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Florencio Zaragoza D̈orwald
Side Reactions in Organic
Synthesis II

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Florencio Zaragoza D̈orwald

Side Reactions in Organic Synthesis II
Aromatic Substitutions

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information contained in these books,
including this book, to be free of errors.
Readers are advised to keep in mind that
statements, data, illustrations, procedural
details or other items may inadvertently be
inaccurate.


The Author
̈
Dr. Florencio Zaragoza Dorwald
Lonza AG
Rottenstrasse 6
3930 Visp
Switzerland

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V

Contents
Preface IX
Glossary and Abbreviations XI

Journal Abbreviation List XIII
1
1.1
1.1.1
1.1.2
1.2
1.2.1
1.2.2
1.2.3
1.2.4
1.3
1.3.1
1.3.2
1.3.3
1.3.4
1.3.5
1.3.6
1.3.7
1.3.8

Electrophilic Alkylation of Arenes 1
General Aspects 1
Catalysis by Transition-Metal Complexes 2
Typical Side Reactions 5
Problematic Arenes 7
Electron-Deficient Arenes 7
Phenols 9
Anilines 13
Azoles 19
Problematic Electrophiles 19

Methylations 19
Olefins 20
Allylic Electrophiles 21
Epoxides 23
α-Haloketones and Related Electrophiles 25
Nitroalkanes 26
Ketones 27
Alcohols 32
References 34

2
2.1
2.2
2.3
2.4

Electrophilic Olefination of Arenes 45
General Aspects 45
Olefinations with Leaving-Group-Substituted Olefins
Olefinations with Unsubstituted Olefins 46
Olefinations with Alkynes 52
References 57

3
3.1
3.2

Electrophilic Arylation of Arenes 61
General Aspects 61
Arylations with Aryl Halides 61


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45


VI

Contents

3.2.1
3.2.2
3.2.3
3.2.4
3.3
3.4
3.5

Via Cationic Intermediates 61
Via Radicals 63
Via Transition-Metal Chelates 65
By Transition-Metal Catalysis 67
Arylations with Diazonium Salts 69
Arylations with Other Functionalized Arenes
Arylations with Unsubstituted Arenes 78
References 79

4
4.1
4.2

4.2.1
4.2.2
4.2.3
4.2.4
4.2.5
4.3
4.3.1
4.3.2
4.3.3
4.3.4
4.3.5

Electrophilic Acylation of Arenes 85
General Aspects 85
Problematic Arenes 88
Dealkylation/Isomerization of Arenes 88
Styrenes 88
Anilines, Phenols, and Thiophenols 90
Electron-Deficient Arenes 92
Azoles 93
Problematic Electrophiles 95
Problematic Acyl Halides 95
Carboxylic Esters and Lactones 98
Carbonic Acid Derivatives 101
Formic Acid Derivatives 106
Mixed Carboxylic Anhydrides and Other Polyelectrophiles 110
References 112

5
5.1

5.2
5.3
5.4
5.5
5.6
5.6.1
5.6.2
5.7
5.7.1
5.7.2
5.7.3
5.8
5.8.1
5.8.2
5.8.3
5.8.4

Electrophilic Halogenation of Arenes 121
General Aspects 121
Typical Side Reactions 121
Regioselectivity 125
Catalysis 128
Fluorinations 129
Electron-Deficient Arenes 132
Pyridines 133
Benzoic Acid Derivatives 134
Electron-Rich Arenes 137
Phenols and Arylethers 138
Anilines 138
Azoles 144

Sensitive Functional Groups 147
Alkenes 148
Amines 148
Ethers 149
Thiols and Thioethers 149

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73


Contents

5.8.5
5.8.6

Aldehydes, Ketones, and Other C–H Acidic Compounds 151
Amides 152
References 152

6
6.1
6.1.1
6.1.2
6.1.3
6.1.4
6.1.5
6.1.5.1
6.1.5.2
6.1.5.3

6.2
6.2.1
6.3
6.3.1

Electrophilic Formation of Aromatic C–N Bonds
Nitration of Arenes 161
Mechanisms 161
Regioselectivity 164
Catalysis 167
Electron-Deficient Arenes 167
Electron-Rich Arenes 169
Anilines 171
Indoles 173
Phenols 173
Electrophilic Aromatic Aminations 175
Typical Side Reactions 177
Electrophilic Aromatic Amidations 177
Typical Side Reactions 177
References 184

7
7.1
7.1.1
7.1.2
7.2
7.2.1
7.2.2
7.3
7.3.1

7.3.2

Electrophilic Formation of Aromatic C–S Bonds 191
Sulfonylation 191
General Aspects 191
Typical Side Reactions 193
Sulfinylation 195
General Aspects 195
Typical Side Reactions 195
Sulfenylation 199
General Aspects 199
Typical Side Reactions 200
References 201

8
8.1
8.1.1
8.1.2
8.1.3
8.1.4
8.2
8.2.1
8.2.2
8.2.3
8.2.4
8.2.5
8.2.6

Aromatic Nucleophilic Substitutions 205
General Aspects 205

Mechanisms 205
Regioselectivity 205
Acid-/Base-Catalysis 211
Transition-Metal Catalysis 211
Problematic Electrophiles 216
Incompatible Functional Groups 216
Non-Activated Arenes 217
Nitroarenes 219
Diazonium Salts 226
Phenols 229
Arylethers and Arylthioethers 229

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161

VII


VIII

Contents

8.2.7
8.2.8
8.3
8.3.1
8.3.2
8.3.3
8.3.4

8.3.5
8.3.6
8.3.7
8.3.8
8.3.9
8.3.10

Other Phenol-Derived Electrophiles 231
Arynes 232
Problematic Nucleophiles 233
Enolates 233
Organomagnesium and Related Organometallic Compounds 235
Ammonia 241
Primary and Secondary Amines 242
Tertiary Amines 244
Azides 247
Hydroxide 248
Alcohols 250
Thiols 252
Halides 253
References 260

Epilogue

Economics, Politics, and the Quality of Chemical Research 277
Prosperity 277
Slavery and Freedom 279
The Quality of Chemical Research 281
References 283
Index


285

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IX

Preface
Our job as chemists is mainly about problem solving. Therefore, the most interesting aspect of chemistry is not what works, but what does not work, and why.
Difficult or ‘‘impossible’’ reactions, poor selectivities, low yields, expensive catalysts, or excessive waste generation are nothing to shrink away from, but great
opportunities for relevant chemical research.
Ten years ago, I wrote ‘‘Side Reactions in Organic Synthesis,’’ with the aim
of highlighting the competing processes and limitations of some of the most
common reactions used in organic synthesis. Although some readers found the
title confusing (and, yes, there are no side reactions), I also received a lot of positive
feedback. For this reason I decided to write a second sequel.
In the first book of this series the focus had been alkylations, that is, substitutions at sp3 carbon. An equally important area of organic synthesis is aromatic
substitution, the main topic of the present book. Again, I try to show the main
problems and limitations of popular synthetic transformations, hoping to help
chemists to identify byproducts and plan better syntheses. As in my earlier titles,
my main aim is to encourage bold experimentation, to inspire, challenge, and
motivate.
Because time is a precious resource, I have kept the texts short (chemists can
assimilate graphical information faster than text), and included in all equations
a short code for the source. This code has the format year-journal-first page. For
instance, 08joc4956 means J. Org. Chem. 2008, 4956. The abbreviations used for
the journals can be found in the ‘‘Journal Abbreviation List.’’ All patents can be
downloaded at worldwide.espacenet.com.
I would like to thank Paul Hanselmann and Marcel Suhartono for proofreading

and for the many instructive chemical discussions. I am also thankful for the
help and support provided by the editors at Wiley-VCH, in particular by Anne
Brennfăuhrer.
Visp, Switzerland
May 2014

Florencio Zaragoza Dăorwald

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XI

Glossary and Abbreviations
Ac
acac
Ada
AIBN
aq
Ar
BINAP
Boc
bpy
CAN
cat
cod
coe

concd
cot
Cp
Cp*
Cy
cym
DABCO
dba
DBU
DCE
DDQ
DMA
DME
DMF
DMI
DMPU
DMSO
DPEphos
dppb
dppf
dppp

Acetyl, MeCO
Acetylacetone, pentane-2,4-dione
Adamantyl
2,2′ -Azobis(2-methylpropionitrile)
Aqueous
Undefined aryl group
2,2′ -Bis(diphenylphosphino)-1,1′ -binaphthyl
tert-Butyloxycarbonyl

2,2′ -Bipyridine
Ceric ammonium nitrate, (NH4 )2 Ce(NO3 )6
Catalyst or catalytic amount
1,5-Cyclooctadiene
cis-Cyclooctene
Concentrated
1,3,5-Cyclooctatriene
Cyclopentadienyl
Pentamethylcyclopentadienyl
Cyclohexyl
Cymene, 4-isopropyltoluene
1,4-Diazabicyclo[2.2.2]octane
1,5-Diphenyl-1,4-pentadien-3-one
1,8-Diazabicyclo[5.4.0]undec-5-ene
1,2-Dichloroethane
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
N,N-Dimethylacetamide
1,2-Dimethoxyethane
N,N-Dimethylformamide
1,3-Dimethylimidazolidin-2-one
1,3-Dimethyltetrahydropyrimidin-2-one
Dimethyl sulfoxide
Bis[(2-diphenylphosphino)phenyl] ether
1,4-Bis(diphenylphosphino)butane
1,1′ -Bis(diphenylphosphino)ferrocene
1,3-Bis(diphenylphosphino)propane

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XII

Glossary and Abbreviations

dtbpy
eq
Fmoc
GDP
Hal
HFIP
HMPA
L
LTMP
Mes
Ms
MS
MW
NBS
NCS
NIS
NMP
Nu
PEGDM
phen
pin
Piv
PPA
pyr
R
SET

SN Ar
SN 1
SN 2
S-phos
st.mat.
TBAB
TBAF
TEMPO
TFA
TFAA
TfOH
THF
TMEDA
TMP
Tol
Ts
wt
xantphos

2,6-Di(tert-butyl)pyridine
Equivalent
9-Fluorenylmethyloxycarbonyl
Gross domestic product
Undefined halogen
1,1,1,3,3,3-Hexafluoro-2-propanol
Hexamethylphosphoric triamide, (Me2 N)3 PO
Undefined ligand
Li-TMP
Mesityl, 2,4,6-trimethylphenyl
Methanesulfonyl

Molecular sieves
Microwave
N-Bromosuccinimide
N-Chlorosuccinimide
N-Iodosuccinimide
N-Methylpyrrolidin-2-one
Undefined nucleophile
Poly(ethylene glycol) dimethacrylate
Phenanthroline
pinacolyl
Pivaloyl, 2,2-dimethylpropanoyl
Polyphosphoric acid
Pyridine
Undefined alkyl group
Single electron transfer
Aromatic nucleophilic substitution
Monomolecular nucleophilic substitution
Bimolecular nucleophilic substitution
2-(2′ ,6′ -Dimethoxybiphenyl)dicyclohexylphosphine
Starting material
Tetrabutylammonium bromide
Tetrabutylammonium fluoride
(2,2,6,6-Tetramethyl-piperidin-1-yl)oxyl
Trifluoroacetic acid
Trifluoroacetic acid anhydride
Triflic acid, F3 CSO3 H
Tetrahydrofuran
N,N,N ′ ,N ′ -Tetramethyl-1,2-ethylenediamine
2,2,6,6-Tetramethylpiperidine
Tolyl

Tosyl, 4-toluenesulfonyl
Weight
4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

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XIII

Journal Abbreviation List
PLEASE NOTE:
Included in all equations is a short code for the source. This code has the format
year-journal-first-page, for instance:
08joc4956 means J. Org. Chem. 2008, 4956.
a
ac
acr
ajc
ang
asc
bcsj
bj
catc
catl
cb
cc
cej
cjc
cl
coc

cpb
cr
ejoc
hca
iec
ja
jbcs
jcat
jcs(p1)
jmc
joc

Arkivoc
Acta Crystallographica
Accounts of Chemical Research
Australian Journal of Chemistry
Angewandte Chemie, International Edition in English
Advanced Synthesis & Catalysis
Bulletin of the Chemical Society of Japan
Biochemical Journal
Catalysis Communications
Catalysis Letters
Chemistry & Biology
Chemical Communications
Chemistry – A European Journal
Canadian Journal of Chemistry
Chemistry Letters
Current Organic Chemistry
Chemical & Pharmaceutical Bulletin
Chemical Reviews

European Journal of Organic Chemistry
Helvetica Chimica Acta
Industrial & Engineering Chemistry
Journal of the American Chemical Society
Journal of the Brazilian Chemical Society
Journal of Catalysis
Journal of the Chemical Society, Perkin Transactions 1
Journal of Medicinal Chemistry
Journal of Organic Chemistry

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XIV

Journal Abbreviation List

jpc
obmc
ol
oprd
oscv(1)
p
pcs
rjoc
sc
sl
syn
tet
thl

zok

Journal făur Praktische Chemie
Organic & Biomolecular Chemistry
Organic Letters
Organic Process Research & Development
Organic Syntheses, Collective Volume 1
Pharmazie
Proceedings of the Chemical Society
Russian Journal of Organic Chemistry
Synthetic Communications
Synlett
Synthesis
Tetrahedron
Tetrahedron Letters
Zhurnal Organicheskoi Khimii

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1

1
Electrophilic Alkylation of Arenes
1.1
General Aspects

For large-scale industrial organic syntheses, electrophilic alkylations of arenes
are essential (Scheme 1.1). Their attractive features include the absence of waste
when alcohols or olefins are used as electrophiles, the large scope of available

starting materials, and the high structural complexity attainable in a single step.
The main issues are low regioselectivity, overalkylations, and isomerization of
the intermediate carbocations. Important products resulting from this chemistry
include isopropylbenzene (cumene – starting material for phenol and acetone),
ethylbenzene (starting material for styrene), methylphenols, geminal diarylalkanes
(monomers for polymer production), trityl chloride (from CCl4 and benzene [1]),
dichlorodiphenyltrichloroethane (DDT) (from chloral and chlorobenzene), and
triarylmethane dyes.
To obtain acceptable yields, careful optimization of most reaction parameters is
often required. Because the reactivity of an arene increases upon alkylation (around
2–3-fold for each new alkyl group), multiple alkylation can be a problem. This
may be prevented by keeping the conversion low, or by modifying the reaction
temperature, the concentration, the rate of stirring, or the solvent used (e.g.,
to provide for a homogeneous reaction mixture). In dedicated plants, processes
are usually run at low conversion if the starting materials can be recycled. In
the laboratory or when working with complex, high-boiling compounds, though,
electrophilic alkylations of arenes can be more difficult to perform.
Typical electrophilic alkylating reagents for arenes include aliphatic alcohols,
alkenes, halides, carboxylic and sulfonic esters, ethers, aldehydes, ketones, and
imines. Examples of alkylations with carbonates [2], ureas [3], nitroalkanes [4],
azides [5], diazoalkanes [6], aminoalcohols [7], cyclopropanes [8], and thioethers
(Scheme 1.14) have also been reported. Amines can be used as alkylating agents
either via intermediate conversion to N-alkylpyridinium salts [9] or by transient
dehydrogenation to imines [10]. Some examples of Friedel–Crafts alkylation are
given in Scheme 1.2.
In most instances, the electrophilic alkylation of arenes proceeds via
carbocations, and complete racemization of chiral secondary halides or alcohols is
usually observed. Only if neighboring groups are present and capable of forming
Side Reactions in Organic Synthesis II: Aromatic Substitutions, First Edition. Florencio Zaragoza Dăorwald.
c 2014 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2014 by Wiley-VCH Verlag GmbH & Co. KGaA.


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2

1 Electrophilic Alkylation of Arenes

OH
R

R
O
R

X
R

R

R

R

R′
N
R

R


R

R
R

R

R
H
−H

Scheme 1.1

Mechanism of the Friedel–Crafts alkylation.

cyclic configurationally stable cations, arylations can occur with retention of
configuration [18].
Stabilized carbocations (e.g., tertiary carbocations) are easy to generate, but they
are less reactive (and more selective) than less stable cations. Thus, the trityl or
tropylium (C7 H7 + ) cations react with anisole but not with benzene. On the other
hand, carbocations destabilized by a further positively charged group in close
proximity will show an increased reactivity [7, 19]. Highly stabilized cations may
even be generated and arylated under almost neutral reaction conditions [20].
1.1.1
Catalysis by Transition-Metal Complexes

Electrophilic alkylations of arenes by olefins or alkyl halides can be catalyzed
by soft electrophilic transition metals, for example, by Pd, Rh, or Ru complexes
(Scheme 1.3). Most of the reported examples proceed via aromatic metallation
through chelate formation. With Ru-based catalysts, selective meta-alkylation can

be achieved when using sterically demanding electrophiles (fifth equation in
Scheme 1.3).
Reactions where carbocation formation is the slowest (rate-determining) step can
be catalyzed by any compound capable of stabilizing the intermediate carbocation
(and thereby promote its formation). This form of catalysis should be most
pronounced in nonpolar solvents, in which free carbocations are only slightly
stabilized by solvation. Some transition-metal complexes, for example, IrCl3 and
H2 [PtCl6 ], catalyze Friedel–Crafts alkylations with benzyl acetates, probably by

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1.1 General Aspects

1.2% AlCl3
45 °C, 1 h

Cl

+

+

08joc4956
4 eq

1 eq

33%


65%

1.06 eq AlCl3
3.06 eq EtBr
0−20 °C, 12 h

(CH2O)n, ZnBr2
HBr (33% in AcOH)
90 °C, 16 h
94%

80−90%

3

Br

Br

10joc6416, 05syn2080
Br
3 eq MeSO3H
MeNO2
OMe
80 °C, 6−12 h

N
H2N

+


OH

S

61%

1 eq

2 eq

CN

OMe
OH

S

1 eq AlCl3
CH2Cl2
20 °C, 0.5 h

+

+

S

1 eq


O

HO
N3

1.05 eq ZnCl2
H2O, 85 °C, 6 h

O
O

+

O

10ja15528

5 eq

OMe

80 : 20

60%

O

AcO

CN

S

S

1.1 eq BF3OEt2
MeCN, 20 °C, 0.5 h
then K2CO3, MeOH

+

Cl

S

08joc2264

OAc

N3

OMe

CN

87%
4 eq

O

S


09ol5154

S
1 eq

OMe

N
H2N

07oprd1059

F
2 eq

1 eq
O

O

O

O
+

F

70%


O

+
F

5%

Scheme 1.2 Examples of Friedel–Crafts alkylations [11–17].

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F

5%

F


1 Electrophilic Alkylation of Arenes

4

5% PdCl2(MeCN)2
3 eq CuCl2, CO, MeOH
25 °C, 3 h
85%
06cej2371

N
H


N
H
5% Pd(OAc)2
2 eq K2CO3
3 eq NaOTf, O2
EtMe2COH
125 °C, 36 h

O
HN
MeO

N

+

I

1 eq

O
HN
MeO

2.5% [RuCl2(p-cymene)]2
30% 1-AdaCO2H
K2CO3, NMP, 100 °C, 20 h

Br


N

84%
11ol4850

3 eq

N
+

CO2Me

N

74%
09ang6045
2.5% [RuCl2(p-cymene)]2
30% 1-AdaCO2H
K2CO3, NMP, 100 °C, 20 h

N
+

N

5%
09ang6045
5% [RuCl2(p-cymene)]2
30% MesCO2H

2 eq K2CO3
dioxane, 100 °C, 20 h

N
+
N

MeO

54%
13ja5877

Br
3 eq

1 eq

5% [RhCl2Cp*]2
20% AgSbF6
2.1 eq Cu(OAc)2
THF, 75 °C, 20 h

N
AcO

+
1 eq

N
N


MeO

N

46%
10ol540

3 eq

OAc
MeO

N
+
O
1.0 eq

N

HN
1.2 eq

Scheme 1.3

RhCp*X

MeO

N


RhCp*X

N

1.1 eq CH2Cl2, 10% CuCl
1.2 eq DBU
MeCN, 85 °C, 12 h
87%
12asc1672

O
N

Transitions-metal-catalyzed arene alkylations [21–26].

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1.1 General Aspects

10% catalyst
80 °C, 20 h

AcO

+

5


Catalyst:
HCl or AcOH or H 2SO4
RhCl3 hydrate (50 °C)
IrCl3 hydrate
PtCl2
H2[PdCl4] hexahydrate
H2[PtCl6] hexahydrate

Excess
05ang238

Yield:
0%
79%
99%
7%
99%
99%

Energy
−X
Ph

Me

+ Cat
−X

Cat
Cat


Cat
Ph

X
Ph

Me

Ph

Me

Me

Ar
Ph

Scheme 1.4 Catalysis of Friedel–Crafts alkylations [28].

transient formation of benzylic metal complexes (Scheme 1.4). Because racemization is also observed in these instances, the intermediate complexes are likely
to undergo fast transmetallation. Ru-based catalysts have been developed that
enable the preparation of enantiomerically enriched alkylbenzenes and alkylated
heteroarenes from racemic alcohols [27] (Scheme 1.18).
1.1.2
Typical Side Reactions

The rearrangement of intermediate carbocations is a common side reaction in
Friedel–Crafts chemistry (Scheme 1.5). Rearrangements can sometimes be avoided
with the aid of transition-metal-based catalysts, because the intermediate complexes

are less reactive than uncomplexed carbocations.
Carbocations can also act as oxidants and abstract hydride from other molecules
[31]. The newly formed carbocations may also alkylate arenes and lead to the
formation of complex product mixtures (Scheme 1.6).
When using noble metal halides as catalysts, or α-haloketones, α-haloesters
(Section 1.3.5), or perhaloalkanes as electrophiles, arenes may undergo
halogenation instead of alkylation (Scheme 1.7). Alkyl halides with the halogen

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Me


6

1 Electrophilic Alkylation of Arenes

BF3
0−20 °C, 2 h

+

F

Br

89%
64joc2317

1 eq


4 eq

Br

5% AuCl3/3 AgOTf
120 °C, DCE, 48 h

+

TfO

+

04ja13596

1 eq

2 eq
Scheme 1.5

40%

50%

Rearrangement of carbocations during Friedel–Crafts alkylations [29, 30].

+

+


10% AlCl3
22 °C, 1 h

Cl

+

H

63joc1624
5 eq

1 eq

1 eq

+

+
10%

60%

11%

Scheme 1.6 Hydride abstraction by carbocations as side reaction during Friedel–Crafts
alkylations [32].

OH

+

CO2Et

EtO2C

82%
01bcsj179

Br

OH

O
CO2Me

Cl
+
Cl

1.0 eq

1.1 eq

+

TfO

+


EtO2C

CO2Et

Br
OH

Cl
Cl
Cl

Cl

OH

neat, 100 °C

DMF, CCl4
20 °C, 24 h
34%
US 2011306621

Cl

0.2 eq AuCl3
0.6 eq AgOTf
DCE
120 °C, 1 h

CO2Me


Cl
+

35% conversion
04ja13596
Scheme 1.7

12%

Halogenation of arenes by alkyl halides and by AuCl3 [30, 33, 34].

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20%


1.2 Problematic Arenes

7

bound to good leaving groups (positions where a carbanion would be stabilized)
are electrophilic halogenating reagents.
If the concentration of alkylating reagent is too low, arenes may undergo
acid-catalyzed oxidative dimerization (Scholl reaction) [35]. This reaction occurs
particularly easily with electron-rich arenes, such as phenols and anilines.

1.2
Problematic Arenes
1.2.1

Electron-Deficient Arenes

Yields of alkylations of electron-deficient arenes by carbocations are usually low.
This is mainly because the reaction is too slow, and the carbocation undergoes rearrangement and polymerization before attacking the arene. If no alternative reaction
pathways are available for the carbocation, though, high-yielding Friedel–Crafts
alkylations of electron-deficient arenes can be achieved (Scheme 1.8).

O
OH

+
1 eq

H2SO4
90 °C, 1.2 h
25% conversion
of benzophenone

2 eq

91joc7160
O

O

O

+

+

0.6%

O

+

O
O

HO2C
1.00 eq

0.85 eq

NO2
+
2.4 eq

Cl

O
1.0 eq

Cl

2.4%

3.2%

19%

CO2H

dialkylated
products

+

O

H2SO4 (27% SO3)
135 °C, 6 h
65%
EP 1118614
H2SO4
50 °C, 1 week

O
HO2C

Cl

35%
US 2758137

Scheme 1.8 Friedel–Crafts alkylation of electron-deficient arenes [36–38].

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NO2



8

1 Electrophilic Alkylation of Arenes

Electron-deficient arenes can be alkylated by olefins or alkyl halides via intermediate arene metallation. Chelate formation is usually required and crucial for
the regioselectivity of transition-metal-catalyzed reactions (Scheme 1.9). The Ruand Rh-catalyzed ortho-alkylation of acetophenones and acetophenone-imines by
alkenes can even proceed at room temperature [39]. With sterically demanding alkyl
halides, Ru complexes can mediate meta-alkylations [24]. When conducted in the
presence of oxidants, these reactions can yield styrenes instead of alkylbenzenes
[40–42] (see also Section 2.3).

ethylene (30 bar), PhMe
10% RuH2(H2)2(PCy3)2
23 °C, 24 h

O

01asc192

Cl

O

O
+

Cl

Cl

89%

OMe
O

N
Cl
+

2.5% [RuCl2(p-cymene)]2
30% 1-AdaCO2H
2 eq K2CO3
PhMe, 100 °C, 20 h

7%

O

N

OMe

61%
09ol4966

O
1.0 eq

O


1.5 eq

N

2% RhCl(PPh3)3
PhMe, 150 °C, 2 h
then hydrolysis

Ph
+

O

95%
02cej485

N
N

+
BF4

1.0 eq

S
CF3

1.5 eq

20% Pd(OAc)2

1 eq Cu(OAc)2
10 eq TFA
DCE, 110 °C, 48 h
53%

N
N
CF3

10ja3648

Scheme 1.9 Ru-, Rh-, and Pd-catalyzed, chelate-mediated alkylation of electron-deficient
arenes [43–46].

The metals used as catalysts for this ortho-alkylation of acetophenones insert
not only into C–H bonds but also at similar rates into C–O and C–N bonds
(Scheme 1.10). The selectivity can sometimes be improved by the precise choice of
the catalyst [47]. Another potential side reaction of the alkylations described above

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1.2 Problematic Arenes

MeO

2.5% [RuCl2(p-cym)]2
15% PPh3
30% NaHCO3
PhMe, 140 °C, 60 h


O
+

Si(OEt)3

1 eq

O

+
1.0 eq

O
B
Ph

4% RuH2(CO)(PPh3)3
PhMe, 111 °C, 20 h

1.0 eq

+

Ph

O
B
Ph
2.0 eq


+

O

07ja6098
Ph

O

25%

87%

O
SiMe3

as above
99%

O

SiMe3

2.0 eq

Scheme 1.10 Ru-catalyzed ortho-alkylation and -arylation of acetophenones [50, 51]. Further
examples: [52, 53].

is aromatic hydroxylation, which can readily occur if oxidants are present in the

reaction mixture [48, 49].
Some heteroarenes, such as pyridine N-oxides, thiazoles, or imidazoles, are
strongly C–H acidic, and can be metallated catalytically even without chelate
formation. In the examples in Scheme 1.11, the intermediates are, in fact, metal
carbene complexes.
Under forcing conditions, fluoro- or nitrobenzenes can also be metallated without chelate formation, and trapped in situ with a number of electrophiles, including
aldehydes and ketones (Scheme 1.12). Owing to the competing Cannizzaro reaction
and the potential cleavage of ketones by strong nucleophiles (e.g., Haller–Bauer
reaction), these reactions may require a large excess of electrophile and
careful optimization.
Electron-deficient arenes and heteroarenes, such as pyridinium salts, can react
with carbon-centered, electron-rich radicals. These can be generated from alkanes,
alkyl halides, carboxylic acids, and some diacylperoxides [58] (Scheme 1.13), or
by oxidation of boranes [59]. The regioselectivity of such alkylations is, however,
often poor.
1.2.2
Phenols

Phenols are inherently problematic nucleophiles in Friedel–Crafts type chemistry
because the free hydroxyl group can deactivate Lewis acids and because phenols

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O

Si(OEt)3
20%

1.2 eq


+

(EtO)3Si

O

09ja7887

2 eq

NH O

N

MeO

9