Stille, Suzuki, and Sonogashira Couplings Cross-Coupling reactions: catalyst R-X + R'-M

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1 Stille, Suzuki, and Sonogashira Couplings Cross-Coupling reactions: catalyst -X '-M -' M-X, ' are usually sp 2 hybridized X= (best), Tf, r, Cl M=Sn,, Zn, Zr, n Catalyst= Pd, sometimes Ni Example: Pd(0) 3 C r 3 C u 3 Snr Mechanism: Pd() Stille eaction reductive elimination from cis complex Pd(0) n 3 C r oxidative addition initially: ' 3 C Pd() n 3 C Pd() n r Pd transmetallation trans cis Pd ' u 3 Snr DS

2 General Cross-Coupling eactions xidative addition initially gives rise to a cis complex that rapidly isomerizes to a trans complex Pd 2 - Pd fast Pd β-hydride elimination occurs for Csp 3 halides other than methyl: Pd() n X Pd() 2 X oth oxidative addition and reductive elimination occur with retention of double bond configuration Transmetallation is usually the rate-determining step, except where poor halide leaving groups (Cl) are used; then oxidative addition is DS. rder of ligand transfer from Sn: > > > benzyl > alkyl Stille-specific conditions: Catalyst: Pd(PPh 3 ) 4, Pd(Ac) 2, Pd 2 (dba) 3 arge rate enhancements are often observed with poorly electron donating ligands: (furyl) 3 P, Ph 3 As Cu can dramatically increase the reaction rate due to copper s free-ligand scavenging ability: Pd 2 (dba) 3 5mol% PPh 3 (20mol%) JC, 1994, mol% Cu relative rate

3 The use of aryl chlorides requires special conditions: Stille Cross-Coupling 3 C Cl Et Pd 2 (dba) 3 5mol% P(t-u) 3 CsF dioxane, 100 C 3 C Et Sn->Cu transmetallation increases the rate of cross-coupling reaction: Nf Pd(PPh 3 ) 4 (10mol%) icl (6 eq), CuCl (5eq) ACEE, 1999, 2411 DMS, 60 C Nf=S 2 (CF 2 ) 3 CF 3 92% JACS, 1999, 7600 Coupling of Acid Chlorides: Cl u 3 Sn 2 N npdcl(pph 3 ) 2 Cu, TF, 50 C 2 N JC, 1993, 343 enzylic coupling: Pd(PPh 3 ) 4 (10mol%) r u 3 Sn TP CCl 3, reflux JC, 1993, % TP

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5 Preparation of Aryl and Vinyl Stannanes From rganolithium reagents via directed ortho-lithiation: 1. t-ui MM 2. u 3 SnCl MM Chem. ev. 1990, 923. ((C 3 ) 3 Sn) 2 T 1997, r N Pd(PPh 3 ) 4 u 3 Sn N Prep of vinyl stannanes: C 3 u 3 Sn AN u 3 Sn C 3 C 3 TP TP TP 85 : 15 a radical reaction, reversible, giving a thermodynamic ratio of products JACS, 1976, 222. Alternatively, C 3 u 3 Sn C 3 PdCl 2 (C 3 CN) 2, 5mol% u 3 Sn 69% Synlett, 1997, 771

6 Alternative Preparations of Vinyl Stannanes Et Et u 3 Sn(u)CuCni 2 TF; C 3 Et Et T, 1991, C 3 ui; u 3 SnCl C 3 Cp 2 Zr()Cl C 3 2 C 3 Et Et Et Zr(Cl)Cp 2 syn hydrozirconation Et Z-vinyl stannane Et Et u 3 Sn(u)CuCni 2 TF; r Et Et T, 1991, 6337 T, 1992, 5861 r t-ui (3 eq) u 3 SnCl u 3 Sn JACS, 1999, 7600 Vinyl stannanes react cleanly with iodine to form vinyl iodides with retention of stereochemistry: TS Pd(PPh 3 ) 2 Cl 2 u 3 Sn TS 2, DCM TS JACS, 1998, 3935 TS C 2 Cl 2, 0 C TS TS

7 Suzuki Coupling Suzuki Coupling is the reaction of vinyl or aryl boronic acids with aryl and vinyl halides or triflates using a palladium catalyst. Example: Pd(Ac) 2 (0.3 mol%) PPh 3 (0.9 mol%) () 2 r C C Na 2 C 3,(1.2 eq) ipr, 2 heat Mechanistic difference with Stille Coupling: oron ate complexes are involved in transmetallation: 2 Pd X - 2 Pd Ar() 2 2 Pd Ar The additive thallium hydroxide (Tl) accelerates the rate of coupling by facilitating hydroxyl-halogen exchange at Pd: JACS, 1987, Again xidative Addition and eductive Elimination occur with retention of configuration eactivity of eaving Groups: > Tf > r >>Cl ates of reductive elimination: aryl-aryl> alkyl-aryl > alkyl-alkyl

8 Transfer of primary alkyl groups utilizing the Suzuki coupling: 9-N r JACS, 1989, 314 CN CN PdCl 2 (dppf) K 2 C 3 DMF, TF, 50 C CN Fe PPh 2 PPh 2 Cl Pd Cl Ph 2 P 99 PPh 2 large "bite" angle of dppf is believed to furnish a catalyst with a more favorable ratio of rate constants for reductive elimination vs.!-hydride eliminiation JACS, 1984, 249 dppf uchwald s room temperature cross-coupling of Aryl chlorides: () 2 Me Cl Pd(Ac) 2 1mol% KF (3 eq), TF Me ACEE, 1999, 2413 P(t-u) 2 91% 2 mol%

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10 Synthesis of oronic Acids 1. (i-pr) 3 i 2. Cl/Et 2 (ipr) 2 rganometallics, 1983, N Tf PdCl 2 (dppf) 3 mol% KAc, DMS, 80 C 2 N 86% JC, 1995, n-ui (ipr) 2 2, indlar 2. (ipr) 3 (ipr) 2 T 1988, 2631, JACS, 1972, 4370 TF, 70 C 80% syn-hydroboration (ipc) 2 C 3 C 2 (Et) 2 syn- hydroboration Chem. ett, 1993, EtZn PdCl 2 (dppf) 1mol%

11 Comparison of the Stille and Suzuki couplings The two methods are comparable, but the higher cost and toxicity of stannanes makes the Suzuki preferable. Me () 2 Sn(Me) 3 Me Me N 2 N 2 82% Pd(PPh 3 ) 4 K 3 P 4 DMA, 85 C Tf N 2 Pd 2 (dba) 3 P(o-tol) 3 icl 80% eterocycles, 1998, 1513 When alkyl boranes and stannanes are in the same molecule, the organoboron group reacts preferentially under basic conditions SnMe 3 88% Synlett, 1991, 687 r PdCl 2 (dppf) K 3 P 4, DMF SnMe 3 ecently, triorganoindium reagents have been found to cross-couple with aryl and vinyl halides in an Atom-efficient manner, transferring all three organic ligands from indium. ndium is environmentally benign. r 1 mol% Pd(0) C 2 Et 1/3 eq. n TF, 60 C C 2 Et JACS, 2001, %

12 Sonogashira Coupling Sonogashira Coupling is the coupling of terminal alkynes with aryl and vinyl halides in the presence of A palladium (0) catalyst, a Cu() co-catalyst, and an amine PdCl 2 (PPh 3 ) 2 X Cu, Et 2 N ' '' X ''' PdCl 2 (PPh 3 ) 2 Cu, Et 2 N ' '' ''' ' X reductive elimination from cis complex Pd(0) n oxidative addition Pd() X ' Pd cis ' transmetallation trans Pd CuX DS Cu ' copper() coordination to alkyne enhances acidity: Cu ' 2 N

13 Examples of Sonogashira Coupling C 3 C 3 PdCl 2 (PPh 3 ) 2 Cu, DMF C 2 C 2 T, 2002, 4703 PdCl 2 (PPh 3 ) 2 C 3 Cu, DMF 87% 3 C JC, 2001, 6037