Organic synthesis Kamil Paruch Masaryk University, Brno Kamil Paruch Organic Synthesis C4450 -■O. TsOH HO. N_= 2. BuLi, THF Br' K 1.l2. HN O N=N K02C C02K AcOH 1. NaCN, DMSO -i 2. NaOH, H20 3. CH2N2 B 1.t-BuLi, THF, -110°C 2. Cul 1. H+, MeOH 2. PPh3.Br2 3. Nal, acetone X t Tetrahedron Lett. 1980, 21, 4243. 2 Kamil Paruch Reactions catalyzed by palladium Organic Synthesis C4450 Ar1-^ + Ar2—MgBr R Ar1-X + Ar2—MgBr Pd cat. Al?pMgBr Ar1-^ R ^ Ar1-Ar2 + MgBrX Reactions catalyzed by palladium • formation of C-C, C-N, C-0 bonds • catalytic amount of Pd compounds • mild reaction conditions; compatible with various functional groups Pd°: electron-rich, nucleophilic Pd°U R1-R2 (reductive elimination) (isomerization trans-cis on Pd) R1-X (oxidative addition) ,*1 LXP<2+ X R2-Y ,R1 LXP<2+ Y can be different metal, e.g. Mg, Sn, Zn (transmetalation) Kamil Paruch Stille reaction Organic Synthesis C4450 Pd cat. R1-R2 (reductive elimination) R1 I 2+ L-Pd-R2 (trans-cis) R1-X R2-SnR3 R1-R2 X-SnR, R: typically Bu or Me Pd°L, R1 I 2+ L-Pd-L R2 (oxidative addition) R2-SnR3 (transmetalation) X-SnR3 stannaries: $$$ R2-X + X = Br, I, OTf R2-Li (MgX) ease of transmetalation Sn -> Pd > Ar > |- > ArCH2 » alkyl COR R-Sn—Sn-R * R R = Me, Bu R R-Sn-CI R Pd cat. R2-SnR, R2-SnR, R = Bu Kamil Paruch Stille reaction Organic Synthesis C4450 advantages: very mild conditions retention of configuration on double bond triflates: possibility to generate kinetic vs thermodynamic OTf (also: can be made from ArOH) 5 Kamil Paruch Stille reaction Organic Synthesis C4450 ketones from acid chlorides O Pd cat. O RAC1 ♦ R'SnBu, -- RAR. U O Pd(PPh3)4 ___ U ^ -► >f C02Bn Bu3Sn. __ ÓSiR, ^ C°2Bn 71% ÓS i R 3 J. Orgf. Cfrem. 1983, 58, 4634. imines from imidoyl chlorides N' PdCI2(PPh3)2 N' DhAri + ^SnBu3 -► JI^ Ph Cl 67% Ph ^ Bull. Chem.Soc.Jpn. 1986,59,677. carbonylative Stille: insertion of CO OTf + TMS^SnM Pd(PPh3)4, CO -^ LiCI, THF 87% TMS reductive elimination J. Am. Chem. Soc. 1984, 106, 7500. Pd. OTf CO (insertion) TMSv^ns (/ ĽPdOTf SnMe3 (transmetalation) TMS Kamil Paruch Stille reaction Organic Synthesis C4450 ease of transmetalation Sn —► Pd R^=|- > Rw^~ > Ar > > ArCH2 » alkyl stannyl enol ethers C0R • acyl equivalents J. Org. Chem. 1998, 63, 7456. 7 Kamil Paruch Suzuki reaction Organic Synthesis C4450 R1-X + R2-BRj R1-R2 (reductive elimination) Pd cat. R1-R2 base Pd°L, R1-X (oxidative addition) boranes, boronates: HO-BR2 (transmetalation) "ate" complex: source of sufficiently nucleophilic R2 $$$ NaOH addition of R2BH on alkenes, alkynes R2-Li (MgX) + ROyOR OR R2-B(OR)2 Pd cat. R2X + ^°B-B°j^ -> /^O' 0^\ base 8 X = Br, I, OTf (K3PO4, KOAc) Kamil Paruch Suzuki reaction Organic Synthesis C4450 advantages: mild conditions (similar to Stille rxn) non-toxic side products I BH cc * OX- B-Q Pd(PPh3)4 Br Ph \=/ Pd(PPh3)4 -» NaOEt, EtOH 87% NaOH, THF ^ShAc 91% OEt H+ 99% CHO N H Ac Suzuki coupling is often used for preparation of sterically hindered bis-(hetero)aryls BocN SEM'N^SEM N' I PdCI2(dba) -► K3PO4, DME, H20 65% BocN / SEM'N>SEM Bioorg. Med. Chem. Lett. 2011, 21, 471 Kamil Paruch Suzuki reaction Organic Synthesis C4450 Suzuki coupling with Csp3 boranes recent review: Organic Reactions 100. cat. Pd(OAc)2 O PCV3 Q MeO^MTB^ * Br^H^CN THFK32P5°oc » MeO^OM^CN 81 % J. Am. Chem. Soc. 2001, 123, 10099. OH OH .1 ♦ BBN^NHBoc Pd cat. ^^^^^NHBoc ^ Angew. Chem. Int. Ed. 2022, 61, e202203186. 10 Iron-catalyzed Suzuki-Miyaura coupling of alkyl halides Scheme 3. Plausible Mechanism .-CI tvárte iron complex 1 Of £ i X—H Cm A- Bu-B -h L i Jí o- BuFin rtelermined by NMR S GC-MS MgBrJ ßu^ P- C v. i Fe'" ^ P vAr ( 11 Aľ-R J. Am. Chem. Soc. 2010, 732, 10674. direct Fe-catalyzed coupling: Nature2021, 559,507. CHaO ]<ÍL Klii Hr. -> 40^ VII. VIII. XIV, >v OPP-3 H BFt (a q.); (x I) DA ST; (x ] I) LIH M DS. Co m L us' rea gent, 5i% (p lu s, separ a tel y, JIM A6' regl ol so me r); (xl 11)' Bu M gC l, Fe (a ca c);; (x Lv) H2, Pd{0 H)JC, 1:1 d r; (x v) BSTFA, Kamil Paruch Nickel-mediated couplings Organic Synthesis C4450 Ni-catalyzed Suzuki-Miyaura coupling • cost-effective variant B(OHh X = I, Br, CI. OTt NiCla'6HaO [N0851](1J ligandsDBU [D1270] 2-MeTHF or DMAcMeOH heat ligand = DPPF: PPh, [B2G27] Org. Process Res. Dev. 2022, 26, 785. 11 Kamil Paruch Nickel-mediated couplings Organic Synthesis C4450 other Ni-catalyzed couplings e.g. XT- 0 N i cat. Cbzx ^ H Ir photocat. Boc blue LED J. Am. Chem. Soc. 2023, 145, 7736. 12 Kamil Paruch Suzuki reaction Organic Synthesis C4450 relative stability/reactivity of boron coupling partners boronicacid (pinacol) boronate (potassium) trifluoroborate MIDA ester TIDA ester http://organicreactions.org/index.php/Cross-coupling_reactions_of_organotrifluoroborates • some boronic acids are unstable (e.g. vinylboronic acid) and/or can undergo rapid protodeborylation > boronates/trifluoroborates are used instead • „the 2-pyridyl problem" and its general solution through MIDA ester Angew. Chem. Int. Ed. 2012, 51,2667. • TIDA esters are very stable towards hydrolytic cleavage > they can be used orthogonally in the presence of other boron coupling partners 13 \— B(OH)7F3K/pin -©KD-" )~Z!7^BTIDA —(©©/©-* Csp^-Csp2 Suzuki-Miyaura coupling Suzuki-Miyaura coupling (Id) Deprotect (cT) Couple (V)Purify Nature 2022, 604, 92. Kamil Paruch Suzuki reaction Organic Synthesis C4450 Rate-determining step can depend on the base KOAc: rds: reductive elimination K2C03: rds: transmetalation (significantly better yield in the „bulk charge" format) Org. Process Res. Dev. 2023, 27, 198. 14 Kamil Paruch Sonogashira reaction Organic Synthesis C4450 15 Kamil Paruch Sonogashira reaction Organic Synthesis C4450 MeO. Pd(PPh3)4 Cul, BuNH2 88% J. Am. Chem. Soc. 1988, 110, 6921. protecting group Tetrahedron Lett. 1988, 29, 2989. 16 Kamil Paruch Pd-catalyzed reactions with RMgX a RZnX organic synthesis C4450 transmetalation from Mg (Kumada coupling) or Zn (Negishi coupling) Pd(PPh3)4 /=\ + TMSCH2MgCI -► . TMe Pr | Pr x—TMS THF 84% Tetrahedron Lett. 1982, 23, 27. TDBSO^y^ ZnCI -OTBDS Pd(PPh3)4 TDBSO THF 82% OTBDS Tetrahedron Lett. 1987, 28, 5075. 17 Kamil Paruch Heck reaction Organic Synthesis C4450 Pd cat. R1-X X: typically Br, I, OTf R2 R1^R, H-X Br R1^R, (Syn ß-elimination of hydride) R1 typically ends up on less substituted C (insertion of alkene) (oxidative addition) (coordination of alkene) Pd(OAc)2 Ar3P Et3N CH3CN 97% BrLPd 18 J. Org. Chem. 1984, 49, 2657. Kamil Paruch Heck reaction Organic Synthesis C4450 J. Org. Chem. 1987, 52, 4130. Acta Chem. Scand. 1992, 46, 597. 19 Kamil Paruch Wacker oxidation Organic Synthesis C4450 PdCI 2 CuCI JP V H20 + solvent ^ mechanistically similar to Heck h ci I ,0 20 -Drl—/ Cl-Pd I H,0 PMBO «fr H---H t HO Cl-Pd-^ I H'% CI CI H-Sl Ph °X° OH C'-Pd^CH3 i R Cl-Pd-H H'°VH .HCl + Pd°L, CuCI, CuCI O U + 2CI 0 ?' 2 Cl-Pd-Cl i CI 0 (coordination of alkene) HoO CI CU .R i CI -CI PMBO Wacker ox. Ph 77% °X° Tetrahedron 2001, 57, 6311 Kamil Paruch Pd-catalyzed formation of C-N bond organic synthesis C4450 Buchwald-Hartwig amination • typically: preparation of arylamines J. Org. Chem. 2000, 65, 1158. recent re view applications of Palladium-Catalyzed C-N Cross-Coupling Reactions"; Chem. Rev. 2016, 116,12564. 21 Kamil Paruch Pd-catalyzed formation of C-N bond organic synthesis C4450 Bioorg. Med. Chem. Lett. 2007, 17, 6216. 22 Kamil Paruch Chan-Lam coupling Organic Synthesis C4450 ArB(OH)2 h'y"r Cu(OAc)2 Ar^R air RYH: anilines, phenols, amides, carbamates, ureas, sulfonamides 23 HN XR2 ArBpin Cu(OAc)2 B(OH)3 -i air CH3CN Ar-N. a) Alkyl amines Ph ^ cr 13a, 70%, 84%,a 81%" 13b: 90% ^so2 13d, 77% 136,71"/ "S07 13f, 85% 13g, 36% .N. J Ph" NH k ,NBoc „N N 13h; 74% 13j, 77»/ CONMe, 13n, 86% Me NMe || Čra 13o, 75% CF313p80% Me N NM Me ^ 13q, 84% b) Aryl amines H Me CONM€ 13v, 94% 13", 62% Me 13x, 44% Ph 15a, 82%, 91%.3 86' Me02C 15b, 83% Me ^^Me N„ BocHN Ph XT'" & P h 15o, 73% 15e. 90% COiMe H ^ .C02H II 15j. 52% Me I N N (TO (TO /^Ó 15q. 73% c) O- and S-nucleophiles CONMe2 15s, 61% 15u, 70% a 3 a' 33a, 70% S ^ Me 34a. 74% 33b, 53%" TV- 34b. 61% d) Sulfonamide and azole nucleophiles Ph ~S02Ph 15n, 63% ď 15h, 7 15g, 84% 15h, 70% 150,74% 15p, 81% N Me COsMe 34c. 63%ä" 15a, 53%e 35b, 71 %s 35c, 74%8 J. Am. Chem. Soc. 2017, 139, 4769 Kamil Paruch Pd-catalyzed formation of C-0 bond organic synthesis C4450 historically somewhat less developed than amination 24 Br + NaOR" Pd(dba)2, BINAP PhCH3 a, Transition-metal-catalyzed coupling of hydroxide with (hetero)aryl halides Fe-, Pd- or Cu-cat. MOH ligand 0"" X = CI, Br, I M = Li, Na, K, Cs... b, Trans ition-metal-calalyzed coupling of hydroxide surrogate with (hetero)aryl halides HO. ^ N Ph Pd-, or Cu- cat. Malonev X = CI, Br, I H20 Ni-organophoto cat. blue LEDs Xue o2 Cu-cat., bv X = CI, Br Cr~ X = CI, Br, I c, Boric acid in the coupling reaction with (hetero)aryl halides {this work) *- R Wu •Cr' R4 I + Bt h X = CI, Br Pd-cat. / L mild conditions •Cr" OR" J. Am. Chem. Soc. 1996, 118, 13109. Org. Lett. 2020, 22, 8470. Kamil Paruch Pd-catalyzed formation of C-S bond organic synthesis C4450 • relatively recent technology Pd(OAc)2 R<=\ ligand R/^\ £ ^-Cl + HSR' ---► ^^-SR' base, DME J. Am. Chem. Soc. 2006, 128, 2180. 25 Kamil Paruch Pd catalysts: ligands Organic Synthesis C4450 • the ligand(s) can have profound impact on the catalyst's activity > can be used in chemoselective couplings Ph p Phx vPh 9 + PPh PPh, Fe PPh, PPh, APhos Xantphos dppf https://www.acros.com/mybrochure/aowhpapdbrochuslow.pdf R = OMe : SPhos R = OiPr : RuPhos cone angle: defined by outer edge of the substituents on P and the metal center PH3: 87 ° PMe3: 118° PPh3: 145° PCy3: 170 ° P(r-Bu)3: 182° P(o-tol)3: 194° bite angle: defined as L-Pd-L angle 26 dppf: 99 ° Xantphos: 107° BINAP:92° J. Chem. Soc. Dalton Trans. 1999, 1519. large bite angle -> faster reductive elimination (the preferred geometry of the Pd(0) product is linear) Kamil Paruch Pd catalysts: ligands Organic Synthesis C4450 • base-activated palladacycles (precatalysts): air stable, form active catalysts in the presence of base 27 Kamil Paruch Chemoselectivity Organic Synthesis C4450 • the ligand(s) can have profound impact on the catalyst's activity > can be used in chemoselective couplings R3-B(OR)2 Pd catalyst base solvent (inseparable mixture) R3-B(OR)2 Pd(OAc)2 DPEPhos -i K3P04 DME, H20 Angew. Chem. Int. Ed. 2019, 58, 1062. R3-B(OR)2 Pd(dppf)CI2 -i K3P04 DME, H20 Eur. J. Med. Chem. 2021, 215, 113299. Kamil Paruch Chemoselectivity Organic Synthesis C4450 • chemoselectivity? Palladium Trimer Catalysis Very Important Paper International Edition: DOI: 10.1002/anie.201811 380 German Edition: DOI: 10.1002/ange.201811380 C—I-Selective Cross-Coupling Enabled by a Cationic Palladium Trimer Claudia J. Diehl, Thomas Scattolin, Ulli Englert, and Franziska Schoenebeck* Abstract: While there is a growing interest in harnessing synergistic effects of more than one metal in catalysis, relatively little is known beyond bimetallic systems. This report describes the straightforward access to an air-stable Pd trimer and presents unambiguous reactivity data of its privileged capability to differentiate C—I over C—Br bonds in C~C bond formations (arylation and alkvlation) of polyhalogenated arenes, which typical Pd" and Pd!-Pd! catalysts fail to deliver. Experimental and computational reactivity data, including the first location of a transition state for bond activation by the trimer, are presented, supporting direct trimer reactivity to be feasible. hile mononuclear catalysis have dominated the field of homogeneous catalysis in the past decades, there is a growing interest in harnessing the synergistic interplay of multi-metal catalysts to access novel reactivities and selectivities.'1' However, with more than one metal in a catalyst, there is also an □ SpBciation of Potentially Reactive Species L„Pd° Pd'-Pd1 - Pd IO>d Pd fric/.irmi," Key Questions: Can mutti-metaliic system be reactive, or is it acting as reservoir7 Special reactivity through metal-metal synergy? □ Open Challenge in Chemoselective Pd Catalysis R CI___ ^ CI 2-Q-MX TfO R C-Clvs. C-Bri/s. C-OTf solved Q-MX Br Br remaining challenge This Work: CI A Br R Pd trimer, toluene, r.l.. Ar Q-Mgx Cs/ŕ and CspJ 1> Br R selective! Pr^P' U>d-PHPh2 Pd" ] Pd liim&r Figure i> Challenges encountered in multi-metal catalysis (top) and in chemoselective palladium-catalyzed cross-coupling reactions (middle). Angew. Chem. Int. Ed. 2019, 58, 211 • removal of residual palladium QuadraPure https://www.sigmaaldrich.com/catalog/product/aldrich/655422?lang=enfSiregion=CZ Kamil Paruch Chemoselectivity Organic Synthesis C4450 • Pd-catalyzed chemoselective dehalogenation debromination of 28 to 29, without interference by the two readily-reduced alkenes Cepharatine A J. Org. Chem. 2022, 87, 1065. 30 Kamil Paruch Reactions catalyzed by palladium Organic Synthesis C4450 3rr OMe 1. BuLi (1 eq.) Et20 2. DMF 1. NaBH4 MeOH 2. PBr3, CH2CI2 B Zn, THF Pd(PPh3)4l THF 1. BuLi, Et20 2. DMF 1 eq. BBr3 CH2CI2 -78 °C to 25 °C TBSOTf Et3N, CH2CI2 G J. Am. Chem. Soc. 2002, 124, 773. 31 Kamil Paruch Reactions catalyzed by palladium organic synthesis c44so Me3S 1.t-BuLi, Et20, -78 °C -» I o o~/^ 1. LiAIH4 Et20 2. NaH, Mel, DMF B ,OPMB t-BuLi, Et20, -100 °C then: 2-thienylCu(CN)Li 1. CSA, MeOH 2. CF3S02CI, Et3N 3. K2C03, MeOH PMB: p-methoxybenzyl 32