Catalysis by Group IV Elements CHEM 966 (Tunge) Good reference: Titanium and Zirconium in Organic Synthesis Ilan Marek Ed., 2002.

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1 Catalysis by Group IV Elements CEM 966 (Tunge) Good reference: Titanium and Zirconium in rganic Synthesis Ilan Marek Ed., Electronegativity: Ti(1.54); (1.33); f(1.3) Much of the chemistry is dominated by the oxophilicity of these metals. There are many, many reactions that are catalyzed by Ti and via Lewis acid activation of polar functional groups. Since these mechanisms are not terribly unique, our focus will not be on these reactions. Since the oxidation state chemistry is dominated by the +4 oxidation state, oxidative addition is not possible and most reactions have to proceed by σ-bond metathesis. xidation State: +4 >> +2 > oxidation state is easiest to achieve for Ti (electronegativity) Making C bonds 2Li >98% terminal >98% E - (IV) (II) The zirconocene butene complex reacts as one would expect for (II). Many similar reagents exist that are referred to as Bn xidative Addition? "" These reactions really proceed through (IV) intermediates. Bn - Bn - Bn Bn ote: Alkene insertion (carbozirconation) to form zirconacyclopentanes is reversible. egishi, E. JCS Chem Comm MgBr MgBr Productive use of alkyl zirconocenes. Br 2 Insertion of polar π-electrophiles is common. Can t reductively eliminate, so zirconium alkyls must be cleaved from the metal by A) β-hydride elimination, B) external reagents, C) transmetalation. Several common reactions are shown below. () a () () I 2 or Br 2 Br () These reactions are often incompatible with catalytic reactions, so they are most often utilized stoichiometrically. Transmetalation of vinyl zirconocenes is important in catalytic C C bond forming reactions. Transmetalation from to: Li, Mg, B, Al, i, Pd, Cu, and Zn are all possible. -X - Br Br

2 Catalysis by Group IV Elements CEM 966 (Tunge) ydrogenation Asymmetric hydrogenation of olefins is often associated with late transition-metal h, Ir, u, and Pd catalysts, however -catalysts are particularly useful for hydrogenation of tetrasubstituted alkenes. chwald, S. L. JACS (EBTI) 2 [ 2 + ][B(C 6 F 5 ) 4 ] 8mol% 8mol%[ 2 + ][B(C 6 F 5 ) 4 ] >1000 psi 2 82% (92% ee, >99:1 dr) (EBTI) 2 (EBTI) Controls Al 3 2 Al tals must cooperate. ow? Dynamic polarization. Aluminum can act to make more electrophilic 2 +Al 3 Al 2 Al2 Al 2 or can act to make Al more electrophilic. δ- Al δ+ X X X=, Al X X Al 2 Al 2 Al X X (EBTI) (EBTI) (EBTI) π -benzyl stabilization may contr ol r egiochemistr y If the metal is more electrophilic (lower LUM), then binding of alkyne is more favorable. Binding of the alkyne to a more electrophilic metal polarizes it (i.e. lowers it s LUM) so metalation is facile. lefin can t be monosubstituted because small alkenes are polymerized rapidly by cationic complexes in a process known as Ziegler-atta olefin polymerization. coordination alkyne M LUM of M M carbometalation LUM of alkyne M M- Carboalumination 3 3 Al + 10 mol% Cp 2 2 Al 2 I 2 chanism of methylalumination: egishi, E. JACS ; JACS I Which mechanism is it? C ) CD 3 (C 3 ) 3 Al C ) I 2 3 C I 92% (no D incorporation)

3 Catalysis by Group IV Elements CEM 966 (Tunge) ote: It is important that the C 3 and CD 3 do not exchange over the time of the experiment. chanism of ethylalumination in nonpolar solvents is different: egishi, E. JACS Al 3 Al Al hexane 6h, 23 o C Al 2 electron count? Al 2 Al 3 Al D >98% D Al 2 Al 2 D 3 Al D Al 92% Al 2 Al 2 chanism is different for 2 Al or ial 3 are different still. Al Uses: polypropionate synthesis. egishi, E. PAS Iterate by repeating Swern-Wittig-ZACA. 2.5 eq. 3 Al 1eq.IBA 5% (-)MI 2 2 startwithhigheereaction 1) Swern 2) Wittig 92%, 90%ee 1.5 eq. 3 Al MA (30%) 5% (-)MI 2 2 then eq. 3 Al MA (30%) 5% (+)MI 2 2 then 2 C 6 8 () 5 8:1 dr (>50:1 purified) 4:1 dr (>40:1 purified) using low ee reaction second still gives high ee product due to statistical asymmetric amplif ication Solvent effect: ct 33% ee * * ct 3 Al 3 Al ct Al ct Al 2 2 hexanes C 3 C 2 2 ct 92%ee Asymmetric Carboalumination (ZACA) egishi, E. JACS ct n-pr 1) (n-pr) 3 Al, cat. Pr C 3 C 2 2) [] ct 62%, 91% ee 1) (n-oct) 3 Al, cat. ct C 3 C 2 2) [] n-pr 59%, 85% ee Stereoselectivity for methylalumination: ca. 75% ee 2 2 Carboalumination is accelerated by 2 or MA (methylalumoxane). Wipf, P. ACIE ; L C 6 13 Al 3 (2 equiv) 2 (0.2 equiv) 2 (1.5equiv) C o C then 3 C 6 13 Al 2 Carboalumination of Dienes: Waymouth,. JACS Titanium-catalyzed Carboalumination: Waymouth,. M. rganomet

4 Catalysis by Group IV Elements CEM 966 (Tunge) Carbomagnesiation: hylmagnesiation see: Dzhemilev, U. M. uss. Chem. ev BrMg MgBr Cp 2 Cp 2 MgBr Cp 2 chanism of regioselective carbomagnesiation: Morkin, J. P.; oveyda, A.. JACS 1992, C 3 CD 2 MgBr 5mol% 2 C 3 C 2 43% D 57% D Asymmetric Carbomagnesiation-Elimination: Morkin, J.; oveyda, A. JACS 1993, Mg 1 65% 97% ee C- alkylation: Jordan,. F. JACS A unique reaction because catalysis takes place under C Cp Cp (TF) B 4 2 -C 4 Cp Cp ydroamination Bergman,. G.; Walsh, P. J. JACS Ar 3mol% Ar 110 o C 0.2 T/h 2 Cp Cp The mechanism of this reaction has been well worked out by Walsh and Bergman. All of the reaction intermediates have been isolated and are observed to undergo the individual stoichiometric reactions. Ar Ar Mg Ar Ar For kintic resolution of allylic alcohol derivatives using catalyzed carbomagnesiation see: oveyda, A.. JACS Ar Ar 2 Ar Ar

5 Catalysis by Group IV Elements CEM 966 (Tunge) ate = k[][alkyne][amine] -1 which step is rate-limiting? Markovnikov ydroamination Asymmetric hydroamination of alkenes. P ( 2 ) 2 P Bergman rganomet mol%, 115 o C, 24 h n = 1: 95% (80% ee) n = 2: 79% (33% ee) n s cat* ( 2 ) 2 s Schafer, L. L. ACIE mol%, 110 o C, 3 h n = 1; 80% (93% ee) n = 2; 91% (29% ee) n Bn B(C 6F 5 ) 4 Scott, P. ChemComm mol% BrC 6 5,100 o C n = 1: 48h, 14% ee, alkene isomerization n=2:3h,100%conv.(82%ee) Titanium catalysts are generally faster than catalysts at alkyne hydroamination. Lanthanide and Actinide catalysts are as well. See: Marks, T. J. JACS owever, Ti catalysts have not been very successful at alkene hydroamination. Exceptions: Schaefer, L. L. L ; dom, A. ACIE 2005, 5972; Ackermann, L. L chanism of Cp 2 Ti 2 -catalyzed alkyne hydroamination. See: Doye, S. ACIEE ote: Small amines do not work well due to dimerization: 2 Cp 2 Ti - Cp 2 Ti t Ti() 2 2 t Beller, M. L mol%, 100 o C, 24 h, tol then acb 3 high yields, good scope cat 2 ' Ti( 2 ) 2 ' dom, A. ChemComm mol%,25 o C, 5 min, moderate yields Anti-Markovnikov ydroamination Ti( 2 ) 2 Ar Schafer, L. L. L 2003, 4733; ChemEurJ mol%,65 o C, benzene; high yields; >99% regio compatible with amides, esters, protect alcohol, imine cat 2 ' ' Ti( 2 ) 4 dom, A. rgmet mol%, tol, 75 o C 2-48h, works only for aromatic amines Ti() 2 2 Beller, M. TL mol%, 100 o C, 24 h, tol high yields, good scope, good regioselectivity; compat with amines, silyl, protected alcohols In general catalysis with titanium is more facile and thus a wider range of reactions are catalyzed by titanium. Furthermore, Ti(II) is much more prevalent than (II), so redox catalysis through Ti(II)- Ti(IV) cycles is more common.

6 Catalysis by Group IV Elements CEM 966 (Tunge) Cyclopropanation 1 C 2 2 MgBr (2 eq) Ti(i-Pr) 4 (5-10 mol%) 2, o C 2MgBr 1 (i-pr) 2 Ti ote: MgBr added via syringe pump over 2-6 h. eductive cyclization Titanacyclopropanes are excellent reagents for reductive coupling. Most of the chemistry is stoichiometric in Ti because cleavage of the resulting metallacycle to regenerate a catalyst is difficult. (i-pr) 2 Ti ' (i-pr) 2 Ti ' (i-pr) 2 Ti (i-pr) 2 Ti ' Alkenes can be coupled with esters by alkene exchange. (i-pr) 2 Ti (i-pr) 2 Ti rg. Syn. Vol. 80, p.111 (2003). + 3 C C 2 n-c 5 9 Mg (i-pr) 3 Ti TF n-mg (i-pr) 3 Ti 2 3 C (i-pr) 2 Ti Example of stoichiometric reductive coupling. Sato, F. ChemComm Ti(i-Pr) 4 2equiv i-prmg (i-pr) 2 Ti TMS TMS Ti() 2 2 TMS 94% 91:9 dr Catalytic Pauson-Khand: chwald, S. L. JACS 1996, 9450; JACS 1999, mol%Cp 2 Ti(C) 2 18 psi C, tol, 90 o C, 12 h C Cp 2 Ti(C) 2 Cp 2 Ti(C) 87% Asymmetric cyclopropanation: Corey, E. J. JACS Isonitriles (i.e. TMSC) can replace C: chwald, S. L. JC 1996, 2713.

7 Catalysis by Group IV Elements CEM 966 (Tunge) Asymmetric Ti-catalyzed Pauson-Khand: chwald, S. L. JACS 1999, E E E=C 2 t 5mol%(S,S)-(EBTI)Ti(C) 2 14 psi C, tol, 90 o C, 12 h Ti favored E E 89% (88% ee) Ti C C (S,S)-EBTI-Ti(C) 2 Catalytic reductive cyclizations of carbonyl compounds. Crowe, W. E. JACS mol % Cp 2 Ti(P 3 ) 2 Si() 3 Si() 3 Si 3 Si 3 P 3 Silanes are good oxophilic reductants. chwald, S. L. JACS 1997, mol% Cp 2 Ti(C) 2 30 mol% P 3 5psiC,100 o C, 36h 88% 1:1 dr Si 3 Cp 2 Ti(P 3 ) n 96% yield Ti(III) catalysis: Titanium(III) is much more prevalent than (III). Ti(III) catalysis usually takes place by atom-abstraction to generate Ti(IV) intermediates. A coreductant (Mn or Zn) is necessary to regernerate Ti(III). irao, T. JC Cp 2 Ti I I 10 mol% Cp 2 Ti 2 Mn, 3 Si, TF 65 o C, 24 h Ar 64%, 85:15 dr Epoxide opening : Stoichiometric: ugent, W. A.; ajanbabu, T. V. JACS ; JACS Catalytic: Gansauer, A. JACS Cp 2 Ti C 2 t 2Cp 2 Ti 2 Mn 10 mol% (tcp) 2 Ti 2 Zn, col* 2Cp 2 Ti Ti()Cp 2 Ti()Cp 2 C 2 t +Mn 2 90%, 94:6 dr C 2 t Cp 2 Ti Ti()Cp 2 Ti()Cp 2 t

8 Catalysis by Group IV Elements CEM 966 (Tunge) McMurry Coupling Furstner, A. JACS mol% Ti 3 TMS, Zn C 3 C rfx, 0.5 h CF 3 CF 3 88% Ti Ti Ti Ti Ti Ti= 2TMS Ti 3 TMSTMS From the same paper not catalytic, but amazing. 28 Ti powder (3 eq) TMS (3 eq) DME reflux, 6 h 0.02 M 90% elson, S. JC (TF) 3 Ti 3 complex dramatically accelerated McMurry type pinicol coupling. 10 mol% 3 Ti(TF) 3,Zn,TMS 30 mol% 1,3-diethylphenylurea TF, 0 o C, 6 h TMS TMS 89%, 88:12 dr 69:31 dr w/o urea