M.C. White, Chem 253 Cross-Coupling -120- Week of ctober 11, 2004 Sonogashira: in situ, metal assisted deprotonation catalytic cycle: ' (h 3 ) n d II The first report: h Sonogashira T 1975 (50) 4467. h 3 ' d II ICu h 3 Cu d II h 3 (h 3 ) 2 d 0 h 3 3 - h 3 d II h 3 (5 mol%) CuI (10 mol%), Et 2 solvent rt, 3h note: can also start with a d(0) source (e.g. d(h 3 ) 4 ). h 3 ' ' d II oxidative addition h 3 ' = aryl, alkenyl = I,, Tf, h 90% yield 100% stereospecificity rder of reactivity of Csp 2 - component: I, > h Et 3 I > >> Mild aryl bromide Sonogashira couplings with (t-bu) 3 d(c 3 C) 2 2 (3%) ' (t-bu) 3 (6%) ' CuI (3%) Et 3 (1.2 eq) = CMe,, Me ' = h, hexyl, dioxane, rt Me, Me 2 C()(C 3 ) 2 70-90% (t-bu)3 is uniquely effective under these conditions. All other phosphines screened (h3, (o-tol)3, dppf, Cy3) gave less than 2% yield. Buchwald & Fu 2000 (2) 1729. Compare pka's: pka = 23 pka = 10.75 Cu ICu 3 - Sonogashira JMC 2002 (653) 46. The acidity of the acetylene hydrogen is enhanced via π-complexation : CuI
M.C. White, Chem 253 Cross-coupling -121- Week of ctober 11, 2004 Sonogashira: Csp-Csp2 coupling method of choice Me Me Me Me Me Me Me eucascandrolide A Me Me Me Tf TBDS oxidative addition d(h 3 ) 4 Me CuI, 2,6-lutidine soft deprotonation d(h 3 ) 4 (10 mo%) CuI (5 mol%) 2,6-lutidine dioxane, rt 84% TBDS Me TBDS h 3 d h 3 Tf - ICu Me anek JC 2002 67 6812-6815 TBDS h 3 h 3 d Me
M.C White/Q. Chen Chem 253 Cross-Coupling-122- Week of ctober 11, 2004 Sonogashira: FG Tolerance MB I Me C 2 Me d(c 3 C) 2 2 (4 mol%), CuI (14%), Et 3 (5 eq) MB C 3 C, -20 C to rt 87% Me C 2 Me in situ deprotonation oxidative addition MB CuI Me d I = C 3 C Me 2 C MB d Me C 2 Me Functional groups well tolerated: ester, free hydroxyl, allylic ether, and benzylic ethers, etc. Me Me illier, M.C.; Meyers, A.I. JC 2001, 66, 6037-6045. Disorazole C 1
M.C White, Chem 253 Cross-Coupling-123- Week of ctober 11, 2004 Sonogashira/Suzuki 3-Component Coupling oxidative addition 1 2 B(ir) 2 Me C 2 Me CuI (5 mol%), d(h 3 ) 2 2 (2.5 mol%) Et 3 (2 eq.) TF, rt; CsF (3 eq.) d 2 dba 3 (1 mol%) 2, acetone 50 o C C 2 Me Me 2 59% Yield 2 B(ir) 2 Me 2 C Me h 3 d h 3 d ICu 1 h 3 d h 3 B(ir) 2 2 1 (ri) 2 B 2 _ F ri B ir CsF- 2 Me 2 C 2 Me 2 CuI Et 3 in situ deprotonation oxidative addition 2 d d 2 dba 3 2 Me C 2 Me Yu T 1998 (39) 9347
M.C. White, Chem 253 Cross Coupling -124- Week of ctober 11, 2004 Migita's original report: Stille: C- bond formation reactions limited to electron neutral aryl bromides (Bu) 3 Sn Migita Chem ett 1983, 927. Elegant mechanistic studies: (o-tol) 3 (o-tol) 3 d (II) 10 mol% toluene, 100 o C, 3h 87% n-bu 3 Sn (o-tol) d (0) 3 (o-tol) 3 3 (o-tol) 3 (Et) 2 d (II) 2 Bu 3 SnEt 2 (o-tol) 3 d (II) 1 (o-tol) 3 3 was independently synthesized to confirm that the reaction procedes via d(0) intermediates. eaction with 3 was faster than those with 2, making it kinetically competent as an intermediate in the reaction. The reaction was retarded by excess phosphine, indicating phosphine dissociation occurs before oxidative addition. Et 2 (o-tol) 3 d (II) (o-tol) 3 Et 2 (o-tol) 3 d (0) (o-tol) 3 d (II) - oxidative addition 2 was isolated /characterized by x-ray crystallography and shown to be a viable catalyst for the aryl amination (yields identical to those obtained for 1). (o-tol) 3 d (II) 4 d (II) (o-tol) 3 artwig JACS 1994 (116) 5969. SnBu 3 Et 2 -SnBu 3 4 was isolated/characterized by x-ray crystallography and shown to react with Bu 3 SnEt 2 to give the arylamine product in 90% yield. The inability of 4 to undergo exchange with other aryl bromides (i.e. p-buar-) indicates that it is a legitimate intermediate in the catalytic cycle.
M.C. White, Chem 253 Cross Coupling -125- Week of ctober 11, 2004 Migita's original report: Stille: C- bond formation reactions limited to electron neutral aryl bromides (Bu) 3 Sn Migita Chem ett 1983, 927. Demonstration of Synthetic Utility: one-pot the more volatile amine is removed via the Ar purge (Bu) 3 Sn ' transamination 80 o C Ar purge Et 2 (o-tol) 3 (Bu) 3 Sn (o-tol) 3 d (II) 10 mol% toluene, 100 o C, 3h 87% ' ' (o-tol) 3 n-bu 3 Sn (o-tol) 3 d (II) toluene, 105 o C 55-88% Buchwald JACS 1994 (116) 7901. 1-2.5 mol% ' ' Buchwald hypothesizes that the lack of generality of Migata's system is due to the high reactivity/instability of aminostannes which hinders their isolation and further use. To address this problem he develops a one-pot procedure that involves in situ generation of the aminostannes coupled with Migata's d catalyzed aryl amination. The substrate scope is significantly expanded to include a wide variety of 2 o aryl /alkyl amines (only example of a 1 o amine is aniline) and aryl bromides substituted with both electron withdrawing and electron donating groups. epresentative examples: Et 2 C h Me 2 h (C 2 ) 17 C 3 88% 81% 79% 66%
M.C. White, Chem 253 Cross Coupling -126- Week of ctober 11, 2004 Sn Free C- bond formation: d-mediated soft deprotonation Initial results limited to coupling of 2 o amines and 1 o amines with electron-deficient aryl bromides 1 o amine: only w/ para electron Buchwald ACIEE 1995 (34) 1348. withdrawing groups: Why? [d(dba) 2 ]/2 (o-tol) 3, 2 mol% h or d 2 ((o-tol) 3 ) 2 Me 2 (h)me Me 2 atbu (1.4 eq) Me h 65-100 o C, toluene 89% 72% artwig T 1995 (36) 3609. 1 o amine n-hexyl n-bu d 2 ((o-tol) 3 ) 2, 5 mol% Me Me Bu i(tms) 2 (1.2 eq) 100 o C, toluene 94% <2% (1:50; amine:arene) bridging amido complex resists (o-tol) 3 d (II) 12 1 2 d (II) (o-tol) 3 1 2 (o-tol) 3 d (0) - Buchwald M 1996 (15) 2745 and 2755. Buchwald M 1996 (15) 3534. oxidative addition Ar- (o-tol) 3 d (0) (o-tol) 3 d (II) educed side-product is observed in large quantities when using 1 o aliphatic amines β-hydride Making use of a bidentate ligand may be a way to inhibit pathways that errode product formation (i.e. β-hydride, bis(amine) aryl halide and bridging amido complex formation). owever, kinetic studies by artwig showing that both oxidative addition and go through 3 coordinate intermediates indicated that bidentate ligands may shut the reaction down. 1 2 (o-tol) 3 d (II) t-bu a soft deprotonation at-bu (C 2 1 ) 2 (o-tol) 3 (o-tol) 3 2 ( 1 2 C) d (II) (C 2 1 ) 2 (C 2 1 ) 2 d (II) (C 2 1 ) 2 (o-tol) 3 d (II) (C 2 1 ) 2 catalytically inactive bis(amine) aryl halide complexes
M.C. White, Chem 253 Cross-Coupling -127- Week of ctober 11, 2004 C- coupling: bidentate ligands extend substrate scope Buchwald JACS 1996 (118) 7215: BIA. 1 o amines coupled with electron rich and deficient aryl bromides. [d 2 (dba) 3 ] BIA 0.5 mol% n-hexyl 2 (n-hexyl) atbu (1.4 eq) C 80 o C, toluene 88% 1 98% n-hexyl t-bu 79% Among bidentate ligands, BIA works uniquely well... igand % Conversion BIA (o-tol) 3 dppe dppp dppb dppf 100 % 88 % 7% >2% 18% 100% ratio of 1 to aryl- 40/1 1.5/1 1.5/4 1/1.6 13.2/1 ratio of 1 to doubly arylated amine 39/1 7.6/1 2.2/1 isolated yield of 1 88% 35% 54% BIA is thought to: effectively prevents β-hydride pathway by blocking cis coordination sites. inhibit formation of catalytically inactive bis(amine)aryl halide complexes inhibit formation of bridging amido complexes that resisist. (C 2 1 ) 2 t-bu a soft deprotonation d II at-bu (C 2 1 ) 2 h h h (±)-BIA d II d0 h (C 2 1 ) 2 - oxidative addition d II (C 2 1 ) 2 Buchwald M 1996 (15) 3534. eviews: artwig ACIEE 1998 (37) 2046; Buchwald Acc. Chem. es. 1998 (31) 805. artwig JACS 1996 (118) 7217: dppf. 1 o amines coupled with electron deficient aryl bromides. Dialkyl amines led to formation of aryl- products. iodides effectively coupled with 1 o aniline derivatives. In general, Buchwald BIA system is more general and higher yielding. h Buchwald has developed a procedure for aryl chlorides using: Buchwald JC 2000 (65) 1144. 2 (n-hexyl) (dppf )d 2 5.0 mol% atbu (1.4 eq) 100 o C, TF (sealed tube) h 96% (t-bu) 2 n-hexyl h olan and artwig have developed procedures for aryl chlorides using in situ generated -heterocyclic carbenes olan 1999 (1) 1307: artwig 2000 (2) 1423 84% BF - 4
M.C. White/Q. Chen Chem 253 Cross-Coupling -128- Week of ctober 11, 2004 Selective C- bond formation K 2 C 3 /glycol 140 o C thermal amination 2 1 (selectivity 1:2 = 6:1) 2 2. F F d 2 dba 3, BIA, atbu, 85 o C d-catalyzed amination 2 (selectivity 2:1 > 35:1) F norastemizole proposed intermediate in d-catalyzed amination The thermal reaction showed selectivity for the more nucleophilic secondary amine to produce 1. In contrast, d-catalyzed amination showed selectivity for amination with the primary amine to produce 2. d = h 2 h 2 Senanayake T 1998, 39, 3121-2124. F
M.C. White, Chem 253 Cross-Coupling -129- Week of ctober 11, 2004 C-C coupling: α-arylation of ketones d 2 (dba) 3, 1.5 mol% Tol-BIA, 3.6 mol% at-bu, TF, 70 o C 76% Bidentate ligands are required to prevent β-hydride when unhindered aliphatic ketones are substrates. Moreover, the steric bulk of BIA is thought to account for the high levels of steric selectivity for ketones with 2 enolizable positions. Buchwald JACS 1997 (119) 11108 Asymmetric generation of all carbon quaternary centers Buchwald JACS 1998 (120) 1918. Milder base extends substrate scope: C 2 Me d 2 (dba) 3, 10-20 mol% (-)-BIA, 12-24 mol% at-bu, tol, 100 o C 66%, 73% ee d 2 (dba) 3, 1.5 mol% antphos, 3.6 mol% K 3 4, TF, 80 o C 74% base sensitive functionality C 2 Me pka = 16.7 Buchwald JACS 2000 (122) 1360. d(ac) 2, 1.0 mol% 1, 2 mol% K 3 4, dioxane, 100 o C 96% C 2 Me h roposed mechanism Ar d II note: pka of K 2 4 ~ 12 deprotonation must be assisted by ketone binding to electrophilic metal C 2 Me a h h (±)-BIA d0 h h a Soft deprotonation when a weak base is used: B: d II h 2 h 2 (t-bu) 2 antphos Buchwald 1 - oxidative addition d II
M.C. White, Chem 253 Cross Coupling -130- Week of ctober 11, 2004 C- coupling: diaryl ether formation Electron-rich, bulky phosphine ligands for diaryl ether formation artwig JACS 1999 (121) 3224. Buchwald JACS 1999 (121) 4369. (t-bu) 2 General conditions: Fe (t-bu) 2-5 mol% d(dba) 2 3 2-5 mol% hosphine pre-formed a phenolate Fc(t-Bu) 2 a Me 5 mol% d(dba) 2 5 mol% (t-bu) 3 toluene, 110 o C, 24h 81% Me Me 2 C Me 2 (t-bu) 2 (t-bu) 2 (1-Adamantyl) 2 1 2 3 in situ formation of K phenolate: adamantane = 2 mol% d(ac) 2, 3 mol% 2 K 2 4, toluene 100 o C 89% Me 2 C General conditions: 2 mol% d(ac) 2 3 mol% hosphine a or K 2 4 ' n d oxidative addition =,, Tf Dimeric species are not thought to be intermediates in the catalytic cycle. reformed dimeric species undergo to form aryl ethers in poor yields: 22%. Moreover, higher yields for the catalytic reaction are observed at lower concentrations (e.g. 82% at 0.2M aryl halide vs. 23% at 1M aryl halide). d d Fc(t-Bu) 2 d (II) d (II)(t-Bu) 2Fc a ' M M base Fc(t-Bu) 2 h d (II) h d (II)(t-Bu) 2Fc ' ' M = a, K artwig JACS 1999 (121) 3224.
M.C. White, Chem 253 Cross-Coupling -131- Week of ctober 11, 2004 In situ reduction of d(ii) to d(0) eduction via : n d II Mg 2 eq. n d II n d 0 Mg eduction by tertiary aliphatic amines: n d II coordination 2 (C 2 ) d II 2 β-hydride n d II n d 0 - - 2 eduction by electron rich phosphines and base n d II coordination 3 - d II 3 :u n d 0 u 3 - phosphonium intermediate gets converted to phosphine oxide in the presence of atmospheric 2. Beletskaya Chem. ev. 2000 (100) 3009. eview of the eck reaction.