transition-metal-catalyzed alkenyl sp2 c–h …...the area of alkenyl sp 2 c–h bond...

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M. Maraswami, T.-P. Loh Short ReviewSyn thesis

SYNTHESIS0 0 3 9 - 7 8 8 1 1 4 3 7 - 2 1 0 XGeorg Thieme Verlag Stuttgart · New York2019, 51, 1049–1062short reviewen

Transition-Metal-Catalyzed Alkenyl sp2 C–H Activation: A Short AccountManikantha Maraswamia Teck-Peng Loh*a,b,c 0000-0002-2936-337X

a Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637616, [email protected]

b Institute of Advanced Synthesis, Jiangsu National Synergetic Innovation Center for Advanced Materials, Nanjing Tech University, Nanjing, Jiangsu 210009, P. R. of China

c Hefei National Laboratory for Physical Sciences at the Microscale, iChEM (Collaborative Innovation Center of Chemistry for Energy Materials), Uni-versity of Science and Technology of China, Hefei, Anhui 230026, P. R. of China

Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue

HR1

R2H+

[M]

R1

R2

[M] = Pd, Rh, Ru, Cu, etc.• Stereoselective alkene synthesis• Atom economical• Versatile products• Synthesis of cyclic alkenes including macrocycles

Received: 23.11.2018Accepted: 14.12.2018Published online: 23.01.2019DOI: 10.1055/s-0037-1611649; Art ID: ss-2018-z0776-sr

License 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 acti-vation and provide useful strategies to synthesize organic buildingblocks in an efficient and sustainable manner.1 Introduction2 Breakthrough3 Controlling E/Z, Z/E Selectivity3.1 Esters and Amides as Directing Groups3.2 The Chelation versus Non-Chelation Concept4 Other Alkene Derivatives5 Intramolecular C–H Activation6 Conclusion and Future Projects

Key words transition metals, enamides, acrylamides, macrocycles,acrylates, alkenylation, alkynylation

1 Introduction

Alkenes and their derivatives feature widely in manynatural products and advanced materials.1,2 Accordingly,significant efforts have been directed towards the develop-ment of new synthetic methods to access this class of com-pounds. Among the many approaches reported, transition-metal-catalyzed cross-coupling reactions3 are the mostcommonly employed since they can be carried out on largeand industrial scale. However, the need to use prefunction-alized environmentally unfriendly organohalides and/or or-ganometallic reagents4 has encouraged researchers tosearch for cheaper and greener approaches. We envisagedthat a straightforward cross-coupling among cheap alkene

feedstocks would provide one of the most straightforwardand practical designs to access this class of important com-pounds. To be successful, we would need to preferentiallyC–H functionalize one of the alkenes and effect cross-cou-pling 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 ef-fect the desired cross-coupling without the formation ofhomo-coupling products. If successful, this design might beapplicable for the stereoselective synthesis of dienes. Fur-ther, an intramolecular version will provide access to cyclicalkenes not available via Diels–Alder or olefin metathesisapproaches. However, when we initiated this research pro-gram in the early 2000s, very little work had been done inthe area of alkenyl sp2 C–H bond functionalization. Further-more, 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 sp2

C–H bond functionalization by first investigating the cross-coupling 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/benzoqui-none (BQ)/O2 and Pd(OAc)/LiNO3/O2 (Scheme 1).5 Theydemonstrated that the reaction progressed via formation ofa σ-vinyl palladium hydride intermediate.

Scheme 1 Palladium-catalyzed dimerization of camphene

H Ocat. Pd(OAc)2cat. LiNO3 or BQ

O2 (1 atm)AcOH, 60 °C

[O]

[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%]

Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 1049–1062

http://orcid.org/0000-0002-2936-337X

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In 2004, Ishii et al. reported an aerobic oxidative cross-coupling of vinyl carboxylates with acrylates in the pres-ence of a Pd(OAc)2/HPMov catalyst employing O2 as the solecritical oxidant (Scheme 2).6

Scheme 2 Oxidative cross-coupling of acrylates with vinyl carboxylates

2 Breakthrough

Straightforward 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).7

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 alkeneover the acrylate. Furthermore, the steric effect of this alkylsubstituent may prevent homo-coupling of the styrene. Ad-ditionally, 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 palla-dium 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 re-moving the alkyl substituent resulted in messy reactions,(3) replacing the aryl substituent with an aliphatic substit-uent 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 devel-oped a coupling reaction among indenes and various elec-tron-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.

Scheme 4 Straightforward cross-couplings of indenes with various electron-deficient alkenes

Teck-Peng Loh (left) is a professor of chemistry at Nanyang Technolog-ical University, Singapore. He received his B.Eng. (1987) and M.Eng. (1989) from the Tokyo Institute of Technology under the supervision of Professor Takeshi Nakai and Professor Koichi Mikami. Under the tutelage of Professor E. J. Corey, Professor Loh obtained his Ph.D. (1994) from Harvard University. He is currently a Professor in the School of Physical and Mathematical Sciences. His research work focused mainly on the development of new synthetic methodology in organic chemistry, green chemistry and synthesis of natural and unnatural products. He has pub-lished more than 330 international refereed papers in reputable chem-istry journals bearing high impact factor. He has been invited to give more than 100 lectures in many institutions in the world and plenary and keynote talks in conferences such as the ICOS, OMCOS, Asian Euro-pean Symposium, etc. He has also served as chairman of many of these conferences. He has been conferred with many awards. He has been awarded outstanding researcher awards from both National University of Singapore and Nanyang Technological University. In 2017 he re-ceived the Yoshida Prize (Japan) and the prestigious President's Science Award (individual) Singapore. He has been elected Fellow, Academia of Sciences, Singapore (2018) and Fellow of Academia of Sciences, Malaysia since 2010. He has been conferred with 1000 talent award, People's Re-public of China. He was also the founding head of the division of Chemis-try and biological chemistry at Nanyang Technological University.Manikantha Maraswami (right) was born in India in 1987. He received his B.Sc. (2008) and M.Sc. (2010) in chemistry from Karnatak Universi-ty, Dharwad (India). He then worked as a Research Associate at Syngene International Pvt. Ltd., Bengaluru (India). In 2018, he obtained his Ph.D. from Nanyang Technological University, Singapore under the joint su-pervision of Assistant Professor Chen Gang and Professor Teck-Peng Loh. In 2017, he received the Excellency in Teaching award for his out-standing work as a Teaching Assistant at Nanyang Technological Univer-sity. He is presently a Research Fellow in Professor Teck-Peng Loh’s group at Nanyang Technological University, Singapore. His work focus-es on transition-metal-catalyzed intramolecular sp2 C–H activation.

AcOH +

O

ORH

O

ORAcO Pd(OAc)2 (10 mol%)

H4PMo11VO40·nH2O (2 mol%)

NaOAc (0.1 equiv)O2 (1 atm), AcOH, 90 °C

O

OnBuAcO

O

OMeAcO

O

OAcO

Et

62%, E/Z = 60/40 45%, E/Z = 56/44 76%, E/Z = 58/42

O

O

R1+ O

O

R1

Pd(OAc)2 (20 mol%)Cu(OAc)2 (1 equiv), O2 (1 atm)

DMSO/AcOH (1:1), 60 °C, 24 hR R

Selected products

CO2tBu

CO2tBu

CO2Me

CO2tBu

71%, E/Z = 87/13

65% E/Z = 84/16

33%, E/Z = 84/16

68%, E/Z = 90/10

Pd(OAc)2 (10 mol%)Cu(OAc)2 (1 equiv), O2 (1 atm)

AcOH, 60 °C, 48 h+ R2

R2R1 R1

R1 = Me, Ph, Cl, Br, OMe, CF3

R2 = CO2Me, CO2Et, CO2tBu, Ph, CN19–70%


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In 2010, an efficient approach to synthesize functional-ized 1,3-butadienes was reported by Yu and co-workers viacross-coupling reactions among terminal alkenes and α-oxoketene dithioacetals in the presence of Pd(OAc)2 as thecatalyst.9

In 2012, Liu et al. developed a double C–H bond activa-tion 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 dis-advantage of overloading of the oxidant (2.5 equiv ofAgOAc) in order to achieve the transformation.

Scheme 5 Pd(II)-catalyzed cross-coupling among two alkenes

Although acrylates are utilized as efficient couplingpartners in forming 1,3-diketones, because of the high po-tential 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 ke-tones 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 vi-tamin A1 and bornelone.

Scheme 6 Synthesis of conjugated dienyl ketones catalyzed by Pd(OAc)2

3 Controlling E/Z, Z/E Selectivity

3.1 Esters and Amides as Directing Groups

Glorius et al. reported the first directed olefin–olefincross-coupling in early 2011. They employed a Rh(III) cata-lyst to form linear 1,3-butadiene derivatives from di or tri-substituted olefins and styrene or acrylates (Scheme 7).12

They obtained remarkably high chemo-, regio- and stereo-selectivity in these reactions and the products were con-verted into unsaturated α-amino acid derivatives.

Following 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 substi-tuted dienamides in up to 91% yield and with good to mod-erate Z/E selectivity. To understand the reaction mecha-nism, we carried out competition and isotope labelling ex-periments. 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 fol-lowed 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 de-veloped method provides an excellent route to synthesize(Z,E)-dienamides in high yields and with moderate to excel-lent stereoselectivities.

In organic synthesis functional conjugated muconatesubunits are very useful synthons.14 This class of com-pounds can be synthesized by a straightforward and atom-economical cross-coupling reaction between two distinctacrylates. The generation of conjugated muconated deriva-tives 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 chal-lenging 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.

RH + H

R1

O

R2

R3

O

R1

O

R2

R3

O

R

Pd(OAc)2 (15 mol%)AgOAc (2.5 equiv)

5% DMSO/DCE110 °C

OAcO Ph

O

OAc

S

70%, Z/E = 74/26 70%, Z/E = 80/20 85%, Z/E = 86/14

O+ O


55% yieldE/Z = 85:15

Scheme 7 Directed olefin–olefin cross-coupling

DGR1

R2 H

+ R3

H

DGR1

R2

R3

[{RhCp*Cl2}]2 (2.5 mol%)AgSbF6 (10 mol%)

Cu(OAc)2 (2.1 mmol)Dioxane, 120 °C, 16 h

OnBu

O

SO2Ph

OnBu

O

NH2

O

NH2

O

54%, Z/E = 45/55 67%, Z/E = 79/2147% 37%, Z/E = 78/22


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Various muconate derivatives with distinct functionalgroups can be easily synthesized via activation of the vinyl-ic C–H bond. [RuCl2(p-cymene)]2 (5 mol%) catalyzed thecross-coupling reaction of n-butyl methacrylate and n-bu-tyl 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 acry-lates were utilized to obtain the cross-coupled muconatederivatives in good to excellent yields and with good che-mo- 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 functionaliza-tions led us to develop a novel and efficient method for thesynthesis of 1,4-diene skeletons. In the presence of a transi-tion-metal catalyst the alkene moiety can react with an al-lylic source to form allylated alkene products. We chose al-lyl 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).18

A wide variety of acrylamides as well as allyl acetates with

distinct functional groups were well tolerated under thesecatalytic conditions. The alkene substrates were allylated ina simple and straightforward manner, with the aid of di-recting groups having weak-coordinating assistance, to pro-vide 1,4-dienes that are of high synthetic value.

Scheme 8 Ruthenium- and rhodium-catalyzed acrylamide coupling with alkenes

R1

R

NR2R3

O

+ R4

R1

R

NR2R3

O

R4

[RuCl2(p-cymene)2] (2.5 mol%)KPF6 (20 mol%)

Cu(OAc)2·H2O (2 equiv)Dioxane/H2O/AcOH

100 °C, 18 h

NHBn

O

CO2nBu

NH

O

CO2nBu

NH

O

CO2nBu

NH

O

CO2nBu

OMe

83%, Z/E = 96/4 70%, Z/E = 99/1 75%, Z/E = 98/2 38%, Z/E = 80/20

R1

R

NR2R3

O

+ R4

R1

R

NR2R3

O

R4

[RhCp*Cl2]2 (2.5 mol%)

Cu(OAc)2·H2O (2 equiv)Acetone

100 °C, 18 h

NHBn

O

CO2tBu

NH

O

CO2tBu

NH

O

CO2tBu

NHBn

O

CO2tBu

BnO

90%, Z/E = 99/1 91%, Z/E = 99/1 86%, Z/E = 89/11 52%, Z/E = 99/1

Scheme 9 Ruthenium-catalyzed weak directing-group-enabled alke-nyl sp2 C–H activation

R1

OR3

O

R2

+H OR4

O

R1

OR3

O

R2

O

OR4

[RuCl2(p-cymene)2] (5 mol%)AgSbF6 (20 mol%)

Cu(OAc)2·H2O (2 equiv)Dioxane, 135 °C, 24 h

OnBu

O

O

OnBu

OEt

O

O

OBn

OEt

O

O

OCH2CF3

OEt

O

SO2Ph

67%, Z/E = 85/15 59%, Z/E = 88/12 74%, Z/E = 91/9 56%, Z/E = 96/4

OEt

O

O

OCH2CF3

OEt

O

O

OCH2CF3

OEt

O

O

OtBu

OEt

O

O

OCH2CF3

51%, Z/E = 98/2 75% 49%, Z/E = 93/7 71%, Z/E = 90/10

Scheme 10 Rhodium-catalyzed allylation of acrylamides

RNHTs

O

H 2H+

RNHTs

O

[Rh]IIINTs

RO

OAc

NTsIII[Rh]

NTs

[Rh]III

O

R

O

O

H

RNHTs

O

H+

[Rh-OAc]III

O

AcO

R

NTs

RhIII-H

O

AcO

R

RhIII

NTs

O

O

O

R

HC–H activation

olefin insertionβ-OAc elimination

R1

R2 H

O

NHTs

R1

R2

O

NHTs[RhCp*Cl2]2, NaOAc+ OAc

MeOH, 80 °C, 12 h

O

NHTs

O

NHTs

O

NHTs

O

NHTs

81% 87% 77% 75%

Ph

O

NHTsPh

O

NHTs

Ph

O

NHTs

35%, E/Z = 77/23 61%, E/Z = 99/1 47%


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Alkynes 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 val-ue of alkynes is further highlighted due to their involve-ment in click chemistry.20 In organic synthesis, both non-conjugated and conjugated alkynes are well exploited.21

Due to their easy synthetic transformations and usefulfunctionality, 1,3-enynes comprise a class of extensive sub-units found widely in pharmaceuticals and natural prod-ucts of biological interest.22

In 2014, Glorius and co-workers demonstrated pioneer-ing work on the synthesis of enynes via a C–H activationprotocol. They reported highly selective alkynylation ofbenzamides and β-substituted acrylamide derivatives. Re-actions of acrylamides with TIPS-EBX (1) in the presence ofthe cationic rhodium complex RhCp*(MeCN)3(SbF6)2 in di-chloromethane at 80 °C afforded alkynylated products inmoderate to excellent yields (Scheme 11).23

Scheme 11 Selective alkynylation of benzamides and β-substituted acrylamides

In the same year, we extended our research of alkynyla-tion 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 re-sponsible for the highly efficient and stereospecific C–Halkynylation of alkene C–H bonds. Operational simplicity,gentle reaction conditions and high functional group toler-ance 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 meth-od, the obtained products were further derivatized into aseries of pyridinone and triazole moieties of synthetic po-tential.

Glorius et al., in 2013, reported the straightforward ha-logenation of readily available acrylamide derivatives in thepresence of a Rh(III) catalyst to obtain a variety of substitut-ed Z-haloacrylic acid derivatives.25 In the same year, Gloriusdeveloped a method to access [3]-dendralenes which in-

volved the coupling reaction of acrylamide derivatives andallenyl carbinol carbamates by alkenyl sp2 C–H activationusing a Rh(III) catalyst (Scheme 13).26

Scheme 13 Coupling reaction between acrylamide derivatives and al-lenyl carbinol carbamates

In 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 synthetic

R1 H

O

NR2R2

R1

O

NR2R2

TIPS

1, CH2Cl2, 80 °C, 16 h

IOO

TIPS

1

RhCp*(MeCN)3(SbF6)2

O

NiPr2

TIPS

O

NiPr2

TIPS

F

O

NEt2

TIPS

O

N

TIPS

94% 84% 76% 62%

Scheme 12 Olefinic C–H alkynylation of electron-deficient alkenes

R1

R2 H

O

NHTs

R1

R2

O

NHTs

TIPS

[RhCp*Cl2]2, NaOAc

1, DCE, rt, 16 h

IOO

TIPS

1

O

NHTs

TIPS

ClO

NHTs

TIPS

O

NHTs

TIPS

94% 87% 96%

O

NHTs

TIPS

O

NHTs

TIPSMeO

O

NHTs

TIPS

BocN

79% 56% 71%

Synthetic transformations

O

NHTs

TIPS

O

NTs

Br

TIPS

O

NTs

O

NTs

Ar

O

NMeTs

NN

N

Bn

NBSMeCN

N2, rt

TBAF/AcOH

THF, 0 °C to rt

(i) K2CO3, MeI, DMF(ii) TBAF/AcOH, THF, 0 °C to rt(iii) CuSO4·-5H2O, Sodium ascorbate tBuOH/H2O, rt

Aryl iodide, TBAFPdCl2(PPh3)2, CuITHF, 0 °C to rt

Ar = NCC6H4, 78%

99%97%

83%

R1

R2

NR3R4

O

+ •

R5

O

OMe

O

R1

R2

NR3R4

O

R5

Cp*Rh(CH3CN)3(SbF6)2 (5 mol%)PivOH (0.5 equiv)

CH2Cl2, 60 °C

NiPr2

O

NiPr2

O

NHnBu

O

NMe

O

Ph OMe

F3C

72% 30% 64% 40%


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organic chemistry. By slightly modifying the reaction con-ditions and using acrylosilanes acryloyl silane as the cou-pling 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 elec-tronic properties which are distinct from those of othercarbonyl compounds.30 We presented an efficient route tosynthesize dihydropyrrol-2-ones and β-alkylated acryl-amides by activation of the sp2 C–H bonds of N-tosyl acryl-amides with tunable acryloyl silane-engaged alkenylation/al-kylation–annulation. The reaction employs Cu(OAc)2·H2O anda Rh(III) complex as the additive and catalyst respectively(Scheme 14).31

Scheme 14 The distinct reaction of acryloyl silanes with acrylamides

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 trifluoromethyla-tion 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 trifluoromethyla-tion of electron-deficient alkenes involves hydrogen elimi-nation and electrophilic addition. However, we postulatedtwo other possibilities in order to understand this transfor-mation: a radical-addition pathway and another following asequence of directing-group-assisted C–H activation andreductive elimination. We studied the copper-catalyzed tri-fluoromethylation of N-tosyl acrylamides to obtain trifluo-romethylated derivatives (Scheme 15),33 which have enor-mous potential in materials science, and in agrochemicaland pharmaceutical industries etc., owing to the unique ef-fect of the CF3 group.34 The reaction is initiated by ligandexchange between the copper catalyst and acrylamide. Var-ious functionalized acrylamides have been trifluoromethyl-ated 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.

Scheme 15 Copper-catalyzed trifluoromethylation of N-tosyl acryl-amides

3.2 The Chelation versus Non-Chelation Concept

Despite these successes, the reactions of more elaboratealiphatic olefins did not afford the desired products. Toovercome this problem, in late 2012, we reported cross-coupling reactions of acrylates with either TIPS-protectedallylic or homoallylic alcohols in the presence of Pd(OAc)2as the catalyst. The corresponding dienyl alcohols were ob-tained 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 1,10-phenanthroline, 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 ap-plication of this method by synthesizing the key C13–C21fragment of palmerolide A.

Cp*Rh(III)2+

RhNTs

OPh

Cp*

TBS

O

NTs

Rh

OPh

OTBS

Cp*Rh(I)

NTs

PhO

TBS

O

CuX2

CuX

HX

PhNHTs

O

O

TBS

path apath b

R1

NHTs

O

R2

+SiR3

3

O

R1

NHTs

O

R2

SiR33

O

RhCp*(MeCN)3(SbF6)2 (5 mol%)Cu(OAc)2·H2O (10 mol%)

Dioxane/H2O/AcOHN2, 60 °C, 12 h

NHTs

O

TBS

O

NHTs

O

TBS

O

NHTs

O

TBS

O

NHTs

O

TBS

O

92% 92% 82% 54%

R1

NHTs

O

R2

+SiR3

3

O

R1

NTs

O

R2

SiR33

O

[RhCp*Cl2]2 (2.5 mol%)Cu(OAc)2·H2O (2 equiv)

AgSbF6 (10 mol%)THF, N2, 60 °C, 12 h

NTs

O

SiR33

O

NTs

O

SiR33

O

NTs

O

SiR33

O

NTs

O

SiR33

O

71% 70% 60% 72%

RNHTs

OR

NHTs

O

CF3

IO

O

CF3

Togni´s reagent

CuCl, DMSO80 °C, N2, 20 h

NHTs

O

CF3

NHTs

O

CF3

NHTs

O

CF3

85% 93% 96%66%

NHTs

O

CF3


1055


Scheme 16 Palladium-catalyzed cross-coupling reaction of TIPS-pro-tected homoallylic or allylic alcohols with acrylates

Over the years, transition-metal-catalyzed aryl sp2 C–Hbond functionalization has progressed significantly,36 onthe other hand, stereoselective alkenyl sp2 C–H bond func-tionalization 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 regio-and stereoselectivity in these compounds by choosing ap-propriate reaction conditions.

In asymmetric synthesis the concept of non-chelationversus chelation has been applied efficiently,37 but has nev-er been applied for tandem cross-coupling reactions andalkenyl C–H bond functionalization. We realized and re-ported the utilization of this strategy for the C–H function-alization 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 oxi-dant, 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 optimiza-

tion studies revealed that 1,4-dioxane was the most suit-able solvent for this transformation, while N-acetyl-l-phe-nylalanine was the best ligand (Scheme 18).38 The alkenestarting materials were reacted with distinct acrylates andthe products were obtained in good stereoselectivities.

Scheme 18 Straightforward C–H bond functionalization and coupling reactions

4 Other Alkene Derivatives

By 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 palladi-um(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 transformation

R

TIPSO

+

CO2R1

R

TIPSO

CO2R1

Pd(OAc)2 (10 mol%)1,10-Phenanthroline (12 mol%)

AgSbF6 (12 mol%)

Cu(OAc)2 (2 equiv)NMP/PivOH120 °C, 24 h

TIPSO

CO2nBu

TIPSO

CO2nBu

TIPSO

CO2nBu

TIPSO

CO2nBu

73%, E/Z = 75/25 65%, E/Z = 80/20

64%, E/Z = 95/5 77%, E/Z = 86/14

Scheme 17 The concept of chelation vs non-chelation

Me

TIPSO

Me

TIPSO

Me

TIPSO

COOR1

[Pd]/L[Pd]/L acrylate

Me

OH

Me

O

H

[Pd]

L

Me

OH

COOR1

acrylate[Pd]/L

Steric effect of OTIPS group

Coordinated effect of the OH groupStereoselctive control

E configuration

Z configuration

n

n n

n

n n

n = 1, 2, 3

Pd(II)/L Me

OH

+

base

Me

OPd

L L

COOtBuMe

OPd

L L

COOtBu

Me

OH

COOtBuF3CH2COCPd

β-H elimination

Pd(0) HPdOCH2CF3

Me

OH

COOtBu

[O]

Me

OH

+ R

Me

OH

R

Pd(OAc)2 (10 mol%Ac-Phe-OH (50 mol%)

Ag2CO3 (1.5 equiv)Cs2CO3 (30 mol%)

CF3CH2OH (5 equiv)

Dioxane, 50 °C, 48 h

Me

OH

CO2MeMe

OH

SiMe3Me

OH

Et

O

Me

OH

CONMe2

76%, Z/E = 86/14 48%, Z/E = 84/16 41%, Z/E = 88/12 77%, Z/E = 82/18

R2

OH

+

R2

OH

Pd(OAc)2 (10 mol%)Ac-Phe-OH (50 mol%)

Ag2CO3 (1.5 equiv)Cs2CO3 (30 mol%)

CF3CH2OH (5 equiv)

Dioxane, 50 °C, 48 h

R1

R

OtBu

O R1

RR3 R3

Me

OH

CO2tBu

CO2tBu

Me

Me

Me

OH

CO2tBu

Ph

Me

OH

CO2tBu

Ph

55%, Z/E = 80/20 54%, Z/E = 85/15 65%, Z/E = 80/20


1056


(Scheme 19).39 This approach was beneficial for the con-struction of a variety of enamide derivatives with distinctaryl groups at the ortho-C–H position.

Scheme 19 Arylation of enamides with organoboronic acids catalyzed by Pd(OAc)2

As there were only a few reports on the arylation of or-ganic compounds using organosilane compounds4b,40 com-pared to organoborane reagents, we developed an efficientmethod for the arylation of alkenyl sp2 C–H bonds of enam-ides using a palladium catalyst. In this transformation weemployed AgF not only for activating the organosilane com-pounds, but also as an oxidant to complete the palladiumcatalytic cycle. We employed 3 equivalents of trialkoxyarylsilanes in the presence of 3 equivalents of AgF and Pd(OAc)2(10 mol%) as the catalyst in dioxane at 80 °C to achieve thearylation of enamides in good to excellent yields (Scheme20).41

Scheme 20 Palladium-catalyzed arylation of enamides with organos-ilanes

In late 2011, we reported an elegant catalytic methodinvolving an oxidative cross-coupling reaction of electron-deficient olefins with enamides in the presence of oxygenas the oxidant and palladium(II) acetate as the catalyst(Scheme 21).42 Detailed mechanistic studies have been con-ducted by synthesizing the six-membered cyclic vinylpalla-dium complex. This metal complex was explored in detailby X-ray analysis and 1H NMR spectroscopy. These mecha-nistic studies provided enough evidence to confirm that thecyclic vinylpalladium complex is the reactive intermediate

in the reaction, which leads to olefination of the enamides.The desired products were accessed in moderate to goodyields under mild conditions.

Scheme 21 Palladium-catalyzed alkenylation of enamides

Although we reported the arylation of enamides, in ourmethod we employed prefunctionalized coupling partnersfor this transformation. Hence, we required a method thatwas able to utilize readily available substances as the cou-pling partners for the arylation of alkenyl sp2 C–H bonds. Asa result of our investigations, we published the first reportemploying unactivated arenes as the arylating source in theC–H functionalization of enamides under palladium cataly-sis. To enhance the chemical stability of the enamides, theenamide nitrogen was doubly protected. This method re-sulted in the formation of highly substituted enamides inan efficient and cost-effective manner with perfect Z selec-tivity (Scheme 22).43

Scheme 22 Direct arylation of enamides using unactivated arenes through double C–H functionalization

In 2014, Glorius and co-workers demonstrated the firstexample of the Rh(III)-catalyzed alkenylation of enol-carba-mates (Scheme 23).44 This method utilized alkyl, aryl andcyclic enolates to synthesize 1,3-dienes in an efficient man-ner. The carbamate moiety of the formed products can beeasily cleaved, and the products are further transformedinto either (E)-3-alkenones or other useful synthetic deriv-atives.

X

NHAc

+

Pd(OAc)2 (10 mol%)Cu(OTf)2 (2 equiv)

X

NHAc

Ar

R1 R1K2CO3 (2 equiv)Dioxane, 80 °C

X = O, CH2, CHCH3

ArB(OH)2

NHAc NHAcCl

O

NHAcNHAc

80% 67% 74% 69%

X

NHAc

+ ArSi(OR)3

Pd(OAc)2 (10 mol%)AgF (3 equiv)

X

NHAc

Ar

R1 R1

Dioxane, 80 °C

X = O, CH2, CHCH3

O

Ph

NHAc

O

NHAcOMe

Ph

NHAc

O

Ph

NHAc

Cl

73% 95%51% 43%

HN O HN O

Pd OAc

SO

HN O

CO2tBu

Pd(OAc)2 (1 equiv)

DMSO, rt, 12 h

tert-butyl acrylate (1 equiv)NaOAc (1 equiv)DMSO, 80 °C, 16 h, air53%

NAcBn +

R1

R2

NAcBn

R1

R2

Pd(OAc)2 (10 mol%)Cu(OAc)2 (1 equiv)

AcOH (5 equiv)110 °C, 24–48 h

R

R

NAcBn NAcBn NAcBn

MeO

NAcBn

67% 65% 72% 68%


1057


Scheme 23 Rhodium(III)-catalyzed alkenylation of enol-carbamates

Following on from the work of Glorius, our lab demon-strated a unique protocol by alkynylating the olefinic C–Hbond of enamides in the presence of Rh(III) catalysis for theconstruction of functionalized 1,3-enyne motifs. The ortho-directing effect of the enamides was explored and utilizedfor the synthesis of cis-enynamide motifs in a stereospecificmanner. In the presence of 2 mol% of Cp*Rh(MeCN)3(SbF6)2,10 mol% of PivOH and TIPS-EBX 1, the enamides reacted atroom temperature to give alkynylated products in excellentyields (Scheme 24).45 A wide range of functional groups wastolerated due to the very mild reaction conditions em-ployed. The enynamide products obtained from C–H alky-nylation were further derivatized into useful organic syn-thons by cycloaddition or Sonogashira coupling reactions.

Until 2012, there were no reports of olefinic C–CF3 bondformation through the direct replacement of an olefinic C–H

moiety. Here in our lab, we developed the first example ofenamide C–H trifluoromethylation for the straightforwardconstruction of olefinic C–CF3 bonds. We employed a novelcationic Cu(I) catalyst to access trifluoromethylated enam-ides with excellent E selectivity and yields (Scheme 25).46

We demonstrated the pivotal role of the copper catalyst by

R

O O

N

+ R1

R

O O

N

R1

[Cp*RhCl2]2 (2.5 mol%)AgSbF6 (10 mol%

Cu(OAc)2 (2.1 equiv)MeOH, 60 °C, 16 h

O O

N

CO2nBu

O O

N

CO2nBuO O

N

CO2nBuN

O O

N

CO2nBu

O

77%, (88/12) 95%, (87/13) 19%, (90/10)

98%, (80/20)

Ph

O O

N

CNPh

O O

N

O

Me

Ph

O O

N

Ph

O O

N

SO2Me

73% 85%

45% 60%

Scheme 24 Rhodium(III)-catalyzed C–H olefinic alkynylation of enam-ides

NHCOMe

R2 H

NHCOMe

R2

TIPS

1, PivOH, Acetone, rt

IOO

TIPS

1

Cp*Rh(MeCN)3(SbF6)2R1

R1

NHCOMe

TIPS

MeO

NHCOMe

TIPS

NHCOMe

TIPS

S

81% 92% 65%

NHCOMe

TIPS

NHCOMe

TIPS

NHCOMe

TIPS

MeO2C

61% 86% 62%

Scheme 25 Trifluoromethylation and oxytrifluoromethylation of enamides

R

NHAc

R

NHAc

CF3

Cu(MeCN)4PF6 (10 mol%)

2 (1.1 equiv), THF, rt, N2, 20 h IO

O

CF32

NHAc

CF3

NHAc

CF3NC

NHAc

CF3Br

NHAc

CF3

90% 83% 85% 87%

R

NHAc

R

CuCl (10 mol%)

2 (1.1 equiv), MeOH, rt, N2, 20 hCF3

AcHNOMe

CF3

AcHN OMeCF3

AcHN OMe

NC

CF3

AcHN OMe

CF3

AcHN OMe

S

99% 97% 98% 96%

Scheme 26 Palladium-catalyzed cross-coupling reaction between N-vinylacetamides and (bromoethynyl)triisopropylsilane

Pd(OAc)2NHAc

HNO

PdII-OAc

AcOHN

O

PdII-OAc

DMSO

HNO

PdIV-OAcBr

TIPS

Br

TIPSAcHN

TIPS

PdOAcBr

AgOAc

AgBr

X

YAc

+ Br TIPS

X

YAc TIPS

X = C, OY = NH, O


CH2Cl2/DMSO (97/3)80 °C

NHAc

TIPS

OAc

TIPS

NHAc

TIPS

Br77% 72% 76%

NHAc

TIPS

AcHN

TIPS

21% 40%


1058


appropriate mechanistic studies. We also carried out theoxytrifluoromethylation of enamides catalyzed by CuCl.

In continuation of our research on the development ofstraightforward olefinic C–H functionalizations, we de-scribed a palladium-catalyzed cross-coupling reaction of(bromoethynyl)triisopropylsilane and N-vinylacetamides.The combination of solvents DMSO/CH2Cl2 (v/v = 3/97)proved to be the best for yielding the desired products(Scheme 26).47 In this transformation DMSO stabilizes thepalladium catalyst by coordinating to the metal center, thusacting as a weak ligand.

Our further studies on the reactivity of enamides withalkynes resulted in our group reporting an efficient methodfor the formation of substituted pyrrole derivatives in thepresence of a palladium catalyst using oxygen as the oxi-dant (Scheme 27).48 The method is quite gentle and hasbroad substrate scope.

Scheme 27 Formation of substituted pyrrole derivatives in the pres-ence of a palladium catalyst

In late 2015, the first Rh(III)-catalyzed C–H bond func-tionalization of enol phosphates with a wide range of acti-vated coupling partners was accomplished by our group.The phosphate group with its strong directing ability facili-tates the substrates to participate in synthetically tunabletransformations through alkenylation with acrylates andhydroalkenylation with enones (Schemes 28 and 29).49 Thehydroalkenylation process proceeds through C–H activationassisted by chelation, in which the vinylrhodium speciesundergo conjugate additions to enones. This strategy canfurther be expanded for the coupling reaction of enol phos-phates with other Michael acceptors such as electron-defi-cient alkynes. Enol phosphates are integral units of manypharmaceuticals and bioactive natural products. In transi-tion-metal-catalyzed cross-coupling reactions, enol phos-phates have been utilized as important intermediates. Com-pared to the triflate and halide partners, enol phosphatesare cheap and have higher stability, due to which they areoften utilized in these coupling reactions.50 To show thewide applicability of the method, an array of cross-couplingreactions with other analogues have been performed andhighly functionalized conjugated alkenes have been ac-cessed with ease. The outstanding features of this methodinclude the versatile applicability of the coupling products,good functional-group compatibility, and high stereo- andregioselectivity.

Scheme 28 Hydroalkenylation of enol phosphates with enones

Synthetic chemists have been using enamines as syn-thetic equivalents of metal enolates. Enamines have beendemonstrated as useful synthetic intermediates in organicsynthesis. Enamines, under very gentle conditions, reactwith an array of electrophiles.51 Although enamines are re-active to most electrophiles, they lack reactivity with steri-cally hindered alkyl halides.

Scheme 29 Rhodium-catalyzed alkenylation of enol phosphates with alkenes and alkynes

Enamides are often considered as derivatives of enam-ines. To solve this reactivity problem and in continuation ofour studies on the C–H functionalizations of enamides, wewere inspired to carry out the transition-metal-catalyzed

R

NHAc+ R1 R2

NH

R

R1

R2and/or

NH

R

R2

R1

Pd(OAc)2 (10 mol%)KOAc (2 equiv)

O2 (1 atm), DMSO80 °C

NH

Ph

PhNH

Ph

PhNH

Ph

Ph

Cl

NH

Ph

Ph

Me

67% 74% 50% 65%

ORP

O

OEt

OEt +

ORP

O

OEt

OEt[{Cp*RhCl2}2] (2.5 mol%)AgSbF6 (10 mol%)

Cu(OAc)2·H2O (60 mol%)THF, 80 °C, 17 h

O

R1

O

R1

OP

O

OEt

OEt

O

Me

OP

O

OEt

OEt

O

Ph

OP

O

OEt

OEt

O

O

OP

O

OEt

OEt

O

H

88%, 97/3 65%, 89/11 35%, 99/1 39%, 99/1

ORP

O

OR1

OR1+ R2

ORP

O

OR1

OR1

R2

[{Cp*RhCl2}2] (2.5 mol%)AgSbF6 (10 mol%)

Cu(OAc)2·H2O (1.1 equiv)THF, 80 °C, 17 h

OP

O

OEt

OEt

CO2Me

OP

O

OMe

OMe

CO2Me

OP

O

NMe2

NMe2

CO2Me

OP

O

OPh

OPh

CO2Me

90%, 89/11 82%, 86/14 88%, 89/11 29%, 94/6

OP

O

OEt

OEt

SO2Ph

OP

O

OEt

OEt

CO2Me

OO

P

O

OEt

OEt

CO2Me

Ph OP

O

OEt

OEt

CO2Me

52%, 96/4 73%, 91/9 78%, 91/9 19%

OP

O

OEt

OEt +

OP

O

R2

[{Cp*RhCl2}2] (2.5 mol%)AgSbF6 (10 mol%)

Cu(OAc)2·H2O (20 mol%)PivOH (1.1 equiv)THF, 40 °C, 17 h

Me

R2

OEtOEt

Me

OP

O OEtOEt

Me

OEt

O

OP

O OEtOEt

Me

Me

O

OP

O OEtOEt

Me

RR

OP

O OEtOEt

Me

OEt

O

F

83%, 96/4 80%, 97/3 60%, 90/10 34%, 98/2


1059


cross-coupling of sterically hindered halides with enam-ides. As expected, this method worked well with a palladi-um catalyst system, providing access to bulky alkyl-substi-tuted alkenes as versatile precursors of γ-lactams, 1,4-di-carbonyls, δ-amino alcohols and γ-amino acids. Notably,the present reaction conditions not only gave the corre-sponding products in good yield but also suppressed theside reaction involving β-hydride elimination (Scheme30).52

Scheme 30 Palladium-catalyzed alkylation reactions of enamides with α-bromo-substituted carbonyl compounds

5 Intramolecular C–H Activation

In early 2017, our group reported an intramolecular C–Nbond-forming reaction catalyzed by a palladium catalyst inthe presence of chloranil as the additive (Scheme 31).53 Thismethod, involving intramolecular oxidative amination, waswidely applicable and various functional groups were welltolerated.

Scheme 31 Palladium-catalyzed formation of multisubstituted dihy-dropyrroles

Macrocycles are integral units of many pharmaceuticalsand bioactive natural products.54 To date, many methodshave been reported for the efficient syntheses of macrocy-cles, e.g., macrolactamizations, macroaldolizations, andmacrolactonizations. In the last two decades, ring-closingmetathesis (RCM) has been widely applied to constructsuch macrocycles with double bonds. Though RCM is uti-lized efficiently to form large rings, the control of E/Z stereo-selectivities in these rings is quite challenging. We havebeen searching for an efficient method to construct macro-cycles with double bonds by applying our well establishedmethod of transition-metal-catalyzed alkenyl sp2 C–H func-tionalization. With this idea in mind, we envisaged that thisclass of macrocycles would be easily accessed via an intra-molecular cross-coupling among two distinct doublebonds. In 2018, we presented the first example of intramo-lecular oxidative cross-coupling between double bonds cat-alyzed by a cationic Rh(III) complex (Scheme 32).55 Themethod is atom economical and the products can be trans-formed into useful derivatives. Distinctive sized macrocy-

Pd(0) Br

O

OEt

O

OEt

NHAc

NHAc

O

OEt

NHAc

O

OEt

LnBrPdII

LnPdIBr

•

•

NHAc

O

OEt

AgBr + AcOH

X

NHAc

+ BrOEt

OX

NHAc

OEt

OR R

Pd(PPh)3 (5 mol%)P(4-MeOC6H4)3 (20 mol%)

AgOAc (1.5 equiv)CH2Cl2

AcHN

CO2Et

AcHN

CO2Et

O

AcHN

CO2Et

O

NHAc

OEt

O

76% 69%, Z/E = 93/7 35% 68%

R1

R2

NHTs

R3

NTs

R1R2

R3

Pd(CH3CN)2Cl2 (10 mol%)chloranil (1 equiv)

Dioxane, air, 80 °C

NTs

NTs

CF3

NTs

82% 75% 25%

NTs

O

EtOPh

NTs

O

EtOPh

Me

98% 94%

Scheme 32 Intramolecular cross-coupling and derivatization of a cross-coupled product

PhNH

O

O

O

Pd/C

H2 (balloon)EA, rt, 5 h

PhNH

O

O

O

CuI, NaOtBuImidazolinium salt

PhMe2Si-BpinTHF

–78 °C, 24 h

PhNH

O

O

O

PhMe2Si

PhNH

O

O

O

NO2

DBU

MeNO2rt, 24 h, Air

DBU, air

MeCN50 °C, 18 h

N O

O

PhO

N O

O

PhO

Cs2CO3

MeCN80 °C, 10 h, Ar

CuI, NaOtBuImidazolinium salt

BPin-Bpin, THF0 °C, 24 h

PhNH

O

O

O

99%

96%

74%99%

74%

73%

R1

NH

O

O

O

R1

NH

O

O

O

[RhCp*Cl2]2 (5 mol%)NaBARF ( 40 mol%)

Cu(OAc)2·H2O (2.5 equiv)Acetone (0.01 M), 100 °C, 24 h

NH

O

O

O

NH

O

O

O

NH

O

O

O

NH

O

O

O

EtO

65% 54% 65% 43%

NH

O

O

O

NH

O

O

O

NH

O

O

O

NH

O

O

O

Ph

Ph

51% 56% 39% 26%

Derivatization of a macrocyclic product


1060


cles were obtained with ease in relatively good yields in thepresence of [RhCp*Cl2]2 (5 mol%), NaBARF (40 mol%) andCu(OAc)2·H2O (2.5 equiv) in acetone at 100 °C. This methodfeatures universal utilization of the diene fragment for deri-vatization, good functional-group compatibility and highstereo- and chemoselectivity.

For the palladium-catalyzed alkenyl sp2 C–H activationwe can draw a generalized mechanism as shown in Scheme33. The palladium catalyst activates the electron-richalkene by generation of vinyl palladium intermediate A.Next, the incoming electron-deficient alkene coordinates tointermediate A, which is followed by migratory insertioninto the palladium–C vinyl bond to form σ-Pd intermediateB. Finally, β-H elimination results in formation of the prod-uct, while the oxidant employed in the reaction reactivatesthe catalyst for the next cycle.

Scheme 33 Generalized mechanism for the palladium-catalyzed alke-nyl sp2 C–H activation

6 Conclusion and Future Projects

It is evident from this short account of our group’s re-search over two decades on alkenyl sp2 C–H activation thatthese methods have emerged as powerful tools to function-alize and synthesize various alkene derivatives. In particu-lar, transition-metal-catalyzed C–H functionalizations offermore scope and are widely applicable. In continuation ofour interest in alkenyl sp2 C–H activation, we are now ex-ploring new arenas for this methodology. After our recentbreakthrough macrocyclization report, we are presentlylooking to expand the application of this method by apply-ing it to distinctive coupling partners in order to obtainmore functionalizable products. We are in search of meth-ods that not only activate alkenyl sp2 C–H groups, but thatalso trigger enantioselectivity through which we canachieve stereoselective reactions via C–H activation. Withour interest in green chemistry and water-promoted reac-tions, we are also searching for metal-free coupling reac-tions in water.

Funding Information

We are thankful to Nanyang Technological University, Singapore Min-istry of Education Academic Research Fund [Tier 1: MOE2015-T1-001-070 (RG5/15), MOE2014-T1-001-102 (RG9/14) and MOE2018-

T1-001-110 (RG12/18)], Nanjing Tech University, and the SingaporeNational Research Foundation (NRF2015NRF-POC001-024) for gener-ous financial support. We gratefully acknowledge the funding sup-port of the State Key Program of the National Natural ScienceFoundation of China (21432009), the National Natural Science Foun-dation of China (21372210, 21672198), the State Key Laboratory ofElemento-organic Chemistry, Nankai University (201620) and theCollaborative Innovation Center of Chemistry for Energy Materials(2011-iChEM) for financial support.Nanyang Technological University, Singapore Ministry of Education Academic Research Fund (MOE2015-T1-001-070 (RG5/15))Nanyang Technological University, Singapore Ministry of Education Academic Research Fund (MOE2014-T1-001-102 (RG9/14))Nanyang Technological University, Singapore Ministry of Education Academic Research Fund (MOE2018-T1-001-110 (RG12/18))Singapore National Research Foundation (NRF2015NRF-POC001-024)State Key Program of the National Natural Science Foundation of China (21432009)National Natural Science Foundation of China (21372210)National Natural Science Foundation of China (21672198)State Key Laboratory of Elemento-organic Chemistry, Nankai University (201620)Collaborative Innovation Center of Chemistry for Energy Materials (2011-iChEM)

Acknowledgment

We acknowledge all the past and present group members for theirdedication and hard work which has helped the research communityto explore a new area of synthesis.

References

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transition-metal-catalyzed alkenyl sp2 c–h …...the area of alkenyl sp 2 c–h bond...

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