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Page 1: Recent Advances in Transition-Metal-Catalyzed, … · Recent Advances in Transition-Metal-Catalyzed, ... class of transition-metal ... which is focused on the development of new transition-metal-catalyzed

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M. C. Henry et al. Short ReviewSyn thesis

SYNTHESIS0 0 3 9 - 7 8 8 1 1 4 3 7 - 2 1 0 XGeorg Thieme Verlag Stuttgart · New York2017, 49, 4586–4598short reviewen

Recent Advances in Transition-Metal-Catalyzed, Directed Aryl C–H/N–H Cross-Coupling ReactionsMartyn C. Henry Mohamed A. B. Mostafa Andrew Sutherland* 0000-0001-7907-5766

WestCHEM, School of Chemistry, The Joseph Black Building, University of Glasgow, Glasgow, G12 8QQ, United [email protected]

DG

DG = directing group

Het NH

H+

R1

R2 DG Het

NR1R2

Mn, Fe, Co, Ni, CuRu, Rh, Pd, Ag

Ir or Au

N

O

N

NO2N

ONNH

O

HN

N

F3C

Received: 06.07.2017Accepted: 14.07.2017Published online: 28.08.2017DOI: 10.1055/s-0036-1588536; Art ID: ss-2017-z0443-sr

License terms:

Abstract Amination and amidation of aryl compounds using a transi-tion-metal-catalyzed cross-coupling reaction typically involves prefunc-tionalization or preoxidation of either partner. In recent years, a newclass of transition-metal-catalyzed cross-dehydrogenative coupling re-action has been developed for the direct formation of aryl C–N bonds.This short review highlights the substantial progress made for ortho-C–Nbond formation via transition-metal-catalyzed chelation-directed arylC–H activation and gives an overview of the challenges that remain fordirected meta- and para-selective reactions.1 Introduction2 Intramolecular C–N Cross-Dehydrogenative Coupling2.1 Nitrogen Functionality as Both Coupling Partner and Directing

Group2.2 Chelating-Group-Directed Intramolecular C–N Bond Formation3 Intermolecular C–N Cross-Dehydrogenative Coupling3.1 ortho-C–N Bond Formation3.1.1 Copper-Catalyzed Reactions3.1.2 Other Transition-Metal-Catalyzed Reactions3.2 meta- and para-C–N Bond Formation4 C–N Cross-Dehydrogenative Coupling of Acidic C–H Bonds5 Conclusions

Key words amination, amines, amides, cross-coupling, dehydrogena-tion, transition metals

1 Introduction

The ubiquitous presence of aryl C–N bonds in naturalproducts, pharmaceuticals, agrochemicals and organic ma-terials has resulted in a wide range of methods for the effi-cient and selective synthesis of this motif.1 Traditionally,aryl C–N bonds were formed using a combination of elec-trophilic aromatic nitration, followed by reduction of theresulting nitrobenzene.2 However, with the development of

catalytic bond-forming reactions (Scheme 1), the use ofcopper- or palladium-catalyzed amination of aryl (pseudo)-halides using Ullmann–Goldberg, Chan–Evans–Lam or

Martyn C. Henry (left) was born in 1993 in Livingston, Scotland. He graduated with a 1st class M.Sc. degree in chemistry from Heriot-Watt University in 2016, while carrying out a placement year with Dr. Chris-topher Levy at Kansas State University and a final-year project under the supervision of Dr. Stephen Mansell on novel nickel complexes for olefin polymerization catalysis. Since 2016, he has been part of the Suther-land group at the University of Glasgow working toward his Ph.D., which is focused on the development of new transition-metal-catalyzed cross-coupling reactions.Mohamed A. B. Mostafa (middle) graduated with a B.Sc. degree (with high distinction) in chemistry from the University of Omar Al-Mukhtar, Libya, in 2003. In 2012, he was awarded an M.Sc. degree from the Uni-versity of Wollongong, Australia, while carrying out a research project under the supervision of Professor Paul Keller on the stereoselective synthesis of chiral biaryl natural products. Since 2014, he has been part of the Sutherland group at the University of Glasgow, working toward his Ph.D. on the development of metal-catalyzed, one-pot multi-reac-tion processes for the preparation of polycyclic scaffolds.Andrew Sutherland (right) was born in 1972 in Wick, Scotland. After graduating with a 1st class B.Sc. Honours degree in chemistry at the University of Edinburgh in 1994, he undertook a Ph.D. at the University of Bristol under the supervision of Professor Christine Willis. This was followed by postdoctoral studies with Professor John Vederas at the Uni-versity of Alberta and Professor Timothy Gallagher at the University of Bristol. In January 2003, he was appointed to a lectureship in the School of Chemistry at the University of Glasgow and currently holds the posi-tion of Reader. His research group’s interests are on the discovery of new transition-metal-catalyzed methodology and the development of radionuclide- and fluorescent-based molecular imaging agents.

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Buchwald–Hartwig protocols have superseded the harshconditions of the nitration/reduction approach.3,4 More re-cently, the surge in methods for transition-metal-catalyzedC(sp2)-H activation has resulted in novel approaches for arylC–N bond formation.5 Initially, these novel transformationsinvolved coupling of nucleophilic-like metalated intermedi-ates with electrophilic or activated aminating reagents.However, methods have now been established that allowdirect cross-dehydrogenative coupling (CDC) between arylC–H bonds and non-activated amines and amides (Scheme1).5 This short review highlights the various methods thathave been reported for both intramolecular and intermo-lecular aryl C–N bond formation using the cross-dehydro-genative coupling approach. In particular, highly regioselec-tive ortho-amination and amidation through transition-metal-catalyzed chelation-directed activation of aryl C–Hbonds will be described, as well as C–N bond formationfrom more reactive acidic aryl C–H bonds. The various one-pot strategies that have been reported for para-aminationand amidation using activating groups are also discussed.

Scheme 1 Transition-metal-mediated C–N bond-forming processes

2 Intramolecular C–N Cross-Dehydrogena-tive Coupling

2.1 Nitrogen Functionality as Both Coupling Part-ner and Directing Group

The first example of an oxidative cross-dehydrogenativecoupling process was reported by Buchwald and co-workersfor the preparation of unsymmetrical N-acylcarbazoles(Scheme 2).6 The palladium-catalyzed process used oxygenand copper acetate as oxidants and allowed the efficientpreparation of a range of N-acylcarbazoles bearing variousfunctional groups and substituent patterns. Importantly,the N-acetamide coupling partner also acted as the direct-ing group, which was necessary to overcome the energybarrier associated with the final C(sp2)–N reductive elimi-nation step.

Scheme 2 Synthesis of N-acylcarbazoles using a palladium-catalyzed CDC process

Other palladium(II)-catalyzed syntheses of carbazolesusing intramolecular C–N bond-forming reactions havebeen reported. Work by the Gaunt7 and Youn8 researchgroups showed that the use of oxidants such as PhI(OAc)2 orOxone permit C–N bond formation at ambient temperature.These studies also extended the substrate scope, demon-strating that N-alkyl and N-sulfonamide groups could beused as coupling partners. A similar cross-dehydrogenativecoupling process of 2-aminobiphenyls using iridium(III) ca-talysis has allowed the synthesis of N–H carbazoles.9 Againthe nitrogen functionality is used as both the coupling part-ner and the directing group (Scheme 3). Following aminecomplexation of the iridium(III) catalyst and C–H activa-tion, reductive elimination then gave the carbazole product.The resulting iridium(I) species was oxidized back to iridi-um(III) using a copper co-catalyst in the presence of air.

Scheme 3 Iridium(III)-catalyzed synthesis of N–H carbazoles

FG

X

FG

NR1R2

FG

H

FG

[TM] C–N bondformation

+ H N

R1

R2

oxidativeaddition

C–Hactivation

NH

OPd(OAc)2 (5 mol%)

Cu(OAc)2, O2

3 Å MStoluene, 120 °C

12–24 h

93% 94% 81% 96%

N

O

NAc NAc NAcNAc

F

MeO

CO2Me

R1 R1

R2R2

Cp*IrX2

NH

76%

NH

77%

F

NH

90%

NH2

H2N IrX2

Cp*

2 HXHN Ir

Cp*NH

Cp*Ir

2 CuX2

2 CuX

air, 2 HX

H2O

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This general approach for intramolecular C–N bond for-mation has been utilized for the preparation of a range ofN-heterocycle-fused arenes. For example, copper-catalyzedprotocols have been developed for the preparation of ben-zimidazoles10 and pyrido[1,2-a]benzimidazoles,11 whilepalladium(II) catalysis has been used for the synthesis of 2-oxoindoles and 2-quinolinones.12,13 For the palladium(II)-catalyzed synthesis of 2-oxoindoles (and 3,4-dihydroquino-linones), Yu and co-workers used N-methoxamides as theintramolecular N-coupling partner and for activation of theC–H bond (Scheme 4).12 Although a CuCl2/AgOAc systemwas used for re-oxidation of the palladium catalyst, result-ing in relatively high temperature reactions, the processwas found to have a broad scope, yielding the products inhigh yields. Furthermore, the N-methoxy groups were read-ily cleaved using either H2/Pd/C or SmI2, allowing efficientaccess to the parent lactam.

Scheme 4 Palladium(II)-catalyzed synthesis of 2-oxoindoles

A lower-temperature intramolecular, palladium(II)-catalyzed C–N amidation process involving biaryl hydra-zones was reported for the synthesis of 3-arylindazoles.14

For unsymmetrical benzophenone tosylhydrazones, the re-gioselectivity of C–H activation and subsequent cyclizationwas controlled by electronic factors. For example, aryl ringsbearing electron-donating substituents accelerated C–H ac-tivation resulting in cyclization on that particular ring (e.g.,Scheme 5). Electron-withdrawing substituents instead de-activated C–H activation, and cyclization was favored forthe more electron-rich unsubstituted benzene ring.

Scheme 5 Palladium(II)-catalyzed synthesis of 3-arylindazoles

2.2 Chelating-Group-Directed Intramolecular C–N Bond Formation

Intramolecular C–N bond-forming reactions that usethe nitrogen nucleophile to direct C–H activation do allowthe efficient generation of cyclic products, however, due to

strong coordination to the transition-metal catalyst, forcingconditions are generally required. In recent years, lowercatalyst loadings and milder conditions have been achievedby using a chelating group to assist and direct transition-metal-catalyzed C–H activation. Several excellent methodsfor chelating-group-directed, copper-catalyzed intramolec-ular C–N coupling have been described,15,16 but the majorityof procedures have utilized palladium catalysis.

In 2012, the groups of Chen and Daugulis reported thedirected palladium-catalyzed activation of C(sp2)–H bondsfor intramolecular C–N bond formation.17,18 Using PhI(OAc)2as the oxidant and picolinamide as the directing group, arange of N-heterocycles was formed using low catalystloadings and mild conditions (Scheme 6). The mild natureof these transformations was exemplified by the successfulcyclization of substrates bearing labile functionality, suchas aryl C–I bonds and the application of this process for thesynthesis of complex natural products.19

Scheme 6 Picolinamide-assisted intramolecular C–N bond formation

More recently, Chen and co-workers extended this pro-cess for the challenging synthesis of benzazetidines.20 Cru-cial for the success of this process was the use of a novel ox-idizing agent, phenyliodonium dimethyl malonate[PhI(DMM)]. Computational studies with this reagent sug-gested a Pd(II)/Pd(III) intermediate with a bridging dimeth-yl malonate ligand as the resting state before reductiveelimination. It was proposed that the rigidity of this inter-mediate would suppress the competing C–O bond-formingreaction and allow the kinetically controlled reductiveelimination, leading to the strained ring products. This the-ory was confirmed by selective benzazetidine formation, incontrast to the outcome with the standard oxidizing agent,PhI(OAc)2 (Scheme 7). Interestingly, the cyclization ofortho-arylbenzylamine substrates with PhI(DMM) favoredformation of benzazetidines over six-membered C–Ncyclization products.

As well as picolinamide, a range of N-directing groupshas been used for palladium-catalyzed intramolecular C–Nbond-forming reactions.21–25 Directing groups such as2-pyridinesulfonyl,21 1-benzyl-1,2,3-triazole-4-carboxylicacid,22 and oxalyl amides24 are all effective chelating groups

Pd(OAc)2 (10 mol%)CuCl2, AgOAc

DCE, 100 °CN2, 6–10 h

N

OMe

O

R1R2

N

O

OMe

R1 R2

N

OMe

O

94%

N

OMe

O

96%

N

OMe

O

78%

H

H

Pd(OAc)2 (10 mol%)Cu(OAc)2, AgOCOCF3

DMSO, 80 °C12 h, 75% N

Ts

NN

Ph

NHTs

PhHOHO

H

Pd(OAc)2 (2 mol%)PhI(OAc)2

toluene, 60 °C24 h, 81%

HN

CO2Me

O

N

H N

CO2Me

ON

PdII

NCO2Me

ON

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for N-heterocycle synthesis (Scheme 8). In particular, theN,O-bidentate oxalyl amide auxiliary, used in combinationwith hexafluoroisopropanol (HFIP) allowed the highly effi-cient synthesis of indoline products under mild conditions(60 °C).24

Scheme 8 Indoline synthesis using various directing groups

The scope of the oxalyl amide directing group was fur-ther demonstrated with application for the efficient syn-thesis of six-membered N-heterocycles.24 Using low palla-dium catalyst loading and PhI(OAc)2 as the oxidant, β-aryl-ethylamines and 2-phenoxyethylamines were cyclizedunder mild conditions to give the corresponding tetrahy-droquinolines and benzomorpholines in good yields(Scheme 9). The process was tolerant of a wide range of arylsubstituents including Br and I.

Modification of the oxalyl amide directing group byZhao and co-workers for a simpler glycine dimethylamidemotif, led to a system which could be used in palladium-catalyzed cascade processes (Scheme 10).25 One-pot se-quential β-C(sp3)–H arylation and intramolecular aryl C–Hamidation processes were developed for the synthesis of adiverse set of 2-quinolinones. Glycine dimethylamide pro-tected 2-phthalimidopropionic acids were excellent sub-strates for the palladium-catalyzed β-C(sp3)–H arylationwith a range of aryl iodides. On completion of this step ofthe one-pot process, addition of PhI(OAc)2 facilitated thesecond palladium-catalyzed reaction, a cross-dehydrogena-tive coupling to give the quinolinone ring in high overall

yields. Removal of the dimethylamide directing group wasdemonstrated under acidic conditions for the synthesis ofthe parent 2-tetrahydroquinolinones.

Scheme 10 2-Quinolinone synthesis using a palladium-catalyzed cas-cade process

3 Intermolecular C–N Cross-Dehydrogena-tive Coupling

3.1 ortho-C–N Bond Formation

The more challenging intermolecular C–H aminationand amidation reactions, which generally require highercatalyst loading and reaction temperatures, have also re-quired activation via a directing group. As a consequence,these processes only provide the ortho-aminated products.

Scheme 7 PhI(DMM)-mediated benzazetidine synthesis

Pd(OAc)2(10 mol%)

chlorobenzene100 °C, 12 h

NHPA

H

CF3 CF3

NPA

NHPA

CF3

O

O R

+

with PhI(OAc)2:

with PhI(DMM):

19% 67% (R = Me)

72% 9% (R = i-Pr)ON

PA =

Pd(OAc)2(1–10 mol%)

HNH

N

DGDG

FF

PhI(OAc)2

N

S

F

N

F

N

F

O

O

N

toluene, 130 °C4 h, 67%

ON

NN

BnDCE, 100 °C

24 h, 60%

OO

N(i-Pr)2

HFIP, 60 °C12 h, 94%

Scheme 9 Oxalyl amide directed synthesis of tetrahydroquinolines and benzomorpholines

Pd(OAc)2 (3 mol%)PhI(OAc)2

HFIP, 60–80 °C24 h

N

X

R

N(i-Pr)2

OO

HN

X

R

N(i-Pr)2

OO

N

N(i-Pr)2

OO

82%

N

N(i-Pr)2

OO

61%

MeO N

N(i-Pr)2

OO

78%

O2N

N

N(i-Pr)2

OO

75%

IN

O

N(i-Pr)2

OO

74%

OMe

N

O

N(i-Pr)2

OO

79%

Cl

X = CH2, O or CHPh

N

N(i-Pr)2

OO

52%

Ph

Pd(OAc)2 (5 mol%)AgOAc, HFIP

N

NPhth

O

O

NMe2

Cl

HN

NPhth

O

O

NMe2

Cl

HN

NPhth

O

O

NMe2

ClH

I +80 °C, air, 12 h

PhI(OAc)2, PivOHHFIP, 100 °C, Ar, 18 h

81% overtwo steps

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While a wide range of transition-metal complexes havebeen used to effect these transformations, the majority ofprocesses developed have utilized copper catalysis.

3.1.1 Copper-Catalyzed Reactions

In 2006, the groups of Yu and Chatani reported the firsttransition-metal-mediated intermolecular C–H amidationreactions.26,27 Both processes used pyridine as the directinggroup and the difficulty of this transformation was demon-strated with the requirement of stoichiometric amounts ofcopper acetate and forcing conditions (Scheme 11).

Scheme 11 Copper-mediated intermolecular C–H amidation of 2-phenylpyridine

Since these seminal reports, other groups have soughtto develop catalytic methods for the cross-dehydrogenativecoupling of 2-arylpyridines with non-activated amines andamides. While catalytic methods have been reported, thesestill require strong oxidants such as tert-butyl peroxide,28 orthe use of high temperatures.29–31 For example, John andNicholas showed that a range of nitrogen nucleophiles in-cluding sulfonamides, amides and anilines could be coupledwith 2-phenylpyridine with only 20 mol% of copper acetate(Scheme 12).29 However, the reactions required high tem-peratures (160 °C) and long reaction times (48 h). The mod-est yield obtained for the coupling reaction with 4-nitroani-line represents the difficulty of transition-metal-catalyzedintermolecular C–N bond formation with strongly coordi-nating amines.

Scheme 12 Copper-catalyzed intermolecular C–H amination and ami-dation of 2-phenylpyridine

The mechanism of copper(II)-catalyzed aryl C–N bondformation is not well understood but catalytic cycles havebeen proposed (Scheme 13).29 The first step involves com-

plexation between 2-phenylpyridine and the copper cata-lyst, with C–H amidation occurring either via a single-electron process or by electrophilic aromatic substitution. Itis generally believed that following ligand exchange of theacetate with the nitrogen nucleophile, a one-electron oxi-dation occurs to give a copper(III) intermediate, which canthen undergo C–N reductive elimination to give the prod-uct. Aerobic oxidation of the resulting copper(I) acetatethen regenerates the copper(II) acetate and completes thecatalytic cycle.

Scheme 13 Proposed catalytic cycle for the copper-mediated intermo-lecular C–H amidation of 2-phenylpyridine

Other directing groups, such as the 8-aminoquinolineauxiliary, have been investigated for copper-mediatedcross-dehydrogenative couplings, which have improvedboth the catalyst loading and the reaction conditions.32–34

The most general procedure was reported by Daugulis andco-workers, who showed that a wide range of secondaryamines could be coupled with 8-aminoquinoline-derivedbenzamides with catalyst loadings as low as 10 mol% and atreaction temperatures of typically 110 °C (Scheme 14).32

Milder conditions have been achieved by further modi-fication of both the aryl substituent and directing group.35–38

In particular, the use of anilines in combination with the pi-colinamide directing group led to room-temperature C–Haminations.36 In this study, Chen and co-workers reasonedthat N-picolinamide-substituted anilines would readily un-dergo ortho-amination due to the formation of a six-membered O-ligated metallacycle (Scheme 15). In the eventthat a single electron transfer pathway was responsible forthe transformation, a similar compact conformation couldalso be rationalized. Copper-catalyzed amination at roomtemperature using PhI(OAc)2 as the oxidant and magnesiumchloride as an additive was complete after four hours andallowed the high-yielding amination of a wide range ofamino-substituted aromatic compounds. In general, a

Cu(OAc)2 (1 equiv)TsNH2, air, MeCN

130 °C (sealed tube)24 h, 74%

N

H

N

NHTs

Cu(OAc)2 (20 mol%)O2, DMSO/anisole

160 °C, 48 h

N

H

N

NHRNHR

H+

N

NHTs

65%

N

HN

66%

CF3

O

N

HN

38%

NO2

Cu(OAc)2

H2NTs

AcOH

N

H

N

CuII

O

O

AcOH

N

CuII

NH

SO O

TolAcOH

O2H+

N

CuIII

HN

OAc

SO2Tol

N

NHTsCu(I)OAc

O2

AcOH H+

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variety of functional groups attached to the aniline compo-nent were tolerated (e.g., OBn, NHBoc, halogens), while six-membered secondary amines gave the highest yields. Bycomparison, pyrrolidine was found to be unreactive (~5%yield) under these conditions.

Scheme 15 Room-temperature copper-catalyzed intermolecular C–H amination of anilines using the picolinamide directing group

3.1.2 Other Transition-Metal-Catalyzed Reactions

Around the same time as the first reported copper-catalyzed intermolecular C–N amidations, Yu and Chedemonstrated that this could also be done using palladiumcatalysis (Scheme 16).39 Unlike analogous copper-catalyzedamidations of 2-phenylpyridines that required high catalystloading and forcing conditions, this procedure was shownto proceed with relatively low catalyst loading and moder-ate temperatures (80 °C). In the same report, aryl-substitutedO-methyl oximes were also ortho-amidated in excellentyields under similarly mild conditions.

Since this key breakthrough, other groups have investi-gated the use of various N-heterocycles or amine-based di-recting groups in combination with rhodium,40–42 rutheni-um43,44 and palladium catalysts45 for ortho-directed amida-tion. For example, Su and co-workers reported theapplication of rhodium(III) catalysis under low catalystloadings and mild conditions for ortho-directed amidationusing sulfonamides (Scheme 17).40 As well as pyridines, arange of N-heterocycles, such as isoquinolines, pyrazolesand oxazolines could be used as the directing group.

More recently, Harrity and co-workers have expandedthe scope of oxazoline-directed, rhodium-catalyzed ortho-C–H amidation and demonstrated that the products of thisprocess could be used for the synthesis of 4-aminoquinazo-lines and quinazolinones (Scheme 18).41,42 The rhodi-um(III)-catalyzed cross-dehydrogenative couplings withtrifluoroacetamide were found to occur efficiently at tem-peratures as low as 25 °C. The resulting aryl trifluoroamideswere hydrolyzed at room temperature and the subsequentcrude anilines were then reacted with formamidine acetateeffecting cyclization to give 4-aminoquinazolines. Thesewere easily hydrolyzed to the corresponding quinazoli-nones under acidic conditions as shown with the prepara-tion of the quinazolinone core of the drug candidate

Scheme 14 Copper-catalyzed intermolecular C–H amination of benz-amides using the 8-aminoquinoline directing group

Cu(OAc)2 (10–25 mol%)Ag2CO3 (12–25 mol%)

HNR2R3, NMO, NMP110 °C, 11–25 h

O NH

N

H

R1

O NH

N

NR2R3

R1

O NH

Q

OMe

N

O

87%

O NH

Q

CO2Me

N

O

68%

O NH

Q

OMe

NBn

82%

O NH

Q

OMe

N

69%

CO2Et O NH

Q

OMe

N

82%

O

O

Q =N

Cu(OAc)2·H2O (10 mol%)MgCl2 (20 mol%)

HNR2R3, PhI(OAc)2dioxane, r.t., 4 h

NH

R1

O

N

NH

NR2R3

R1

O

N

N

R1

O

N

Cu

Cu

via:

PA =

O

NNH

PA

N

O

91%

NHPA

N

O

88%OMe

NHPA

N

O

90%I

N

NHPA

N

NBoc

89%

NHPA

N

91%

CO2Et

OMeMeO

Scheme 16 Palladium-catalyzed intermolecular C–H amidation of 2-phenylpyridines

Pd(OAc)2 (5 mol%)K2S2O8, MgO

DCE, 80 °C, 7–12 h

N

HNHCOR2

H+

N

77%

N

HN

92%

CF3

O

N

97%

R1

N

NHCOR2

R1

HN

HN CF3

O

OMe

O

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halofuginone (Scheme 18). This approach was further ex-emplified with the efficient synthesis of erlotinib, a 4-ami-noquinazoline-containing tyrosine kinase inhibitor.

Scheme 18 Rhodium-catalyzed intermolecular aryl C–N bond forma-tion for the synthesis of 4-aminoquinazolines and quinazolinones

As well as N-heterocycle-directed C–N bond-formingreactions, various procedures have been developed usingcarbonyl-based auxiliaries.46 In particular, benzamide de-rivatives have been widely used as substrates in combina-tion with cobalt,47,48 nickel49 and iridium catalysts for C–Hamination coupling reactions.50,51 The development of effi-cient metal-catalyzed cross-dehydrogenative coupling reac-tions with strongly coordinating amines has been challeng-ing. Niu and Song reported the use of cobalt(II) catalysis forthe amination of 2-benzamidopyridine 1-oxides with alkyl-amines (Scheme 19).47 Silver nitrate was found to be themost effective oxidant and in combination with the biden-tate N,O-directing group, resulted in efficient cross-coupling with various six-membered cyclic secondaryamines. However, in a similar fashion to some of the

copper-catalyzed C–N bond-forming processes, the use ofpyrrolidine or non-cyclic secondary amines led to ineffi-cient reactions.

Chang and co-workers have used sterically encumberedN-adamantylbenzamides for the iridium(III)-catalyzed,room-temperature cross-dehydrogenative coupling withanilines (Scheme 20).50 It was proposed that the use of thebulky N-alkyl group would facilitate formation of the irida-cyclic intermediate. On identification of the optimal

Scheme 17 Rhodium-catalyzed intermolecular aryl C–N bond forma-tion with sulfonamides

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

PhI(OAc)2, CH2Cl260–100 °C, 24 h

N

H

HN

H+

N

76%

R1

NHTs

N

NHSO2R2

R1

SO2R2

N

74%

NHTs

OMe

N

90%

NHTs

CF3

N

70%

NHTs

NN

NHTs

62%

O N

NHTs

84%

N

HN

S

O O

66%

N

HN

SBn

O O

65%

H2NCOCF3

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

PhI(OAc)2, CH2Cl240 °C, 16 h, 76%

Cl

Br

N

O

Cl

Br

N

O

NHCOCF3

Cl

Br N

N

HNOH

Cl

Br N

NH

O

NaOH, EtOHr.t., 6 h

then: Δ, 14 hformamidineacetate, 83%

6 M HClΔ, 4 h, 94%

Scheme 19 Cobalt-catalyzed intermolecular C–H amination of 2-benz-amidopyridine 1-oxides

Co(OAc)2·4H2O (10 mol%)AgNO3, NaOAc, KNO3

HNR2R3, MeCN85 °C, 12 h

O NH

N+

O-

H

R1

O NH

N+

O-

NR2R3

R1

O NH

PyO

N

O

82%

O NH

PyO

N

O

65%

O NH

PyO

NBn

14%

O NH

PyO

N

73%

CN O NH

PyO

N

81%

O

O

N+

O-PyO =

Scheme 20 Iridium-catalyzed intermolecular C–H amination of N-ada-mantylbenzamides with electron-deficient anilines

IrCp*(OAc)2 (10 mol%)AgNTf2, Cu(OAc)2

DCE, 25 °C, 24 h

O NH

H

R1

O NH

Ad

HN

85%

Ad =

O NH

HN

R1 R2H2N

R2

CF3

O NH

Ad

HN

R3 = NMe2 (61%),OPh (33%), Me (50%)

O NH

Ad

HN

75%

CF3

O NH

Ad

HN

76%

CF3

t-Bu

SO2R3

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oxidant (AgNTf2) and acetate additive [Cu(OAc)2], the iridi-um(III)-catalyzed aminations with a wide range of electron-deficient anilines were found to proceed in high yield. Elec-tron-rich or N-alkyl variants were found to be unreactivefor this process. Further work by the Chang group led to thedevelopment of an analogous iridium(III)-catalyzed amina-tion of benzamides with primary alkylamines.51 Secondaryamines were completely inactive as coupling partners inthis process due to the involvement of a nitrene insertionpathway.

Many of the limitations associated with general metal-catalyzed cross-dehydrogenative couplings with stronglycoordinating amines such as electron-rich anilines, as wellas secondary amines have recently been overcome using aligand-promoted rhodium(III)-catalyzed activation pro-cess.52 Coordination of 2-methylquinoline with the metalcenter of Cp*RhCl was found to accelerate C–H bond cleav-age during amination of N-pentafluorophenylbenzamides(Scheme 21). The scope of the C–N coupling was found tobe general for a wide range of amines. In particular, second-ary amines, electron-rich and N-alkyl anilines were allfound to couple efficiently with a broad range of substitut-ed benzamides.

Scheme 21 Ligand-promoted, rhodium(III)-catalyzed intermolecular C–H amination of N-pentafluorophenylbenzamides

Based on the substrate scope, control experiments, ki-netic isotope measurements and the characterization of arhodacycle intermediate by X-ray crystallography, a mecha-nism was proposed for this coupling (Scheme 22).52 Thepathway begins with complexation of 2-methylquinolinewith the rhodium(III) species followed by C–H activation ofthe N-pentafluorophenylbenzamide to give the rhodacycleintermediate. Ligand exchange with the amine and reduc-tive elimination generates the ortho-aminated product. Theresulting rhodium(I) species is then oxidized back to Rh(III)by silver carbonate to complete the catalyst cycle. Thisstudy represents the current state of the art for transition-metal-catalyzed aryl C–H/C–N coupling reactions withamines.

Scheme 22 Proposed catalytic cycle for rhodium(III)-catalyzed inter-molecular C–H amination

3.2 meta- and para-C–N Bond Formation

Activation of meta-C–H bonds and subsequent cross-dehydrogenative coupling with non-activated amines andamides is not known. The only directed meta-C–H amina-tion process, reported by Yu and co-workers, uses activatedamines.53 This approach combines directed ortho-pallada-tion with Catellani’s norbornene-mediated relay process,54

for an overall meta-functionalized product. This transfor-mation has been used for the efficient meta-amination ofanilines, phenols and benzylamines with a range of O-ben-zoyl hydroxylamines (Scheme 23).

The use of cross-dehydrogenative couplings for para-amination and amidation is similarly sparse. Again, reac-tions using activated nitrogen coupling partners are known.For example, Zhang and co-workers reported highly regio-selective, palladium-catalyzed, para-directed amidation ofbulky 2-methoxyphenyl amides using N-fluorobenzenesul-fonamide.55

A few metal-catalyzed C–H/N–H coupling reactions thatgenerate para-aminated products have been reported,however, there are limitations associated with these

[RhCp*Cl2]2 (5 mol%)Ag2CO3, PhCO2Na

HNR2R3, toluene90 °C, 16 h

O NH

H

R1

O NH

C6F5

N

O

81%

F

F

F

F

F

O NH

NR2R3

R1

F

F

F

F

F

N(20 mol%)

O NH

C6F5

N

O

74%

MeO

O NH

C6F5

N

O

60%NO2

O NH

C6F5

N

70%

O NH

C6F5

N

62%

O

OO NH

C6F5

NEt2

52%

O NH

C6F5

NPh

Et

80%t-Bu

O NH

C6F5

HN

63%

O NH

C6F5

HN

65%

NO2

[RhIII]Ag2CO3

NHC6F5

O

HAg0

[RhIII]N

O

C6F5

L

NH

O

[RhIII]

NR1R2

C6F5

[RhI]

NHC6F5

O

NR1R2

HNR1R2

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transformations. Hartwig and co-workers have described apalladium-catalyzed intermolecular cross-dehydrogenativecoupling of arenes with phthalimide.56 The regiochemistryof the reaction was controlled by steric effects, but pro-duced mixtures of meta- and para-N-aryl phthalimides. Theregiochemistry of aryl C–H/N–H couplings with phthalim-ides has been improved using gold(I) catalysis.57 The reac-tion is proposed to proceed by oxidation of the Au(I) cata-lyst to Au(III), which then undergoes electrophilic aromaticmetalation with the arene. Following transmetalation witha phthalimide-derived iodane, reductive elimination formsthe new C–N bond. This approach has allowed the prepara-tion of a wide range of para-substituted-phthalimide-pro-tected anilines (Scheme 24). However, eight equivalents ofthe oxidant PhI(OAc)2 are required for maximum yields.

Scheme 24 Gold-catalyzed para-amidation

Another drawback of both of these procedures is the re-quirement of the reactions to be run in neat arene.56,57 Thislimits the scope of these transformations to relatively sim-ple aryl substrates. Metal-catalyzed para-directed amida-tions have been reported that use the aryl coupling partneras the limiting reagent. Wang and co-workers reported theone-pot, two-step synthesis of succinimide-protected ani-lines using gold(III) catalysis.58 This process involves gold-

catalyzed C–H activation to initially form the para-bromi-nated intermediate (Scheme 25). The addition of copperthen promotes an Ullmann–Goldberg-type coupling withthe residual succinimide, yielding protected anilines in highyields as single regioisomers.

Scheme 25 Gold(III)-catalyzed synthesis of p-succinimide-protected anilines

This approach of converting aryl C–H bonds into C–Nbonds via an initial oxidation process before then imple-menting a copper-catalyzed coupling with a nitrogen nu-cleophile for the preparation of para-aminated aryl com-pounds has also been described by the Suna and Sutherlandresearch groups.59,60 Suna and co-workers showed that elec-tron-rich arenes can be activated by hypervalent iodoniumreagents to form unsymmetrical diaryl-λ3-iodanes, whichwere then smoothly coupled with amines using copper ca-talysis.59 Sutherland and co-workers have used sequentialiron and copper catalysis for the one-pot, two-step C–H/N–Hcoupling of anisoles, phenols, anilines and acetanilide-typearyl compounds with nitrogen nucleophiles (Scheme 26).60

The para-C–H bond was initially brominated by iron(III) tri-flimide activation of NBS, via an electrophilic aromatic sub-stitution reaction. Copper-catalyzed coupling with nitrogennucleophiles such as N-heterocycles, amides and sulfon-amides then completed the one-pot process. While bothapproaches are efficient and highly regioselective for thegeneration of para-substituted products, this type of one-pot cross-dehydrogenative coupling is restricted to elec-tron-rich arenes.

4 C–N Cross-Dehydrogenative Coupling of Acidic C–H Bonds

The other key approach to regioselective aryl C–N bondformation is the activation and coupling of acidic C–Hbonds with amines or amides. This was first reported in

Scheme 23 Directed meta-amination using activated amines

Pd(OAc)2 (10 mol%)AgOAc, K3PO4DCE, 100 °C

24 h, 74%

N

Boc

N

OMeH

(10 mol%)

N

Boc

N

OMeN

O

N

OBz

+

O

CO2Me

N

F3C NH

OH

O

Cy3PAuCl (10 mol%)PhI(OAc)2

100 °C, 24 h

H

R

NPhth

R

(solvent)

N

O

O

H+

MeO

NPhth

78%o/m/p = 1:0:6

Cl

NPhth

27%o/m/p = 0:0:1

I

NPhth

68%o/m/p = 0:1:2

AuCl3(0.1–1 mol%)

NBS, DCE25–60 °C, 1–11 h

H

R

N

R

N

O

O

[Au]

R Br

AuIII

HN

O

O

Br

R +Cu, DMF

150 °C (MW)0.5 hO

O

N

O

O

MeO

78%

N

O

O

57%

ClN

O

O

65%

OO

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2009 when the groups of Mori and Schreiber described thecopper-catalyzed cross-dehydrogenative coupling of the C-2position of azoles with both amines and amides.61,62 Underaerobic conditions, the coupling was found to be efficientand general for a wide range of heteroaromatic compounds(Scheme 27).61

Scheme 27 Copper-catalyzed amination of azoles

The proposed mechanism for this transformation in-volves the deprotonation of the acidic C-2 hydrogen atom,followed by formation of an organocopper intermediate(Scheme 28).61,62 Deprotonation of the nitrogen nucleo-phile, ligand exchange and reductive elimination then gen-erates the coupled product. The catalytic cycle is completedby regeneration of the active copper species by oxidationwith oxygen.

Since these initial reports, a number of subsequent pa-pers have described variants of this transformation, includ-ing alternative nitrogen coupling partners and an intramo-

lecular version.63–67 For example, Hirano, Miura and co-workers reported a one-pot copper-catalyzed C–H/N–Hcoupling and annulation reaction of azoles with ortho-alky-nylanilines for the synthesis of N-azolylindoles (Scheme29).65 The domino sequence again used oxygen as the soleoxidant and was applied to the preparation of pharmaceuti-cally relevant heterocyclic scaffolds.

Scheme 29 Copper-catalyzed domino reaction for the synthesis of N-azolylindoles

While copper is most commonly used in the C–N cross-dehydrogenative coupling reaction of azoles, other transi-tion metals such as cobalt, manganese and nickel have alsobeen used for this transformation.68–70 For example, cobaltwas particularly effective for the amination of benzoxazoleswith secondary amines at low catalyst loading and undermild conditions (Scheme 30).68 In the same study, primaryamines were coupled with benzoxazoles at slightly elevatedtemperatures (70 °C) using manganese(II) acetate as thecatalyst.68

As well as using azole-based acidic C–H bonds, a num-ber of other acidic aryl C–H bonds have been utilized in C–Ncross-dehydrogenative couplings. Schreiber,62 Miura63 andSu71 have shown that polyfluoroarenes can undergo cop-per-catalyzed C–N bond coupling reactions with a widerange of nitrogen nucleophiles. For example, Su and co-workers

Scheme 26 One-pot C–H/N–H coupling using sequential iron and copper catalysis

H

R1

NR2R3

R1

N

O

O

H

R1 Br

FeIII

Br

R1

FeCl3 (2.5 mol%)[BMIM]NTf2(7.5 mol%)

HNR2R3

CuI (10 mol%)

NBS, toluene40 °C, 4 h

DMEDA (20 mol%)H2O, 130 °C, 18 h

MeO

N

78%

MeO

NN

76%

MeO

HN

88%

SPh

O O

HO

N N

64%

F

N N

84%

OH2N

HN

71%

CF3

Ph

O

Cu(OAc)2 (20 mol%)PPh3 (40 mol%)

O2, xylene140 °C, 20 h

+ N

R2

R1

HZ

NH

Z

NN

R1

R2

Z = S, O, NMe

N

SN

Ph

73%

O

NN

Ph

71%

O

NN

72%

S

NN

Ph

81%

NMe

NN

Ph

51%

O

NN

Et

Et

47%

Scheme 28 Proposed mechanism for the copper-catalyzed amination of azoles

LnCuX2

S

NNR1R2

S

NH

+ base

XH·base

S

NCu

X

Ln

HNR1R2

HXS

NCu

NR1R2

Ln

O2

Cu(OAc)2 (20 mol%)1,10-phenanthroline

(20 mol%)

O2, K2CO3, tolueneΔ, 10 h

+

NH2

Ph

NH

Ph

N

N

O

CF3

N

N

O

CF3

H

NPh

N

N

O

CF3

89%

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used a combination of oxygen and TEMPO as the oxidant forthe copper acetate catalyzed coupling of polyfluoroben-zenes with electron-deficient anilines (Scheme 31).71 Usinga range of polyfluorobenzenes, they found that the couplingreaction was highly dependent on the acidity of the C–Hbond.

Scheme 31 Copper-catalyzed amination of polyfluorobenzenes

Copper-catalyzed amination and amidation of acidic C–Hbonds has been extended to the selective C-2 substitutionof quinoline N-oxides.72–74 Under relatively mild conditions,reactions have been developed for coupling with lactams,oxazolidin-2-one (Scheme 32), secondary amines72,73 andsulfoximines.74 Following the coupling reaction, the quino-line N-oxides can be readily reduced to the parent quinolineusing phosphorus trichloride. Interestingly, pyridine N-ox-ides are not substrates for this transformation.

Zhang and co-workers have shown that activation ofquinolines to the corresponding N-oxides for C–N bondcross-dehydrogenative coupling reactions can be circum-

vented using Selectfluor as the oxidant.75 Following optimi-zation studies, which identified potassium carbonate as themost efficient base and nitromethane as the optimal sol-vent, an examination of the scope demonstrated that awide range of substituted quinolines could be directly cou-pled with N-heterocycles (Scheme 33). Unlike N-oxide sub-strates, simple pyridines and other N-heterocycles couldundergo C-2 coupling using this procedure. Based on con-trol and kinetic isotope experiments, a C-2-fluorination fol-lowed by an SNAr mechanism was ruled out. Instead, theauthors proposed a reductive elimination pathway via aCu(III) species.

5 Conclusions

As described in this short review, a number of differentstrategies and procedures have now been developed that al-low transition-metal-catalyzed directed C–N cross-dehy-drogenative coupling of aryl C–H bonds with a range ofnon-activated amines and amides. The majority of earlytransformations used copper or palladium catalysis in com-bination with oxidizing agents such as PhI(OAc)2. Recently,the development of more advanced methods, with the tun-ing of catalytic activity and using other transition-metalcomplexes such as those of cobalt, iridium or rhodium haveresulted in milder conditions and transformations withbroader scope. Many methods are now known for efficientaryl C–N bond formation through chelation-directed ortho-C–H activation or via activated acidic C–H bonds. However,while a few approaches for para-C–N bond formation havebeen reported using one-pot, transition-metal-catalyzedcross-dehydrogenative-like couplings directed by activatinggroups, there is still a need for additional methods that per-mit the highly regioselective para-amination of electron-deficient arenes. Furthermore, we still await the first tran-sition-metal-catalyzed meta-directed C–H/N–H couplingreaction.

Scheme 30 Cobalt-catalyzed amination of benzoxazoles

Co(OAc)2 (2 mol%)T-HYDRO, AcOH

HNR2R3, MeCN25–40 °C, 12 hO

NH

O

NN

R2

R3

O

NN

90%

O

NN

81%

O

NN

82%

O

NN

Et

Et

49%

Ph Cl

Ph

R1 R1

Cu(OAc)2 (20 mol%)TEMPO, t-BuOK

O2, DMF40 °C, 24 h

H

F

F

F

F

R1

HN

F

F

F

F

R1

R2

HN

F

F

F

F

MeO

83%

NO2

HN

F

F

F

F

MeO

77%

NO2

HN

F

F

F

F

65%

NO2

HN

F

F

F

F

Ph

64%

NO2

OMe

H2N

R2

Scheme 32 Copper-catalyzed coupling of quinoline N-oxide with oxaz-olidin-2-one

Cu(OAc)2 (10 mol%)Ag2CO3, benzene

80 °C, 24 h, 93%

N

O–

H + N

O–

N+

+

OO

N N

OO

PCl3, toluene50 °C, 0.5 h 92%

N

OO

H

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Funding Information

Martyn C. Henry is supported by an EPSRC DTA studentship(EP/M508056/1).EPSRC (EP/M508056/1)

Acknowledgment

Financial support from EPSRC (studentship to M.C.H.), the Ministry ofHigher Education and Scientific Research, Omar Al-Mukhtar Universi-ty, Libya (studentship to M.A.B.M.) and the University of Glasgow isgratefully acknowledged.

References

(1) (a) Hili, R.; Yudin, A. K. Nat. Chem. Biol. 2006, 2, 284. (b) AminoGroup Chemistry: From Synthesis to the Life Sciences; Ricci, A.,Ed.; Wiley-VCH: Weinheim, 2007.

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7043.

Scheme 33 Direct copper-catalyzed selective C-2 amination of heterocycles

Cu(OAc)2 (10 mol%)Selectfluor, K2CO3

MeNO2120 °C, 12 h

N H

NR1R2

H+

N NR1R2

N N

NN

89%

N

N N

NN

73%

N N

NN

66%MeO2C

N N

N

74%

Cl

N N

NN

67%

N

NN

81%

N

NN

83%

HN O

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Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 4586–4598


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