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- Herausgeber: Wiley-VCH
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
- Veröffentlichungsjahr: 2014
This new textbook is the successor to the volume "Side Reactions in Organic Synthesis - A Guide to Successful Synthesis Design" (2004), written by the same author. Whereas the predecessor mainly covered the limitations of aliphatic substitution reactions, this new volume focuses on the most important aromatic substitution reactions, both electrophilic and nucleophilic, such as amination reactions, halogenation reactions, Friedel-Crafts acylations, or transition metal-catalyzed arylation reactions. Each chapter not only describes the scope of a specific reaction type, but also reveals what cannot be achieved with this reaction, i.e. what type of side reactions are to be expected with certain starting materials or electrophiles/nucleophiles. With its unique approach, this is a must-have book for graduate students in organic chemistry and synthetic chemists both in academia and industry!
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Seitenzahl: 326
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Table of Contents
Cover
Related Titles
Title Page
Copyright
Preface
Glossary and Abbreviations
Journal Abbreviation List
Chapter 1: Electrophilic Alkylation of Arenes
1.1 General Aspects
1.2 Problematic Arenes
1.3 Problematic Electrophiles
References
Chapter 2: Electrophilic Olefination of Arenes
2.1 General Aspects
2.2 Olefinations with Leaving-Group-Substituted Olefins
2.3 Olefinations with Unsubstituted Olefins
2.4 Olefinations with Alkynes
References
Chapter 3: Electrophilic Arylation of Arenes
3.1 General Aspects
3.2 Arylations with Aryl Halides
3.3 Arylations with Diazonium Salts
3.4 Arylations with Other Functionalized Arenes
3.5 Arylations with Unsubstituted Arenes
References
Chapter 4: Electrophilic Acylation of Arenes
4.1 General Aspects
4.2 Problematic Arenes
4.3 Problematic Electrophiles
References
Chapter 5: Electrophilic Halogenation of Arenes
5.1 General Aspects
5.2 Typical Side Reactions
5.3 Regioselectivity
5.4 Catalysis
5.5 Fluorinations
5.6 Electron-Deficient Arenes
5.7 Electron-Rich Arenes
5.8 Sensitive Functional Groups
References
Chapter 6: Electrophilic Formation of Aromatic C–N Bonds
6.1 Nitration of Arenes
6.2 Electrophilic Aromatic Aminations
6.3 Electrophilic Aromatic Amidations
References
Chapter 7: Electrophilic Formation of Aromatic C–S Bonds
7.1 Sulfonylation
7.2 Sulfinylation
7.3 Sulfenylation
References
Chapter 8: Aromatic Nucleophilic Substitutions
8.1 General Aspects
8.2 Problematic Electrophiles
8.3 Problematic Nucleophiles
References
Epilogue Economics, Politics, and the Quality of Chemical Research
Prosperity
Slavery and Freedom
The Quality of Chemical Research
References
Index
End User License Agreement
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Guide
Table of Contents
List of Illustrations
Scheme 1.1
Scheme 1.2
Scheme 1.3
Scheme 1.4
Scheme 1.5
Scheme 1.6
Scheme 1.7
Scheme 1.8
Scheme 1.9
Scheme 1.10
Scheme 1.11
Scheme 1.12
Scheme 1.13
Scheme 1.14
Scheme 1.15
Scheme 1.16
Scheme 1.17
Scheme 1.18
Scheme 1.19
Scheme 1.20
Scheme 1.21
Scheme 1.22
Scheme 1.23
Scheme 1.24
Scheme 1.25
Scheme 1.26
Scheme 1.27
Scheme 1.28
Scheme 1.29
Scheme 1.30
Scheme 1.31
Scheme 1.32
Scheme 1.33
Scheme 1.34
Scheme 1.35
Scheme 1.36
Scheme 1.37
Scheme 1.38
Scheme 1.39
Scheme 1.40
Scheme 1.41
Scheme 1.42
Scheme 2.1
Scheme 2.2
Scheme 2.3
Scheme 2.4
Scheme 2.5
Scheme 2.6
Scheme 2.7
Scheme 2.8
Scheme 2.9
Scheme 2.10
Scheme 2.11
Scheme 2.12
Scheme 2.13
Scheme 2.14
Scheme 2.15
Scheme 3.1
Scheme 3.2
Scheme 3.3
Scheme 3.4
Scheme 3.5
Scheme 3.6
Scheme 3.7
Scheme 3.8
Scheme 3.9
Scheme 3.10
Scheme 3.11
Scheme 3.12
Scheme 3.13
Scheme 3.14
Scheme 3.15
Scheme 3.16
Scheme 3.17
Scheme 4.1
Scheme 4.2
Scheme 4.3
Scheme 4.4
Scheme 4.5
Scheme 4.6
Scheme 4.7
Scheme 4.8
Scheme 4.9
Scheme 4.10
Scheme 4.11
Scheme 4.12
Scheme 4.13
Scheme 4.14
Scheme 4.15
Scheme 4.16
Scheme 4.17
Scheme 4.18
Scheme 4.19
Scheme 4.20
Scheme 4.21
Scheme 4.22
Scheme 4.23
Scheme 4.24
Scheme 4.25
Scheme 4.26
Scheme 4.27
Scheme 4.28
Scheme 4.29
Scheme 4.30
Scheme 4.31
Scheme 4.32
Scheme 4.33
Scheme 4.34
Scheme 4.35
Scheme 5.1
Scheme 5.2
Scheme 5.3
Scheme 5.4
Scheme 5.5
Scheme 5.6
Scheme 5.7
Scheme 5.8
Scheme 5.9
Scheme 5.10
Scheme 5.11
Scheme 5.12
Scheme 5.13
Scheme 5.14
Scheme 5.15
Scheme 5.16
Scheme 5.17
Scheme 5.18
Scheme 5.19
Scheme 5.20
Scheme 5.21
Scheme 5.22
Scheme 5.23
Scheme 5.24
Scheme 5.25
Scheme 5.26
Scheme 5.27
Scheme 5.28
Scheme 5.29
Scheme 5.30
Scheme 5.31
Scheme 5.32
Scheme 5.33
Scheme 5.34
Scheme 5.35
Scheme 5.36
Scheme 5.37
Scheme 5.38
Scheme 5.39
Scheme 5.40
Scheme 5.41
Scheme 6.1
Scheme 6.2
Scheme 6.3
Scheme 6.4
Scheme 6.5
Scheme 6.6
Scheme 6.7
Scheme 6.8
Scheme 6.9
Scheme 6.10
Scheme 6.11
Scheme 6.12
Scheme 6.13
Scheme 6.14
Scheme 6.15
Scheme 6.16
Scheme 6.17
Scheme 6.18
Scheme 6.19
Scheme 6.20
Scheme 6.21
Scheme 6.22
Scheme 6.23
Scheme 6.24
Scheme 6.25
Scheme 6.26
Scheme 6.27
Scheme 6.28
Scheme 7.1
Scheme 7.2
Scheme 7.3
Scheme 7.4
Scheme 7.5
Scheme 7.6
Scheme 7.7
Scheme 7.8
Scheme 7.9
Scheme 7.10
Scheme 7.11
Scheme 7.12
Scheme 8.1
Scheme 8.2
Scheme 8.3
Scheme 8.4
Scheme 8.5
Scheme 8.6
Scheme 8.7
Scheme 8.8
Scheme 8.9
Scheme 8.10
Scheme 8.11
Scheme 8.12
Scheme 8.13
Scheme 8.14
Scheme 8.15
Scheme 8.16
Scheme 8.17
Scheme 8.18
Scheme 8.19
Scheme 8.20
Scheme 8.21
Scheme 8.22
Scheme 8.23
Scheme 8.25
Scheme 8.24
Scheme 8.26
Scheme 8.27
Scheme 8.28
Scheme 8.29
Scheme 8.30
Scheme 8.31
Scheme 8.32
Scheme 8.33
Scheme 8.34
Scheme 8.35
Scheme 8.36
Scheme 8.37
Scheme 8.38
Scheme 8.39
Scheme 8.40
Scheme 8.41
Scheme 8.42
Scheme 8.43
Scheme 8.44
Scheme 8.45
Scheme 8.46
Scheme 8.47
Scheme 8.48
Scheme 8.49
Scheme 8.50
Scheme 8.51
Scheme 8.52
Scheme 8.53
Scheme 8.54
Scheme 8.55
Scheme 8.56
Scheme 8.57
Scheme 8.58
Scheme 8.59
Scheme 8.60
Scheme 8.61
Scheme 8.62
Scheme 8.63
Scheme 8.64
Scheme 8.65
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Side Reactions in Organic Synthesis
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Florencio Zaragoza Dörwald
Side Reactions in Organic Synthesis II
Aromatic Substitutions
The Author
Dr. Florencio Zaragoza Dörwald
Lonza AG
Rottenstrasse 6
3930 Visp
Switzerland
Extra material for lecturers can be found under: http://www.wiley-vch.de/publish/en/books/ISBN978-3-527-33721-7
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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 Brennführer.
Visp, Switzerland
Florencio Zaragoza Dörwald
May 2014
Glossary and Abbreviations
Ac
Acetyl, MeCO
acac
Acetylacetone, pentane-2,4-dione
Ada
Adamantyl
AIBN
2,2′-Azobis(2-methylpropionitrile)
aq
Aqueous
Ar
Undefined aryl group
BINAP
2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl
Boc
tert
-Butyloxycarbonyl
bpy
2,2′-Bipyridine
CAN
Ceric ammonium nitrate, (NH
4
)
2
Ce(NO
3
)
6
cat
Catalyst or catalytic amount
cod
1,5-Cyclooctadiene
coe
cis
-Cyclooctene
concd
Concentrated
cot
1,3,5-Cyclooctatriene
Cp
Cyclopentadienyl
Cp*
Pentamethylcyclopentadienyl
Cy
Cyclohexyl
cym
Cymene, 4-isopropyltoluene
DABCO
1,4-Diazabicyclo[2.2.2]octane
dba
1,5-Diphenyl-1,4-pentadien-3-one
DBU
1,8-Diazabicyclo[5.4.0]undec-5-ene
DCE
1,2-Dichloroethane
DDQ
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
DMA
N,N
-Dimethylacetamide
DME
1,2-Dimethoxyethane
DMF
N,N
-Dimethylformamide
DMI
1,3-Dimethylimidazolidin-2-one
DMPU
1,3-Dimethyltetrahydropyrimidin-2-one
DMSO
Dimethyl sulfoxide
DPEphos
Bis[(2-diphenylphosphino)phenyl] ether
dppb
1,4-Bis(diphenylphosphino)butane
dppf
1,1′-Bis(diphenylphosphino)ferrocene
dppp
1,3-Bis(diphenylphosphino)propane
dtbpy
2,6-Di(
tert
-butyl)pyridine
eq
Equivalent
Fmoc
9-Fluorenylmethyloxycarbonyl
GDP
Gross domestic product
Hal
Undefined halogen
HFIP
1,1,1,3,3,3-Hexafluoro-2-propanol
HMPA
Hexamethylphosphoric triamide, (Me
2
N)
3
PO
L
Undefined ligand
LTMP
Li-TMP
Mes
Mesityl, 2,4,6-trimethylphenyl
Ms
Methanesulfonyl
MS
Molecular sieves
MW
Microwave
NBS
N
-Bromosuccinimide
NCS
N
-Chlorosuccinimide
NIS
N
-Iodosuccinimide
NMP
N
-Methylpyrrolidin-2-one
Nu
Undefined nucleophile
PEGDM
Poly(ethylene glycol) dimethacrylate
phen
Phenanthroline
pin
pinacolyl
Piv
Pivaloyl, 2,2-dimethylpropanoyl
PPA
Polyphosphoric acid
pyr
Pyridine
R
Undefined alkyl group
SET
Single electron transfer
S
N
Ar
Aromatic nucleophilic substitution
S
N
1
Monomolecular nucleophilic substitution
S
N
2
Bimolecular nucleophilic substitution
S-phos
2-(2′,6′-Dimethoxybiphenyl)dicyclohexylphosphine
st.mat.
Starting material
TBAB
Tetrabutylammonium bromide
TBAF
Tetrabutylammonium fluoride
TEMPO
(2,2,6,6-Tetramethyl-piperidin-1-yl)oxyl
TFA
Trifluoroacetic acid
TFAA
Trifluoroacetic acid anhydride
TfOH
Triflic acid, F
3
CSO
3
H
THF
Tetrahydrofuran
TMEDA
N,N,N
′,
N
′-Tetramethyl-1,2-ethylenediamine
TMP
2,2,6,6-Tetramethylpiperidine
Tol
Tolyl
Ts
Tosyl, 4-toluenesulfonyl
wt
Weight
xantphos
4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
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
Arkivoc
ac
Acta Crystallographica
acr
Accounts of Chemical Research
ajc
Australian Journal of Chemistry
ang
Angewandte Chemie, International Edition in English
asc
Advanced Synthesis & Catalysis
bcsj
Bulletin of the Chemical Society of Japan
bj
Biochemical Journal
catc
Catalysis Communications
catl
Catalysis Letters
cb
Chemistry & Biology
cc
Chemical Communications
cej
Chemistry – A European Journal
cjc
Canadian Journal of Chemistry
cl
Chemistry Letters
coc
Current Organic Chemistry
cpb
Chemical & Pharmaceutical Bulletin
cr
Chemical Reviews
ejoc
European Journal of Organic Chemistry
hca
Helvetica Chimica Acta
iec
Industrial & Engineering Chemistry
ja
Journal of the American Chemical Society
jbcs
Journal of the Brazilian Chemical Society
jcat
Journal of Catalysis
jcs(p1)
Journal of the Chemical Society, Perkin Transactions 1
jmc
Journal of Medicinal Chemistry
joc
Journal of Organic Chemistry
jpc
Journal für Praktische Chemie
obmc
Organic & Biomolecular Chemistry
ol
Organic Letters
oprd
Organic Process Research & Development
oscv(1)
Organic Syntheses, Collective Volume 1
p
Pharmazie
pcs
Proceedings of the Chemical Society
rjoc
Russian Journal of Organic Chemistry
sc
Synthetic Communications
sl
Synlett
syn
Synthesis
tet
Tetrahedron
thl
Tetrahedron Letters
zok
Zhurnal Organicheskoi Khimii
1Electrophilic 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.
Scheme 1.1Mechanism of the Friedel–Crafts alkylation.
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.
Scheme 1.2Examples of Friedel–Crafts alkylations [11–17].
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 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 (C7H7+) 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).
Scheme 1.3Transitions-metal-catalyzed arene alkylations [21–26].
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 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).
Scheme 1.4Catalysis of Friedel–Crafts alkylations [28].
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.
Scheme 1.5Rearrangement of carbocations during Friedel–Crafts alkylations [29, 30].
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).
Scheme 1.6 Hydride abstraction by carbocations as side reaction during Friedel–Crafts alkylations [32].
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 bound to good leaving groups (positions where a carbanion would be stabilized) are electrophilic halogenating reagents.
Scheme 1.7 Halogenation of arenes by alkyl halides and by AuCl3 [30, 33, 34].
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).
Scheme 1.8 Friedel–Crafts alkylation of electron-deficient arenes [36–38].
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 Ru- and 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).
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 is aromatic hydroxylation, which can readily occur if oxidants are present in the reaction mixture [48, 49].
Scheme 1.10Ru-catalyzed ortho-alkylation and -arylation of acetophenones [50, 51]. Further examples: [52, 53].
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.
Scheme 1.11Metallation and alkylation of C–H acidic heteroarenes [54–56].
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.
Scheme 1.12 Metallation and alkylation of C–H acidic arenes [57].
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.
Scheme 1.13 Alkylation of arenes with radicals [59–64]. Further examples: [65].
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 are tautomers of enones and may themselves act as electrophiles (see below). Moreover, phenols readily dimerize to biaryls in the presence of oxidants.
Under suitable reaction conditions, though, phenols can be alkylated at carbon, without extensive O-alkylation. Stabilized carbocations are soft electrophiles, and react preferentially with soft nucleophiles, such as arenes or olefins. Phenol O-alkylation under acidic conditions is observed only with hard alkylating reagents (diazomethane, dimethyl carbonate, methanol, methyl esters, alkoxyphosphonium salts (Mitsunobu reaction), or acetals). O-Alkylated phenols sometimes rearrange to C-alkylated phenols in the presence of acids [66] (Scheme 1.14).
Scheme 1.14 C-Alkylation of phenols and thiophenols under acidic conditions [67–71].
At high temperatures, phenols and aluminum phenolates are C-alkylated by olefins (Scheme 1.15). This reaction proceeds less readily and has a narrower scope than the corresponding reaction of aluminum anilides (see next section). Although ortho-alkylation occurs first, upon prolonged reaction with an excess of olefin, 2,4,6-trialkylated and higher alkylated phenols result [72, 73]. At high pressure, even Diels–Alder reactions with the olefin may occur [74]. Today, a number of important alkylphenols are prepared by high-temperature alkylations with olefins in the presence of heterogeneous catalysts [73, 75].
Scheme 1.15Alkylation of aluminum phenolates with alkenes [76, 77].
Some bis-electrophiles can alkylate phenols both at oxygen and at carbon. 1,3-Dienes, for instance, react with phenols in the presence of acids [78] or Rh complexes [79] to yield chromanes (Scheme 1.16).
Scheme 1.16 Formation of chromanes from phenols [68, 80].
Phenols are tautomers of cyclohexadienones, and may react as such. In particular, 1- or 2-naphthols, 1,3-dihydroxybenzenes, and 1,3,5-trihydroxybenzenes show strong cyclohexenone character. Phenols and arylethers react with arenes in the presence of aluminum halides or HF/SbF5 to yield 3- or 4-arylcyclohexenones [81–83]. The precise outcome of these reactions is difficult to predict; depending on the amount of acid used and the basicity of the phenol, either conjugate arylation of an enone or arylation of a dication can occur (Scheme 1.17). Moreover, 4,4-disubstituted cyclohexenones, which also may be formed, undergo acid-mediated rearrangement to 3,4-disubstituted cyclohexanones. Phenols substituted with leaving groups (halides, hydroxyl groups) can undergo elimination after the arylation and yield 3- or 4-arylphenols.
Scheme 1.17Acid-mediated arylation of phenols [84, 85].
1.2.3 Anilines
Regardless of being N-protonated by acids, anilines can be alkylated at carbon and at nitrogen under acidic reaction conditions. Suitable alkylating reagents include alcohols, ethers, alkenes, aldehydes, ketones, and alkyl halides.
Despite the electron-withdrawing effect of ammonium groups, Friedel–Crafts alkylations of anilines usually proceed with ortho and para selectivity, and more readily than Friedel–Crafts alkylations of the corresponding benzenes. Thus, although aniline hydrochloride can be para-tritylated in acetic acid (first example in Scheme 1.18), benzene does not react with the trityl cation.
Scheme 1.18Examples of C-alkylations of anilines [27, 86–90].
The precise outcome of the reaction of anilines with alkylating reagents can be difficult to predict. Stoichiometric amounts of strong acids usually favor C-alkylations. At high temperatures or in the presence of acids, N-alkylanilines may be dealkylated and act as alkylating agents themselves [91–93]. Occasionally, mixtures of N- and C-alkylated products are obtained (Scheme 1.19).
Scheme 1.19Examples of C- and N-alkylations of anilines [94–97]. Further examples: [98, 99].
If anilines are treated with aldehydes or ketones in the presence of acids at room temperature, reversible aminal, imine, or enamine formation usually occurs. Upon heating, irreversible alkylation at carbon can take place. Thus, if aniline is treated with formaldehyde at a low temperature, only aminals, benzylamines, or Tröger's base are formed. At higher temperatures, though, diarylmethanes are the main products (Scheme 1.20). Hydride transfer from aldehydes or anilines to intermediate iminium salts causes the formation of N-alkylanilines as byproducts.
Scheme 1.20 Formation of diarylmethanes from anilines and formaldehyde [100–103].
One side reaction often observed during the preparation of diarylmethanes from anilines is the formation of triarylmethane dyes. A suitable oxidant is air, and the oxidation can be catalyzed by vanadates (Scheme 1.21). Even if oxygen is rigorously excluded, small amounts of these dyes will result from oxidation by the intermediate iminium salts.
Scheme 1.21 Formation of triarylmethane dyes from diarylmethanes [104].
Anilines can be selectively ortho-alkylated with olefins under basic reaction conditions. This requires conversion of the aniline into an aluminum anilide by treatment with Al/AlCl3 (Scheme 1.22). This interesting reaction is, however, of little scope, and not well suited to alkylate phenols [76].
Scheme 1.22 Alkylation of anilines with olefins [105–107]. Further examples: [108].
1.2.4 Azoles
Azoles with a free NH group can be alkylated at nitrogen or at carbon. The outcome of such reactions is barely predictable, in particular for substrates containing arenes (e.g., indoles, benzimidazoles, etc.). Azoles may also be alkylated after stoichiometric metallation, which enhances the scope of regioselectivities even further. N-Alkylation is favored by hard electrophiles (e.g., methylating reagents), while soft electrophiles (e.g., olefins) lead sometimes to clean C-alkylations. Illustrative examples of the alkylation of non-metallated azoles are given in Scheme 1.23.
Scheme 1.23 Alkylation of azoles [109–111].
1.3 Problematic Electrophiles
1.3.1 Methylations
Because Friedel–Crafts alkylations require the formation of free carbocations or carbocation-like intermediates, methylations do not proceed readily. Phenols can be C-methylated with MeOH, but high temperatures are required (Scheme 1.24). In acid-catalyzed methylations, free methyl cations are probably not formed, and a complex of catalyst with the methylating reagent is more likely to be the reactive intermediate [112].
Scheme 1.24Methylation of arenes with methanol, methyl chloride, and methyl radicals [112–115].
1.3.2 Olefins
Upon reaction with an arene under acidic reaction conditions, unsymmetric olefins can yield two different products: the one resulting from the more stable carbocation (the Markovnikov product), or the one resulting from the less stable but more reactive carbocation (the anti-Markovnikov product). As with other acid-mediated additions to alkenes, arenes are usually alkylated by the predominant, more stable carbocation. This can also be the case for transition-metal-catalyzed alkylations [116]. Catalysts have been developed, however, that enable the preparation of linear alkylarenes from terminal olefins [117, 118] (Scheme 1.3).
Olefins substituted with electron-withdrawing groups (Michael acceptors) alkylate arenes with the more electrophilic β-carbon (e.g., [119]). Nitroalkenes do so, too, but may be hydrolyzed to ketones upon treatment with strong aqueous acids (Scheme 1.25).
Scheme 1.25 Aromatic alkylations with olefins [120, 121].
A typical side reaction of acid-mediated alkylations with olefins is the oligomerization of the alkene. Styrenes and acrylates polymerize particularly easily. This can sometimes be avoided by keeping the concentration of alkene low, because olefins require a minimum concentration to polymerize. In the presence of oxidants or transition metals, the reaction of arenes with olefins can yield styrenes instead of alkylarenes (Section 2.3).
1.3.3 Allylic Electrophiles
The reaction of arenes with allylic electrophiles often yields mixtures of isomeric products. It is not always the dominant (more stable but less reactive) resonance formula that controls regioselectivity; steric effects also influence the course of the reaction (Scheme 1.26). The results may always be rationalized somehow, but the predictive value of such rationalizations is limited.
Scheme 1.26Examples of the alkylation of arenes with allylic electrophiles [122–124]. Further examples: [125, 126].
In the presence of acids, allylic electrophiles are synthetic equivalents of the 1,3-propylene dication. Accordingly, one potential side reaction is the cyclization of the product to yield indanes. Such cyclizations can sometimes be avoided by a large excess of arene. If Pd-based catalysts are used, Heck-type vinylations (instead of allylic substitution) are a further side reaction to be expected (Scheme 1.27).
Scheme 1.27 Cyclizations and Heck reaction of allylic electrophiles [126–128].
Acrylates are a further type of 1,3-dielectrophile that can cause the formation of bicyclic products upon acid-mediated reaction with arenes (Scheme 1.28).
Scheme 1.28 Acid-mediated reactions of acrylic acids with arenes [129].
1.3.4 Epoxides
Arenes are usually alkylated by epoxides at the carbon atom that forms the more stable carbocation. Alkyl-, aryl-, or alkenylepoxides will therefore mostly yield primary alcohols, while epoxides substituted with electron-withdrawing groups will mostly yield secondary alcohols. Epichlorohydrin and glycidyl ethers also tend to yield secondary alcohols upon acid-mediated reaction with arenes (Scheme 1.29).
Scheme 1.29Examples of the alkylation of arenes with epoxides and aziridines [130–132]. Further examples: [133].
Epoxides are reactive intermediates and may lead to product mixtures if the reaction conditions are not carefully chosen. Typical side reactions include rearrangement of the oxiranes to aldehydes or ketones, dimerization or oligomerization of the oxirane, and alkylation of the arene by the newly formed alcohol (Scheme 1.30).
Scheme 1.30 Side reactions during the alkylation of arenes by epoxides [134–136].
1.3.5 α-Haloketones and Related Electrophiles
Alkylhalides with the halogen attached to a C–H acidic position (α-haloketones, α-haloesters, α-halonitriles, etc.) display a peculiar reactivity. Removal of the halide to produce a (destabilized) carbocation is difficult, and only a few examples of acid-catalyzed arene alkylations with such electrophiles have been reported [137, 138] (Scheme 1.31). Nucleophilic substitutions at such alkyl halides, however, can proceed with ease. Initial addition of the nucleophile to the carbonyl group is a possible reason for the enhanced reactivity of these electrophiles [139].
Scheme 1.31 Electrophilic alkylation of arenes with α-haloketones and related electrophiles [140–143].
Because arenes can also react with ketones, esters, and nitriles, this is a side reaction to be expected when alkylating arenes with α-haloketones and related electrophiles (Scheme 1.32). Moreover, α-haloketones may also act as halogenating reagents or oxidants [144], and can dimerize or trimerize in the presence of bases.
Scheme 1.32Arene alkylation or acylation with α-chloroketones and -nitriles [145–148].
Ketones and esters may also be converted to radicals, which can then add to arenes or heteroarenes. The most common strategies to generate these radicals include the photolysis of α-haloketones or -esters, and the oxidation of ketones (Scheme 1.33). Because aliphatic α-haloesters absorb UV light of short wavelengths only, the arene cannot usually be used as solvent, because it would not allow the required UV light to reach the haloester (second example in Scheme 1.33).
Scheme 1.33Arylation of α-haloesters and ketones via radicals [149–151].
α-Diazoketones or α-diazoesters are precursors to metal carbene complexes, which can undergo direct insertion into aromatic C–H bonds (Scheme 1.34). The intermediate carbene complexes, though, are highly reactive and electrophilic, and can alkylate many functional groups and abstract hydride and cyclopropanate alkenes, alkynes, and even arenes. For this reason, diazocarbonyl compounds (or diazoalkanes [6]) are only rarely used as electrophilic alkylating reagents for arenes.
Scheme 1.34Reaction of α-diazoesters with arenes [152, 153].
The arylation of α-haloketones and related electrophiles via vicarious nucleophilic substitution is discussed in Section 8.2.3.
1.3.6 Nitroalkanes
A few examples have been reported of the alkylation of arenes with nitroalkanes, with the nitro group acting as leaving group [4] (Scheme 1.35). This reaction is complicated by numerous potential side reactions. Nitro groups can act as carbon electrophiles without loss of the nitro group. Moreover, in the presence of strong acids, nitro groups can react with arenes at oxygen. For instance, 2-aryl-1-nitroethanes are converted to O-aryloximes when treated with triflic acid (Scheme 1.35). In this type of reactions, nitro groups become electrophilic at oxygen. Examples have also been reported of electrophilic aromatic aminations with nitro groups (last example, Scheme 1.35).
Scheme 1.35Reactions of nitroalkanes with arenes [154–157]. Further examples: [158].
In the presence of dehydrating reagents, primary nitroalkanes (RCH2NO2) can be converted to nitrile oxides, which are highly reactive and readily dimerize, polymerize, rearrange to isocyanates, react with nucleophiles, or undergo 1,3-dipolar cycloadditions.
1.3.7 Ketones
Upon catalysis by acids, simple dialkylketones react cleanly with only electron-rich arenes, such as phenols, anilines, or pyrroles, but not with benzene or toluene. The resulting tertiary benzylic alcohols usually alkylate a second arene molecule, to yield geminal diaryl alkanes. Dehydratization of the intermediate alcohols and oligomerization of the resulting olefin are also occasionally observed. If the alcohol is the desired product, a mildly acidic catalyst and carefully optimized conditions will often be required.
Isopropenylbenzene, for instance, cannot be directly prepared from acetone and benzene (for recent research, see [159]) because the readily formed cumyl cation reacts with benzene [160]. The direct preparation of isopropenylbenzene from acetone would be valuable because, during the production of phenol from cumene hydroperoxide, one equivalent of acetone is formed, which cannot currently be used directly for the preparation of cumene. Processes have been developed in which acetone is hydrogenated to isopropanol, which is then converted to propene and used to alkylate benzene (Scheme 1.36). The direct alkylation of benzene with isopropyl alcohol is possible [161, 162], but most catalysts for Friedel–Crafts alkylations are deactivated by water, and isopropylations with propene are therefore more convenient than isopropylations with isopropanol.
Scheme 1.36Preparation of phenol and acetone from benzene.
Only ketones substituted with electron-withdrawing groups, such as trifluoromethylketones, 1,2-diketones, or α-ketocarboxylic esters, react with unactivated arenes. Fluorenones are also quite reactive because O-protonated fluorenones are antiaromatic. The initially formed alcohols do not form carbocations readily and can often be isolated (Scheme 1.37).
Scheme 1.37 Alkylation of arenes and heteroarenes by ketones [163–167].
Potential side reactions of the Friedel–Crafts alkylation with ketones is the formation of diarylmethanes, the oligomerization of the products, and aldol condensation of the starting ketone. Moreover, in the presence of oxidants, ketones may be α-arylated via intermediate radical formation [151]. If Friedel–Crafts alkylations with ketones are conducted in the presence of hydride donors, a reductive alkylation of arenes can occur (Scheme 1.38).
Scheme 1.38Reductive aromatic alkylation with ketones [168].
Strongly C–H acidic ketones, such as β-ketoesters, are readily palladated at carbon. The resulting intermediates can undergo β-hydride elimination to yield α,β-unsaturated ketones. The latter are Michael acceptors, capable of alkylating electron-rich arenes (Scheme 1.39).
Scheme 1.39Dehydrogenation as side reaction of the Pd-catalyzed arylation of ketones [169].
Occasionally, benzylic electrophiles are attacked by nucleophiles not at the benzylic position but at the arene (e.g., first equation in Scheme 1.37). Examples have been reported of the electrophilic arylation of unsubstituted arenes with tetralones and related aryl ketones (Scheme 1.40).
Scheme 1.40Arylation of benzene with tetralone [83].
