transition-metal-catalyzed alkyl heck-type reactions€¦ · transition-metal-catalyzed alkyl...

985

D. Kurandina et al. ReviewSyn thesis

SYNTHESIS0 0 3 9 - 7 8 8 1 1 4 3 7 - 2 1 0 XGeorg Thieme Verlag Stuttgart · New York2019, 51, 985–1005reviewen

Transition-Metal-Catalyzed Alkyl Heck-Type ReactionsDaria Kurandina‡ Padon Chuentragool‡ Vladimir Gevorgyan* 0000-0002-7836-7596

Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607-7061, [email protected]

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

‡ These authors contributed equally.

Alkyl-X R RAlkylM-cat.

Alkyl-M(n+2)-X Alkyl M(n+1)-XR

RAlkyl

M(n+2)-X

RAlkyl

M(n+1)-X

Alkyl Heck-Type Reactions

– HMn-Xoxidative addition

migratory inserion

b-H elimination

1 2 3Mn

+

Received: 28.12.2018Accepted: 30.12.2018Published online: 07.02.2019DOI: 10.1055/s-0037-1611659; Art ID: ss-2018-z0870-r

License terms:

Abstract The Heck reaction is one of the most reliable and usefulstrategies for the construction of C–C bonds in organic synthesis. How-ever, in contrast to the well-established aryl Heck reaction, the analo-gous reaction employing alkyl electrophiles is much less developed. Sig-nificant progress in this area was recently achieved by merging radical-mediated and transition-metal-catalyzed approaches. This review sum-marizes the advances in alkyl Heck-type reactions from its discoveryearly in the 1970s up until the end of 2018.1 Introduction2 Pd-Catalyzed Heck-Type Reactions2.1 Benzylic Electrophiles2.2 α-Carbonyl Alkyl Halides2.3 Fluoroalkyl Halides2.4 α-Functionalized Alkyl Halides2.5 Unactivated Alkyl Electrophiles3 Ni-Catalyzed Heck-Type Reactions3.1 Benzylic Electrophiles3.2 α-Carbonyl Alkyl Halides3.3 Unactivated Alkyl Halides4 Co-Catalyzed Heck-Type Reactions5 Cu-Catalyzed Heck-Type Reactions6 Other Metals in Heck-Type Reactions7 Conclusion

Key words Heck reaction, cross-coupling, alkyl halides, alkenes, tran-sition-metal catalysis

1 Introduction

The Mizoroki–Heck reaction1 is one of the most power-ful approaches towards multisubstituted alkenes. This reac-tion represents the first example of Pd-catalyzed C–C bond-forming reactions,2 which follow a classical Pd(0)/Pd(II) cat-alytic cycle enabling coupling of aryl and vinyl electrophileswith olefins.

The Heck reaction has been exhaustively employed inorganic synthesis, drug discovery, electronics, and in indus-try,3 which has led to its recognition with a Nobel Prize in2010. Current research in this area is directed towards theuse of decreased loadings of palladium,4 the employment oflow-cost transition metals,5 and the development of asym-metric protocols.6 Historically, aryl halides/pseudohalideswere the electrophiles of choice for all cross-coupling reac-tions, thus, not surprisingly, they were also extensivelyused in Heck reactions. Throughout years, this research hasbeen summarized in many excellent reviews.7 In contrast,alkyl electrophiles were found to be more challenging cou-pling partners, mostly due to the competing β-H elimina-tion process2 and the slower rates of the oxidative additionstep.8 Nonetheless, under more recently developed condi-tions, alkyl halides9 were shown to be suitable partners forthis transformation. However, the number of reports on al-kyl Heck reactions remains scarce compared to those em-ploying aryl substrates.

In general, alkyl Heck reactions feature the same mech-anism as the classical Heck reaction between aryl halidesand alkenes, involving: (1) oxidative addition, (2) migratoryinsertion, (3) β-hydrogen elimination, and (4) catalyst re-generation steps (Scheme 1). However, in contrast to thearyl Heck reaction, its alkyl version is often presumed to in-volve radical intermediates, thus operating via a hybrid or-ganometallic–radical scenario. Mechanistic studies, such asradical trapping,10 radical clock experiments,11 as well asESR studies, have proved the presence of radical species insome alkyl Heck reactions. The mechanisms of their forma-tion, which may depend on the nature of the alkyl compo-nent, the leaving group, and the metal catalyst, are still notcompletely understood. It was shown that employment ofvisible light allows alkyl Heck reactions to be accomplishedunder milder conditions; over recent years this area of re-search has grown significantly. Various complexes of Co,

Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 985–1005

http://orcid.org/0000-0002-7836-7596

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Ir/Ru, Au, Pd, and other transition metals were found to cat-alyze this reaction under visible-light irradiation, with sig-nificantly expanded scope. This review highlights the ad-vances in the field of alkyl Heck-type reactions of alkylelectrophiles with alkenes since its discovery in the earlyseventies.1d It is organized by the type of electrophile used,such as benzylic, activated (possessing a carbonyl or equiva-lents at the β-position), perfluorinated, and unactivated al-kyl electrophiles. Related transformations, such as Heck-type reactions involving a β-X elimination step and cascadetransformations commencing with radical addition to analkene moiety are not discussed herein.12

2 Pd-Catalyzed Heck-Type Reactions

2.1 Benzylic Electrophiles

The first example of the coupling of an alkyl halide withan olefin was reported by Heck in his original seminal workin 1972 (Scheme 2).1d Benzyl chloride (1) reacted withmethyl acrylate (2) in the presence of 1 mol% of Pd(OAc)2and Bu3N as the base to deliver a regiomeric mixture ofalkenes 3. In 1995, Zhuangyu and co-workers developed abase-free alkyl Heck reaction of benzyltris(n-butyl)ammo-

nium bromide salts 4 toward exclusive formation of theconjugated products 6 (Scheme 2).13 Both electron-rich andelectron-deficient alkenes 5 were efficiently benzylated un-der these conditions. Based on ESR studies, the authors sug-gested the involvement of benzyl radicals, which wouldform via the reductive cleavage of the benzyl quaternaryammonium salt in the presence of the palladium(0) species.Later, the coupling of benzyl chlorides with olefins was ele-

Scheme 1 Mechanism of transition-metal-catalyzed alkyl Heck-type reactions

LnMn

HM(n+2)X

oxidative addition

Alkyl X

R

RAlk

B

B HX

Alkyl-M(n+2)-X Alkyl M(n+1)-X

RAlkyl

M(n+2)-X

RAlkyl

M(n+1)-X

β-H elimination

1

23

4

migratory insertion

catalystregeneration

Biographical Sketches

Daria Kurandina received her BS degreefrom St. Petersburg State University, Russia.In 2014, she joined Prof. Gevorgyan’s groupat the University of Illinois at Chicago as aPhD student. Her work focuses on the devel-opment of novel transition-metal-catalyzedsynthetic methodologies.

Padon Chuentragool obtained his BS andMS degrees from Chulalongkorn University,Bangkok, Thailand. He received his PhD in

2018 under the guidance of Prof. Gevorgyanat the University of Illinois at Chicago, wherehis work focused on the development of se-lective methods for C(sp3)–H functionaliza-tions via photoexcited Pd catalysis.

Vladimir Gevorgyan received his PhD in1984 from the Latvian Institute of OrganicSynthesis, where he then worked as a groupleader. After postdoctoral research at To-hoku University with Prof. Y. Yamamoto as a

JSPS Postdoctoral Fellow and then as a Ciba-Geigy International Postdoctoral Fellow, hejoined the faculty at the same institute in1996. In 1999, he moved to the University ofIllinois at Chicago (UIC) as an associate pro-fessor and was promoted to full professor in2003. In 2012, he received the LAS Distin-guished Professor Award. His group is inter-ested in the development of novel syntheticmethodologies.


987


gantly utilized by Kita to obtain the key intermediate 8 inthe synthesis of beraprost, a vasodilator and antiplateletagent (Scheme 2).14 In this work, the Heck reaction followedby hydrogenation was shown to be superior over othermethods tested for installation of an alkyl chain at the ben-zylic position of compound 7.

Scheme 2 Pd-catalyzed Heck reactions of benzyl halides; r.r. = regiomeric ratio

In 2000, Pan and co-workers observed an interestingPd-catalyzed rearrangement in the vinylation reaction of α-chloromethylnaphthalene (9) (Scheme 2).15 In reactionswith N-vinylimides, besides the expected Heck products 11,a product with an olefin attached at the peri position of thenaphthalene ring was detected. This unusual rearrange-ment product 12 was proposed to form via the cyclopalla-dation intermediate 14, when the nitrogen-containing

alkene served as a stabilizing ligand for benzylpalladiumspecies 13. Later, Pan described the Pd-catalyzed cascadereaction of benzyl halides with N-allyl-N-(2-butenyl)-p-tol-uenesulfonamide (17) to furnish dihydropyrroles 18 withexcellent regioselectivity (Scheme 2).16

In addition to benzyl halides, benzyl trifluoroacetateswere also found to be compatible coupling partners for theHeck reaction. In 1999, Yamamoto reported that mixingbenzyl trifluoroacetate with phosphine-coordinated Pd(0)led to the formation of an oxidative addition complex.17 In2004, Shimizu showed that the reaction of this complexwith ethyl acrylate under heating produced the correspond-ing Heck reaction product.18 Based on these initial discover-ies, the catalytic benzylation of olefins with benzyl trifluo-roacetates 19 was developed (Scheme 3).18 Moreover, theauthors were able to achieve the benzylation of p-methyl-styrene (22) with p-methoxybenzyl alcohol (21) using tri-fluoroacetic anhydride as an additive. Later, Zhou intro-duced an asymmetric Heck reaction of benzyl trifluoroace-tates 19 with five-membered cyclic olefins 24.19 In thepresence of Pd/phosphoramidite ligand 26, 2,3-, and 2,5-di-hydrofurans, N-Boc-2,3-pyrroline, and cyclopentene (24a–c) were smoothly alkylated with electronically diverse ben-zyl trifluoroacetates leading to the corresponding products25a–f in high yields, and with high degrees of regioselectiv-ity and enantioselectivity (Scheme 3).

Scheme 3 Pd-catalyzed Heck reactions of benzyl fluoroacetates; r.r. = regiomeric ratio

Ph Cl CO2Me CO2MePh

76% (r.r. = 7.4:1)

1 mol% Pd(OAc)2

Bu3N, reflux

Heck, 1972

1 2

NBu3BrR2

1 mol% Pd(OAc)2

DMF 100–130 °C

6, 20–89%R1

R1 = H, 4-Me, 4-Cl, 3-O2N, 4-NCR2 = CO2Me, CONH2, Ph, N-phtalimido, etc.

Zhuangyu, 1995

R1

R2

4 5

O

Cl

OO

H

H

O

OO

H

H

MeO2C

1 mol% Pd(OAc)2

(n-C12H25)3N110 °C

8, 94%

Key beraprost intermediate

[H]

Kita, 2003

7

CO2Me2

3

Cl

R2

R1

R1

R21 mol% Pd(OAc)2

Bu3N

DMF 130–140 °C

R1

R2

Pan, 2000

PdClH Pd

HCl

PdClR2

R1

Pan, 2003

X

RN

TsN

Ts

Rcat. Pd

47–76%

X = Cl, Br

9 10

13 14 15

10

11 12

16 17

18

22–75%

R = H, p-Me, o-Me, p-Cl, p-Br, m-CO2Me, etc.

Ar OCO2CF3R2 R2Ar

21–81%

5 mol% Pd(OAc)2

20 mol% PPh3

DMF, 100 °C

Shimizu, 2004

19 10

R1 R1

Zhou, 2012

Ar OCO2CF3

10 mol% Pd(dba)2

12 mol% L

Li2CO3, 2-MeTHF40 °C or 60 °C

19

X X

Ar

24a, X = O24b, X = NBoc24c, X = CH2

Ar = Ph, p-MeOC6H4, p-ClC6H4, p-FC6H4, 2,4,6-Me3C6H2, 3,5,6-(MeO)3C6H2

R1 = CO2Et, Ph, p-MeC6H4, p-ClC6H4, 2-pyridinylR2 = H or Ph

O

OP N

Ph

20

25

L, 26

OH

MeO

3 equiv (CF3CO)2O5 mol% Pd(OAc)2

20 mol% PPh3

DMF, 100 °C, 39 h

MeO

21

2223 42%

Scope, representative examplesO

OHC25a, 92%,

92% ee, r.r. 10:1

N

R

25c, R = MeO, 86%, 92% ee, r.r. 30:1

25d, R = CO2Me, 75%,88% ee, r.r. 20:1

Boc

25e, R = 2-Me, 85%, 80% ee, r.r. >100:125f, R = Cl, 95%, 93% ee, r.r. 56:1

O

25b, 92%, 95% ee, r.r. 24:1

S R


988


The first intramolecular Heck reaction of benzyl halideswas developed by Negishi to access five- to seven-mem-bered cyclic compounds (Scheme 4).20 The initial screeningof the leaving group on the o-allylbenzyl electrophile 27 re-vealed that Cl, Br, and OMs were acceptable leaving groups,leading almost exclusively to the formation of 2-methylene-indane (28). In the cases of I and OCO2Me leaving groups,the cyclization occurred quite efficiently but with low regi-oselectivity, as the formation of regioisomer 29 was detect-ed in significant amounts.

Scheme 4 Intramolecular Pd-catalyzed Heck reactions of benzyl halides

Lastly, o-allylbenzyl acetate was practically unreactive.Interestingly, attempts to induce this cyclization under typ-ical radical conditions led to the hydrostannation product30 only, thus illustrating the superiority of the Heck reac-tion pathway for this type of cyclization. The developed in-tramolecular Heck reaction was also able to deliver six- andseven-membered cyclic compounds 31 and 32 from thecorresponding benzyl chlorides in good yields and regiose-lectivity. However, attempts to obtain four- and eight-membered rings using this strategy (33 and 34, respective-ly) were unsuccessful (Scheme 4).

In 2008, Chen applied an intramolecular Heck-type ap-proach for the synthesis of 3-alkyl-1H-quinolin-2-ones 35via cyclization of benzyl halides with α,β-unsaturated am-ides.21 In 2011, Pan introduced another regioselective intra-molecular Heck-type coupling for the assembly of a biologi-cally important core compounds, i.e., 4-aryldihydropyrroles36.22 In this case, cyclization favored products with an en-docyclic double bond, so that most of these dihydropyrroleswere obtained as single regioisomers. In 2014, Gharpure

disclosed a straightforward synthesis of isochromene deriv-atives 37 via the intramolecular Heck reaction of benzyl ha-lides and vinylogous carbonates (Scheme 4).1b

2.2 α-Carbonyl Alkyl Halides

In the 1980s, Ban and Mori performed the initial studyon the Pd(PPh3)4-catalyzed intramolecular alkylation of ole-fins using α-carbonyl alkyl halides 38.23 The reaction pro-ceeded with low selectivity, delivering mixtures of atomtransfer radical cyclization (ATRC) and Heck products (39and 40, respectively) in moderate yields (Scheme 5). In2003, Glorius reported an intermolecular Heck reaction of2-chloroacetamides 41 with 2,3-dihydrofuran (24a), butylvinyl ether (43) and styrenes 45 (Scheme 5, eq 1).24 Alkyla-tion of 24a and 43 led to the exclusive formation of α-al-kylated olefins 42 and 44, respectively, thus supporting thereaction mechanism involving palladium enolates ratherthan alkyl radical intermediates. Conversely, the reaction of

X 5 mol% Pd(PPh3)4

Et3N, MeCNreflux

R

R = H, 65%R = Me, 72% 0% 0%

CO2EtCO2Et

64%

Negishi, 1989

MeH+

Scope, representative examples:

XClBrIOMsOCO2MeOAc

time, h10.50.515 days2 days

yield 28 (%) yield 29 (%)8282646026<1

<1<118<123<1

X

SnBu3

Bu3SnHAIBN, PhHrefluxX = Br, I

Chen, 2008

N

R2

OH

R1

36–91%

Pan, 2011

R1

N-R2

43–95%

O

CO2R4

R3

R1

R2

65–88%

Gharpure, 2014

27 28 29

30

31 33 3432

35 36 37

CO2Et

CO2Et

Scheme 5 Pd-catalyzed Heck reactions of α-carbonyl alkyl halides

N

O

Cl

Glorius, 2003O

5 mol%Pd(PPh3)2Cl2

(i-Pr)2NEtMeCN, 110 °C

R = Et, Hex, t-BuR' = H, Et

R

R'

65-75%

44a, R = n-Hex, 53% 44b, R = t-Bu, 63%

N

O

OBu

Me

R

H

O

ArN

O

Ar

46a, Ar = Ph, 39%46b, Ar = p-MeOC6H4, 35%

n-Hex

H

OBu

41

24a

43

42

4645

44

N

O

R R'

NO

I

Ban & Mori, 1982 & 1985

n

N

n

O

n = 1 or 2

I

N

n

O

Pd(PPh3)4

48–75%38

NC Br5 mol% Pd(PPh3)2Cl2

(i-Pr)2NEtMeCN, 110 °C47 O

NC

30%

39 40

48

(1)

(2)

Gevorgyan, 2018

ArR1

EtO2C

50a, R1 =Me, Ar = Ph, 92%50b, R1 = CO2Et, Ar = 4-MeOC6H4, 54%

NEtO2C

EtO2C

50c, 47%

O

EtO2C

EtO2C

50d, 51%

10 mol% Pd Xantphos G3R3

49 10

BrR1

EtO2C

R1

EtO2C

R2

50(i-Pr)2NEt

benzene, rt


R2

R3

24a


989


bromoacetonitrile (47) with 24a produced β-alkylated 2,3-dihydrofuran 48 in 30% yield as a single product (Scheme 5,eq 2). This reaction was suggested to proceed via a radicalpathway.

More recently, Gevorgyan showed that activated tertiaryalkyl bromides possessing an α-carbonyl moiety 49 can ef-ficiently react with styrenes and electron-rich alkenes atroom temperature (Scheme 5).25 Catalyzed by a Pd Xant-phos G3 complex, the reaction furnished the Heck products50a–d in moderate to high yields. A radical clock experi-ment suggested that the catalytic cycle might involve analkyl Pd-radical hybrid species.

2.3 Fluoroalkyl Halides

In 1988, Chen reported the first Pd-catalyzed additionof perfluorinated alkyl iodides 51 to alkenes 52 leading toalkyl iodides 53, i.e., the atom transfer radical addition(ATRA) products (Scheme 6).26 The radical nature of thistransformation was strongly supported by the mechanisticstudies, which led the authors to propose the involvementof a Pd(0) complex in a radical initiation event. In 2012, Re-utrakul developed the Pd(PPh3)4-catalyzed Heck reaction of(bromodifluoromethyl)sulfones 54 with alkenes (Scheme6).27 The reaction proceeded smoothly in toluene at 100 °Cdelivering the coupling products 55a–f in moderate yields.Later, Zhang reported the first Heck reaction of perfluori-nated alkyl halides with vinyl arenes/heteroarenes (57a–g),diene (57h), and electron-rich olefins (57i,j) (Scheme 6).28

The reaction features a quite general scope leading to valu-able fluoroalkylated alkenes in good to excellent yields.Moreover, this method was shown to be effective for thesynthesis of complex molecules possessing fluorinatedfragments (57k,l). In follow-up work, the same groupdemonstrated that a similar catalytic system involving aPd(II)-precatalyst and Xantphos as the ligand enabled aHeck-type coupling of secondary trifluoromethylated alkylbromides (Scheme 6, products 59a–c).29 The performedmechanistic studies supported a hybrid Pd-radical mecha-nism and ruled out the possible involvement of the corre-sponding ATRA products (bromide-containing analogues of53) for both reactions.28,29

2.4 α-Functionalized Alkyl Halides

In 2014, Gevorgyan reported the Pd-catalyzed endo-se-lective Heck-type reaction of iodomethylsilyl ethers 61 em-ploying ferrocene-derived bidentate phosphine ligand 64(Scheme 7).30 The reaction was able to deliver seven-, eight-,and nine-membered siloxycycles 62a–i in good yields,which could further be converted into the correspondingallylic alcohols (see 63g,i as examples) via oxidation. For-mally, this transformation provides a tool for the selective(Z)-hydroxymethylation of phenols and alkenols 60. The

mechanistic studies suggested a hybrid Pd-radical mecha-nism for this Heck reaction. Also, the silicon atom wasfound to be crucial for the observed endo selectivity.

In 2017, Gevorgyan’s group developed the first visible-light-induced Pd-catalyzed Heck reaction of alkyl halides atambient temperature under exogenous photosensitizer-free conditions to furnish valuable allylic systems of diverseelectronic nature (Scheme 7).31 Allylic silanes (66a,b,k–o),boronates (66c,j), germane (66d), stannane (66e), pivalate(66f), phosphonates (66g,p), phthalimide (66h), and to-sylate (66i) derivatives were easily synthesized from prima-ry and secondary α-functionalized alkyl halides and vinyl

Scheme 6 Pd-catalyzed Heck reactions of fluoroalkyl halides

Zhang, 2015 & 2017

Rf Br(I), 56

5 mol% Pd(PPh3)2Cl2 or 10 mol% Pd(MeCN)2Cl2

10–20 mol% XantphosM2CO3 or KOAc

1,4-dioxane or DCE, 80 °C

F3C(F2C)4F2C

R

57a, R = H, 89%57b, R = t-Bu, 87%57c, R = t-BuO, 94%57d, R = CO2Me, 55%57e, R = CHO, 80%

O

F3C(F2C)4F2C

N

O

F3C(F2C)4F2CF3C

57h, 47%57i, 81%

57j, 57%

NO

EtO2CF2C57g, 69%

CO2Me

HN

OOMe

F F

57k, 75%

O

H

H

H

F3C


57l, 49%

SN

F3C(F2C)4F2C

Me

57f, 40%

Chen, 1988

Rf I

R2

R3

R1

I

R3

R1

R2

Rf1 mol% Pd(PPh3)4

51 52 53

10 mol% Pd(PPh3)4

54

Br

F

PhO2S

F F

PhO2S

F

R2

55

K2CO3PhCH3, 100 °C

Reutrakul, 2012

F

PhO2S

F

Ar

55

F

PhO2S

F

O

F

PhO2S

F

SPh

55d, 41%


55a, Ar = Ph, 41%55b, Ar = 4-ClC6H4, 60%55c, Ar = 4-MeC6H4, 52%

R3

R2

R3

R1 52

R1

F

PhO2S

F

Ph

55e, 45%Ph

55f, 69% (E/Z 1.7:1)

34–97%

R2

R3

R1 52

R2

R3

R1 57

Rf

F3C

Alkyl

Br

5 mol%Pd(PPh3)2Cl2

58

7.5 mol% XantphosKOAC, DCE, 80 °C

R2

R3

R1 59

Alkyl

F3C

CF3

HON

CF3

CN59a, 85%

O

59b, 61%

Ph59c, 71%

CF3

Ph


990


arenes/heteroarenes. The obtained allylic systems can befurther modified, for example, via a Hosomi–Sakurai reac-tion (66j → 67). Later, the same group applied these photo-induced conditions for the Heck reactions of α-heteroatom-substituted tertiary alkyl iodides with styrene (Scheme 7,products 66q–s).25

Notably, in this case, presumably due to the insuffi-ciently low reduction potentials of the activated tertiarysubstrates, activation by light was not necessary to obtainthe Heck reaction products. The performed radical clockand radical trapping experiments described in these re-ports25,31 support a radical-type mechanism. It was alsoshown that Pd(0)Ln complexes were the single light-absorb-ing species in this reaction. The excited state is quenched byan alkyl halide, presumably via a SET event, which was cal-culated to be ‘barrierless’,12c to form the alkyl Pd hybrid spe-cies 68 that adds to an alkene producing the new radical

species 69 (Scheme 8). Subsequent β-H elimination fromthe latter delivers the product 66, while the base regener-ates the Pd(0) catalyst.

Scheme 8 Gevorgyan’s mechanism for the visible-light-induced Pd-catalyzed Heck reaction

Scheme 7 Pd-catalyzed Heck reactions of α-functionalized alkyl halides

G I(Br) +R2

R1

Cs2CO3 or (i-Pr)2NEt PhH, Blue LED, rt

10 mol% Pd(OAc)2

20 mol% XantphosR2

R1

G

G

66a, G = TMS, 88%, 55% (from AlkBr)66b, G = Si(OEt)3, 65%66c, G = Bpin, 70%66d, G = GeMe3, 68%66e, G = SnBu3, 71%66f, G = OPiv, 76%66g, G = P(O)(OEt)2, 58%66h, G = NPhthl, 72%66i, G = Ts, 61%

TMS66l, R = OMe, 82%66m, R = CN, 80%66n, R = Br, 59%66o, R = F, 73%R

PhMe2PhSi

Bpin

66j, 90%

N

(EtO)2(O)P

OMe66p, 77%

Gevorgyan, 2014

OHn

ClSiCH2I

On Si I

SiOn

[O]

n10 mol% Pd(OAc)2

20 mol% L

AgOTf(i-Pr)2NEt

PhMe, 75 °C

HO

OH


SiO

i-Pr i-Pr

62g, 60%

SiO

i-Pri-Pr

R

62a, R = H, 79%62b, R = 3-MeO, 87%62c, R = 3-F, 74%62d, R = 4-O2N, 33%62e, R = 2-MeO, 90%

SiO

i-Pri-Pr

62f, 75%

7 7 8

OSi

9

i-Pri-Pr

Ph

62h, 44%

60 61 62 63

OH

OH

63g

Me

H

H

H

HO

HO63i

Gevorgyan, 2017 & 2018

L, 64

10 mol% Pd Xantphos G3

or


65 10 66

Fe

PPh2

P(t-Bu)2

R3R3

66q, G = Ts, 85% (from AlkBr)66r, G = Bpin, 99%66s, G = P(O)(OEt)2, 85%

GTMS

TMS

66k, 90%

(no light)

Bpin

Ph

Me

OMe

DME TiCl4

67

[O]

Me

H

H

H

62i, 82%Si Oi-Pri-Pr

7 [O]

80%

87%

55%

LnPd(0)

hv

LnPd0 *65

PdIX

10

PdIX

HPdIIX

X

R2

B

B HXG

R1

R3

G

R3

R1

R2

G

R3 R1

R2

G

R3

68

69

66


991


2.5 Unactivated Alkyl Electrophiles

The first Heck reaction of unactivated alkyl halides withalkenes was reported by Waegell and de Meijere in 1998(Scheme 9).32a In this report, 1-bromoadamantane (70), asubstrate which is not disposed to β-hydrogen elimination,was employed. Upon this Pd/C-catalyzed reaction at 120 °C,a number of substituted olefins 72 were obtained in low tomoderate yields. In 2007, Fu introduced the first protocolfor the Heck reaction of unactivated alkyl bromides andchlorides containing eliminable β-hydrogens (Scheme10).32b The employment of the bulky NHC-ligand 75 on thePd catalyst was the key for the success of this transforma-tion, allowing an intramolecular insertion of the alkyl-Pdspecies into a double bond to proceed faster than the pre-mature β-hydrogen elimination. Cyclopentane derivativespossessing an exo-alkene moiety 74a–g were obtained in

high yields and regioselectivities from the correspondingunsaturated alkyl bromides and even chlorides 73 at elevat-ed temperatures. The stereochemical outcome of this trans-formation supports the SN2 mechanism for the oxidativeaddition step, thus eliminating involvement of radical inter-mediates in this reaction.

Scheme 9 Waegell and de Meijere’s first Pd-catalyzed Heck reaction of unactivated alkyl halides

In 2011, Alexanian developed a protocol for an intramo-lecular alkyl-Heck reaction, which relied on radical reactiv-ity (Scheme 10).33 Following his previous work on the car-

Ar10 mol% Pd/C

K2CO3DMF, 120 °C

Waegell & de Meijere, 1998

BrAr

R

R72, 15–41%70 71

Scheme 10 Pd-catalyzed intramolecular Heck reactions of unactivated alkyl halides; d.r. = diastereomeric ratio

XR R

5 mol% Pd2(MeO-dba)3 20 mol% SIMes·HBF4

X = Br, Cl

20 mol% KOt-Bu

Cs2CO3 or K3PO4

N N MesMes

HSIMes·BF4

–

Ar EtO2CEtO2C

Fu, 2007


74a, Ar = 2-naphthyl, 73%a

74b, Ar = 4-MeOC6H4, 78%a, 72%b

74c, Ar = 4-F3CC6H4, 79%a

74d, Ar = 2-benzofuranyl, 83%b

n-Oct

74e, 85%a, 80%b 74f, 75%a, 71%b 74g, 81%a

AlkBr (MeCN, 65 °C)a or AlkBr (NMP, 110 °C)b

XRR10 mol% Pd(PPh3)4

10 atm CO

Alexanian, 2011 & 2017


(i-Pr)2NEtPhMe, 130 °C

O

n

R

4-MeOC6H4 O OBu

Me

78a, 80%a, 90%b 78b, 73% (d.r. 83:17),a

73% (d.r. 89:11)b

EtO2C

EtO2C

78c, 70%,a 82%b

O

H

H

Me

78d, 66% (d.r. >95:5),a

93% (d.r. >95:5)b

5 mol% Pd(allyl)Cl220 mol% dtbpf

Et3NPhCF3, 100 °C

nn

Rn

X = I X = Br

first generationa second generationb

O

TsN

ArTsN

10 mol% Pd(dppf)Cl2

Cy2NMe PhMe, 110 °C Ar

R1

I

R1

R2

R2

R1 = H, Ph, i-Pr, i-Bu, or MeR2 = H or MeAr = Ph, 3-MeOC6H4, 4-NCC6H4, 4-FC6H4, 4-ClC6H4, etc.

51–89%

Ar

TsNR1

R25-exo-trig cyclization

TsN

Ar

R1

R2

Liu, 2016

6-endo-trig cyclization

73 74 75

76, X = I77, X = Br

78 7879, not observed

80 81 82

83

TsNH

H

78e, 74%,a

77%b

BF4–


992


bonylative Heck-type reaction,34 he showed that under in-creased CO pressure, Pd(PPh3)4 was capable of catalyzingthe 5- or 6-exo-trig cyclization reaction of alkenyl iodides76, leading to the exclusive formation of Heck reactionproducts 78a–e rather than the corresponding cy-cloalkenones 79. Interestingly, in the absence of CO, the re-action proceeded as well, albeit with lower efficiency andregioselectivity. In contrast to Fu’s work,32b mechanisticstudies, including a radical trapping experiment, indicatedthe formation of radical species under these conditions. Ac-cordingly, a hybrid Pd-radical mechanism was postulated.In 2017, the same group introduced a second-generationPd-based catalytic system for an intramolecular Heck-typereaction, thus enabling efficient carbocyclization of unsatu-rated alkyl bromides 77 under CO-free conditions (Scheme10).35 Moreover, in this work, the authors investigated thedifference in the reactivity of alkyl iodides versus alkyl bro-mides in this cyclization. It was hypothesized that, in thecase of alkyl bromides, the cyclization proceeds via auto-tandem catalysis (Scheme 11). Initiated by the Pd(0) com-plex, ATRC leads to the formation of alkyl bromide 86,which could be isolated from the reaction mixture. Subse-quently, the Pd(0)-catalyzed dehydrohalogenation of 86 de-livers the Heck reaction product. Alternatively, for alkyl io-dides, the radical chain mechanism initiated by the Pd(0)catalyst was suggested as a more likely scenario.

In 2016, Liu reported a related Pd-catalyzed radicalHeck-type cyclization utilizing alkyl iodides 80 possessing a1-aryl-substituted alkene moiety (Scheme 10).36 The use ofthese specific substrates resulted in the exceptional endo-selective cyclization. This outcome is attributed to a muchhigher stability of the forming tertiary benzyl radical inter-mediate 81 versus a non-stabilized primary radical species83, which would arise via an alternative 5-exo-trig cycliza-tion. Thus, a number of 5-aryl-1,2,3,6-tetrahydropyridines82, which are structural motifs found in a variety of naturalproducts and pharmaceutical compounds, were synthe-sized using this approach.

In 2014, Alexanian developed an intermolecular versionof alkyl Heck reaction of unactivated alkyl iodides (Scheme12).37 By employing Pd(dppf)Cl2 as a catalyst, both primaryand secondary alkyl iodides 88 reacted smoothly with sty-rene and acrylonitrile derivatives producing alkylated ole-fins 91a–k in moderate to excellent yields. Shortly after,Zhou applied a combination of a Pd(0) precatalyst and dppfas a ligand, which allowed intermolecular Heck reactions ofstyrenes to proceed with alkyl iodides 88, bromides 89 andeven chlorides 90 (Scheme 12).38 The use of LiI as an addi-tive in the reaction was crucial for achieving higher yieldswith halides 89 and 90, presumably due to in situ genera-tion of more reactive iodide species. As a result, the corre-sponding Heck reaction products 91a,h–k were obtained inyields comparable to those reported by Alexanian employ-ing alkyl iodides. Similar to the previously described Heck-

type cyclization reactions, the mechanistic studies in bothreports were consistent with a hybrid Pd-radical pathway,thus further illustrating the prominence of this pathway forovercoming premature β-hydrogen elimination in alkylHeck reactions.

Until recently, all the reported methods for the Heck re-action of unactivated alkyl halides required elevated tem-peratures. In 2017, Gevorgyan’s group demonstrated thepossibility of achieving a room temperature Heck reactionof unactivated primary and secondary alkyl halides undervisible-light-induced exogeneous photosensitizer-free con-ditions employing a Pd(0)/Xantphos catalytic system(Scheme 12, products 92a–c).31 Shortly after, the groups ofShang and Fu independently developed a similar methodfor the reactions of primary and secondary unactivated al-kyl bromides with styrenes to provide the Heck reactionproducts 92d–h in excellent yields and E/Z ratios.39

Moreover, challenging tertiary alkyl bromides were alsofound to be capable coupling partners (products 92i–n). Inaddition to styrenes, unactivated tertiary alkyl bromides re-acted with electron-deficient alkenes in a highly efficientmanner (products 92o,p). The mechanistic studies of thiswork strongly supported a radical pathway, which was ini-tiated by a SET event from the photoexcited Pd(0) complexto an alkyl halide (see Scheme 8). Furthermore, the per-formed X-ray photoelectron spectroscopy studies detectedpalladium in three oxidation states: Pd(0), Pd(I), and Pd(II),thus demonstrating that the Pd(0)–Pd(I)–Pd(II) catalytic cy-cle is a highly feasible scenario for these visible-light-in-duced conditions. Shortly after, Gevorgyan independentlyreported analogous efficient alkyl Heck reactions of unacti-vated tertiary alkyl iodides with styrenes and acrylonitrile(Scheme 12, products 92q–v).25

Very recently, Gevorgyan’s group reported a photoin-duced, Pd-catalyzed radical relay Heck reaction at remoteunactivated C(sp3)–H sites of aliphatic alcohols, which syn-ergistically combines a C–H activation via a hydrogen atom

Scheme 11 Alexanian’s mechanism for the Pd-catalyzed carbocycliza-tion of unactivated alkyl bromides via auto-tandem catalysis

LnPd(0)

TsNBr

TsN

LnPd(I)Br

TsNH

H

LnPd(I)Br

TsNH

H

Br

TsNH

H

LnPd(I)Br

TsNH

H

Pd(II)Br

B

B HBr77e

86

78e

atom transfer radical cyclization

catalytic dehydrohalogenation

84

8585

87


993


abstraction (HAT) process and an alkyl Heck reaction(Scheme 13).40 The control of the β-, γ-, or δ-sites in this re-gioselective Heck reaction was achieved by the employ-ment of easily installable/removable iodomethyl silyl teth-ers on alcohols 93. These tethers are known to engage in aSET process with the photoexcited Pd complex to form thePd-radical hybrid species 95.30,31 Remarkably, 95 bypassesthe potential side-reaction processes, such as hydrodehalo-genation or premature Heck reaction (97), but rather un-dergoes a selective 1,5-, 1,6- or 1,7-HAT to produce thetranslocated Pd-radical hybrid species 96. Subsequently,the latter is able to couple with acrylonitrile, acrylate orstyrene derivatives to afford the remote Heck reactionproducts 94a–m in good yields. Interestingly, the iodine-

atom transfer intermediate 96′ was observed during this re-action, which presumably is formed via a reversible I-atomtransfer from the Pd(I)I species.

Lately, the scope of alkyl electrophiles in the Heck reac-tion has been expanded. Thus, in 2018, Zhou’s group re-ported a Heck-type reaction of cyclic (98) and acyclic (99)epoxides using a Pd(0)-Xantphos catalytic system (Scheme14).41 Styrenes, conjugated dienes, and electron-deficientolefins were efficiently alkylated to give ring-opening prod-ucts 100a–h and 101a,b with retention of the stereochem-istry of the original epoxides. The authors proposed thatthe reaction proceeds via the in situ generation of β-iodo-hydrins 104 from the epoxide 98g and Et3N·HI, which un-dergoes a SET reduction by the Pd(0) complex to form the

Scheme 12 Pd-catalyzed intermolecular Heck reactions of unactivated alkyl halides

Alexanian, 2014a

10 mol% Pd(dppf)Cl2

Cy2NMe or K3PO4PhCF3, 110 °C X

R3

Alk

R3Alk


Ar OTBS

Me

O

CN

PhR

TsN

CN

Me

91a, Ar = C6H5, 84%a (76% from AlkBr)b

91b, Ar = 4-MeOC6H4, 66%a

91c, Ar = 4-F3CC6H4, 82%a

91d, 61% (d.r. 50:50, E/Z 33:66)a

91e, 35%a91f, 79% (E/Z 66:33)a

91g, R = n-Hex, 46%a

91h, R = n-Oct, 74% (E/Z 4:1) from AlkBrb

91i, R = n-Dec, 74% (E/Z 4:1) from AlkClb

Ph

91j, 80% (d.r. >95/5, E/Z 88:12),a

72% (E/Z 24:1) from AlkBrb

Zhou, 2014b

R3Alk

5–10 mol% Pd(dba)2 orPd(PPh3)4

7–14 mol% dppf

LiI, Cy2NMe PhCF3, 110 °C

X = I X = I, Br, Cl

Ph

91k, 70% (E/Z 86:14),a

76% (E/Z 13:1) from AlkBrb

Alk X

R2

R1

K2CO3, H2O DMA, Blue LED, rt

5 mol% Pd(PPh3)2Cl26 mol% Xantphos

R2

R1

Alk

92

88 or 89

10+

R

92i, R = OMe, 94%b

92j, R = Bpin, 91%b

92k, R = F, 85%b

92l, R = Ph, 85%b

92m, 71%b 92n, 45%bOMe

OHC

O

N

O

92o, 58%b

N

92p, 61%b

Shang & Fu, 2017b


Cs2CO3 PhH, Blue LED, rt

10 mol% Pd(OAc)2

20 mol% Xantphos

Gevorgyan, 2017a & 2018c

R2

R1

Alk

92

Ph

X = BrX = I

R2

R1

52

R1

R2 R2

R1

88, X = I89, X = Br90, X = Cl

9191

CN

Ph

92v, 59% (E/Z 1.5:1)c

4-MeOC6H4

92d, R = OH, 77%b

92e, R = OTIPS, 65%b

R5 Ph

Cl5

92f, 55%b

92g, 81%b

N

BocN

Ph

PhO

92h, 81%b

92q, R = H, 92%c

92r, R = OMe, 97%c

92s, R = CN, 99%c

92t, R = CO2Me, 92%c

92u, R = CONMe2, 88%cR

8

92a, 79%a Ph92c, 76%a

Ph

92b, 87%a


994


alkyl Pd-hybrid radical species 105 (Scheme 15). Subse-quently, this species adds to the double bond of alkene toform a new radical species 106, which gives the reactionproduct via recombination with Pd(I) and subsequent β-Helimination. The measured redox potentials of the reactioncomponents are consistent with this hypothesis, thus rul-ing out an alternative radical polar crossover pathway in-volving oxidation of benzyl radical species 106 by Pd(I) intothe corresponding benzyl cation 108.

In addition to alkyl halides and epoxides, the redox-active esters have also been found to undergo an efficientHeck-type reaction. In 2018, the groups of Shang, Fu andGlorius independently discovered a photoinduced Pd-cata-lyzed Heck reaction of redox active esters, aliphatic N-(acy-loxy)phthalimides 102, with styrenes (Scheme 14).42

The reactions of primary, secondary and tertiary sub-strates proceeded smoothly at room temperature (products103a–s), thus providing an alternative approach towards al-kylated alkenes starting from readily available carboxylicacids. Overall, the scope of these transformations was com-parable with that of the visible-light-induced Heck reac-tions of alkyl halides. Likewise, mechanistic studies haveproven a radical-type mechanism initiated by a SET eventbetween a photoexcited Pd(0) complex and a redox-activeester, followed by its decarboxylative fragmentation to-wards an alkyl hybrid Pd-radical species. The latter wouldbe engaged in the hybrid Pd-radical catalytic cycle, ulti-mately generating the corresponding Heck reaction prod-ucts. Furthermore, photophysical studies revealed that thePd complex is the only light-absorbing species in this trans-formation, while N-(acyloxy)phthalimides 102 showed noabsorption in the visible light region.

Scheme 13 Pd-catalyzed aliphatic radical relay Heck reaction at unactivated C(sp3)–H sites of alcohols

selective 1,n-HATO

Hα

Hβ

Hγ

Hδ

SiR2

I-PdI

On

I-PdI

H

HSiR2

H

Hε

95

96

R1O

H

SiR2

93

n

I

HO

94

n

R2

10 mol% Pd(OAc)220–30 mol% Xantphos

Cs2CO3 PhH or PhCF3 Blue LED, rt

then deprotection

R1R2

5

+

OH

94a, 71% (Z/E 2:1)

CN OH

94b, 57%

CO2Bu

OH

94c, 66%

OH

Cl94e, 67%

OH

94f, 55%

ClOAc NC

94g, 51% (Z/E 4:1)

H

OH

94i, 65% (Z/E 3:1)

NC OHCl

94j, 56%

OAc

CN

94k, 58%(Z/E 1:1, β/δ 2.5:1)

94l, 52%

OH OH

Cl94m, 53%

n-Pr

(d.r. 1:1)

Cl

OH

N

N

94d, 55%

OAc

NC

94h, 55% (Z/E 4:1)

γ γ γ γ

γ γγ

γγ β β

β

δ

δ

δγ

Gevorgyan, 2018


via:

On R1

SiR2

R2

97

On

H

HSiR2

H

96'I


995


3 Ni-Catalyzed Heck-Type Reactions

3.1 Benzylic Electrophiles

Following his work on the Ni-catalyzed allylic alkenyla-tion,43 in 2011, Jamison introduced a protocol for Heck cou-pling of benzyl chlorides with terminal aliphatic alkenes. Anumber of branched Heck reaction products 110 were effi-ciently obtained at room temperature in the presence ofNi(COD)2, the monodentate phosphine ligand PCy2Ph andTESOTf as an additive (Scheme 16).44 The reaction was pro-posed to occur via a cationic Heck reaction pathway(Scheme 17). First, the oxidative addition complex 115 un-dergoes counteranion exchange with TESOTf to generatethe cationic benzyl-Ni(II) species 116, followed by an olefincoordination and sterics-controlled migratory insertion.Subsequent β-H elimination of the formed alkyl-Ni(II) com-plex 117 affords the branched Heck reaction product 110and HNi(II)OTf, which upon reduction to Ni(0) returns tothe catalytic cycle. This protocol is unique for alkyl Heck re-actions as it provides access to 1,1-dialkyl-substitutedalkenes 110a–i in excellent yields and regioselectivities(>95:5 for most cases). Two years later, the same group dis-covered the precatalyst 111 that allows this reaction to pro-ceed much faster and, most remarkably, to be carried outunder open-flask conditions, where no exclusion of air, wa-ter, or degassing of solvents and reagents is required.45 Rely-ing on these new conditions, a diverse range of allylbenzene

Scheme 14 Pd-catalyzed intermolecular Heck reactions of epoxides and redox-active esters

X

OR

or

OR'

R

Zhou, 2018

5 mol% Pd(PPh3)47 mol% Xantphos

20 mol% Et3N·HIPhCF3 or dioxane, 110 °C

R3

R2

R1

X

HO

R

R1

R3

R2

R' R2

OH

RR3

R152

98

99

100

101Scope, representative examples:

HO

Ar

100a, Ar = 4-MeC6H4, 82% (trans/cis 7:1)100b, Ar = 4-F3CC6H4, 78% (trans/cis 7:1)100c, Ar = 2-naphtyl, 58% (trans/cis 6:1)100d, Ar = 4-AcOC6H4, 65% (trans/cis 9:1)

HO

100g, 85% (trans/cis 3:1)

HO

Ph

CO2Et

100e, 46% (trans/cis 2.6:1)

101f, 52% (trans/cis 2.5:1)

HO

MeN

O Me

PhMe OH

100h, 60% (cis/trans 3:1)

OH

Ph

101a, 62%, 99.7% ee(r.r. 9:1)

OH

Ph

101b, 60% (r.r. 20:1)

O

O

5 mol%PdCl2(PPh3)2

6 mol% Xantphos 5 mol% Pd(PPh3)4

N

O

OOAlk

O

103e, R = H, 95%a

103f, R = t-Bu, 94%a

103g, R = Bpin, 96%a

103h, R = NPh2, 85%a

103i, R = Br, 55%a

103j, R = Cl, 85%a

R

Ph

103r, 73%b

PhCl

103a, 68%a

4

Ph103l, 93%b

NBoc

103m, R = H, 86%b

103n, R = t-Bu, 77%b

103o, R = Cl, 79%b

R

BocN

Ph

103c, 54%b

16Ph

103b, 55%a

3

BocN

103p, R = H, 95%,a 103q, R = Bpin, 78%a

102

R2

R1

AlkR2

R1

Alk

103103

R1

R2

10

Glorius, 2018bShang & Fu, 2018a

OMe103k, 78%a

R

OAc

PhO

103d, 66%b

OAc

t-Bu

103s, 41%b

OAc

Ph

via: 102Pd(0)Ln 102 Alk + CO2 + Phth–

PhO

or

n n

K2CO3, H2O DMA, Blue LED, rt

THF, Blue LED, rt


Scheme 15 Zhou’s mechanism for the Pd-catalyzed Heck reaction of epoxides

[HPdLn]+ LnPd(0)base

HO I

(E1/2 = –2.2 V)

LnPd(I)I

(E1/2 = –1.5 V)

HO

PhHO

Ph

LnPd(I)I

HOPh

Pd(II)LnI

HOPh

HOPh

104

O

98g

105

106

100g Ln = Xantphos

(E1/2 = ~0.0 V)

107

108

base100g

– base H+

Et3N·HI


996


derivatives 110h–j was efficiently synthesized in compara-ble yields to those reported under the previous protocolconditions (Scheme 16).

In 2014, Jarvo developed a highly efficient, stereospecif-ic, Ni-catalyzed intramolecular Heck reaction of chiralmethyl benzyl ethers 112 to give methylenecyclopentanes113 (Scheme 16).46 The stereochemical outcome of this re-action arose from inversion during the oxidative additionevent, thus providing a single enantiomer of the key alkyl-Ni intermediate 114. The stereochemistry at this carboncenter remained unchanged throughout the followingsteps.

Recently, Hu and Huang reported the Ni-catalyzed Heckreaction of benzylamines 118 proceeding via a C–N bondactivation (Scheme 18).47

Scheme 16 Ni-catalyzed Heck reactions of benzylic electrophiles

Ar

Jamison, 2011 & 2013

Cl R2

5 mol% Ni(COD)2a

10 mol% PCy2Ph

TESOTf, Et3NPhMe or neat, rt

Ar


R1110a, R1= 4-H, 99%a

110b, R1 = 4-CN, 73%a

110c, R1 = 3-Br, 82%a

110d, R1 = 3-MeO, 90%a

110e, R1 = 2-I, 68%a

S

R2

110g, 86%a

Me

Me

OPh 110f, 97% (r.r. >95:5)a

NiCl PCy2Ph

PhCy2P

MePrecatalyst, 111

Jarvo, 2014

Ar

OMe10 mol% Ni(PCy3)2Cl2

MeMgIPhMe, rt Ar

H


Ar

H

113a, Ar = 2-naphthyl, 74%, 99% ee113b, Ar = 2-furyl, 93%, 99% ee

Ar

H Me

Me

113c, Ar = 2-naphthyl, 80%, 89% ee

R

Ph

R

O

H

H

110

112 113

5 mol% precatalyst 111b

TESOTf, Et3NCH2Cl2, rt

or

NPhthF3C F3C OMe

OTMS110i, 78% (r.r. >95:5)a

83% (r.r. 99:1)b

110j, 96%(r.r. >99:1)b

Ph

110h, 77% (r.r. 91:9)a

70% (r.r. 93:7)b

via: Ar

Ni(II)

R

114

113d, 74% (d.r. >20:1)

109 5

Scheme 17 Jamison’s mechanism for the Ni-catalyzed Heck reaction of benzylic chlorides

Ni(0)L2

115Ni

L Cl

L

NiL L

OTf

R2

NiL L

NiL

L OTf

H

TESOTf, L

TESCl

R2

116117

Ar Cl

ArR2

5

110

R1

R1R1

109

OTf


997


Scheme 18 Ni-catalyzed Heck reaction of benzylamines

The reaction is believed to occur via a charge transfer(CT) complex 121, which undergoes an SET with the Ni(0)catalyst to form alkyl radical species 122. The latter can becaptured with styrene derivatives to produce Heck reactionproducts 120a–i in moderate to good yields.

3.2 α-Carbonyl Alkyl Halides

In 2012, Lei reported the Ni-catalyzed Heck-type reac-tion of α-carbonyl-substituted alkyl halides 123 with sty-renes to construct α-alkenyl carbonyl derivatives 124(Scheme 19).48 Both amide- and ester-possessing secondaryand tertiary alkyl bromides were reactive underNi(PPh3)4/dppp-catalyzed conditions leading to the prod-ucts 124a–k. Interestingly, the authors showed that a Ni(I)-complex such as Ni(PPh3)4Cl was able to catalyze this reac-tion, as well. Thus, the following radical-type mechanismhas been proposed (Scheme 20). Presumably, the Ni(I) spe-cies is generated in situ from the Ni(0)-catalyst and an alkylbromide via a SET event. The second SET event would pro-duce the Ni(II)-complex and alkyl radical species 125,which undergoes radical addition to the alkene to formbenzylic radical 126. A subsequent radical polar crossoverprocess would regenerate the active Ni(I)-catalyst and pro-duce cationic intermediate 127, which upon base-assisteddeprotonation provides the final product. The involvementof a radical polar crossover pathway was supported by thepresence of the lactam cyclization by-product in significantamounts in the reaction towards 124f (Scheme 19).

3.3 Unactivated Alkyl Halides

The first example of Ni-catalyzed Heck reactions of un-activated alkyl halides was reported by Beletskaya in 1988(Scheme 21). The Ni(PPh3)4Cl2/Zn/pyridine system was

shown to be capable of catalyzing the reaction of unactivat-ed primary and secondary alkyl bromides with styrene to-ward the Heck reaction products 129a–c in low to moder-ate yields.49

In 2012, Álvarez de Cienfuegos and Cuerva introduced aHeck-type cyclization of alkyl iodides 130 under Ni/Ti-syn-ergetic catalysis at room temperature (Scheme 21).50 Inter-estingly, depending on the conditions, the reaction couldprovide either normal or reductive Heck products (131a–dor 132, respectively). In the case of standard Heck reactionconditions, the Ni(I) complex is suggested to be the activecatalyst that initiates the radical-type mechanism via SETwith an alkyl iodide; whereas the role of Ti(III) is believed toexecute a hydrogen atom transfer (HAT) from the interme-diate 133. The latter hypothesis seems to be consistent withthe results on the more efficient production of 132 in thereactions of less hindered alkenes. This outcome is attribut-ed to the ability of Ti(III) to irreversibly trap less bulky radi-cal intermediates 133, thus providing the corresponding re-duced products upon acidic quenching. Recently, Alexaniandeveloped the Ni-catalyzed intramolecular and intermolec-

Ar2Ar2

2.5 mol% NiCl23 mol% Cy-Xantphos

20 mol% I2, PhOMe, 150 °C

Hu & Huang, 2018

118 119

Ar1 Ar1

120Ar NAlk2

R1

Ar

R1

Ph

R

R

120d, R, R = Me, 88%120e, R, R = F, 92%120f, R, R = NMe2, 67%

Ph

R120g, R = OMe, 56%120h, R = CF3, 51%

Ph

F120i, 25%

Ph

Ph

120a, R = 2-Me, 95%120b, R = 4-Cl, 83%120c, R = 4-Ac, 80%

R

Ar NAlk2

R1I2

Ar N

R1

Alk

AlkI2

Ni(0)

Ni(I)-NAlk2

CT-complex, 121

Ar

R1

I2

118 122

via:


Scheme 19 Ni-catalyzed Heck reaction of α-carbonyl alkyl halides

Lei, 2014

EWG Br +R3

R2

K3PO4PhCH3, 60–100 °C

R3

R2

EWG

5 mol% Ni(PPh3)46 mol% dppp

123 10 124

R1 R1


OMeO

R

124a, R = Et, 80%124b, R = Ph, 82%124c, R = NHn-Bu, 22%

Ph

O

R

Ph

124d, R = Et, 80%124e, R = NHn-Bu, 92%

Ph

Et

O

H2N

Ph

124f, 46%

RO

EtO124g, R = MeO, 85%124h, R = 4-tolyl, 93%124i, R = Cl, 70%124j, R = F, 70% CF3

O

EtO

Ph

124k, 95%

Scheme 20 Lei’s mechanism for the Ni-catalyzed Heck reaction of α-carbonyl alkyl halides

R2

R3

LnNi(I)X LnNi(II)X

126

125

EWG Br

123

R1

EWG R1

10

R3

R2

EWG

R1

H

B

127

R3

R2

EWG

R1

R3

R2

EWG124

R1

E·HBr


998


ular Heck reactions of alkyl bromides 134 (Scheme 21).51

Employing a Ni/Xantphos catalyst and Mn reductant, thisreaction produced cyclized products 135a–d in good yieldsand enhanced alkene regioselectivity compared to the pre-viously developed Pd-catalyzed carbocyclizations.35 More-over, using these conditions, an intermolecular coupling ofprimary and secondary alkyl bromides with electron-defi-cient alkenes was accomplished (products 135e–g). Mecha-nistic studies suggested a radical-type scenario commencedby SET between Ni(0) and an alkyl bromide. In contrast tothe Pd-catalyzed carbocyclization of alkyl bromides,35 noATRC product was observed in the course of this transfor-mation.

4 Co-Catalyzed Heck-Type Reactions

The area of Co-catalyzed alkylation reactions has arisenafter the seminal discovery by Tada on the generation of al-kyl radicals from alkyl halides in the presence of cobalox-ime(I) as the catalyst.52 A number of reports on intramolec-ular Co-catalyzed Heck reactions by Scheffold53 and oth-ers,54 as well as on the intermolecular version byBranchaud,55 appeared at the early stage of its development(Scheme 22). These initial protocols usually employedstrong reductive conditions, and electrochemical or pho-toinduced activation of hydroxocobalamin (vitamin B12a) orcobaloxime complexes. In 2002, and his follow-up work in2006, Oshima reported the Co-catalyzed Heck reaction ofalkyl halides in the presence of Grignard reagents such asTMSCH2MgCl (Scheme 22).56 Alkyl iodides, bromides, andeven chlorides reacted efficiently with styrene derivatives,producing the Heck reaction products 140a–i in goodyields. Spectroscopic and crystallographic studies support-ed a SET process between the in situ generated Co(0) com-plex and an alkyl halide leading to the alkyl radical speciesengaged in the hybrid-radical mechanism. In 2004, thesame group applied these conditions towards Heck reac-tions of epoxides 98 and 99 (Scheme 22).57 The reactionproceeded through in situ generation of 2-bromomagne-sium methoxide 143 followed by the Co-catalyzed Heck re-action of alkyl bromides analogous to the prior work.56 Thereaction was fairly effective for Heck reactions of symmetri-cal epoxides 141a–d, while asymmetrical substrates yield-ed a mixture of regioisomers 142a and 142a′.

In 2011, Carreira developed a room-temperature visi-ble-light-induced intramolecular Heck reaction employinga cobaloxime catalyst 148 (Scheme 23).58 In contrast to thepreviously reported Co-catalyzed Heck reactions, the meth-od relied on the Hunig’s base [N(i-Pr)2Et]-promoted Co(I)-catalyst turnover via deprotonation of the Co(III)–H inter-mediate. Therefore, strong reductants such as RMgX or Znwere no longer required, which significantly expanded thefunctional group compatibility of the Co-catalyzed Heck re-action. Excitingly, the authors were able to apply this mildprotocol for the late-stage cyclization step in the total syn-thesis of (+)-daphmanidin.58 Later, Carreira reported an in-termolecular version of this coupling using 2,2,2-trifluoro-ethyl iodide (146) and styrene derivatives (Scheme 23).59

The intramolecular and intermolecular Heck reactions pro-ceeded uneventfully, generating the Heck products 145a–dand 147a–e in good to excellent yields. Sensitive function-alities such as amides, esters, ketones, and aldehydes werewell tolerated. Recently, Wu and co-workers developed aroom temperature Heck reaction of widely available alkylcarboxylic acids 149 using organo photoredox/cobaloximedual catalysis (Scheme 24).60 The scope of this reaction wasfairly broad as primary, secondary and tertiary alkyl radi-

Scheme 21 Ni-catalyzed Heck reactions of unactivated alkyl halides

Beletskaya, 1988

Alk Br Ph AlkPh

129

5 mol% Ni(PPh3)2Cl2

Zn, pyridineMeCN, 65 °C

Álvarez de Cienfuegos & Cuerva, 2012

X

R2

R1

I

20 mol% NiCl2 40 mol% PPh3

Cp2TiCl2, MnTMSCl, neat, rt

X

R2

R1

TsN TsN

131a, 55% 131b, 45%

MeO2C

MeO2C131d, 69%

O

p-MeOC6H4

131c, 86%

Alexanian, 2018

X

R2

R1

Br

10 mol% NiBr2·glyme10 mol% Xantphos

Mn, Et3N, MeCN, 80 °CX

R2

R1

MeEtO2C

EtO2CTsN O O

H

H

Me

135a, 94% (E/Z 1.1:1)

TsN

135b, 80% (r.r. 3.1:1)

135c, 73% (d.r. >95:5)

135d, 64% (r.r. >25:1)

CN

MeO

135e, 64% (Z/E 5.7:1)

CN

135g, 47% (Z/E 5.6:1)



135f, 31%

4

CO2Me

130 131

134 135

129a, Alk = c-Hex, 65%129b, Alk = 2-C5H11, 48%129c, Alk = 1-C4H9, 15%


X

R2

R1

132

X

R2

R1

133via:

H Ti(III)

89 128


999


cals, generated from carboxylic acids, could be efficientlycoupled with vinyl arenes/heteroarenes leading to the cor-responding products 150a–g in good to excellent yields. Vi-nyl boronates and vinyl silanes (products 150h and 150i, re-spectively) were also shown to be competent alkene cou-

pling partners in this reaction, which further extended thesynthetic utility of this protocol.

Moreover, under the developed conditions, an unprece-dented three-component coupling of alkyl carboxylic acid,acrylates, and styrenes was demonstrated to afford highlyfunctionalized vinyl arenes in good yields and as single re-gioisomers with exclusive E configuration (products 150jand 150k). Mechanistic studies, as well as DFT calculations,supported a radical-type mechanism (Scheme 25). Accord-ing to which, a SET process from the carboxylate to the ex-cited Mes-Acr+* species is followed by radical decarboxyl-

Scheme 22 Co-catalyzed Heck reactions using strong reducing reagents

Scheffold, 1990

Ar

140, 65%

5 mol% Co(dpph)Cl2

TMSCH2MgClEt2O, reflux

O

OEt

O

EtO

Br3.5 mol% vitamin B12a

NaBH4 EtOH, 60 °C

137, 71%

Branchaud, 1988–1993

Oshima, 2002 & 2006

Alk Br + PhZn, MeCN, reflux

PhAlkCo(dmgH)2py

89 138

Alk X ArAlk

PhR

140a, R = n-C12H25, 76%140b, R = c-C6H11, 98%140c, R = t-Bu, 67%140d, R = Ad, 90%

X = I, Br or Cl

Me

Cl140e, 55%

c-C6H11

140f, R = 4-Me, 87%140g, R = 3-Cl, 82%140h, R = 3-CONBn2, 95%140i, R = 3-CO2t-Bu, 66%

R


5 mol% Co(dpph)Br2

TMSCH2MgBrEt2O, reflux

Oshima, 2004O

R

or

OR'

R

Ph

HO

R

Ph

R' Ph

OH

R

98

99 142

HO Ph

141b, 42%


XH

Ph

141c, X = O, 81%141d, X = NSO2Ph, 36%

c-C6H11Ph

OH

c-C6H11OH

Ph

58% (142a/142a' 63:37)

OH

Ph

141a, 65% (trans/cis 77:23)

or

hv

136

BrMgOR

143

Br

nn


141

142a 142a'

via:

Ph

138a, 60%

EtO2C PhEtO2C

138b, 45%

Ph

138c, 42%7

128

13988–90

Scheme 23 Carreira’s Co-catalyzed Heck reaction using Hunig’s base

Carreira, 2011 & 2013

X

R2

R1

I 10 mol% catalyst

N(i-Pr)2Et, MeCNBlue LED, rt

144n

X

R2

R1

145n

n = 1 or 2


CoN

N N

NMe

Me

Me

Me

OH

O

O

Ph3Sn

N

H O

catalyst, 148

O

145a, 86%

4-MeOC6H4

O

H H

Me

MeO 145b, 83%

OBocN

145c, 89%

N

145d, 91%

O

F3CR

147a, R = 4-MeO, 76%147b, R = 4-CHO, 73%147c, R = 4-CO2Me, 68%147d, R = 4-MeS, 59%

or

F3C I F3C R2

R1or

Ph

Ph

F3C

147e, 51%

146 147

R2

R1

Scheme 24 Wu’s Co-catalyzed Heck reaction of carboxylic acids

Wu, 2018

R3

150

4 mol% Mes–Acr+ ClO48 mol% Co(dmgH)2(DMAP)Cl

10 mol% K3PO4PhMe, Blue LED, 40 °C149

Alk COOH R3Alk


Ph5

150a, 62% (E/Z 15:1)

Ph

150b, 51% (E/Z 22:1)

PhEtO2C

Ph

150c, 57% (E/Z 48:1)

Ph

150d, 71% (E/Z 23:1)

Ph

O

150e, 49% (E/Z >99:1)

N

O Cl

MeO

Ph

150f, 55% (E/Z 22:1)

OO

150g, 45%

+ H2 + CO2

MeO2C

Bpin

150h, 82% (E/Z 12:1)

SiMe3Ph

150i, 76% (E/Z 6:1)

Ph

150j, 63% (E/Z >99:1)

CO2Et

O Ph

150k, 44% (E/Z >99:1)

CO2Et

52

R2

R1

R2

R1


1000


ation to produce the alkyl radical species 151. Subsequenttrapping of the latter by an alkene, and then by the Co(II)-catalyst, leads to alkyl-Co(III) species 153, which undergoesβ-H elimination towards the Heck reaction product 150 anda Co(III)-H species. Deprotonation of this species, followedby an SET with the reduced photocatalyst regenerates bothactive catalysts, Co(II)Ln, and Mes-Acr+. This represents thefirst method for the Heck reaction of unactivated alkyl car-boxylic acids, with H2 and CO2 being the only by-products.

5 Cu-Catalyzed Heck-Type Reactions

In 2013, Chemler reported the first Cu-catalyzed alkylHeck reaction (Scheme 26). In contrast to many alkyl Heckreactions, this reaction employed alkyl nucleophiles, suchas alkyltrifluoroborates 154, as coupling partners for thealkenes.61

Scheme 26 Chemler’s Cu-catalyzed Heck reaction of alkyl trifluorobo-rates

The outcome of TEMPO-trapping and radical clock ex-periments indicated the radical nature of this transforma-tion. The authors proposed that, under oxidative condi-tions, generation of alkyl radical species 157 and a Cu(I)species occurred via homolysis of the Cu–C bond in thecomplex 156, which formed via transmetalation of theCu(II) catalyst with alkyl trifluoroborate 154 (Scheme 27).Addition of 157 to an alkene, followed by subsequent oxida-tion and deprotonation produced the Heck reaction prod-uct 155. Yet, to regenerate the catalyst, the Cu(I) species hadto be oxidized by an external oxidant such as MnO2. Thisoxidative transformation features a quite general scopewith regards to the trifluoroborate salt, as benzylic, unacti-vated primary, and secondary alkyl substrates could effi-ciently react with styrene derivatives to afford the Heckproducts 155a–i in good yields.

Scheme 27 Chemler’s mechanism for the Cu-catalyzed Heck reaction of alkyl trifluoroborates

In the same year, Nishikata developed the Cu(I)/tri-amine (161)-catalyzed Heck reaction of activated tertiaryalkyl bromides 159 with styrenes (Scheme 28).62 Ester-, ni-tro-, or keto-group-possessing tertiary alkyl bromides weredemonstrated to couple with electron-rich styrenes (prod-ucts 160a–e) under mild conditions, presumably via theformation of ATRA intermediate 162. A TEMPO-trapping

Scheme 25 Wu’s mechanism for the Co-catalyzed Heck reaction of carboxylic acids

LnCo(III)

cobaltcatalysis

photoredoxcatalysis

LnCo(III)-H

Ln-Co(I)B

BH

R2Alk

LnCo(III)

LnCo(II)

Mes-Acr

Mes-Acr+

Mes-Acr+

hv

AlkCOOH+ B, – HB

Alk

149 – CO2

H2 H+ + B HB

151

153

152

R3

52

R2

R1

R1R3

150

R3Alk

R2

R1

R3Alk

R2

R1

*

–

Alk R3 R3Alk

40–85%

20 mol% Cu(OTf)2

20 mol% 1,10-phen

3 equiv MnO2

DCE, 105–120 °C

Chemler, 2013

154 52

R2 R2

155

BF3K

Ph Ph

PhR

155a, R = H, 43%155b, R = Me, 50%155c, R = OMe, 45%

X

Ph

155e, X = O, 80%155f, X = CH2, 82%

155d, 85%

O155h, 60%

t-BuO

Ph

Ph

155g, 46%O

CO2Et

155i, 73%

n

R1 R1


CuN N

TfO OTfAlk BF3K

CuN N

TfO Alk

Alk52

R3

158

R2

Alk

R3Alk

R2

155

156

157

[O]

CuL2OTf

– H+

MnO2– OTf

R1

154

R1


1001


experiment confirmed the intermediacy of a tertiary alkylradical species in this reaction. Later, the same group intro-duced a modified Cu(I)/triamine-based catalytic system toaccomplish the Heck reaction of amido-possessing alkylbromides, which were unreactive under the previous con-ditions,62 with both electron-rich and electron-deficientstyrene derivatives (Scheme 28).63 The reaction requiredhigher temperatures and tri-(2-picolyl)amine (TMPA) as aligand to furnish products 160f–k in reasonable yields. In2014, Lei developed the Cu(I)/1,10-phen-catalyzed Heck re-action of primary benzylic and activated secondary and ter-tiary alkyl bromides with electron-rich styrenes (Scheme28, products 163a–k).64 An EPR experiment supported theSET event between the Cu(I) catalyst and an alkyl bromide.

Scheme 28 Cu-catalyzed Heck reactions of activated alkyl halides

In 2014, Chu and Tong synthesized CuB23 alloy shortnanotubes, which were found to be capable of catalyzingthe Heck reaction of unactivated alkyl iodides 88 underligand-free conditions (Scheme 29).65 Under these condi-tions, unactivated primary and secondary substrates react-ed smoothly, presumably via a radical pathway (products164a–e). This method provided slightly superior yieldscompared to the Pd-catalyzed Heck reaction.37 Moreover,the catalyst showed a great recycling performance.

Scheme 29 Cu-catalyzed Heck reaction of unactivated alkyl halides

Regioselectivity has been an issue in the Heck reactionsof unactivated aliphatic olefins due to the undifferentiatedC–H sites for β-H elimination. Very recently, the first regio-selective Heck reaction of alkyl bromides with unactivatedaliphatic olefins was reported by Bi and co-workers(Scheme 30).66

The high reactivity and regioselectivity of this transfor-mation were governed by the aminoquinolone directinggroup (AQ) on the alkene 165, coordination of which to theCu(I) catalyst activated the double bond (167) and also pro-vided control of the regioselectivity for the β-H eliminationstep (168). Detailed mechanistic studies and DFT calcula-tions indicated a radical pathway involving a dimethyl sulf-oxide assisted concerted H–Br elimination event from aconformationally strained Cu(III) cyclic transition state. Ac-tivated primary, secondary and tertiary alkyl bromideswere suitable substrates in this reaction leading to products166a–h.

6 Other Metals in Heck-Type Reactions

In 2003, Kambe reported the titanocene-catalyzedHeck-type reaction of alkyl halides with vinyl arenes(Scheme 31).67 The reaction proceeded efficiently at 0 °C forunactivated primary and secondary alkyl bromides andeven chlorides (products 169a–e), however, considerableamounts of by-products were observed in some cases. TheTi(III)-complex formed in situ from the Ti(IV)-catalyst andthe Grignard reagent is believed to generate alkyl radicals,

Nishikata, 2013a & 2017b

10 mol% CuIa

1 equiv L

TBAB, PhMe30–60 °C


Ar Ar160

EWG

R1R2

Me2N MeN

Me2NL, 161

O

MeO2C CO2Me160a, 73%a

O CN

OO

NO2

3

160b, 53%a

NMe2

CO2Me

160c, 92%a

ArR1

RR Br

via:

NEt

CO2Et

160d, 65%a

OMe

PhOC

160e, 84%a

20 mol% CuCI40 mol% 1,10-phen

Na2CO3 DMF, 100 °C


CNAr

163a, R = p-MeO, 82%163b, R = o-Me, 67%163c, R = t-Bu, 80%

R

163g, R = CO2Et, 22%163h, R = CN, 70%

EtO2C

163i, 76%

PMP EtO2C

163k, 85%

PMP

Lei, 2014

EWG Br

R2

R1 or10 mol% CuIb

5 mol% TMPA

TBAB, PhMe100 °C

O

NHPh

Et

160f, 47%b

EtO

NHPh

Et

160g, 61%b

O

NHPhR

160h, R = NH2, 84%b

160i, R = F, 58%b

160j, R = Cl, 50%b

160k, R = CO2Me, 63%b

ArAr

163EWG

R1R2

EWG Br

R2

R1

R OMe

163d, Ar = o-CF3C6H4, 95%163e, Ar = o,o’Cl2C6H3, 97%163f, Ar = o-BrC6H4, 82%

OMe

EtO2C

163j, 83%

PMP

159 139

162

159 139

Alk R2 R2Alk2 mol% CuB23 nanotubes

Na2CO3

NMP, 80 °C

Chu & Tong, 2014

88 10 164

I


CO2Me

164a, 78%

n-Hex

Ph

OTBS

CN

164b, n = 1, 73% (E/Z 88:12)164c, n = 2, 87%164d, n = 3, 80%

164e, 76% (d.r. 50:50, E/Z 33:66)

n


1002


as well as to trap the benzylic radical intermediate towardsan alkyl Ti(IV) species 170, which upon β-H elimination de-livers the Heck product 169.

Scheme 31 Ti-catalyzed Heck reaction

In 2013, Lei’s group applied Rh- and Ir-photoredox ca-talysis for the Heck reaction of activated alkyl bromideswith vinyl arenes (Scheme 32).68 The reaction operates via aradical-polar crossover pathway, where a photoredox cata-lyst is involved in SET with an alkyl bromide, and in oxida-tion of the benzylic radical intermediate towards the carbo-cation 172. Activated tertiary and secondary alkyl bromidesreacted efficiently under the Rh-catalyzed conditions(171a–f), whereas activated primary alkyl bromides re-quired Ir-catalyzed conditions for the same coupling(171g–k). Later, Cho employed ethyl 2-bromo-2,2-difluoro-acetate (173) in a photoinduced Ir-catalyzed Heck reaction

(Scheme 32).69 Besides styrene derivatives (products 174a–c), unactivated aliphatic alkenes (products 174d–f) werealso suitable partners in reactions with alkyl bromide 173,which is quite rare for alkyl Heck reactions.

In 2015, the Fe-catalyzed Heck reaction of benzyl chlo-rides 175 under UV irradiation was reported by Mankad(Scheme 33).70 The authors favored a classical Heck reactionmechanism for this transformation, where UV irradiationpromoted the CO dissociation to reveal reactive, coordina-tively unsaturated Fe-containing intermediates. A radical-type process was considered to be an unproductive path-way under these conditions, competing with the Heck reac-tion and leading to decomposition. Therefore, the reactionsuffered from moderate yields and regioselectivity due toalkene isomerization (products 176a–g). In 2017, Bao re-ported another Fe-catalyzed Heck reaction using peresters177 as the source of alkyl radicals (Scheme 33).71 This reac-tion was proposed to occur via a radical-polar crossovermechanism initiated by the Fe(II)-catalyst. Methylated andethylated styrene derivatives 178a–g, enyne 178h, and di-ene 178i were obtained in reasonable yields under theseconditions.

In 2014, decarbonylative Heck-type reactions employ-ing tert-butyl peroxide and a catalytic amount of MnBr2were reported by Li (Scheme 34).72 Peroxide-induced H-atom abstraction from aldehyde 179 gives the carbonyl rad-ical 181, which upon releasing CO fragments into an alkylradical 182 (Scheme 35). Subsequent radical addition of thelatter to the alkene, followed by oxidation and deprotona-tion furnishes the Heck-type product 180. The reaction

Scheme 30 Fu, Guan and Bi’s directed Cu-catalyzed Heck reaction of unactivated olefins

EWG Br

R2

R1 40 mol% CuI 1 equiv Cs2CO3

DMSO, 60 °C

Fu, Guan & Bi, 2018

165 166

AQ

O

AQ

O


166d, 59%

AQ

O

EtO2C

166g, 61%

AQ

O

EtO2C

Ph

166h, 64%AQ

OCN

NH

N

AQ

166e, 74%

AQ

O

EtO2C

166a, R = C4H9, 78%166b, R = i-Pr, 80%166c, R = allyl, 68%

AQ

O

EtO2C

NNCu

OEtO

ON

NCu

O

CO2Et

Ha

Hb

167 168

via:

R

166f, 72%

AQ

O

EtO2C

159

R2

EWG

R1

R3R3

BrBr

Kambe, 200320–30 mol% Cp2TiCl2

n-BuMgCl

Et2O, 0 °C89–90

Ar

139

Alk X

X = Br, Cl

ArAlk

169

ArAlk

TiCp2Bu

170

Ph

169e, X = Br, 84% X = Cl, 65%

Phn-C10H21

PhCl

4

Ph Ph6

169a, 78%

169b, 64%Fe Et

Et

169d, 59%

169c, 64%



1003


proceeds well with primary, secondary, and tertiary alde-hydes, however, it is limited to 1,1-disubstituted styrenes(products 180a–f).

In 2016, Hashmi’s group showed that dinuclear goldcomplex 186 could catalyze the Heck reaction of alkyl bro-mides under UVA irradiation (315–400 nm) (Scheme 36).73

In this reaction, electron-rich vinyl arenes were efficientlyalkylated with primary, secondary, and tertiary alkyl bro-mides to afford Heck products 185a–f in good yields. Themethod was also applicable for the late-stage functionaliza-tion of a complex molecule, e.g., pregnenolone derivative185c. Mechanistic studies supported an Au-catalyzed radi-cal polar-crossover mechanism induced by SET from thephotoexcited Au(I)–Au(I) complex to an alkyl bromide.

7 Conclusion

Although the first alkyl Heck reaction was reported byRichard Heck in his original work,1d this transformation hasremained underdeveloped until recently, especially for un-

Scheme 32 Rh- and Ir-catalyzed Heck reactions

Lei, 20132 mol% [RhCl2(bpy)3]

40 mol% 4-methoxypyridinea

or1 mol% fac-[Ir(ppy)3]b

Et3N, NaHCO3 DMF, CFL, rt89

R2

10

Alk Br R2Alk

171

R1


Ph

Ph

R

171a, R = CO2Et, 91%a

171b, R = CN, 54%a

Ph

Ph

R

171e, R = CO2Et, 53%a

171f, R = CN, 74%a

171g, R = 2-Br, 76%b

171h, R = 4-F3C, 56%b

171i, R = 2-I, 40%b

R1

R2Alk

R1via:

Cho, 2014

173

R2

5

EtO2CCF2 Br R2EtO2CCF2

174

1 mol% fac-[Ir(ppy)3] K2CO3, DBU

DMF Blue LED, rt

EtO2C

OMe171c, R = H, 92%a

171d, R = Me, 75%a

R

172

R

OMe

171j, R = Me, 40%b

171k, R = t-Bu, 41%b

R

CN

EtO2CCF2


8

EtO2CCF2NH

O

6

EtO2CCF2

R174a, R = F, 89%174b, R = Cl, 90%174c, R = t-Bu, 87%

174d, 89%

174e, 89%

EtO2CCF2 Ph

174f, 89%

2

Scheme 33 Fe-catalyzed Heck reactions

Mankad, 2015

25 mol% [FeCp(CO)2]Na

NaOt-Bu, Bu2O UV, rt175

Ar

139

Ar

176Ar1 Cl Ar1


176a, R = Me, 52%176b, R = Ph, 51%176c, R = CO2Me, 28%176d, R = F, 50% (r.r. 2.3:1)

R

176e, R = Me, 88% (r.r. 2.4:1)176f, R = F, 34% (r.r. 1.7:1)176g, R = Br, 45%

R

Bao, 2017

2.5–5 mol% Fe(OTf)3

dioxane, 80 °C177

Ar

139Ar

Alk

178

O

AlkO

O

Me

R

178a, R = H, 80%178b, R = 4-F, 75%178c, R = 4-B(OH)2, 57%178d, R = 4-COOH, 60%

Et

R

178e, R = 4-CH2Cl, 81%178f, R = 4-MeO, 67%178g, R = 2-Cl, 82%

R178i, 63%

Et

Et

178h, 50%

Et


Scheme 34 Mn-catalyzed Heck reaction

Li, 2015

5 mol% MnBr2

(t-BuO)2

PhCl, 130 °C179R2

10

R2

180Alk H

OAlk

R1 R1

Ph

Ph

R

180a, R = CH2CH2Ph, 40%180b, R = c-Pentyl, 75%180c, R = t-Bu, 92%


n-Hex

180e, X = CH2, 73% (Z/E 5.6:1)180f, X = O, 80% (Z/E 3.2:1)

X

Ph

Phn-C5H11

180d, 72% (d.r. 1.2:1)

Scheme 35 Li’s mechanism for the Mn-catalyzed Heck reaction

179 R H

O

181R

O

CO

R

10

183184

[O]

180

t-BuO

Mn(III)Ot-BuMn(II) 182R2Alk

R1

R2Alk

R1

R2Alk

R1


1004


activated hindered alkyl halides possessing eliminable β-hydrogens. However, a merger of radical- and transition-metal-catalyzed approaches has significantly driven this ar-ea. Nowadays, in addition to Pd, other transition metalssuch as Ni, Co, Cu, Fe, and others have been shown to effi-ciently catalyze Heck-type reactions, generally following ahybrid-organometallic radical mechanism. Unactivated al-kyl electrophiles possessing eliminable β-hydrogens ap-peared to be non-problematic for this mechanism. More-over, the employment of mild photoinduced conditions hasfurther broadened the scope of the alkyl Heck reaction. Al-though, significant effort has been made to expand thescope with regards to the alkyl component, the scope of thealkenes remains mostly limited to good radical acceptorssuch as styrenes and acrylate derivatives. Examples of thealkylation of unactivated aliphatic alkenes are rare. There-fore, the future direction of this transformation may rely onthe development of new systems that enable unactivatedalkenes to undergo selective and efficient Heck-type reac-tions. Obviously, detailed mechanistic studies are warrant-ed for better understanding of alkyl Heck-type reactions.

Funding Information

We thank the National Institutes of Health (GM120281) and NationalScience Foundation (CHE-1663779) for the financial support of thiswork.National Institutes of Health (GM120281)National Science Foundation (CHE-5 1663779)

References

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Scheme 36 Au-catalyzed Heck reaction

Hashmi, 2016

3 mol% catalyst 18650 mol% Na ascorbate

NaHCO3 MeCN, UVA, rt

89R2

10

Alk Br R2Alk

185

R1

Ph2P PPh2

Au AuPh2P PPh2

catalyst, 186

R1


Ph

Ph

185a, 80%

EtO

O

3Ph

Ph

HO

185b, 51%

4 H

H H

O

Ph

Ph

185c, 74%

Ph

Ph

185d, 71%

Pht-Bu

Ph

185e, 60%

PMPEtO2C

185f, 63%

2OTf

2+


1005


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