Use of 2 TiCl in Synthesis eagent Control of adical eactions Jeff Kallemeyn May 21, 2002
eactions of 2 TiCl 1. Pinacol Coupling H H H 2. Epoxide pening H H E H Chemoselectivity Activated aldehydes (aromatic, a,b-unsaturated) more reactive than aliphatic aldehydes. Esters, nitriles, ketones unaffected. Br, Cl, tosylate stable. Mild radical initiator.
Preparation of 2 TiCl Zn or Mn THF 15 min Ti IV Cl Cl Zn, neat Tl 2 III TiCl 3 Ti III Cl Cl M Cl Cl III Ti M=Zn ether Ti III Cl Cl Ti III Solvent (S) 2 Ti III Cl S Ti(III): [Ar] 3d 1 2 TiCl generated by in situ reduction with Mn or Zn. Both dimer and trimer work equally well in most cases. In situ regeneration of Ti(III) possible allowing it to function catalytically. M-Ti-M : 132 o. Jungst; D. Sekutiwski; J. Davis; M. Luly; G. Stucky, Inorg. Chem. 1977, 16, 1645.
Substrate Controlled Stereoselective adical eaction Substrate directs the stereoselectivity of the reaction. 1. Substrate has stereogenic center TMS TMS I Bu 3 SnH AIBN H H 72% yield D. Curran, D. akiewicz, Tetrahedron, 1985, 41, 3943. 2. Chiral Auxiliary t-bu N N t-bui Bu 3 SnH AIBN N N 70% yield, 86-97% ee. N. Porter, D. Scott, I. osenstein, B. Giese, A. Viet, H. Zeitz, J. Am. Chem. Soc. 1991, 113, 1791.
eagent Controlled Stereoselective adical eaction 1. Complexation t-bui, Et 3 B, 2 N Zn(Tf) 2, Ligand 5 mol% SnBu 3 t-bu N 92% yield, 90% ee N N Ph Ligand Ph Control Features: Chelation locks substrate into rigid conformation. Chiral ligand allows only 1 face of radical to be accessible. M. Sibi, N. Porter, Acc. Chem. es. 1999, 32, 163.
eagent Controlled Stereoselective adical eaction 2. Chiral Hydrogen Source Ac + Ph 3 SiH Ph 3 Si Ac Ac SH Ac 5 mol % Ph 3 Si H 72% yield, 50% ee M. Haque, B. oberts, Tetrahedron. Lett. 1996, 37, 9123. Ph Br CMe "Sn" Et 3 B Ph H CMe SnH Me 30% yield, 41% ee 3. Formation of radical: 2 TiCl D. Nanni, D. Curran, Tetrahedron Asymm. 1996, 37, 2417.
Pinacol Coupling H + S Cl Ti Ti 2 Cl Ti 2 Cl Cl 2 Ti Ti 2 Cl H 3 + H H General Mechanism Ti IV Cl CH 3 Distorted Tetrahedral Bond Lengths and angles Ti- 1.839 Cl-Ti- 93.8 Ti-Cl 2.412 -Ti_M(1) 109.6 Ti-M 2.088 -Ti-M(2) 105 Ti-M 2.093 Cl-Ti-M(1) 105 -C 1.367 Cl-Ti-M(2) 106.3 M(1)-Ti-M(2) 130.8 Ti--C 141.4 Y. Handa, J. Inanaga, Tetrahedron Lett. 1987, 28, 5717. D. Gibson, Y. Ding, M. Mashuta, J. ichardson, Acta Crys. 1996, 52, 559.
Pinacol Coupling Cl Cl Proposed intermediate leading to high diastereoselectivity. Y. Handa, J. Inanaga, Tetrahedron Lett. 1987, 28, 5717.
Development of Catalytic Pinacol Coupling Cl 2 Ti Ti 2 Cl 2 TMSCl TMS TMS + 2 Ti 2 Cl 2 Product resting state before hydrolysis T. Hirao, B. Hatano, M. Asahara, Y. Muguruma, A. gawa, Tetrahedron Lett. 1998, 39, 5247.
Development of Catalytic Pinacol Coupling TMSCl and Zn can effect the pinacol coupling and proceeds with low diastereoselctivity. Initial catalytic reactions gave worse diastereoselectivities than stoichiometric (86:14 to 50:50). Silylation of Ti alkoxide determined to be the slow step in the reaction. Low diastereoselectivies solved by slow addition of TMSCl, MgBr 2 and aldehyde to Ti(III) and Zn. cis:trans A. Gansäuer, Synlett. 1998, 801.
Modification of Catalytic Pinacol Coupling adicals are stable under protic conditions. Selection of correct base important as to not oxidize the metal reductant or complex with the Titanium catalyst. Addition of Amine HCl salt leads to increased diastereoselectivity, faster turnover compared to TMSCl catalyzed system. H H Ar Ar Ar Ar 1 H 2 H 2,4,6-Collidine eference A. Gansäuer, D. Bauer, J. rg. Chem. 1998, 63, 2070.
Enantioselective Pinacol Coupling M. Dunlap, K. Nicholas, Syn. Comm. 1999, 29, 1097. A. Bensari, J. enaud,. iant, rg. Lett. 2001, 3, 3863.
Mechanism of Epoxide pening Product ratios show higher substituted radical formed. Titanium attached to radical it created--reagent control. Ti 2 Cl Ti 2 Cl 2 TiCl Ti 2 Cl Ti 2 Cl D 3 + D D Ti 2 Cl D D 8 eductive termination pathway depends on reactivity of intermediate radical. + D 7 T. ajanbabu, W. Nugent, J. Am. Chem. Soc. 1994, 116, 986. A. Gansäuer, H. Bluhm, Chem. ev. 2000, 100, 2771.
Epoxide pening and Trapping C 8 H 17 + CN 1) 2 TiCl 2) H 3 + H CN H 17 C 8 H17 C 8 H 88% 12% adical formation at the higher substituted carbon. CN Electrophilic workup Complementary to nucleophilic epoxide opening T. ajanbabu, W. Nugent, J. Am. Chem. Soc. 1994, 116, 986.
Diastereoselectivity in 5-member ring formation H CH 3 Y Y= CH 2, NTs, 10 mol% 2 TiCl 2 Mn, Coll*HCl THF H Y A. Gansäuer, M. Pierobon, H. Bluhm, Synthesis 2001, 2500
Diastereoselectivity in 5-member ring formation A. Gansäuer, M. Pierobon, H. Bluhm, Synthesis 2001, 2500.
Deoxygenation of Epoxides Deoxygenation discouraged in the presence of trapping agents with inverse addition of 2 TiCl to minimize the concentration of Ti(III). Effective for sensitive functional groups, especially acid sensitive. T. ajanbabu, W. Nugent, J. Am. Chem. Soc. 1994, 116, 986
Effects of Solvent and Water Conditions (+)-3a-hydroxyreynosin A. Barrero, J. ltra, J. Cuerva, A. osales, J. rg. Chem. 2002, 67, 2566.
Effects of Solvent and Water Proposed concerted transition state leads only to 6-endo cyclization with no 5-exo product. Tertiary radical hindered--it is not trapped by Ti(III) or reduced by 1,4- cyclohexadiene. Deuterium incorporation is observed at C4 when D 2 is used. A. Barrero, J. ltra, J. Cuerva, A. osales, J. rg. Chem. 2002, 67, 2566.
Formation of a-glycosides eaction Scheme Complementary to Nucleophile eaction Scope J. Parrish,. Little, rg. Lett. 2002, 4, 1439
Formation of a-glycosides eduction Lewis acidic epoxide opening yields the undesired product. Trapping agent must be of the correct electronic nature. J. Parrish,. Little, rg. Lett. 2002, 4, 1439
Catalytic Epoxide pening A. Gansäuer, H. Bluhm, Chem. ev. 2000, 100, 2771 A. Gansäuer, M. Pierobon, H. Bluhm, Angew. Chem, Int. Ed. 1998, 37, 101
Catalytic Asymmetric Epoxide pening 6 A. Gansäuer, H. Bluhm, Chem. ev. 2000, 100, 2771. A. Gansäuer, H. Bluhm, M. Pierobon, M. Keller, rganometallics, 2001, 20, 914. 7
Catalytic Asymmetric Epoxide pening 7 7 7 7 6 6 6 6 eference A. Gansäuer, H. Bluhm, T. Lauterbach, Adv. Synth. Catal. 2001, 343, 785
Conclusion 2 TiCl is a mild reducing agent for pinacol and epoxide opening reactions. pposite chemoselectivity to nucleophilic epoxide opening. eagent controlled enantioselective modifications to the Ti(III) reagent now emerging. A wide range of functional groups are tolerated. The oxidation/reduction of reagents and substrates can have significant effect on success of reaction.
. Flowers, Tetrahedron Lett. 1997, 1137 T. Skrydstrup, Chemistry, 2001, 435 Li--Li + + e Na--Na + + e Mg --> Mg 2+ + 2e Al --> Al 3+ + 3e Mn --> Mn 2+ + 2e Zn --> Zn 2+ + 2e Fe --> Fe 2+ + 2e Ni --> Ni 3+ + 3e E o reduction potential 3.05 2.71 Ti(IV) --> Ti(II) 2.37 1.66 1.18 Ti(IV) --> Ti(III) 0.76 0.44 Ti(III) + MCl x --> Ti(IV) + M 0.25 D. Sekutowski, Low Valent rganometallic Titanium Compounds, Dissertation, UIUC, 1975