Transition-Metal-Catalyzed Alkenyl Sp2 C-H Activation: A Short Account
SYNTHESIS0039-78 1 437-210XGeorg Thieme Verlag Stuttgart · New York2019, 51, 1049–10621049short reviewenSyn thesisShort ReviewM. Maraswami, T.-P. LohTransition-Metal-Catalyzed Alkenyl sp2 C–H Activation:A Short AccountManikantha MaraswamiaTeck-Peng Loh*a,b,c[M]0-02936-7XR1aDivision of Chemistry and Biological Chemistry, School of Physical andMathematical Sciences, Nanyang Technological University, Singapore637616, Singaporeteckpeng@ntu.edu.sgbInstitute of Advanced Synthesis, Jiangsu National Synergetic InnovationCenter for Advanced Materials, Nanjing Tech University, Nanjing, Jiangsu210009, P. R. of ChinacHefei National Laboratory for Physical Sciences at the Microscale, iChEM(Collaborative Innovation Center of Chemistry for Energy Materials), University of Science and Technology of China, Hefei, Anhui 230026, P. R. ofChina[M]H HR1R2 Pd, Rh, Ru, Cu, etc.R2 Stereoselective alkene synthesis Atom economical Versatile products Synthesis of cyclic alkenesincluding macrocyclesPublished as part of the 50 Years SYNTHESIS – Golden Anniversary IssueReceived: 23.11.2018Accepted: 14.12.2018Published online: 23.01.2019DOI: 10.1055/s-0037-1611649; Art ID: ss-2018-z0776-srLicense terms:Abstract Alkenes are ubiquitous in Nature and their functionalizationcontinues to attract attention from the scientific community. On theother hand, activation of alkenyl sp2 C–H bonds is challenging due totheir chemical properties. In this short account, we elucidate, discussand describe the utilization of transition-metal catalysts in alkene activation and provide useful strategies to synthesize organic buildingblocks in an efficient and sustainable manner.1Introduction2Breakthrough3Controlling E/Z, Z/E Selectivity3.1 Esters and Amides as Directing Groups3.2 The Chelation versus Non-Chelation Concept4Other Alkene Derivatives5Intramolecular C–H Activation6Conclusion and Future ProjectsKey words transition metals, enamides, acrylamides, macrocycles,acrylates, alkenylation, alkynylation1IntroductionAlkenes and their derivatives feature widely in manynatural products and advanced materials.1,2 Accordingly,significant efforts have been directed towards the development of new synthetic methods to access this class of compounds. Among the many approaches reported, transitionmetal-catalyzed cross-coupling reactions3 are the mostcommonly employed since they can be carried out on largeand industrial scale. However, the need to use prefunctionalized environmentally unfriendly organohalides and/or organometallic reagents4 has encouraged researchers tosearch for cheaper and greener approaches. We envisagedthat a straightforward cross-coupling among cheap alkenefeedstocks would provide one of the most straightforwardand practical designs to access this class of important compounds. To be successful, we would need to preferentiallyC–H functionalize one of the alkenes and effect cross-coupling with the second alkene without them undergoinghomo-coupling reactions. We envisaged that by tuning theelectronic and steric properties of the olefins, we might beable to preferentially activate one of the two alkenes to effect the desired cross-coupling without the formation ofhomo-coupling products. If successful, this design might beapplicable for the stereoselective synthesis of dienes. Further, an intramolecular version will provide access to cyclicalkenes not available via Diels–Alder or olefin metathesisapproaches. However, when we initiated this research program in the early 2000s, very little work had been done inthe area of alkenyl sp2 C–H bond functionalization. Furthermore, the high activation energy required to activate thealkenyl sp2 C–H bond in a highly selective manner posestremendous challenges for organic chemists. Despite thesechallenges and considering the many benefits of thesemethods, we initiated a research program on alkenyl sp2C–H bond functionalization by first investigating the crosscoupling between two distinct olefins.In early 2001, dimerization of camphene catalyzed bypalladium under aerobic oxidative conditions was reportedby Gusevskaya et al. in the presence of Pd(OAc)2/benzoquinone (BQ)/O2 and Pd(OAc)/LiNO3/O2 (Scheme 1).5 Theydemonstrated that the reaction progressed via formation ofa σ-vinyl palladium hydride intermediate.HOcat. Pd(OAc)2cat. LiNO3 or BQ[O]O2 (1 atm)AcOH, 60 C[Pd(OAc)2 (2 mol%), LiNO3 (0.72 equiv), 8.5 h, conversion 80%][Pd(OAc)2 (2 mol%), BQ (0.1 equiv), 6 h, conversion 22%]Scheme 1 Palladium-catalyzed dimerization of campheneGeorg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 1049–1062
1050Syn thesisShort ReviewM. Maraswami, T.-P. Loh2BreakthroughStraightforward cross-coupling reactions using simplealkenes to form dienes had not been explored by virtue ofthe difficulties in activating the alkenyl C–H bond. The firstever cross-coupling reaction among acrylates and simpleolefins by using a catalytic amount of a palladium catalystwas reported by our group (Scheme 3).7Pd(OAc)2 (20 mol%)Cu(OAc)2 (1 equiv), O2 (1 atm)O RTeck-Peng Loh (left) is a professor of chemistry at Nanyang Technological University, Singapore. He received his B.Eng. (1987) and M.Eng.(1989) from the Tokyo Institute of Technology under the supervision ofProfessor Takeshi Nakai and Professor Koichi Mikami. Under the tutelageof Professor E. J. Corey, Professor Loh obtained his Ph.D. (1994) fromHarvard University. He is currently a Professor in the School of Physicaland Mathematical Sciences. His research work focused mainly on thedevelopment of new synthetic methodology in organic chemistry, greenchemistry and synthesis of natural and unnatural products. He has published more than 330 international refereed papers in reputable chemistry journals bearing high impact factor. He has been invited to givemore than 100 lectures in many institutions in the world and plenaryand keynote talks in conferences such as the ICOS, OMCOS, Asian European Symposium, etc. He has also served as chairman of many of theseconferences. He has been conferred with many awards. He has beenawarded outstanding researcher awards from both National Universityof Singapore and Nanyang Technological University. In 2017 he received the Yoshida Prize (Japan) and the prestigious President's ScienceAward (individual) Singapore. He has been elected Fellow, Academia ofSciences, Singapore (2018) and Fellow of Academia of Sciences, Malaysiasince 2010. He has been conferred with 1000 talent award, People's Republic of China. He was also the founding head of the division of Chemistry and biological chemistry at Nanyang Technological University.Manikantha Maraswami (right) was born in India in 1987. He receivedhis B.Sc. (2008) and M.Sc. (2010) in chemistry from Karnatak University, Dharwad (India). He then worked as a Research Associate at SyngeneInternational Pvt. Ltd., Bengaluru (India). In 2018, he obtained his Ph.D.from Nanyang Technological University, Singapore under the joint supervision of Assistant Professor Chen Gang and Professor Teck-PengLoh. In 2017, he received the Excellency in Teaching award for his outstanding work as a Teaching Assistant at Nanyang Technological University. He is presently a Research Fellow in Professor Teck-Peng Loh’sgroup at Nanyang Technological University, Singapore. His work focuses on transition-metal-catalyzed intramolecular sp2 C–H activation.In 2004, Ishii et al. reported an aerobic oxidative crosscoupling of vinyl carboxylates with acrylates in the presence of a Pd(OAc)2/HPMov catalyst employing O2 as the solecritical oxidant (Scheme 2).6AcOHH Pd(OAc)2 (10 mol%)H4PMo11VO40·nH2O (2 mol%)ORAcOOnBuAcOAcOOMeOO62%, E/Z 60/4045%, E/Z 56/44ORCO2tBuCO2MeCO2tBu71%, E/Z 87/13CO2tBu33%, E/Z 84/1668%, E/Z 90/1065% E/Z 84/16Scheme 3 Cross-coupling of alkenes with various acrylates catalyzedby Pd(OAc)2Our initial investigation focused on the coupling of α-alkyl styrenes and acrylates (Heck-type coupling). We envisaged that the α-alkyl substituent on the styrene may preferentially activate the C–H functionalization of the alkeneover the acrylate. Furthermore, the steric effect of this alkylsubstituent may prevent homo-coupling of the styrene. Additionally, the acrylate may promote cross-coupling. Amidstthese simple hypotheses, we carried out the cross-couplingof α-alkyl styrenes with acrylates in the presence of a palladium catalyst. To our delight, the desired cross-couplingproducts were obtained in moderate yields. Despite thissuccess, this approach had limited scope and applications.(1) A high catalytic loading of the palladium catalyst (20mol%) was necessary to obtain the products in moderateyields, (2) alkyl-substituted styrenes were necessary as removing the alkyl substituent resulted in messy reactions,(3) replacing the aryl substituent with an aliphatic substituent resulted in a low yield of the product, and (4) the E/Eand E/Z selectivities of the products were low to moderate.In order for this approach to be useful in organic synthesis,we would need to solve some of these problems, if not all.Later, we modified our previous procedure and developed a coupling reaction among indenes and various electron-deficient alkenes by employing Pd(OAc)2 (10 mol%) asthe catalyst and oxygen as the oxidant in AcOH (Scheme 4).8Various indene derivatives were employed to afford good tomoderate yields of the products.R1 R2Pd(OAc)2 (10 mol%)Cu(OAc)2 (1 equiv), O2 (1 atm)R1AcOH, 60 C, 48 hR2OOEt76%, E/Z 58/42Scheme 2 Oxidative cross-coupling of acrylates with vinyl carboxylatesR1Selected productsOAcODMSO/AcOH (1:1), 60 C, 24 hOORNaOAc (0.1 equiv)O2 (1 atm), AcOH, 90 COOR1R1 Me, Ph, Cl, Br, OMe, CF3R2 CO2Me, CO2Et, CO2tBu, Ph, CN19–70%Scheme 4 Straightforward cross-couplings of indenes with variouselectron-deficient alkenesGeorg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 1049–1062
1051Syn thesisShort ReviewM. Maraswami, T.-P. LohIn 2010, an efficient approach to synthesize functionalized 1,3-butadienes was reported by Yu and co-workers viacross-coupling reactions among terminal alkenes and αoxoketene dithioacetals in the presence of Pd(OAc)2 as thecatalyst.9In 2012, Liu et al. developed a double C–H bond activation method to access conjugated dienes by straightforwardolefination of unactivated alkenes with electron-richalkenes in the presence of a palladium catalyst (Scheme5).10 They even achieved the olefination of styrenes without2-substituents unlike in the previously reported method.7Although they developed an efficient design, it had the disadvantage of overloading of the oxidant (2.5 equiv ofAgOAc) in order to achieve the transformation.R1RH HR3OR2OPd(OAc)2 (15 mol%)AgOAc (2.5 equiv)R1RR3O5% DMSO/DCE110 CR2OOOAcO70%, Z/E 74/2670%, Z/E 80/20OAcPhS85%, Z/E 86/14Scheme 5 Pd(II)-catalyzed cross-coupling among two alkenesAlthough acrylates are utilized as efficient couplingpartners in forming 1,3-diketones, because of the high potential for polymerization, unsaturated ketones such asmethyl vinyl ketone are rarely employed in cross-couplingreactions. Later, in 2013, our group developed a general andefficient protocol for the synthesis of conjugated dienyl ketones catalyzed by Pd(OAc)2 involving a coupling reactionamong vinyl ketones and simple alkenes (Scheme 6).11 Weshowed the importance of this method by synthesizing vitamin A1 and bornelone.OPd(OAc)2 (15 mol%)AgOAc (2.0 equiv) O55% yieldE/Z 85:15Scheme 6 Synthesis of conjugated dienyl ketones catalyzed byPd(OAc)233.1Controlling E/Z, Z/E SelectivityEsters and Amides as Directing GroupsGlorius et al. reported the first directed olefin–olefincross-coupling in early 2011. They employed a Rh(III) catalyst to form linear 1,3-butadiene derivatives from di or trisubstituted olefins and styrene or acrylates (Scheme 7).12They obtained remarkably high chemo-, regio- and stereoselectivity in these reactions and the products were converted into unsaturated α-amino acid derivatives.R1DG R2HR3Cu(OAc)2 (2.1 mmol)Dioxane, 120 C, 16 hHOOOnBu[{RhCp*Cl2}]2 (2.5 mol%)AgSbF6 (10 mol%)OOnBuR1DGR2R3ONH2NH2SO2Ph54%, Z/E 45/5547%67%, Z/E 79/2137%, Z/E 78/22Scheme 7 Directed olefin–olefin cross-couplingFollowing this, our group developed ruthenium- andrhodium-catalyzed directing-group-assisted cross-couplingamong acrylamides and a broad range of alkenes possessingvarious functional groups (Scheme 8).13 In a mixed solventsystem of dioxane/water/acetic acid (v/v/v 8/4/1) in thepresence of RuCl2(p-cymene)]2 as the catalyst, KPF6 as theadditive and Cu(OAc)2·H2O as the oxidant, 1,3-butadienederivatives were obtained in up to 91% yield and 99/1 (Z/E)selectivity. Similarly, we employed RhCp*Cl2 as the catalystand Cu(OAc)2 as the oxidant in acetone to prepare substituted dienamides in up to 91% yield and with good to moderate Z/E selectivity. To understand the reaction mechanism, we carried out competition and isotope labelling experiments. Based on the results, we proposed that thereaction is supposedly triggered by cyclometalation of theacrylamide by amide-directed C–H bond activation. Next,the alkene coordinates to the metal center which is followed by the formation of a seven-membered rhodacycle orruthenacycle species by insertion of the carbon–carbondouble bond. Finally, β-elimination results in the formationof the desired dienamide with (Z,E)-configuration. The developed method provides an excellent route to synthesize(Z,E)-dienamides in high yields and with moderate to excellent stereoselectivities.In organic synthesis functional conjugated muconatesubunits are very useful synthons.14 This class of compounds can be synthesized by a straightforward and atomeconomical cross-coupling reaction between two distinctacrylates. The generation of conjugated muconated derivatives with distinctive functional groups from commerciallyavailable acrylates through C–H functionalization bystraightforward cross-coupling is difficult and challenging.From previous literature, it is evident that the ester groupcoordinates poorly with the metal center;15 the most challenging task is to employ the ester as the directing group forthe alkenylation of acrylates via chelation assistance.16 Inour previous report,7 we observed that substitution at theα-position of the alkene is an essential criterium to carryout the alkenyl C(sp2)–H direct functionalization. Later, in2015, we developed a unique cross-coupling reaction oftwo distinct acrylates in a highly stereo and chemoselectivemanner by employing [RuCl2(p-cymene)2] as the catalyst.Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 1049–1062
1052Syn thesisOOOR1NR2R3R4 [RuCl2(p-cymene)2] (2.5 mol%)KPF6 (20 mol%)R1Cu(OAc)2·H2O (2 equiv)Dioxane/H2O/AcOH100 C, 18 hROOONHBn83%, Z/E 96/4NHCO2nBuCO2nBu70%, Z/E 99/175%, Z/E 98/2R4ROR4Cu(OAc)2·H2O (2 equiv)Dioxane, 135 C, 24 h38%, Z/E 80/20Cu(OAc)2·H2O (2 equiv)Acetone100 C, 18 hOR3R2ONH[RhCp*Cl2]2 (2.5 mol%) HOO67%, Z/E 85/15OONR2R3OOR3R1[RuCl2(p-cymene)2] (5 mol%)AgSbF6 (20 mol%)R2R4ONHCO2nBuONR2R3R1RR1Short ReviewM. Maraswami, T.-P. Loh59%, Z/E 88/12NR R74%, Z/E 91/9OO2 3OOEtOEtR56%, Z/E 96/4OOOEtOEtR4OOOCH2CF3OCH2CF3OONHBnCO2tBu90%, Z/E 99/1NHNHCO2tBuCO2tBu91%, Z/E 99/186%, Z/E 89/11BnOOtBuOOOCH2CF3OONHBn51%, Z/E 98/2CO2tBu75%49%, Z/E 93/771%, Z/E 90/10Scheme 9 Ruthenium-catalyzed weak directing-group-enabled alkenyl sp2 C–H activation52%, Z/E 99/1Scheme 8 Ruthenium- and rhodium-catalyzed acrylamide couplingwith alkenesVarious muconate derivatives with distinct functionalgroups can be easily synthesized via activation of the vinylic C–H bond. [RuCl2(p-cymene)]2 (5 mol%) catalyzed thecross-coupling reaction of n-butyl methacrylate and n-butyl acrylate along with AgSbF6 (20 mol%), and Cu(OAc)2·H2Oin 1,2-DCE at 135 C for 24 hours to provide the desiredcross-coupled product in 48% isolated yield with a 92/8Z,E/E,E ratio. After further optimization studies, we foundthat 1,4-dioxane was the most suitable solvent for thistransformation, affording the product in 67% yield (Scheme9).17 In this report, both aryl- and alkyl-substituted acrylates were utilized to obtain the cross-coupled muconatederivatives in good to excellent yields and with good chemo- and stereoselectivity. From mechanistic studies, it wasproved that the Ru complex coordinates with the estergroup to provide the products. Further studies showed thatthe chemoselectivity and reactivity of the acrylates wereinfluenced by the substituents at the α-position. Throughthis method multisubstituted (Z,E)-1,3-diene motifs can besynthesized efficiently.Our continued interest in alkene sp2 C–H functionalizations led us to develop a novel and efficient method for thesynthesis of 1,4-diene skeletons. In the presence of a transition-metal catalyst the alkene moiety can react with an allylic source to form allylated alkene products. We chose allyl acetates as the electrophiles for this transformation. Inpresence of a rhodium catalyst, electron-deficient alkenesundergo olefinic allylation with allyl acetates to provide thedesired products in good to excellent yields (Scheme 10).18A wide variety of acrylamides as well as allyl acetates withdistinct functional groups were well tolerated under thesecatalytic conditions. The alkene substrates were allylated ina simple and straightforward manner, with the aid of directing groups having weak-coordinating assistance, to provide 1,4-dienes that are of high synthetic value.OOR1NHTs R2R1[RhCp*Cl2]2, NaOAcOAcMeOH, 80 C, 12 HTs35%, E/Z 77/2361%, E/Z 99/1ORNHTsNHTs47%ORNHTsHONHTsRNTs2H RhIIIOHC–H activationO[Rh-OAc]IIIOOROROAcNHTsβ-OAc eliminationRNTsNTs[Rh]IIIRhIII-Holefin insertionAcOOROH RNTs[Rh]IIINTsIII[Rh]OAcOHOScheme 10 Rhodium-catalyzed allylation of acrylamidesGeorg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 1049–1062
1053Syn thesisShort ReviewM. Maraswami, T.-P. LohAlkynes can be transformed into a variety of functionalgroups and can be merged into the structural backbone ofvarious organic molecules; in synthetic chemistry alkynesare also one of the most versatile functionalities.19 The value of alkynes is further highlighted due to their involvement in click chemistry.20 In organic synthesis, both nonconjugated and conjugated alkynes are well exploited.21Due to their easy synthetic transformations and usefulfunctionality, 1,3-enynes comprise a class of extensive subunits found widely in pharmaceuticals and natural products of biological interest.22In 2014, Glorius and co-workers demonstrated pioneering work on the synthesis of enynes via a C–H activationprotocol. They reported highly selective alkynylation ofbenzamides and β-substituted acrylamide derivatives. Reactions of acrylamides with TIPS-EBX (1) in the presence ofthe cationic rhodium complex RhCp*(MeCN)3(SbF6)2 in dichloromethane at 80 C afforded alkynylated products inmoderate to excellent yields (Scheme 11).23OOR1NHTs1, DCE, rt, 16 hR2TIPSCl1, CH2Cl2, 80 C, 16 etic transformations71%ONTsAr NCC6H4, 78%ArAryl iodide, TBAFPdCl2(PPh3)2, CuITHF, 0 C to rtOONBSMeCNNTsINHTsTBAF/AcOHNTsTHF, 0 C to rtN2, rtTIPS97%(i) K2CO3, MeI, DMF(ii) TBAF/AcOH, THF, 0 C to rt(iii) CuSO4·-5H2O, Sodium ascorbatetBuOH/H2O, 6)2NR2R2OTIPSONHTsR2HOOOOR1[RhCp*Cl2]2, NaOAcNOTIPSTIPSTIPSNMeTsTIPSN94%84%76%62%Scheme 11 Selective alkynylation of benzamides and β-substitutedacrylamidesIn the same year, we extended our research of alkynylation chemistry and developed a method for olefinic C–Halkynylation of electron-deficient alkenes in the presence ofa Rh(III) catalyst (Scheme 12).24 The tosyl-imide group wasselected as a directing group for this transformation. Thedirecting group, with its weak coordinating ability, was responsible for the highly efficient and stereospecific C–Halkynylation of alkene C–H bonds. Operational simplicity,gentle reaction conditions and high functional group tolerance were the key advantages of this protocol. Hence thismethod represents an efficient process for the synthesis of1,3-enyne moieties. To show the applicability of the method, the obtained products were further derivatized into aseries of pyridinone and triazole moieties of synthetic potential.Glorius et al., in 2013, reported the straightforward halogenation of readily available acrylamide derivatives in thepresence of a Rh(III) catalyst to obtain a variety of substituted Z-haloacrylic acid derivatives.25 In the same year, Gloriusdeveloped a method to access [3]-dendralenes which in-NN83%BnScheme 12 Olefinic C–H alkynylation of electron-deficient alkenesvolved the coupling reaction of acrylamide derivatives andallenyl carbinol carbamates by alkenyl sp2 C–H activationusing a Rh(III) catalyst (Scheme 13).26OOR1R5NR3R4 R2Cp*Rh(CH3CN)3(SbF6)2 (5 mol%)PivOH (0.5 equiv)OMeOCH2Cl2, 60 4%40%Scheme 13 Coupling reaction between acrylamide derivatives and allenyl carbinol carbamatesIn 2017, we came up with a strategy called ‘substratecontrol strategy’ with alkenyl sp2 C–H activation. From ourprevious report,27 we knew that the acylsilane functionalgroup acts as a divergent functionalization tool in syntheticGeorg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 1049–1062
1054Syn thesisShort ReviewM. Maraswami, T.-P. Lohorganic chemistry. By slightly modifying the reaction conditions and using acrylosilanes acryloyl silane as the coupling partners, either alkylation or alkenylation productswere obtained successfully, which is not possible in thecase of acrylates28/α,β-unsaturated ketones.29 The distinctreactivity of acylsilanes is attributed to their inherent electronic properties which are distinct from those of othercarbonyl compounds.30 We presented an efficient route tosynthesize dihydropyrrol-2-ones and β-alkylated acrylamides by activation of the sp2 C–H bonds of N-tosyl acrylamides with tunable acryloyl silane-engaged alkenylation/alkylation–annulation. The reaction employs Cu(OAc)2·H2O anda Rh(III) complex as the additive and catalyst respectively(Scheme 14).31OOR1SiR33 NHTsNHTsR2Dioxane/H2O/AcOHN2, 60 C, 12 hOR2R1RhCp*(MeCN)3(SbF6)2 (5 mol%)Cu(OAc)2·H2O (10 92%82%Transition-metal-catalyzed alkyl C–CF3 and aryl C–CF3bond-forming reactions have been very well developed inrecent years.32 But on the other hand, the trifluoromethylation of electron-deficient alkenes has not been explored tothe same extent. In 2013, we realized that this class ofalkenes could be trifluoromethylated by employing suitabledirecting groups. It was believed that the trifluoromethylation of electron-deficient alkenes involves hydrogen elimination and electrophilic addition. However, we postulatedtwo other possibilities in order to understand this transformation: a radical-addition pathway and another following asequence of directing-group-assisted C–H activation andreductive elimination. We studied the copper-catalyzed trifluoromethylation of N-tosyl acrylamides to obtain trifluoromethylated derivatives (Scheme 15),33 which have enormous potential in materials science, and in agrochemicaland pharmaceutical industries etc., owing to the unique effect of the CF3 group.34 The reaction is initiated by ligandexchange between the copper catalyst and acrylamide. Various functionalized acrylamides have been trifluoromethylated to afford the corresponding products in excellentyields. Further, we investigated the reaction mechanismthrough a set of control experiments, which confirmed theinvolvement of radical species in this catalytic cycle.54%OR1NHTs[RhCp*Cl2]2 (2.5 mol%)Cu(OAc)2·H2O (2 equiv)SiR33 RTogni s reagentNHTsNTsR2AgSbF6 (10 mol%)THF, N2, 60 C, 12 hOR2OCuCl, DMSO80 C, N2, 20 R33OOOOR1CF366%CF396%Scheme 15 Copper-catalyzed trifluoromethylation of N-tosyl acrylamides3.2The Chelation versus Non-Chelation ConceptCp*Rh(III)2 CuXOCuX2PhNTsRhOPhOPhCp*Cp*Rh(I)NHTsTBSNTsTBSOpath bOOOpath aPhNTsTBSHXRhTBSOScheme 14 The distinct reaction of acryloyl silanes with acrylamidesDespite these successes, the reactions of more elaboratealiphatic olefins did not afford the desired products. Toovercome this problem, in late 2012, we reported crosscoupling reactions of acrylates with either TIPS-protectedallylic or homoallylic alcohols in the presence of Pd(OAc)2as the catalyst. The corresponding dienyl alcohols were obtained with good stereoselectivity and in moderate to highyields. We achieved this transformation employing 10 mol%of Pd(OAc)2, 2 equivalents of Cu(OAc)2, 12 mol% of 1,10phenanthroline, and 12 mol% of AgSbF6 with substitutedalkenes and acrylates in a solvent mixture of NMP/PivOH(1/1) (Scheme 16).35 In addition, we demonstrated the application of this method by synthesizing the key C13–C21fragment of palmerolide A.Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 1049–1062
1055Syn thesisShort ReviewM. Maraswami, T.-P. LohTIPSOPd(OAc)2 (10 mol%)1,10-Phenanthroline (12 mol%)AgSbF6 (12 mol%)RTIPSO CO2CO2R1RCu(OAc)2 (2 equiv)NMP/PivOH120 C, 24 hR1TIPSOtion studies revealed that 1,4-dioxane was the most suitable solvent for this transformation, while N-acetyl-l-phenylalanine was the best ligand (Scheme 18).38 The alkenestarting materials were reacted with distinct acrylates andthe products were obtained in good stereoselectivities.TIPSOCO2nBuCO2nBuOH 73%, E/Z 75/25R65%, E/Z 80/20MeTIPSOTIPSOCO2nBuCO2nBuPd(OAc)2 (10 mol%Ac-Phe-OH (50 mol%)Ag2CO3 (1.5 equiv)Cs2CO3 (30 mol%)CF3CH2OH (5 equiv)OHOHOHRMeDioxane, 50 C, 48 hOHOHO64%, E/Z 95/577%, E/Z 86/14CO2MeMeScheme 16 Palladium-catalyzed cross-coupling reaction of TIPS-protected homoallylic or allylic alcohols with acrylates76%, Z/E 86/14TIPSOn[Pd]/LTIPSOTIPSOnacrylaten [Pd]/LMeMeMeCOOR1Steric effect of OTIPS groupE ed effect of the OH groupStereoselctive control[Pd]MeZ configurationn 1, 2, 3Scheme 17 The concept of chelation vs non-chelationCOOR1RMe48%, Z/E 84/16OR1 OtBu241%, Z/E 88/12OHRRR1CO2tBu2OHOHMePhPhCO2tBuMe77%, Z/E 82/18R3Dioxane, 50 C, 48 hOHMeCO2tBuMe55%, Z/E 80/2054%, Z/E 85/15OHOH baseβ-H CO2tBuMe65%, Z/E 80/20Pd(II)/L[O]MeCONMe2Et MePd(OAc)2 (10 mol%)Ac-Phe-OH (50 mol%)Ag2CO3 (1.5 equiv)Cs2CO3 (30 mol%)CF3CH2OH (5 equiv)OHRR3Over the years, transition-metal-catalyzed aryl sp2 C–Hbond functionalization has progressed significantly,36 onthe other hand, stereoselective alkenyl sp2 C–H bond functionalization has not been developed to the same extent.Keeping this in mind, we thought of achieving the C–Hbond functionalization of allylic and homoallylic alcohols,which are obtained easily from commercial sources and aremuch cheaper. We found that we could control the regioand stereoselectivity in these compounds by choosing appropriate reaction conditions.In asymmetric synthesis the concept of non-chelationversus chelation has been applied efficiently,37 but has never been applied for tandem cross-coupling reactions andalkenyl C–H bond functionalization. We realized and reported the utilization of this strategy for the C–H functionalization of alkenes and alkenyl derivatives (Scheme 17).Highly substituted alkene derivatives are easily obtainedthrough this method in very high stereoselectivities. Fromthe literature, we knew that straightforward C–H bondfunctionalizations can be easily mediated by the combinedcatalytic system of an amino acid ligand and a palladiumcatalyst. In the presence of Ag2CO3 (1.5 equiv) as the oxidant, N-acetyl-l-valine (50 mol%) and Pd(OAc)2 (10 mol%),the desired cross-coupled product was obtained in 59%yield with 84/16 (Z/E) stereoselectivity. Further me 18 Straightforward C–H bond functionalization and couplingreactions4Other Alkene DerivativesBy early 2000, many reports had been published on theformation of C–C bonds through aromatic C–H activationcatalyzed by transition-metal catalysts. However, alkenylC–H activation was in its infancy without many publishedreports. Our group reported the first palladium-catalyzedortho-C–H functionalization of cyclic enamides to effectcross-coupling. The enamide, derived from α-tetralone, wascoupled with phenylboronic acid in the presence of palladium(II) acetate as the catalyst, an oxidant and a base. Afteroptimization, we found that K2CO3 was a suitable base andthat Cu(OTf)2 was a suitable oxidant for this transformationGeorg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 1049–1062
1056Syn thesisShort ReviewM. Maraswami, T.-P. Loh(Scheme 19).39 This approach was beneficial for the construction of a variety of enamide derivatives with distinctaryl groups at the ortho-C–H position.NHAcR 1ArB(OH)2NHAcPd(OAc)2 (10 mol%)Cu(OTf)2 (2 equiv)ArHNOHNPd(OAc)2 (1 equiv)R1K2CO3 (2 equiv)Dioxane, 80 CXin the reaction, which leads to olefination of the enamides.The desired products were accessed in moderate to goodyields under mild conditions.OPd OAcDMSO, rt, 12 hXSOX O, CH2, CHCH3NHAcNHAcClNHActert-butyl acrylate (1 equiv)NaOAc (1 equiv)DMSO, 80 C, 16 h, air53%NHAcO80%67%74%69%HNOScheme 19 Arylation of enamides with organoboronic acids catalyzedby Pd(OAc)2CO2tBuScheme 21 Palladium-catalyzed alkenylation of enamidesAs there were only a few reports on the arylation of organic compounds using organosilane compounds4b,40 compared to organoborane reagents, we developed an efficientmethod for the arylation of alkenyl sp2 C–H bonds of enamides using a palladium catalyst. In this transformation weemployed AgF not only for activating the organosilane compounds, but also as an oxidant to complete the palladiumc
Scheme 3 Cross-coupling of alkenes with various acrylates catalyzed by Pd(OAc) 2 Our initial investigation focused on the coupling of α-al-kyl styrenes and acrylates (Heck-type coupling). We envis-aged that the α-alkyl substituent on the styrene may pref-erentially activate the C-H functionalization of the alkene over the acrylate.
Transition Metal-Catalyzed Cross Coupling Reactions R-M R'-X R-R' M-X catalyst Named Reaction R-M R'-X Kumada-Corriu R-MgX or R-Li aryl, alkenyl . Stille R-Sn(alkyl) 3 aryl, alkynyl, acyl Heck alkene aryl, alkenyl, alkyl (no βhydrogen) Unactivated alkyl halides: that are not functionalized with activating groups in the αposition.
Iron-Catalyzed Cross-Coupling Following Kochi's report, Fe-catalyzed couplings with alkenyl electrophiles developed rapidly sp2-sp2 sp3-sp3 with various aryl and alkyl Grignard reagents Fe Julia, Tetrahedron Lett. 1982, 23, 2469. Molander, Tetrahedron Lett. 1983, 24, 5449. Cahiez, Pure & Appl. Chem.1996, 68669. Cahiez, Synthesis 1998, 1192 .
Among the myriad of transition metal-catalyzed reactions, the Pd-catalyzed C(sp2)-C(sp) bond-forming reactions from terminal alkynes and aryl and alkenyl halides or pseudohalides have emerged as a highly fascinating methodology of primary importance in synthetic organic chemistry.
transition metal-catalyzed processes [14, 15, 16] which have the biggest role in the synthesis of these heterocycles and the metal free-catalyzed processes. Herein, this review will focus on recently methodology using transition metal-catalyzed (Pd, Ni, Cu, Au, Fe and Rh) as well as transition metal free-catalyzed methods. 2. 1.
Abstract The plethora of transformations attainable by the transition-metal-catalyzed reactions of arynes has found immense contemporary interest in the scientific community. This review highlights the scope and importance of transition-metal-catalyzed aryne reactions in the field of synthetic organic chemistry reported to date. It covers transfor-
product for the metal-free electroreductive carboxylation. 11 The transition-metal-catalyzed electroreductive carbox-ylation of aryl halides with CO 2 is a promising tool for the preparation of arenecarboxylic acids.12 However the reac-tion scope is quite restricted. In 2009, Correa and Martín re-ported a Pd-catalyzed carboxylation reaction of .
In recent years, GVL has been used in several transition metal catalyzed processes such as, among others, the palladium-catalyzed Hiyama,[23] Mizoroki-Heck[24] and Sonogashira[25] cross-coupling reactions, platinum-[26] and rhodium-catalyzed[27] hydroformylations and palladium-catalyzed aminocarbonylation reactions.[28]
Homework #4 - Answer key 1. Bargaining with in–nite periods and N 2 players. Consider the in–nite-period alternating-o er bargaining game presented in class, but let us allow for N 2 players. Player 1 is the proposer in period 1, period N 1, period 2N 1, and so on. Similarly, player 2 is the proposer in period 2, period N 2, period 2N 2, and so on. A similar argument applies to any .
