1.63OPh5.24OCF31.05SCF30.395Durley , R.C., et al, J. Med. Chem., 2002, 45, 3891-3904
IntroductionElementHBeBCNFClBrRadius (pm)29.983.076.770.265.961.9102.3119.9Gianotti., A,J; Tower, P.A. Sheley, J.H, Conte, P.A, Spiro,C, Ferro, A.J., Fitchen, J.H, Riscoe, M.K; J BiolChem, 1990, 265, 831-837.6
IntroductionHansch constant (π), a number to present lipophilicproperties .substituentπsubstituentπX H0.00X CH30.56X F0.14X CF30.88X Cl0.71X OCF31.04X Br0.86X SCF31.44X I1.12X CH(CH3)21.53Lipophilicity Increments π as Assessed for MonosubstitutedBenzenes H5C6 -XLipophilic compounds have a tendency to be oxidized byliver enzymes.7Hansch, C,. Leo, A,. Unger, S.H,. Kim, K.H, Xikaitani, D and Lien, EJ, J. Med. Chem., 1973, 16 (11), 1207
IntroductionBohm, H. J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Muller, K.; Obst-Sander, U.; Stahl, M.,Chembiochem 2004, 5, 637-643.8
IntroductionImportant intermediate for the synthesis of trifluoromethylsulfones and sulfoxides9Ancel, JE., Vidal, J., US patent 7323574 B2, Jan. 29, 2008
Previous Indirect methodsSubstitution of halogen atoms by fluorine Corrosive Low boiling point of HF (19.4 ) Pre-purification of SbF3 - sublimation10Scherer, B., Angew. Chem, 1939, 52. 457-459
Previous Indirect methodsTrifluoromethylationLong synthesis steps11Umemoto, T., Ishihara , S., J. Am. Chem. Soc. 1993, 115, 2156-2164
Previous Indirect methodsTrifluoromethylationRYield (%)m-Br82p-NO288o-NH282m-NH272 Its impact sensitiveness is similar to that of TNT. And highly explosive to heat.Eisenerger, P., Gischig, S., Togni, A., Chem. Eur. J, 2006, 12, 2579-2586Fiederling, N., Haller , J., Schramm, H., Org. Process Res. Dev. 2013, 17, 318-31912
Previous Indirect methodsRadical reaction4-NHCO2CH370%9%2-NH266%7%4-NO224% Disulfide bond formation Must be performed in Liquid NH3 Low yield for some substituents13Wakselman, C ., Tordeux, M., Chem. Comm., 1984, 793-794
Outline1. Introduction2. Direct trifluoromethylthiolation Electrophilic trifluoromethylthiolation Transition metal-catalyzed nucleophilictrifluoromethylthiolation3. Summary14
Direct trifluoromethylthiolationCl-SCF3Electrophilic methodAg-SCF3Nucleophilic method15
Electrophilic methodsR must be an electron-donating groupCroft, T,S., Phosphorus Sulfur Relat. Elem, 1976, 2, 133-139.Gerstenberger, M, R,C., Hass, A, J., J. Fluorine. Chem. 1983, 23, 525-54016
17Sheppard, W.A., J. Org, Chem, 1964, 29, 895-898
Electrophilic methods Hypervalent Iodine reagent Trifluoromethanesulfenamide Trifluoromethanesulfonyl hypervalent iodonium ylide(iodonium ylide)18
Hypervalent Iodine reagent19Shao, X.; Wang, X.; Yang, T.; Lu, L.; Shen, Q., Angew. Chem. Int. Ed, 2013, 52 , 3457-3460.
Hypervalent Iodine reagentStereoselective introduction of SCF3 groups togenerate chiral centers to beta-ketoestersSubstitution (R)H2-Me 4-OMe 2,3-diOMe3-Cl2-Br 3-Br 4-BrYield (%)9097959187838182ee (%)928694949293928920Wang, X.; Yang, T.; Cheng, X.; Shen, Q., Angew. Chem. Int. Ed , 2013, 52. 12860-12864
Hypervalent Iodine reagent21Wang, X.; Yang, T.; Cheng, X.; Shen, Q., Angew. Chem. Int. Ed , 2013, 52. 12860-12864
Hypervalent Iodine reagentCatalystYield (%)ee (%)19192 (R)28388 (S)3 5N/A22Wang, X.; Yang, T.; Cheng, X.; Shen, Q., Angew. Chem. Int. Ed , 2013, 52. 12860-12864
Hypervalent Iodine reagentLee, J.-H.; Yoo, M.-S.; Jung, J.-H.; Jew, S.-s.; Park, H.-g.; Jeong, B.-S., Tetrahedron 2007, 63 , 7906-7915.Wang, X.; Yang, T.; Cheng, X.; Shen, Q., Angew. Chem. Int. Ed , 2013, 52. 12860-1286423
Hypervalent Iodine reagent24Wang, X.; Yang, T.; Cheng, X.; Shen, Q., Angew. Chem. Int. Ed , 2013, 52. 12860-12864
Electrophilic methods Hypervalent Iodine reagent Trifluoromethanesulfenamide Trifluoromethanesulfonyl hypervalent iodonium ylide26
TrifluoromethanesulfenamideA New SCF3 source: Found as a sideproduct of ; Billard, T.; Langlois, B. R.; Bacque, E.;. J. Org. Chem. 2008, 73, 9362–9365
Trifluoromethanesulfenamide28Ferry,A.; Billard, T.; Langlois, B. R.; Bacque, E.;. J. Org. Chem. 2008, 73, 9362–9365
TrifluoromethanesulfenamideApply to various primary and secondary aminesFerry,A.; Billard, T.; Langlois, B. R.; Bacque, E, J. Org. Chem. 2008, 73, 9362–9365Ferry, A.; Billard, T.; Bacqué, E.; Langlois, B. R., J Fluorine Chem 2012, 134, 160-16329
TrifluoromethanesulfenamideThen apply to alkenes and alkynes30Ferry, A.; Billard, T.; Langlois, B. R.; Bacque, E. Angew. Chem. Int. Ed 2009, 48 , 8551-8555.
Trifluoromethanesulfenamide31Ferry, A.; Billard, T.; Langlois, B. R.; Bacque, E. Angew. Chem. Int. Ed 2009, 48 , 8551-8555.
Trifluoromethanesulfenamide32Ferry, A.; Billard, T.; Langlois, B. R.; Bacque, E. Angew. Chem. Int. Ed 2009, 48 , 8551-8555.
TrifluoromethanesulfenamideIntramolecular cyclization33Xiao, Q.; Sheng, J.; Chen, Z.; Wu, J. Chem Comm, 2013, 49 , 8647-8649.
Trifluoromethanesulfenamidesynthesize SCF3 contained pyrrolidinoindoline derivatesEntryAcidTemp ( )Time (h)ratioIsolated yield1TsOH50121:1952TsOHrt12 20:1963( )-CSArt12 337BF3-OEt2rt48Nearly only 1b97Yang, Y.; Jiang, X.; Qing, F. L., J. Org. Chem 2012, 77 , 7538-7547.34
TrifluoromethanesulfenamideDrawback 1Drawback 2Ferry, A.; Billard, T.; Langlois, B. R.; Bacque, E. Angew. Chem. Int. Ed 2009, 48, 8551-8555.Liu, J., Chu, L., and Qing, FL., Org. Lett., 2013, 15, 894-89735
lCH3COClCH3COClSolventDCMDCMDCMDMFDMACYield (%)261337788436Liu, J., Chu, L., and Qing, FL., Org. Lett., 2013, 15, 894-897
TrifluoromethanesulfenamideExtension to Grignard reagent & terminal alkynes37Baert, F.; Colomb, J.; Billard, T., Angew. Chem. Int. Ed 2012, 51 , 10382-10385
Trifluoromethanesulfenamide38Alazet, S.; Zimmer, L.; Billard, T., Angew. Chem. Int. Ed 2013. 52, 10814-10817
Electrophilic methods Hypervalent Iodine reagent Trifluoromethanesulfenamide Trifluoromethanesulfonyl hypervalent iodonium ylide39
Iodonium Ylide40Yang, Y. D.; Azuma, A.; Tokunaga, E.; Yamasaki, M.; Shiro, M.; Shibata, N., J. Am. Chem. Soc. 2013, 135 , 8782-8785.
Iodonium Ylide41Yang, Y. D.; Azuma, A.; Tokunaga, E.; Yamasaki, M.; Shiro, M.; Shibata, N., J. Am. Chem. Soc. 2013, 135 , 8782-8785.
Iodonium Ylide42Yang, Y. D.; Azuma, A.; Tokunaga, E.; Yamasaki, M.; Shiro, M.; Shibata, N., J. Am. Chem. Soc. 2013, 135 , 8782-8785.
Comparison of 2 Hypervalent Iodine reagent43Yang, Y. D.; Azuma, A.; Tokunaga, E.; Yamasaki, M.; Shiro, M.; Shibata, N., J. Am. Chem. Soc. 2013, 135 , 8782-8785.Shao, X.; Wang, X.; Yang, T.; Lu, L.; Shen, Q., Angew. Chem. Int. Ed, 2013, 52 , 3457-3460.
Iodonium YlideYang, Y. D.; Azuma, A.;Tokunaga, E.; Yamasaki,M.; Shiro, M.; Shibata, N.,J. Am. Chem. Soc. 2013,135 , 8782-8785.44
Iodonium Ylide250.999345Yang, Y. D.; Azuma, A.; Tokunaga, E.; Yamasaki, M.; Shiro, M.; Shibata, N., J. Am. Chem. Soc. 2013, 135 , 8782-8785.
Iodonium Ylide46
Electrophilic methods Hypervalent iodine reagent can selective introduceSCF3, but it is potential explosive chemicals. Trifluoromethanesulfenamide, a stable SCF3 source. Trifluoromethanesulfonyl hypervalent iodonium ylide, canbe effectivly applied to enamines, beta-keto esters,indoles.47
Outline1. Introduction2. Direct trifluoromethylthiolation Electrophilic trifluoromethylthiolation Transition metal-catalyzed nucleophilictrifluoromethylthiolation3. Summary48
Transition metal-catalyzed nucleophilictrifluoromethylthiolationRYield (%)H554-Me304-NO275 Cheap and efficient metal catalyst Stable SCF3 source49Yagupolskii, L, M, Kondratenko, N, V, Sambur, V, P., Synthesis, 1975, 721-723.
Nucleophilic trifluoromethylthiolationPalladium catalyzed nucleophilic method50Teverovskiy, G.; Surry, D. S.; Buchwald, S. L., Angew. Chem. Int. Ed 2011, 50 , 7312-7314.
Nucleophilic trifluoromethylthiolation51Zhang, C. P.; Vicic, D. A., J. Am. Chem. Soc . 2012, 134 , 183-185.
Nucleophilic trifluoromethylthiolation52Zhang, C. P.; Vicic, D. A., Chem. Asian J , 2012, 7 , 1756-1758.
Nucleophilic trifluoromethylthiolationFrom element Sulfur53Weng, Z.; He, W.; Chen, C.; Lee, R.; Tan, D.; Lai, Z.; Kong, D.; Yuan, Y.; Huang, K. W., Angew. Chem. Int. Ed , 2013, 52, 1548-1552.
Nucleophilic trifluoromethylthiolation54Weng, Z.; He, W.; Chen, C.; Lee, R.; Tan, D.; Lai, Z.; Kong, D.; Yuan, Y.; Huang, K. W., Angew. Chem. Int. Ed , 2013, 52, 1548-1552.
Nucleophilic trifluoromethylthiolationPath APath B55Chen, C.; Xie, Y.; Chu, L.; Wang, R. W.; Zhang, X.; Qing, F. L., Angew. Chem. Int. Ed , 2012, 51 , 2492-2495.
Nucleophilic trifluoromethylthiolation56
Nucleophilic trifluoromethylthiolation57
Nucleophilic trifluoromethylthiolation58Chen, C.; Xie, Y.; Chu, L.; Wang, R. W.; Zhang, X.; Qing, F. L., Angew. Chem. Int. Ed , 2012, 51 , 2492-2495.
Nucleophilic trifluoromethylthiolation59Chen, C.; Chu, L.; Qing, F. L., J. Am. Chem. Soc 2012, 134 , 12454-12457.
Nucleophilic trifluoromethylthiolationTotal synthesis of Toltrazuril60A. Gunther, K.-H. Mohrmann, M. Stubbe, H. Ziemann (Bayer AG), DE3516630, 1986
Nucleophilic trifluoromethylthiolation Pd catalyst 260/g Ligand 200/g61Teverovskiy, G.; Surry, D. S.; Buchwald, S. L., Angew. Chem. Int. Ed 2011, 50 , 7312-7314.
Nucleophilic methods From Palladium to Nickel, then to Copper, to find acheaper but highly efficient catalyst. Improvement of unstable or inconvient M-SCF3source.62
Summary Electrophilic methods Hypervalent Iodine sulfony hypervalent iodonium ylide Nucleophilic methods Optimize the reaction catalyst.One pot reaction.63
Acknowledgements Dr. Xuefei Huang Group members: Zhaojun, Weizhun, Hovig,Herbert, Qian, Berm, Peng, Mehdi, Jicheng, Bo,Keisuke, Jingguang, Issac, Sherif My friends All your attention64
5 Potential Inhibitor of Cholesteryl Ester Transfer Protein Inhibitor R IC 50 (μM) in buffer 1 OMe 15 2 OEt 1.6 3 OPh 5.2 4 OCF 3 1.0 5 SCF 3 0.39 Durley , R.C., et al, J
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started guide. The Connect:Direct F ile Agent Help contains instruct ions for configuring File Agent. direct Connect:Direct for UNIX Administration Guide Connect:Direct for UNIX Administration Guide Connect:Direct for UNIX Administration Guide Connect:Direct for UNIX Administration Guide . Connect:Direct for UNIX Administration Guide
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1. Agile methods are undisciplined and not measurable. 2. Agile methods have no project management. 3. Agile methods apply only to software development. 4. Agile methods have no documentation. 5. Agile methods have no requirements. 6. Agile methods only work with small colocated teams.-7. Agile methods do not include planning. 8.
contents of the tool box" used for validation. The methods and techniques listed in the report are grouped as - review - models - analysis - dynamic methods - methods regarding formality - development methods The validation methods have to be combined together in a validation plan. The plan shall list requirements and validation methods.
contents of the tool box" used for validation. The methods and techniques listed in the report are grouped as - review - models - analysis - dynamic methods - methods regarding formality - development methods The validation methods have to be combined together in a validation plan. The plan shall list requirements and validation methods.
Iterative methods for solving general, large sparse linear systems have been gaining popularity in many areas of scientific computing. Until recently, direct solution methods were often preferred to iterative methods in real applications because of their robustness and predictable behavior.Cited by: 18757Publish Year: 2003Author: Y. SaadExplore furtherIterative Methods for Sparse Linear Systems Society for .epubs.siam.org9. Preconditioned Iterations Iterative Methods for �道 - Baiduzhidao.baidu.comMIL-STD-453 C INSPECTION RADIOGRAPHICeveryspec.comASTM-E1742 Standard Practice for Radiographic .www.document-center.comRecommended to you based on what's popular Feedback
statistical reconstruction methods. This chapter1 reviews classical analytical tomographic reconstruction methods. (Other names are Fourier reconstruction methods and direct reconstruction methods, because these methods are noniterative.) Entire books have been devoted to this subject [2-6], whereas this chapter highlights only a few results.
