1. TRANSITION METAL CATALYZED REACTIONS. A REVOLUTION IN ORGANIC SYNTHESIS Prof. Dr. Ender Erdik Ankara University Science Faculty 27th National Chemical Congress, 23-28 August 2015, Turkey

2. 2 Contents 1. Transition metal catalysis in organic reactions 2. The development of transition metal catalyzed coupling reactions 3.Pd ve Ni catalyzed coupling reactions 4.Reactions catalyzed by other transition metals 5.Examples of the use of transition metal catalyzed coupling reactions in the synthesis of natural products and compounds of medicinal, pharmaceutical and agrochemical interest 6.Concluding remarks

3. 3 Transition metal catalyzed reactions Today, transition metal catalyzed coupling are the mostly used reactions for the formation of C – C and C-Heteroatom bonds. R. Bates, Organic Synthesis Using Transition Metals, Wiley, 2012 M. Meller, R. Bolm (Eds.), Transition Metals for Organic Synthesis, 2 Vols, Wiley, 2004 R – M+ E + R – E “Geçiş metali, M 1 ” LiMgZnBSi AlSn R1AR1A R 1 COR 2 d Block metals Ti FeCoNiCu ZrRu Rh Pd Ag OsIrPtAu R – M + R 1 – A (or R – H / Base) “M1”“M1” R – R 1 Cross coupling Nu – H / Base + R 1 – A (Nu = N, O nucleophile) “M1”“M1” Nu – R 1 C – Heteroatom coupling C – C coupling

4. 4 Transition metal catalyzed coupling reactions High yield and selective reactions Reaction variety by changing RM, RH, R 1 and M 1 Importance in formation of C – C and C – Heteroatom bonds Mostly preferred methodology for synthesis of organic compounds and also carrying out one or more steps in total syntesis More green reactions and cleaner products E. Negishi (Ed), Handbook of Organopalladium Chemistry for Organic Synthesis, Wiley, 2002 A.D. Meijere, F. Diederich (Eds), Metal Catalysed Cross Coupling Reactions, 2 Vols, Wiley-VCH, 2004 Reactions that have revolutionized in organic synthesis RM veya RH / Baz NuH / Baz R 1 A, “M 1 ” RR 1 NuR 1

5. 5 Pd and Ni catalyzed coupling reactions are widely applicable in laboratory and in industry Transition metal, especially Pd and Ni catalysed coupling reactions are intensively used In research laboratories, For the synthesis of natural products, In medical chemistry, biochemistry, supramolecular chemistry, catalysis and coordination chemistry. In industry, For the large scale synthesis of biactive chemicals, drug molecules and agrochemicals. E. Negishi, Bull. Chem. Soc. Japan, 2007, 80, 238 C.C.C.J. Seechurn, M.O. Kitching, T.J. Colacat, V. Snieckus, Angew. Chem. Int. Ed., 2012, 51, 5062 R.F. Heck, E. Negishi, A. Suzuki, Pd catalysed C–C coupling, 2010 Nobel Prize

6. 6 Reactions catalysed by other transition metals are also used in laboratory and in industry Catalytic hydrogenation: P. Sabatier, Catalytic hydrogenation of alkenes, 1900 NobelPrize W.S. Nobles ve R. Noyori, Asymetric catalytic hydrogenation of alkenes, 2001 Nobel Prize RCH = CH 2 “Pd, Rh” RCH 2 – CH 3 RCOR 1 + H 2 “Ni, Rh, Pd” RCH(OH)R 1 Hydroformylation of alkenes(Oxo prosesi): RCH = CH 2 + H 2 + CO “Rh” RCH 2 CH 2 CHO ( H 2 “Ni” RCH 2 CH 2 CH 2 O) Alkoxycarbonylation of organyl halides: RX + MeOH + CO “Rh” RCOOMe + HX (Monsanto asetic acid process) MeOH + CO “HI, Rh” MeCOI H2OH2O MeCOOH (Cativa asetic acid process) “HI, Ru ve Ir” MeCOOH MeOH + CO

7. 7 Wacker oxidation: K.B. Sharpless, Asymetric catalytic dihydroxlation of alkenes, 2001 Nobel Prize RCH = CH 2 + ½ O 2 “Pd ve Rh” RCH 2 CHO Polymerization of alkenes (Ziegler-Natta polymerisation: n RCH = CH 2 “Ti” R – (CHR – CH 2 ) n – CHR – CH 3 OsO 4 catalyzed dihydroxylation of alkenes (Sharpless dihydroxylation): RCH = CH 2 + Me 3 NO 1. “OsO 4 ” RCH – CH 2 + Me 3 N (R = H:acetaldehyde synthesis) 2. “H 2 O” OH Y. Chouvin, R.H. Grubbs ve R.F. Schrock, Alkene Metathesis, 2005 Nobel Prize Alkene metathesis (Isomerisation of alkenes): R 1 CH = CHR 1 + R 2 CH = CHR 2 “Rh” 2R 1 CH = CHR 2

8. 8 A summary for the development of transition metal catalysed coupling of RM compounds In the first half of 20.Century, Classic Ullmann reaction, 1901: M.S. Kharasch, O. Reinmuth, Grignard reactions of nonmetallic substances, Prentice Hall, New York, 1954 G.A. Silverman, P.E. Rakita, Handbook of Grignard Reagent, Marcel Dekker, New York, 1996 RMgBr(Li) + E + R – E R Br + Cu R Cu 110 °C R1R1 Br YH R R1R1 Y (Y=RO, R 2 N) Cu supported and hard reactions ! Until 1950, Grignard and organolithium reagents are the mostly used reagents for C – C bond formation. reagents. E : R 1 A, R 1 COR 2, R 1 COCl, etc. However, synthetic applicability of Grignard and organolithium reagents, RM (M=Mg, Li) are somewhat limited: Electrophiles do not react with each R group. Reactions are fast and produce co- and side products ( low yields ). Reactions can not give the expected product when FG – R groups (FG=Fonctional group) sre used instead of R groups. R

9. 9 RMgBr + R 1 A In order to increase the synthetic applicability of Grignard reagents, catalytic coupling reactions were investigated: RMgBr + R 1 ARR Homo coupling product ! However, Cu(I) catalyzed coupling has also some disadvantages in synthetic application : Grignard reagents produce co- and side products. Reaction conditions are not mild in each coupling. Each R – R 1 coupling is not possible. RR 1 “Cu(I)” Kharasch coupling, 1941 “Co(II)” R=Aril RMgBr + R 1 ARR 1 + RR Co-/side product Kochi coupling, 1970 “Cu(I)” R, R 1 = Alkil, aril

10. 10 RM (or RH / Base) + R 1 A Reaction parameters in transition metal catalyzed coupling reactions have been investigated in detail: RH compounds are also used instead of RM reagents: RR 1 “M 1 ” Nucleophilic partner, RM or RH Electrophilic partner, R 1 A Catalyst, M 1 Reactivity increases, selectivity decreases Nucleophilic partner For milder reaction conditions, the activity of RM reagents should be lower than that of RMgBr reagents. The metals which have higher elektronegativities than Mg, are preferred to use in the preparation of RM regents: RM (M = Mg, Zn, Sn, Si, B) RH = Alkene (R 2 CH = CH 2 ), alkyne (R 2 C ≡ CH) J. Hassan, M. Sevignon, C. Grozzi, E. Schulz, M. Lemaire, Chem. Rev. 2002, 102, 1359

11. 11 RM + R 1 A In the catalyzed coupling, Electrophilic partner, R 1 A: RM → R –Transition metal conversion (transmetalation) should be also easily carried out. To solve these problems, more suitable catalysts than Cu(I) have been developed : RR 1 “M 1 ” (or RH/Base)Electrophilic partner Catalyst M 1 = Ni(0), Pd(0) F.L. Adam, G.C. Fu, Angew. Chem. Int. Ed., 2002, 41, 4176 R.N. Matthew, G.C. Fu, Adv. Synth. Catal., 2004, 346, 1525 A.C. Frisch, M. Beller, Angew. Chem. Int. Ed., 2005, 44, 674 R and R 1 = Alkyl, allyl, propargyl, benzyl, alkenyl, alkynyl, aryl R 1 = Aryl is reactive, R 1 = Alkyl gives side product (generally) A = Br ve I; Cl not reactive (Heteroaryl Cl can be used) R 1 OTf: High reactiviy, however hard to prepare, expensive R 1 OTos ve ROMes: Low reactiviy, however easy to prepare, Reactivity of R 1 A changes depending on RM and M 1.

12. 12 Transition metal catalysts Transition metal catalyst (M 1 ) : Ti FeCoNiCu Zr RuRhPdAg OsIrPtAu M 1, M 1 L n, M 1 X n, M 1 X n L m (X = Halogen, OAc, acac, OTf; L = Ligand) Asymmetric synthesis with L* (chiral ligand) M 1 X n + L Cocatalysis and dual catalysis I.P. Beletskaya, A.V. Cheprakov, Coordination Chem. Rev., 2004, 248, 2337 The most used ligands and PEPPSİ (NHC – Pd) catalysts R R1R1 R R1R1 NN Cl Pd Cl N Ph 2 P Fe PPh 2 dppf Me 2 P Fe PMe 2 dmpf NN phen PPh 2 (R)-Binap R = i-Pr Pd-PEPPSİ-i-Pr R = i-Pent Pd-PEPPSİ-i-Pent O Ph dba Ph 2 P PPh 2 dppe Ph 2 PPPh 2 dppp Me 2 P PMe 2 dmpe PPh 2 O Xantphos cod

13. 13 RM (M = Mg, Zn, B, Si, Sn) + R 1 A In the second half of 20. Century, Ni ve Pd catalysed couplings of RM (M = Mg, Zn, B, Si, Sn) reagents have gained importance : MM 1 Reaction, year MgBrNiKumado-Corriu coupling, 1972 (Grignard reagent) MgBrPdMurahashi, Fauverqueve Ishikawa coupling, 1975-1977 ZnCl (ZnR)Ni veya PdNegishi coupling, 1976 (Organozinc reagent) BY 2 (Y = R, OR)Ni veya PdSuzuki-Miyaura coupling, (Organoborane)1979(Pd catalyst),1996(Ni catalyst) RR 1 “Pd” veya “Ni” R – M + R 1 – A RR 1 + MA “M 1 ”

14. 14 RH/Base +R 1 A MM 1 Reaction, year RSiR 2 3 PdHiyama coupling, 1988 (Organosilane) RSnR 2 3 PdStille coupling, 1978 (Organostannane) RR 1 “Pd” R – H / B + R 1 – A RR 1 + BH + A – “M 1 ” NuH/Base +R 1 A NuR “Pd” RHM 1 Reaction, year R 2 CH = CH – H PdHeck coupling, 1972 R 2 C ≡ C – H Pd, Cu(I)Sonogashira coupling, 1975 Nu – H / B + R 1 – A NuR 1 + BH + Al – “M 1 ” Buchwald-Hartwig amination, 1995; etherification, 1996 RNH 2 (R 2 NH)/RONa + R 1 A RNHR 1 (R 2 NR 1 ) “Pd” ROH (RSH)/RONa + R 1 A ROR 1 (RSR 1 ) “Pd” E. Negishi (Ed.), Handbook of Organopalladium Chemistry for Organic Synthesis, Wiley, 2002 R.H. Crabtree, The Organometallic Chemistry of the Transition Metals, 6th edn., Wiley, 2014

15. 15 RM or RH as nucleophilic partner in coupling More green reactions with R – H, Preparation of some R – M reagents may be difficult, Stereoselectivity is lower with R 2 CH = CH 2 and R 2 C ≡ CH, TON is lower with R – H, i.e. more catalyst should be used (In “Pd” catalysis, TON: 10 6 with RZnBr), If the parameters for the reactions are same and outcome are similar, R – H is preferred for R 1 = Alkenyl and alkynyl coupling. R1AR1A “M 1 ” R 2 CH = CHR 1 R – M R 2 CH = CH – H / Base or R 2 C ≡ C – H / Base RR 1 or R 2 C ≡ CR 1

16. 16 The best transition metal catalyst: Pd Pd catalysts are used in 1-5 mol % in laboratory and in 0,01-0,1 mol % in industry. Pd catalysts can be used as homogen catalysts, Heterogen catalysts ( preferred in industry), Solid phase supported catalysts (more reactive, preferred in industry), Colloidal Pd, Pd black and Pd nanoparticles. 4567891011 TiCrMnFeCoNiCu ZrRuRhPdAg OsIrPtAu CatalystPercentage of usage Pd68.4 Ni10.6 Cu9.5 Fe2.4 Rh2.2 Co1.3 Pt1.0 CuNiPdFe, Co Low cost Hard conditions Low cost TON = 10 4 -10 6 Mild conditions Side products Toxicity High cost TON = 10 6 -10 9 Mild conditions High selectivity Very low cost More green reaction Conditions, TON Selectivity R.H. Crabtree, The Organometallic Chemistry of the Transition Metals, Wiley, 2014

17. 17 Transition metal catalysis changes the coupling mechanism of the organometalic reagents Reaction type Polar (or radicalic) reactions Mechanism : Substitution R δ – – M δ + + E + R – E Main metal (Li, Mg, Zn, B, Si, Sn) R – M + E + M 1 X n or M 1 X n L m [R – M 1 L m ] Intermediate R – E Transition metal catalyzed reactions Mechanisms : Ligand coordination and elimination Lewis acid coordination and elimination Oxidative addition and reductive elimination 1,2-Group insertion and elimination 1,1-Group insertion and elimination C – M 1 bond : Synergistic bond In the intermediate(s), transition metal complexes obey 18- electron rule

18. 18 R R Mechanism of Cu(I) catalyzed coupling of RMgBr ve RZnCl reagents M = Li, MgBr, ZnClL = Ligand Reaction steps : (a) Transmetalation ( with CuX and RCu ) (b) Oxidative addition, A: Cu(I), B: Cu(I), C: Cu(III) (c) Reductive elimination RM + R 1 A – RR 1 + MA “Cu(I)” RM + CuXL (a) MX RCuL Cu + M L B A (a) RM (b) R1AR1A MA (c) RR 1 Cu R R R1R1 L C

19. 19 Mechanism of Pd(0) or Ni(0) catalyzed coupling of RM (M = Mg, Zn, B, Si, Sn) reagents M 1 = Ni, Pd L = Ligand M = MgBr, ZnX, ZnR, BY 2, SiY 3, SnY 3 (Y = R, OR) Reaction steps: (a) Transmetalation (b) Oxidative additıon, A: M(0), B: M(II), C: M(II) (c) Reductive elimination RM + R 1 ARR 1 + MA “M1L2”“M1L2” M 1 X 2 L 2 veya M 1 L 4 2L M1L2M1L2 B A (b) R1AR1A (a) RM MA (c) RR 1 M R1R1 L R L C M1M1 R1R1 L L A

20. 20 Kumada – Corriu coupling Grignard reagents are easily prepared; however air,moisture sensitive Mild conditions High reactivity W. Li, Z. Wang, R.S.C. Advances, 2013, 3 25565 RMgBr + R 1 A NiX 2 orNiX 2 L 2 Et 2 O or THF R = Aryl, alkylR 1 = Aryl, alkenyl PhMgBr + Ph Br Ni (acac) 2 Ph Et 2 O, r.t. 1 h 70% EtMgBr + NiCl 2 (dppe) Et 2 O, r.t. 10 h 80% Et K. Tamao, M. Kumada, et al. J. Am. Chem. Soc., 1972, 94, 4374 J.P. Corriu, J.P. Masse, Chem. Commun., 1972, 144

21. 21 Murahashi – Fauverque - Ishikawa coupling (Pd Catalyzed Kumada – Corriu coupling) RMgBr + R 1 A PdL 4 orPdL 2 Et 2 O or THF R = Aryl,alkylR 1 = Aryl, alkenyl MeMgBr +Br Pd (PPh 3 ) 4 Benzene, r.t. 4 h S. Murahashi, et al., J. Organomet. Chem., 1975, 91, C39 J.F. Fauverque, A. Jutane, Bull. Soc. Chim. France, 1976, 76 A. Sekiya, N. Ishikawa, J. Organomet. Chem., 1977, 125, 281 M.H. Heravi, F. Hajiabasi, Monatsch. Chem., 2012, 143, 1575 RR 1 PhMePh FG-RMgBr reagents can be coupled with FG-R 1 A: FG I+ i-PrMgBr THF, -25°C FG MgBr FG 1 MgBr THF, 40°C FG 1 = H, COOR, CONR 2, CN FG 2 = Br, COOEt, CN FG 2 A+ “Pd”or“Ni” P. Knochel, et al. J. Am. Soc., 2007, 129, 3844, 2003, 42, 4302 O. Vechorkis, V. Proust, X. Hu, J. Am. Chem. Soc., 2009, 131, 9756 FG 1 FG 2

22. 22 Negishi coupling RZnCl + R 1 A M1X2L2M1X2L2 orM1L4M1L4 M 1 = Ni, Pd RR 1 CN ZnCl E. Negishi, et al., J. Org. Chem., 1977, 42, 1821 E. Negishi, Acc. Chem. Res. E. Negishi, Bull. Chem. Soc. Japan, 2007, 80, 233 R = All organyl groups R 1 =All organyl groups except alkyl, R 1 CO +I PdCl 2 (PPh 3 ) 2 THF, r.t., 2 h CN 74% ZnCl+ Brn-Bu Pd (PPh 3 ) 4 THF, r.t., 1 h n-Bu 80% Organozinc reagents are easily prepared: Coupling of FG-RZnCl and/or FG-R 1 A can be carried out. Mild conditions High reactivity and selectivity Reaction variety (More than 600 different coupling ) No. of synthesized natural products and compounds of medicinal interest : >300 RMgBrRZnCl ZnCl 2

23. 23 Suzuki – Miyaura coupling RBX 2 + R 1 A Pd (PPh 3 ) 4 X = R(Borane), OH(Boronic acid), OR(Boronate ester) R = Alkenyl, arylR 1 = Alkyl, alkenyl, alkynyı, aryl RR 1 N. Miyaura, A. Suzuki, Chem. Rev., 1995, 95, 2457 92% + B(OMe) 2 n-Pr Reagents are commercially available; however air, moisture sensitive Product(s) can be isolated easily Coupling is mostly applied in industry N. Miyaura, K. Yamada, A. Suzuki, J. Chem. Soc. Chem. Commun., 1979, 866 N. Miyaura, A. Suzuki, Synth. Cummun., 1981, 11, 513 H 2 O or apolar solvent, Base B(OH) 2 + n-C 6 H 13 ClMeOOC Pd (PPh 3 ) 4 H 2 O, NaOH, 100°C n-C 6 H 13 MeOOC 85% Et Br Pd (PPh 3 ) 4 Benzen, aq. Na 2 CO 3, reflux Et Base increases reactivity: RBX 2 + OH – [RBX 2 (OH)] –

24. 24 R – B S. Saito, M. Sakai, N. Miyaura, Tetrahedron Lett., 1996, 37, 2993 F. Han, Chem. Soc. Rev., 2013, 42, 52270 RB(OH) 2 veya R 1 B(OR) 2 + R 1 A “Ni” R, R 1 = ArylA = Br, I, Cl RR 1 B (OH) 2 +Cl RR “Pd” or “Ni” K 3 PO 4, Dioxane, 70°C R =p-COOMep-COMep-Mem-OMep-NH 2 “Pd” =-64%1%1%- “Ni” =96%98%89%94%86% O O + R 1 A NiCl 2 (dppe) NaOH, Dioxane, 110°C RR 1 70-92% R = Me, OMe, COOMe R 1 = OMe, COOMe, CN, NH 2

25. 25 Stille coupling RSnR 2 3 + R 1 A PdX 2 L 2 veya PdL 4 R = Alkyl, alkenyl, alkynyl, arylR 2 = Me, n-Bu R 1 = Aryl, RCO RR 1 P. Espinet, A.M. Echavarren, Angew. Chem. Int. Ed., 2004, 43, 470 RMgBr + R 1 COCl D. Milstein, J.K. Stille, Angew. Chem. Int. Ed., 1978, 100, 3636 J.K. Stille, Angew. Chem. Int. Ed., 1986, 25, 508 PdX 2 L 2 THF/HMPA, 65°C, 3 h I Sn(n-Bu) 3 + %86 “Ni” veya “Pd” RCOR 1 1. RMgBr 2. H 2 O R 2 C(OH)R 1 Compared to R 4 Sn + R 1 COCl Pd(PPh 3 ) 2 Cl(CH 2 Ph) RCOR 1 77-90% Coupling is easy, however Sn reagents are toxic ! Sn reagents are expensive Polymer supported tin Atom-economic reagent Sn n-Bu R RSnX 3 (X = Halojen, OR) HMPA

26. 26 Hiyama coupling RSiR 2 3 + R 1 A PdCl 2, PPh 3 R = Alkenyl, arylR 2 = AlkylR 1 = Allyl, alkenyl, aryl RR 1 N. Yakao, T. Hiyama, Chem. Soc. Rev., 2011, 40, 4893 RSiY 3 + R 1 A S.E. Denmark, D. Wehrli, J.Y. Choi, Org. Lett., 2000, 2, 2491 Pd(OAc) 2, PPh 3 TBAF, DMF, 60°C I 70-90% “Pd” RR 1 Y = OH, OR An activator is necessary More green coupling TBAF (2 eq.), THF, r.t. S.E. Denmark, R.F. Sweis, Acc. Chem. Res., 2002, 35, 835 RSiMe 3 + Me R Y. Hatanaka, T. Hiyama, J. Org. Chem., 1988, 53, 918 Y. Hatanaka, T. Hiyama, J. Am. Chem. Soc., 1990, 112, 7793 F – donor TBAF (t-Bu 4 NF) increases the reactivity of R, RSiR 2 3 + F – [RSiR 2 3 F] –

27. 27 Heck (veya Mizoroki – Heck) coupling R 2 CH = CH 2 + R 1 A PdL 4 Base R 2 = Alkyl, alkenyl, aryl, FG–aryl R 1 = Benzyl, alkenyl, aryl R 2 CH = CHR 1 I.P. Beletskaya, A.V. Cheprakov, Chem. Rev., 2000,100, 3009 Coupling is easily applied FG–R 1 A can be used trans-Stereoselectivity is one of the benefits Alkenes, dienes and polymers can be easily synthesized T. Mizoroki, K. Mori, A. Ozaki, Bull. Chem. Soc. Japan, 1971, 44, 581 74% Ph+ Me PdCl 2, KOAc (1 eq.) MeOH, 120°C, 2 h Ph Me R.F. Heck, J.P. Nolley, Jr., J. Org. Chem., 1972, 37, 2320 75% Ph+ PhI Pd (OAc) 2, t-Bu 3 N (1 eq.) 100°C, 2 h Ph Br R 2 CH = CHM M = Mg, Zn, B R 1 A, “Pd” H R2R2 R1R1 H E – R A, “Pd” R 2 CH = CH 2

28. 28 Mechanism of Heck reaction Reaction steps : (a) Oxidative addition (b) Ligand coordination (c) 1,2–group insertion to R 1 – Pd bond of alkene R 2 CH = CH 2 + R 1 AR 2 CH = CHR 1 + HA PdL 2 PdX 2 L 2 veya PdL 4 2L PdL 2 B (a) R1AR1A (b) (e) HA (d) β–Hydride elimination (e) Formation of catalyst and HA from HPdL 2 A complex (f) Neutralisation of HA with base Base L 2 Pd R1R1 A BH + A – H–PdL 2 A (d) H R2R2 R1R1 H R1R1 H2CH2CCHR 2 PdL 2 A (c) R1R1 H2CH2CCHR 2 PdL 2 A CC H R2R2 H H (f)

29. 29 Sonogashira coupling R 2 CH ≡ CH + R 1 A PdL 4 (and CuI) Base R 2 = Alkyl, aryl, FG–alkyl, FG–aryl R 1 = Alkenyl, aryl Baz = R 2 NH, R 3 N, piperidine R 2 C ≡ CR 1 R. Chincilla, C. Najera, Chem. Soc. Rev., 2011, 40, 5084 A.V. Avmas, A. Sujatha, G.A. Lumar, Chem. Soc. Rev., 43, 2168 Coupling is easily applied Pd catalyst is used in 0,5-2 mol % Milder conditions with Cu(I) catalysis R. Sonogashira, Y. Tahda, N. Hagihara, Tetrahedron Lett., 1975, 16, 4467 %90 PhC ≡ CH+ PhI PdCl 2 (PPh 3 ) 2, CuI Et 2 NH (1 eq.), r.t., 1 h R 2 C ≡ CH R 2 C ≡ CM M = Mg, Zn, B R 1 A, “Pd” “Pd” R 2 C ≡ CR 1 PhC ≡ CPh 76% HOCH 2 C ≡ CH+ PdCl 4, CuI Et 2 NH, r.t., 6 h CH 2 = CHBr HOCH 2 C ≡ C – CH = CH 2

30. 30 L R1R1 Mechanism of Sonogashira reaction Reaction steps : (a) Oxidative addition (b) Transmetalation (c) Reductive elimination R 2 C ≡ CH + R 1 AR 2 C ≡ CR 1 + HX PdL 2, CuX Pd (a) 2L (b) R 2 C≡CCu CuX (c) R – ≡ – R 2 Pd R L R2R2 L PdX 2 L 2 veya PdL 2 PdL 4 R1AR1A A L ≡ BH + X – – I ≡ – R 2 H ≡ – RH ≡ – R B

31. 31 Buchwald-Hartwig amination (C–N coupling) RNH 2 (RR 2 NH) + R 1 A PdX 2 L 2, Base Toluene or dioxane, 60-100°C R, R 2 = Alkyl, alkyl; alkyl, H; alkyl, aryl R 1 = Aryl, FG–aryl Baz = RONa, LiHMDS (LiN(SiMe 3 ) 2 ) RNHR 1 (RR 2 NR 1 ) D.S. Surry, S.L. Buchwald, Angew. Chem. Int. Ed., 2008, 47, 6338 Yields and selectivity are higher compared to S N reactions –NH 2, –NHR ve –NR 2 groups can be coupled FG containing electrophilic partner can be aminated J.F. Hartwig, et al. 1996, 118, 7217 S.L. Buchwald, et al. 1996, 118, 7215 Me PdCl 2 (PPh 3 ) 2, t-BuONa Dioxane, 70°C 87% RR 2 NH + Br Me NRR 2 J.F. Hartwig, et al. Tetrahedron Lett., 1995, 36, 3609 S.L. Buchwald, et al. Angew. Chem. Int. Ed., 1995, 34, 1348 FG Hartwig: Pd/dppf, Buchwald: Pd/BINAP t-BuONa, toluene, 100°C RNH 2 + I FG NHR

32. 32 Mechanism of Buchwald-Hartwig amination Reaction steps : (a) Oxidative addition (b) Ligand coordination (c) Neutralisation of H and A with B (d) Reductive elimnation R 2 NH + R 1 AR 2 NR 1 PdL 2 Base PdX 2 L 2 veya PdL 4 2L PdL 2 (a) R1AR1A (c) (d) R 2 NR 1 Pd R1R1 NR 2 L2L2 Pd R1R1 A L2L2 R 2 NR (b) B BH + A – Pd R1R1 NHR 2 L2L2 A +

33. 33 Buchwald-Hartwig C–O ve C–S eşleşmeleri ROH + R 1 A (RSH) PdX 2, PdX 2 L 2 veya PdX 2 /L Base, Toluene, r.t. R = prim-, sec-, tert- alkyl, aryl R 1 = Aryl Base = RONa, M 2 CO 3 (M = K, Cs) ROR 1 (RSR 1) M. Palucki, J.P. Wolfe, S.L. Buchwald, J. Am. Chem. Soc., 1996, 118, 10333 G. Mann, J.F. Hartwig, J. Am. Chem. Soc., 1996, 118, 13109 K.E. Torraca, X. Huang, C.A. Parrish, S.L. Buchwald, J. Am. Chem. Soc., 2001, 123, 10770 Pd(OAc) 2, Cs 2 CO 3 Toluene, 70% n-BuOH + Br MeO OH(SH) + t-BuONa + t-BuBr Pd(dba) 2, t-BuONa Toluene, 110°C MeO O (S) t-Bu 75-87% Me On-Bu Me %90

34. 34 Buchwald-Hartwig C–C couplings D.A. Culkin, J.F. Hartwig, Acc. Chem. Res., 2003, 36, 234 X. Liao, Z. Weng, J.F. Hartwig, J. Am. Chem. Soc., 2008, 130, 195 R1R1 + Pd(dba) 2 t-BuONa,Toluene,60°C 80-90% α-Ketone (ester and amide) arylation O H Y Y = R, NR 2, OR Br, dppf O Y R2R2 R2R2 R1R1 R1R1 + “Pd” O – Y Br R2R2 − M + + H R R2R2 O R1R1 Br Ni(cod) 2 LiN(SiMe 3 ) 2, THF, r.t. R R2R2 O R1R1 70-90% P.-O. Norrby, et al. J. Am. Chem. Soc., 2015, 137, 7019 α-Ketone alkenylation

35. 35 Interest on the investigation of the transition metal catalyzed reactions 2011 Frontiers in Transition Metal Catalyzed Reactions, Chem. Rev., 2011, Özel Sayı 3 Percentage of investigation in 2001-2010: R 1 –A R 3 B / Pd veya Ni Suzuki R 2 CH = CH 2 / Pd Heck RC ≡ CH / Pd / Cu Sonogashira R 3 SnY / Pd Stille ZnCl / Pd veya Ni Negishi RMgBr / Pd veya Ni Kumada R 2 NH / Pd Buchwald-Hartwig R 3 SiY / Pd Hiyama RCH 2 COR / Pd α-Ketone arylation 35 22 12 9 8 4 5 3 2

36. 36 Transition metal catalyzed addition reactions E. Negishi, Bull. Chem. Soc. Japan, 2007, 80, 233 No. of synthesized natural products : ~100 D.E. vanHorn, E. Negishi, J. Am. Chem. Soc., 1978, 100, 2252 R2R2 Me Y AlMe 2 Zr catalyzed carboalumination of alkynes, 1978 R 2 C ≡ CY Me 3 Al, “ZrCp 2 Cl 2 ” Me 3 Al E + R2R2 Me Y E Z –>80% Regioselectivity > 90% Stereoselrctivity > 90% Y = H, R (Alkyl, aryl) Cp = Cyclopentadiene Intermediate: [MeZrCp 2 ] + Cl – – AlMe 2 Cl Zr catalyzed asymmetric carboalumination of alkenes (ZACA reaction), 1996 D.Y. Kondakov, E. Negishi, J. Am. Chem. Soc., 1996, 118, 377 R 2 CH = CH 2 + MeR 2 Al ZrCl 2 L 2 * R2R2 Me H AlR 2 O2O2 R2R2 Me H OH 70-85% Stereoselectivity >90% R 2 = Alkyl, aryl

37. 37 Some examples for the use of Negishi coupling in the synthesis of natural products and compounds of medicinal, agrochemical and cosmetical interest J.P. Corbet, G. Mignani, Chem. Rev., 2006, 106, 2651 2011 Frontiers in Transition Metal Catalyzed Organic Reactions, Chem. Rev., 2011, Özel Sayı 3 E. Negishi, Bull. Chem. Soc. Japan, 2007, 80, 238 J. Magano, J.D. Dunetz, Chem. Rev., 2011, 111, 2177 OH HO Magnolol, 1995 [Bioactive lignan] Egenol, 1995 [Local antiseptic, anesthetic] PDE472, 2003 [Inhibitor of phosphoodiesterase] H 3 CO HO R O O O N N N O

38. 38 Z-Tamoksifen, 1990 [Antagonist for ostrogen reseptor, an anti-cancer reagent] UB-165, 2003 [Nicotinic asetilcholin reseptor] Savinin, 1997 [Lignan for treatment of tumor] O Ph NMe 2 F N HNHN O O O O O O

39. 39 Vitamin A, 1991β-Carotene, 2001 Harveynone, 2000 [Bioactive epoxiquinone ] OH O O

40. 40 α-Farnesene, 1981 [A perfumery additive and an agrochemical ] Qenzyme Q3, 1998 O O 2 MeO O Dendrolasin, 1980 [A perfumery additive] OAc A pheromone ofYellow Scale insect, 1989 [An agrochemical]

41. 41 Zetia, 1998 [Used for treatment of high cholesterol ] Amphidinolide, 2003 [For treatment of cancer] (A marine natural product) PDE472, 2003 [Inhibitor of phosphoodiesterase] MeO N N N O Negishi couplingeşleşmesi Kumada coupling OH F O N F O O O HO O

42. 42 Some examples for the use of Heck, Suzuki and Buchwald -Hartwig couplings in the synthesis of compounds of medicinal and cosmetical interest and monomers C.C.C.J. Seechurn, M.O. Kitching, T.J. Colacot, V. Snieckus, Angew. Chem. Int. Ed., 2012, 51, 5062 R. Jana, T.P. Pathak, M.S. Sigman, Chem. Rev., 2011, 111, 1417 A.J. Berke, C.S. Marques, Catalytic Arylation Methods from the Academic Laboratory to Industrial Processes, Wiley, 2004 NAPROKSEN, 1994 [Anti-inflammatory drug] (Dow) TERBİNAFİN, 1996 [Antifungal LAMİSİL active component] (Sandoz) EHMC (2-ETYLHEXYNE-p-METHOXYCINNAMATE), 1993 [UV protected suncare creme] (Hoescht) O Heckcoupling N O O O

43. 43 4-VİNYLTOLUENE, 1994 (Comonomer for vinyl polymers) (Dow) NABUMETAN, 1993 [Anti-inflammatory drug] (Hoescht) LASARTAN, 1994 [Used for treatment of hypertension] (Merck) Heck eşleşmesi O O Heck eşleşmesi ve çift bağ indirgemesi NN HNN N N Cl OH Suzuki coupling

44. 44 2-CYANO-4’-METHYİLBİPHENYL, 1998 [Used for treatment of hypertension] (Clariant AG) GLEEVEC (IMATINIB), 2003 [Used for treatment of bowel tumors] (Novartis) CRIZOTINIB, 2011 [Used for treatment of cancer] (Pfizer) Suzuki couspling Buchwald-Hartwig coupling CN HN N N N O N N Me F Cl O N NH 2 NN NH Suzuki coupling

45. 45 Mokupalide, 1980 [Bioactive compound] (A marine natural product) Amphidinolide B, 1999 [Used for treatment of cancer] (A marine natural product) Bafilomycin A 1, 2003 [Used for autophagy] (A marine natural product) O O 3 OH O O O O HO Me OH O O O HO Me OMe Me OH Some examples for the use of ZACA (Zr catalyzed carboalumination) in the synthesis of natural products and compounds of medicinal interest

46. 46 Concluding remarks 1. If industrial scale synthetic methods for chemicals are compared, Pd and Ni catalysed coupling reactions are the most widely applicable reactions since 1980 due to their versatality, selectivity, specificity and other reaction characteristics, such as being a green reaction with cleaner products. However, some reactions still could not find application in industry because of the high cost of Pd and difficulty in catalyst regeneration! Y = RO, R 2 N Cu,the oldest catalyst with a low cost, is now being extremely used both in laboratories and in industry : 2.The use of new transition metal catalysts : Cu(I) catalysed C – Heteroatom coupling, 2001 YH + R 1 Br “Cu(I)”, L R1YR1Y DMF, 80-110°C, 4-12 h Ullmann type reactions S.V. Levy, A.W. Thomas, Angew. Chem. Int. Ed., 2003, 42, 5400 I.P. Beletskaya, A.V. Cheprakov, Coord. Chem. Rev., 2004, 248, 2337

47. 47 M = MgBr, ZnCl, B(OH) 2, Si(OR) 3, MnCl Cu(I) catalyzed C – C coupling RM + R 1 A “Cu(I)” RR 1 U. Tekale, et al. Mini Rev. in Org. Chem., 2013, 10, 281 Coupling of organometallics, RM (R= Mg, Zn, B, Si, Mn) are now being carried out with higher yields by using soluble catalysts (e.g. CuBr.Me 2 S.LiBr) and donor solvents (e.g. NMP) and/or Lewis acid additives. Ru veya Rh catalyzed Heck coupling and C–H fonctionalisation H + RH (veya YH) “Ru” veya “Rh” R (Y) R = Aryl Y = RO, RNH, RCONH L.A. Ackermann, et al. Angew. Chem. Int. Ed., 2015, 54, 5513 2012, 51, 8251 The use of Heck reaction for C–Heteroatom coupling is now one of the main topics under investigation:

48. 48 3.The use of transition metal catalysis and organic catalysis: Reactions which are unsuccesful in the presence of transition metal catalysis can take place in the presence of organic cocatalysis. Yield and/or selectivity possibly increses and stereospesificity, which is not observed in some reactions can be observed. M 1 X n (orM 1 X n L m ) / Organic catalyst Organic catalyst: Lewis acid, AlCl 3, H 3 PO 4 ; Lewis base, amines, carbenes; Brønsted acid, H 3 PO 4 ; Brønsted base, OH – 4.The use of new technologies : The use of Çözücü olarak wateror ionic liquids as solvents or nonsolvent reactions, Solid supported reactions, Microwave-assisted reactions. 5.Transition metal catalyzed reactions still have some problems to be solved such as: sp 3 C–sp 3 C and sp 2 C–sp 3 C coupling in RM + R 1 A reaction, Steric and electronic effects of ligands, L, More easily applicable methods for asymmetric synthesis with L*. However, they will keep their importance as being indispensable synthetic methodology for C–C ve C–Heteroatom couplings.