Organo-transition Metal Chemistry

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1 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg 1 rgano-transition tal Chemistry 1. Some Basics Chemistry involves intermediates containing transition-metal carbon bonds tal-carbon sigma bond Coordination sp3 C sp2 C C sp C C C ligand sphere L 2 L 1 L 3 M C Ln M C L 5 L 4 Electron Counting: Formal neutral ligand (L): P 3, 3, C, alkyne, Alkene Formal anionic ligand ():, Ar,,, C, C 3 P 3 P Pd P 3 P 3 ML 4 Pd(0) d 10 = 10 e P3 2 e 4 = 8 e 18 e 3 P 3 P Pd ML 2 Pd(0) d 10 = 10 e P3 2 e 2 = 4 e 14 e 3 P 3 P Pd Ar Ar ML 2 2 Pd() d 8 = 8 e Ar, 2 e, 2 e = 4 e P3 2 e 2 = 4 e 16 e

2 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg 2 Ligand Exchange: Ligand Association and Ligand Dissociation Ligand association L' ML n :L' Ligand dissociation 3 P P 3 Pd 3 P P 3 L-dissociation - P 3 3 P P 3 Pd P 3 L-dissociation - P 3 P 3 Pd P 3 xidative Addition/eductive Elimination Vacant site usually polar bond M(n)L n Y xidative Addition. eductive Elimination Y M(n2)L n P 0 Pd 0P 3 P 3 P 3 3 P Pd P 3 Pd 2 P 3 xidative Addition. eductive Elimination P Pd 2 3 P 3 Pd(P 3 ) 2 Ligand effect: Electron donating ligands facilitate oxidative addition (e.g. P 3,, ); electron withdrawing ligands facilitate reductive elimination (e.g., C, C, olefins). Migratory nsertion/de-insertion: Migration of one ligand to a neighboring unsaturated ligand (C, C, alkyne, alkene), generating a vacant site. Usually reversible. Vacant site is cis to the newly formed ligand. C nsertion De-insertion 2 C C L M n 2

3 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg 3 Carbometallation/β-elimination Carbometallation β-elimination Dehydropalladation L n M vacant site Φ = 0 Pd L n Pd β-ydride Elimination L n Pd PdL n Carbometallation: nsertion into alkene/alkyne group Migrating aptitude of β-eliminaton : >> Alkyl, Ar > C> β-ydride Elimination : Very common pathway for the decomposition of alkylmetal complexes 2. eck eaction C 2 10 mol % Pd(Ac) 2 P 3, K 2 C 3 C 3 C 100 o C, 90 % C 2 cat. Pd Base, P 3 1: Aryl, Vinyl, Benzylic, Allylic, Acyl : 2 > > ~S2CF3 >> Cl (relative rate of oxidative addition) Pd: Pd(0) or Pd(). Active Pd(0) species can be instantaneously made from Pd() in reaction media Base : Scavenger of P 3 : Prevents Pd(0) from precipitation to make palladium mirror Solvent: ften coordinating solvents such as MP, DMA, DMF, acetonitrile but sometimes toluene can be used Temperature: room temp. to 140 o C

4 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg 4 Catalytic cycle: Pd(P 3 ) 4 eductive Elim ination Base - Pd(0)(P 3 ) 2-2 P 3 1 xidative Addition 1 Pd()(P 3 ) Pd ()(P 3 ) 2 Pd ()(P 3 ) 2 Pd ()(P 3 ) Syn-β--Elimination 1 Syn- Carbopalldation Pd(P 3 ) 2 1 Pd(P 3 ) internal rotation ntramolecular eck Cascade Pd(0) PdL n' PdL n PdL n Si 3 Si 3 Si 3 Si 3 xidative addition ligand association Carbopalladation β--elimination PdL n PdL n Si 3 Si 3 Si 3 ligand association Carbopalladation PdL n Dehydropalladation Beta--elimination Tandem eck eaction ntermolecular eck reaction followed by intramolecular one Syn-Carbopalladation leads to only one geometric isomer

5 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg 5 Stable rgano-pd intermediate without syn β- 3 mol % Pd(P 3 ) 4 C eq. Et o C, 12 h 80 % L n Pd L n Pd 2 C Syn-carbopalladation Sequential Tandem eck eaction tbu (: o-t ol) Syn- 10 % carbopalladation tbu P tbu Pd(Ac) 2, Pd Ac 22 % P 3, L n Pd 2.0 eq 60 o C, 60 h. 120 o C C 3 C, DMF nbu 4 (Ac) More eactive Syn- Elimination e tbu a e tbu L n Pd a L n Pd 63 % Stable rgano-pd ntermediates ntermediate organo-palladium species are thermally stable due to the absence of hydrogen β-syn to palladium 1 PdL n 1 PdL n PdL n - Pd L 2 1 PdL n 1 PdL n 1 PdL n 1 PdL n

6 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg 6 3. Stille Coupling eaction 10 mol % Pd(P 3 ) 4 3 C Bu 3 Sn C3 100 o C 3 C 1 cat. Pd 2 SnBu SnBu 3 1, 2 : sp2-hybridized carbon : > S2CF3 > >> Cl Ability for transmetalation: alkynyl> alkenyl> benzyl, allyl> alkyl Exceptional functional group tolerance igh cost and toxicity of organotin reagent 4. Suzuki Coupling eaction 10 mol % Pd(Ac) 2 C () 2 B P 3, a 2 C 3 ipr, 2, reflux. 86 % C B C 3 mol % PdCl 2 (dppf) 2.0 eq. K 2 C 3 DMF, TF, 50 o C 81 % C Less expensive, less toxic alternative to Stille coupling Sp3 carbon can be involved in coupling partner elative rates of reductive elimination: aryl-aryl > alkyl -aryl> alkyl-alkyl Somewhat basic conditions needed

7 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg 7 Catalytic Cycle of Stille/Suzuki Coupling 1 2 eductive Elimination Pd(0)L n 1 xidative Addition Pd()L n Pd()L n M M 1 Pd()L n 2 2 M Transmetallation Transmetallation step is supposed to be the slowest in the Stille coupling Depending on the leaving group, oxidative addition can be a rate determining step in Suzuki coupling Termination with Carbonylation Pd()L n C stable organo-pd species Pd()L n C ' eck Pd()L n u u Suzuki Stille u 2 Ar 2 3 igher affinity and fast insertion of C ligand to Pd elative migratory insertion rate: alkyne > carbon monoxide (ca. 1 atm) > alkene

8 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg 8 1 SnBu C Pd catalyst 1 2 SnBu 3 2 = Aryl-, Alkyl-, Allylhalogenide und -triflate SnBu 3 (P 3 ) 2 PdCl 2 11 bar C 70% J. K. Stille J. Am. Chem. Soc. 1984, 106, Sn TPS tbu 2.5 mol % Pd 2 (dba) 3 22% 3 As C (12 bar) LiCl, MP 70 o C 80% TPS tbu L. E. verman J. Am. Chem. Soc. 1993,115,3966 Examples of the Stille reaction: SnBu Bu3 3 3 Sn 20 mol% Pd(C) 2 Cl 2 i-pr 2 Et 25 C DMF/TF 48 hours M e M e K. C. icolaou, Chem. Eur. J. 1995, 1, SnBu 3 2 Cl 2 Pd catalyst 2 1 Cl SnBu 3 1 =Alkyl,Alkenyl,Aryl,Alkynyl, 2 =Alkyl,Alkenyl,Aryl,Alkynyl The coupling of acid chlorides proceeds without Pd catalyst in many cases. Boc Sn 3 2 CCl Pd 2 dba 3 CCl 3 K 2 C 3 i-pr 2 Et Boc 2

9 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg 9 Stille reactions with triflates Lii-Pr 2 2. Tf 2 Tf 1 2 Tf = CF 3 S 2 1. Lii-Pr 2 (< 1 equivalent) 2. Tf 2 Tf 3 Sn Si 3 Pd(P 3 ) 4 LiCl TF, Δ Si 3 W. D. Wulff Tetrahedron Lett. 1988, 29, Preparation of stannanes from triflates: Tf Sn 3 3 Sn Sn 3 Pd(P 3 ) 4 LiCl, Li 2 C 3 oder ( 3 Sn) 2 Cu(C)Li 2 W. D. Wulff J. rg. Chem. 1986, 51, 277. eterocycles: Bu 3 Sn Pd(P 3 ) 4 37% T.. Kelly J. rg. Chem. 1997, 62, 2774.

10 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg 10 Palladium on charcoal can be used as a source of the catalyst: SnBu mol % Pd (10 mol % Pd/C) 10 mol % Cu 20 mol % As 3 12 hrs. (88%) 3 C 95 % trans SnBu mol % Pd (10 mol % Pd/C) 10 mol % Cu 20 mol % As 3 16 hrs. 3 C (82 %) 100 % trans Liebeskind, L.,Tetrahedron Letters, 1995, 36, Examples of the Suzuki reaction: 1 B() 2 Pd(Ac) 2 (2 mol%) K 2 C 3, 2, 25 C, 2h Bu % =, C S 1 B() 2 Pd(Ac) 2 (2 mol%) K 2 C 3, 2, 25 C, 2h Bu % =, C The addition of tetrabutylammonium bromide facilitates the reaction. Bu B 2 3 mol% Pd(P 3 ) 4 2MaEtinEt C 6 6, Δ Bu B 2 Yield E:Z B : 6 B(c-C 6 11 ) : 17 B(i-Pr) 2 98 >97 : 3

11 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg 11 Yields with alkyl boron compounds are often low because of protodeboronation. Boronates are better reagents. ate of protodeboronation: 9-BB > B(c-C 6 11 ) 2 > B() 2 Coupling of primary alkylboron compounds: TBS B C 2 PdCl 2 (dppf) 3 As Cs 2 C 3 DMF/TF/ 2 25 C 70-80% TBS C 2 Johnson, C..; aun, M. P. J. Am. Chem. Soc. 1993, 115, Diazonium salts can be coupled in Suzuki reactions: 2 () 2 B Pd(Ac) 2 1,4-dioxane 22 C 79% J.-P. Genêt Bull. Soc. Chim. Fr. 1996, 133, Although not very reactive, chloroarenes can be used in the Suzuki reaction: Cl () 2 B 5 mol% PdCl 2 ( ) 2 CsF, MP 100 C 98% W. Shen Tetrahedron Lett. 1997, 38,5575.

12 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg Pd-catalyzed allylic alkylation (Tsuji Trost reaction) Ac 10 mol % Pd(P 3 ) 4, P 3 ac(c 2 Et) 2 TF, reflux C 2 Et C 2 Et General reactivty of substrates: alide, Carbonate > Acetate > epoxide (?) ucleophile: C-nucleophile- malonate, active methylene nucleophile; heteroatom (,, S, P, Si)-based nucleophile; hydride (B-, Sn-, Al- and formates); organometallics (Zn-, Zr-, Sn- etc.). Catalytic cycle: u Ligand dissociation Pd(0) Ligand association L n Pd u u L n Pd u-attack Second invesrion Pd L L - Pd L xidative Addition S 2'-like (invesrion) Active cationic form of η3- allyl Pd complex intermediate is favoured by the bidentate phosphine ligand. Stereoselectivity: etention of the carbon atom configuration by double inversion. u u PdL n PdL n PdL n

13 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg 13 Allylic alkylation with ketone enolates Enolates can be used as the nucleophile in allylic alkylations, which broadens the scope of the reaction even further. n the example on the left, the enantioselectivity of the reaction (the direction of attack of the nucleophile to the prochiral allyl cation) is controlled by the chiral C2 symmetric ligand ()-BAP. The example on the right uses the same chemistry, but a different C2 symmetric chiral ligand to control the enantioselectivity of the reaction. Literatur: Angew. Chem. nt. Ed. 2006, 45, 6952.

14 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg Palladium-catalyzed Amination Cl 1 2 Pd(Ac) 2 (1-2 mol%) Ligand (2-4 mol%) atbu (1.4 equiv) Toluol, aumtemp h 1 1 P(tBu) 2 Ligand = Bn 98% 94% 90% 99% ucleophilic aromatic substitution. Pd-catalysis allows reaction of non-activated arenes. Catalytic cycle:

15 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg 15 Examples: ickel-catalyzed aromatic amination Copper-catalyzed aromatic amination Diarylethers are accessible by a similar reaction using phenols as nucleophile.

16 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg 16 A variation is the coupling of aryl boronic acids with amines or phenols. The reaction is called the Chan-Lam coupling. chanism: 7. Palladium-catalyzed Alkyne coupling reactions A. Castro-Stevens Kupplung 1 Cu B. The Sonogashira-agihara Kupplung 1 1 =,,Cl PdCl 2 (P 3 ) 2 (2 mol%) Cu oder CuAc(1 mol%) Amin = Et 2, Et 3 oder 25 C

17 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg 17 The amine is necessary to deprotonate the alkyne. Best coupling results are obtained in TF. The mechanism is similar to the Suzuki or Stille coupling, but an organocopper species is transmetallated. Cu 1 1 Cu The halide, substituents in both coupling components, the catalyst and the amine influence the rate of the reaction. TF or amines are usually used as solvents. = > Ar > > Ar Cl 2 Pd(P 3 ) 2 Cl 2 (cat) 2 1 Cu (cat) 1 Et 3, TF 1 2 eaction conditions Yield [%] 4-C 4-C 2-C 2 3-C 2 4-C 2 4-C 4-C 4-C 3 Si 3 Si 3 Si 3 Si 3 Si n-bu 25 C / 1h 25 C / 1h 25 C / 16h 25 C / 16h 25 C / 16h 25 C / 16h 25 C / 16h 25 C / 16h C 5 11 C 5 11 C 5 11 Cl [Pd] (5%), Cu (10%), Amin, T C 5 11 [Pd] amine time [h] yield [%] PdCl 2 (C) 2 piperidine PdCl 2 (P 3 ) 2 piperidine Pd(P 3 ) 4 piperidine Pd(P 3 ) 4 n-pr

18 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg 18 chanisms: Palladium-copper co-catalysis (left); copper-free (right) Examples: 3Si Si 3 Si i Pr 3 1) Pd(0) / Cu() 2) K 2 C 3, Pr i 3 Si Si i Pr 3 F. Diederich, Angew. Chem. 1993, 105,

19 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg 19 Si 3 1) Pd(0) / Cu() 2) K, 28% K.P.C. Vollhart, Angew. Chem. 1986, 25, ndole synthesis: Ligand (10 mol%) All in one: Tandem eck-stille-sonogashira eaction Bn TBS Bu 3 Sn 3mol% Pd(P 3 ) eq. Et o C, 12 h 80 % Bn transmetallation SnBu 3 PdL ' n Bn Bu 3 Sn TBS PdL n ed. Elim. TBS TBS Pd(P 3 ) 4,Cu Bn Bn

20 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg Palladium--heterocyclic carbene (C) ligands for cross coupling reactions Synthetically useful C ligands derived from imidazolium () and 4,5 dihydroimidazolium (S) salts. Aldrichimica Acta, 2006, 39, 97. General description of C generation from various precursors and their complexation with palladium C Cl Precursors typically used in in situ cross-coupling protocols

21 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg 21 Active Pd-precatalysts with C ligands Use of C ligands in the Suzuki cross coupling reaction Ligand 13 Use of C ligands in -aryl coupling reactions

22 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg lefin tathesis lefin tathesis: metal-catalyzed exchange of olefins 1 2 M Catalysts: tal-carbene Complex ucleophilic Electrophilic d 0 Schrock-carbene (metal-alkylidene) Fishcer-carbene (etero-atom stabilized) Pre-catalysts with a defined structure have been developed Cl W Cl i-pr F 3 C F Mo 3 C F 3 C CF 3 i-pr Cl u Cl Cl s s u Cl Aldehydes Ketones lefins Esters, amides Aldehydes lefins Ketones Esters, amides lefins Aldehydes Ketones Esters, amides xophilic reactive Cl u Cl Distorted Square planar Cl 2 u Cl 2 u s s Cl 2 u

23 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg 23 verview: Modern olefin metathesis catalysts eaction mechanism: Sequence of reversible formal [22] cycloaddition/ cycloreversion processes. pre-catalyst 1 start ML n C ML n

24 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg 24 Direction of metathesis reactions: CM (ing-closing metathesis) A B C D n M (ing-opening metathesis) C B A CM (Cross metathesis) A B D MP (ing-opening metathesis polymerization) C B E M A B C n n n n n ( a times) a n E n Ways to push the process in one direction: M n n n polymer Ethylene gas generally decreases CM rate Lower concentration can prevent polymerization and cross metathesis igher temperature usually promotes CM process ( ΔS gain)

25 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg 25 Factors influencing the ring closing metathesis: Cl 2 u 31 eq. ' ' Cl 2 u PCy k rel Substrate specific reactivity of catalysts still difficult to predict! = C(C 2 Et) 2 1 A 1 B 2A > 99 % > 99 % > 99 % Cl 2 u 1 A 20 % > 99 % > 99 % 0 % 0 % > 31 % > 99 % 93 % 0 % s s Cl 2 u 1 B 39 % E/Z 1.6: 1 35 % E/Z 2:1 15 % E/Z 1.6: 1 Ar' Mo 2A Examples of CM in synthesis: rcinal A C Fluvirucin Dactylol EM Sugar

26 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg 26 S 1 2 Yield (E/Z) 2 1 epothilone A TBS TBS 86 % (1: 2) 65 % (1: 2) Fluvirucin B synthesis Cyclophane synthesis Large scale pharmaceutical synthesis ote: Many functional groups are tolerated.

27 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg 27 Double CM reactions: 25 mol % PMB Cl 2 u C 2 Cl 2 45 o C PMB 88 % 20 mol % Cl 2 u PMB C 2 Cl 2 45 o C PMB 77 % Synthesis of macrocycles: Presence of functional group that serves to assemble the reacting sites (not too basic) % Appropriate distance from functional group to olefin (not too close) Low steric congestion near the olefin : 52 % - : C 3 10 % 72 % Cl 2 u Yield of CM product using ing opening and cross metatheses reaction in synthesis:

28 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg 28 Examples of cross metathesis reactions: 2.0 eq. cat. A C C 92 % (E/Z >20:1) =AcC 2 (C 2 ) 2 Bz 2.0 eq. cat. A Bz 81 % (E/Z >4:1) =AcC 2 (C 2 ) eq. Si(Et) 3 81 % (E/Z >11:1) cat. B Si(Et) 3 =AcC 2 (C 2 ) 2 s cat. A s Cl 2 u s cat. B s Cl 2 u C 3 C 3 Diyne tathesis Catalyst (Schrock alkylidyne complex) (t-bu) 3 W 1 3 ' chanism:

29 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg 29 Examples 1 = ; 70 % Alkyne CM in combination with Lindlar partial hydrogenation is a selective way to generate macrocyclic (Z)-olefins ' 2 Z n n > 4 n Lindlar cat. n

30 Prof. Dr. Burkhard König, nstitut für rganische Chemie, Universität egensburg 30 Alkane metathesis

Additions to Metal-Alkene and -Alkyne Complexes

Additions to Metal-Alkene and -Alkyne Complexes Additions to tal-alkene and -Alkyne Complexes ecal that alkenes, alkynes and other π-systems can be excellent ligands for transition metals. As a consequence of this binding, the nature of the π-system