Study of 1,3-Dipolar Cycloaddition Reactions in Organic Synthesis, Study notes of Organic Chemistry

Download Study of 1,3-Dipolar Cycloaddition Reactions in Organic Synthesis and more Study notes Organic Chemistry in PDF only on Docsity! RECENT ADVANCES IN 1,3-DIPOLAR CYCLOADDITIONS OF AZOMETHINE YLIDES Marina Tanasova 1,3-Dipolar Cycloadditions - the best and most convenient method for construction of five-member heterocycles. B A C R2 R1 B A C R2 R1 + R3 R4 C B AR2 R1 R4R3 Five-member heterocycles Introduction Five-member heterocycles - building blocks for a variety of biologically active molecules. Possibility to construct different ring systems. Formation of several contiguous stereocenters in one pot. HN N N O OMeO MeO O HN O CO2Me N Me MeO Me Spirotryprostatin B Formation of spiro-system by 1,3-dipolar cycloaddition Synthesis of Spirotryprostatin B by 1,3-Dipolar Cycloaddition Sebahar, P.R.; Hiroyuki, O.; Usui, T.; Williams, R.M. Tetrahedron 2002, 58, 6311-6322. OPh Ph O CO2Me H HN N N O OMeO MeO O Improved approach to the diastereocontrol of 1,3-dipolar cycloaddition of azomethine ylides with electron deficient mono- and di-substituted olefins. Investigation and application of some chiral catalysts in order to increase enantiocontrol of cycloaddition. Introduction of chirality through chiral vinyl sulfinyloxides. Recent approach to functionalized 2,5-dihydropyrroles. Outline Formation of substituted pyrrolidines through 1,3-dipolar cycloaddition of azomethine ylides. 1,3-dipolar cycloaddition of azomethine ylides with substituted imines, resulting in formation of different imidazo-compounds. R3 R2 N R1 O OR R3 R2 N R1 O OR R3 R2 N R1 O OR R3 R2 N R1 O OR H M MX / Base Generation of Azomethine Ylides Grigg, R.; Kemp, J. J. Chem. Soc., Chem. Commun. 1978, 101,109-112. Kanemasa, S.; Yamamoto, H. Tetrahedron 1990, 113, 3633-3636. Padwa, A.; Burgess, E.M.; Gingrich, H.L.; Roush, D.M.J. Org. Chem. 1982, 47, 786-791. R2 R3 O H2N R1 O OR + R3 R2 N R1 O OR H ∆ N O R1 R3 O HO N R1 O R3 O Ac2O R2 R2 BnO R N OR1 N O RBnO O + RO O O Ar N H RO2C Ar CO2R1 N OR1 O Ar RO2C CO2R N H RO2C Ar CO2R1 CO2R + + Karlsson, S.; Hofberg, H.E. Tetrahedron: Asymmetry 2001, 123, 1977-1982. Chen, C.; Schreiberg, S.L. J. Am. Chem. Soc. 2003, 125, 10714-10715. Longmire, J.M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400-13401. N H H H Substitution Pattern on Resulting Pyrrolidines 3 4 4 2 3 5 2 3 4 5 2 3 4 5 H 4 3 4 2 3 5 Formation through the concerted mechanism N H EtO2C Ph endo: 65% N H EtO2C Ph Ph N CO2Et Me + + Michael adduct: 10% exo: 25% Ph N CO2 Pr Me CO2Et LiX / Base 1,3-Dipolar Cycloaddition of Azomethine Ylide with Ethyl Acrylate Ph N CO2 Pr Me M i i CO2 Pri CO2 Pri CO2 Pri Possible mechanism? Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossio, F. J. Am. Chem. Soc. 2000, 122, 6078-6092. N H O H H Li Single Favorable Conformation for Metal Complexed Azomethine Ylide Computational and Mechanistic Studies of Azomethine Ylide Cycloadditions N H H H O LiX O2N N H O N Li O H N Li O H O2NO2N endo exo + + 2 3 4 Substitution Effect in 1,3-Dipolar Cycloaddition Reactions Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossio, F. J. Am. Chem. Soc. 2000, 122, 6078-6092. 5 LiX / Base C2 - C3 bond formation B 2 3 2 34 5 A O2N N H O N Li O H N Li O H O2NO2N endo exo + + 2 3 4 Substitution Effect in 1,3-Dipolar Cycloaddition Reactions Li Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossio, F. J. Am. Chem. Soc. 2000, 122, 6078-6092. 5 LiX / Base C 4 5 2 34 5 C2 - C3 bond formation B 2 3 A O2N N H O N Li O H N Li O H O2NO2N endo exo + + 2 3 4 Substitution Effect in 1,3-Dipolar Cycloaddition Reactions Li Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossio, F. J. Am. Chem. Soc. 2000, 122, 6078-6092. 5 LiX / Base C 4 5 2 34 5 C2 - C3 bond formation B 2 3 A endo iN CO2 PrPh Me N H CO2 iPr Ph EtO2C + N H CO2iPr Ph EtO2C + Ph N CO2Et CO2iPr endo exo Michael adduct Solvents Bases AgOAc 20-25 oC CO2Et THF; Toluene; MeCN; CH2Cl2; MeOH KOH; NaOH; K2CO3; LiOH; Et3N; DBU Casas, J.; Grigg, R.; Najera, C.; Sansano, J.M. Eur. J. Org. Chem. 2001, 123, 1971-1982. Application of Silver to the Cycloadditions + N CO2 PrPh Me N H CO2 iPr Ph EtO2C + N H CO2 iPr Ph EtO2C + Ph N CO2Et CO2iPr endo exo Michael adduct CO2Et Casas, J.; Grigg, R.; Najera, C.; Sansano, J.M. Eur. J. Org. Chem. 2001, 123, 1971-1982. Investigation of Better Conditions for Cycloadditions + AgOAc -10 mol% KOH - 10 mol% Toluene, CH2Cl2, THF - 100% conversion, but 75 - 80h, 88 - 92% yield of endo product MeCN - 68% conversion, 90% - endo, 10% - exo MeOH - 100% conversion, but 1:1:1 ratio of products i N CO2 PrPh Me N H CO2 iPr Ph EtO2C + N H CO2 iPr Ph EtO2C + Ph N CO2Et CO2iPr endo exo Michael adduct CO2Et Casas, J.; Grigg, R.; Najera, C.; Sansano, J.M. Eur. J. Org. Chem. 2001, 123, 1971-1982. Use of Silver Acetate under PTC Conditions + AgOAc -10 mol% KOH - 10 mol% PTC Toluene, TBAA - 51 - 73% conversion, 24 - 48 h. TBAA, TBAH, TBAC - solid - liquid phase transfer catalysts THF, TBAA - 100% conversion, 94% - endo product, 1% Michael adduct i Bu N Bu Bu Bu X R-BINAP (1) PPh2 PPh2 HN O Ph2P (R,R)-Trost Ligand (2) P P (R,R)-Me-DuPhos (3) N H O PPh2 P P (R,S,R,S)-PennPhos (4) H H PPh2 PPh2 (R,R,R,R)-BICP (5) NH HN OO Fe PPh2 Ph2P Fe (S,S,Sp)-FAP (6) Chiral Phosphine Ligands Screened for the AgOAc Catalyzed Cycloaddition Longmire, J.M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400-13401. Longmire, J.M.; Wang, B.; Zhang, X. Tetrahedron Lett. 2000, 41, 5435-5439. 13% ee, endo/exo = 3:1 23% ee 59% ee 27% ee 13% ee Variation of the R-Substituents for the Cycloaddition Catalyzed by Ag(I) - FAP Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400-13401. R N CO2Me AgOAc / FAP iPr2NEt, Toluene N H CO2MeMeO2C R CO2Me endo + Entry yield, % ee, % 1 2 3 4 5 6 7 phenyl p-anisole p-chlorophenyl p-cyanophenyl 2-naphthyl i-propyl cyclohexyl MeO2C CO2Me 87 98 96 96 98 98 82 87 92 92 96 97 70 81 R ! N H MeO2C CO2Me CO2MePh N H MeO2C CO2Me CO2MePhN H PrO2C CO2iPr CO2MePh N H MeO2C CO2MePh N H BuO2C CO2MePh N H CO2MePh Me N OO Cycloaddition with Various Dipolarophile Substrates Catalyzed by Ag(I)-FAP 52% ee, 88% yield 87% ee, 87% yield87% ee, 85% yield 60% ee, 90% yield 79% ee, 87% yield60% ee, 90% yield t i cis-olefintrans-olefin Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400-13401. N PPh2 (S)-QUINAP Looking for an Alternative to FAP and BOX P, N-ligand QUINAP along with silver acetate showed excellent levels of diastereo- and enantioselectivity. Catalyst loading is reduced to 1 mol%. Reactions proceed with good yield, de and ee even at -45oC or -20oC. Chen, C.; Li, X.; Schreiber, S.L. J. Am. Chem. Soc. 2002, 125, 10174-10175. N O Ar OMe H OtBu O iPr2NEt AgOAc (S)-QUINAP THF, -45oC 20 h N H Ar CO2Me BuO2C t + Exploration of the Reactivity of the Aromatic Moiety Entry 1 2 3 4 5 Ar Yield, % ee, % 4-methoxyphenyl 4-bromophenyl 4-cyanophenyl 2-naphthyl 2-tolyl 93 89 92 89 95 95 95 96 94 89 N PPh2 (S) - QUINAP Chen, C.; Li, X.; Schreiber, S.L. J. Am. Chem. Soc. 2002, 125, 10174-10175. N O Ph OMe H OtBu O iPr2NEt AgOAc (S)-QUINAP THF, -45oC 20 h N R Ph CO2Me BuO2C t + Cycloadditions with α-substituted 1,3-dipoles Entry 1 2 3 R Yield, % ee, % methyl iso-butyl benzyl 98 77 93 80 80 77 Chen, C.; Li, X.; Schreiber, S.L. J. Am. Chem. Soc. 2002, 125, 10174-10175. R Application of QUINAP with AgOAc to 1,3-dipolar cycloaddition reaction can provide excellent diastereo- and enantioselectivity. Obtained selectivity is comparable to results obtained with FAP and BOX catalysts.! S O p-TolH3C S O p-TolH3CO O S O p-TolH3CO O 1: (R)-methyl p-tolyl sulfoxide 2: (R)-2-(p-tolylsulfinyl) acetate 3: (S)-2-(p-tolylsulfinyl) acrylate 97%ee Ruano, J.L.G.; Tito, A.; Peromindo, T. J. Org. Chem. 2002, 67, 981-987. Synthesis of (S)-2-(p-TolylSulfinyl)Acrylate (a) LiHMDS, -78oC, THF (c) HCHO, Me2NH, rt, 48 h (d) MeI, CaCO3, MeCN, rt 76% yield (b) ClCO2Me, -78oC, THF 87% yield Ar Ph Ph Nph Nph Solvent THF THF THF THF T, oC rt 0 rt 0 1 2 65 72 72 87 35 28 28 13 S CO2Me p-Tol O CO2MeNAr N H MeO2C Ar MeO2C SOp-Tol + AgOAC/DBU 1 2 + Influence of the Solvent on Selectivity of the Cycloaddition Ruano, J.L.G.; Tito, A.; Peromindo, T. J. Org. Chem. 2002, 67, 981-987. Nph MeCN reflux 90 10 Yield, % Ph MeCN reflux 70 30 Ph MeCN 0 27 73 (1.5/1.0 eq) N H MeO2C Ar CO2Me p-TolOS Nph MeCN rt 19 81 S p-Tol O OCH3 O rotamer A rotamer B Facial Selectivity at Dipolarophile in MeCN in THF S p-Tol O OCH3 O Ag N H MeO2C Ar CO2Me p-TolOS N H MeO2C Ar MeO2C SOp-Tol N H MeO2C Ar CO2Me N H MeO2C Ar CO2Me Toluene Toluene Desulfination of Obtained Pyrrolidines Optimal Conditions for Desulfination: Toluene, reflux for 3h - 86-89% yield Ruano, J.L.G.; Tito, A.; Peromindo, T. J. Org. Chem. 2002, 67, 981-987. ∆ ∆ N H RO2C H H Ar CO2Me p-TolOS N H RO2C H H Ar CO2Me N H RO2C Ar CO2Me Toluene Toluene O N Ph O R CO2Me CO2Me O N Me Ph R CO2Me CO2MeOMe -CO2 N H Ph R CO2MeMeO2C Advanced Ways for Construction of Functionalized Pyrroles Ruano, J.L.G.; Tito, A.; Peromindo, T. J. Org. Chem. 2002, 67, 981-987. Peddibhotla, S.; Tepe, J.J. Synthesis 2003, 9, 1433-1440. ∆ ∆ N OMe Ph O NAr HN N Ph ArMeO2C S p-Tol O MeMe Imidazolidine, 53% + LDA, THF -78oC 4oC endo : exo = 95 : 5 S p-Tol O Ruano, J.L.G.; Tito, A.; Peromindo, T. J. Org. Chem. 2002, 67, 981-987. Peddibhotla, S.; Jayakumar, S.; Tepe, J.J. Organic Letters 2002, 4, 3533-3535. N O Ph Me O NPh Bn TMSCl CH2Cl2 N O N O Bn Ph Me H TMS Ph N N Ph Ph Me COOH Bn Imidazoline, 75% Formation of Imidazo-Compounds through Cycloaddition Reactions endo : exo = 95 : 5 1,3-Dipolar cycloaddition of azomethine ylides can be diastereomerically and enantiomerically controlled by use of metal salts (AgOAc or Zn(OTf)2) in presence of a suitable base. Enantiocontrol can be provided by application of FAP, BOX or QUINAP as the chiral catalyst. Use of chiral vinyl sulfinyloxides gives not only excellent enantiocontrol, but also has the potential to alterate the selectivity of cycloaddition by changing the solvent or reaction conditions. Summary 1,3-Dipolar cycloaddition of aminoacid derived ylides and muchnone ylides with substituted imines gives formation of different imidazo-compounds with good diastereo- and enantioselectivity. Thank You !