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 CCl 4 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 D¨ orwald. c 2014 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2014 by Wiley-VCH Verlag GmbH & Co. KGaA.
Transcript
1
1Electrophilic Alkylation of Arenes
1.1General Aspects
For large-scale industrial organic syntheses, electrophilic alkylations of arenesare essential (Scheme 1.1). Their attractive features include the absence of wastewhen alcohols or olefins are used as electrophiles, the large scope of availablestarting materials, and the high structural complexity attainable in a single step.The main issues are low regioselectivity, overalkylations, and isomerization ofthe intermediate carbocations. Important products resulting from this chemistryinclude 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), andtriarylmethane dyes.
To obtain acceptable yields, careful optimization of most reaction parameters isoften required. Because the reactivity of an arene increases upon alkylation (around2–3-fold for each new alkyl group), multiple alkylation can be a problem. Thismay be prevented by keeping the conversion low, or by modifying the reactiontemperature, the concentration, the rate of stirring, or the solvent used (e.g.,to provide for a homogeneous reaction mixture). In dedicated plants, processesare usually run at low conversion if the starting materials can be recycled. Inthe 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, andimines. 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 agentseither via intermediate conversion to N-alkylpyridinium salts [9] or by transientdehydrogenation to imines [10]. Some examples of Friedel–Crafts alkylation aregiven in Scheme 1.2.
In most instances, the electrophilic alkylation of arenes proceeds viacarbocations, and complete racemization of chiral secondary halides or alcohols isusually observed. Only if neighboring groups are present and capable of forming
Scheme 1.1 Mechanism of the Friedel–Crafts alkylation.
cyclic configurationally stable cations, arylations can occur with retention ofconfiguration [18].
Stabilized carbocations (e.g., tertiary carbocations) are easy to generate, but theyare less reactive (and more selective) than less stable cations. Thus, the trityl ortropylium (C7H7
+) cations react with anisole but not with benzene. On the otherhand, carbocations destabilized by a further positively charged group in closeproximity will show an increased reactivity [7, 19]. Highly stabilized cations mayeven be generated and arylated under almost neutral reaction conditions [20].
1.1.1Catalysis by Transition-Metal Complexes
Electrophilic alkylations of arenes by olefins or alkyl halides can be catalyzedby soft electrophilic transition metals, for example, by Pd, Rh, or Ru complexes(Scheme 1.3). Most of the reported examples proceed via aromatic metallationthrough chelate formation. With Ru-based catalysts, selective meta-alkylation canbe achieved when using sterically demanding electrophiles (fifth equation inScheme 1.3).
Reactions where carbocation formation is the slowest (rate-determining) step canbe catalyzed by any compound capable of stabilizing the intermediate carbocation(and thereby promote its formation). This form of catalysis should be mostpronounced in nonpolar solvents, in which free carbocations are only slightlystabilized by solvation. Some transition-metal complexes, for example, IrCl3 andH2[PtCl6], catalyze Friedel–Crafts alkylations with benzyl acetates, probably by
1.1 General Aspects 3
+Cl
1 eq 4 eq
1.2% AlCl345 °C, 1 h
+
65% 33%
08joc4956
(CH2O)n, ZnBr2HBr (33% in AcOH)
90 °C, 16 h
94%80−90%
BrBr
Br
10joc6416, 05syn2080
1.06 eq AlCl33.06 eq EtBr
0−20 °C, 12 h
OH+
3 eq MeSO3HMeNO2
80 °C, 6−12 hOMe
61%
N
SH2N
N
SH2N
1 eq 2 eq09ol5154
OMe
S
S OH
CN
+
OMe1 eq AlCl3
CH2Cl220 °C, 0.5 h
S
S
CN
S
S
CNOMe
OMe87%
80 : 20
+
1 eq 4 eq08joc2264
O
N3
OAc
AcO
+O
1.1 eq BF3OEt2MeCN, 20 °C, 0.5 hthen K2CO3, MeOH
O
N3
HO
O
60%
5 eq1 eq 10ja15528
OO
+Cl
F
2 eq 1 eq
1.05 eq ZnCl2H2O, 85 °C, 6 h
OO
F
OO
F
+ + O
F F70% 5% 5%
07oprd1059
Scheme 1.2 Examples of Friedel–Crafts alkylations [11–17].
Scheme 1.4 Catalysis of Friedel–Crafts alkylations [28].
transient formation of benzylic metal complexes (Scheme 1.4). Because racemi-zation is also observed in these instances, the intermediate complexes are likelyto undergo fast transmetallation. Ru-based catalysts have been developed thatenable the preparation of enantiomerically enriched alkylbenzenes and alkylatedheteroarenes from racemic alcohols [27] (Scheme 1.18).
1.1.2Typical Side Reactions
The rearrangement of intermediate carbocations is a common side reaction inFriedel–Crafts chemistry (Scheme 1.5). Rearrangements can sometimes be avoidedwith the aid of transition-metal-based catalysts, because the intermediate complexesare 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 theformation 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 undergohalogenation instead of alkylation (Scheme 1.7). Alkyl halides with the halogen
6 1 Electrophilic Alkylation of Arenes
+ F Br
BF3
0−20 °C, 2 h
89%
Br
64joc23174 eq 1 eq
+ TfO
1 eq 2 eq
5% AuCl3/3 AgOTf
120 °C, DCE, 48 h+
40% 50%
04ja13596
Scheme 1.5 Rearrangement of carbocations during Friedel–Crafts alkylations [29, 30].
+Cl
+
5 eq 1 eq 1 eq
10% AlCl322 °C, 1 h
+ H
11%
+ +
60% 10%
63joc1624
Scheme 1.6 Hydride abstraction by carbocations as side reaction during Friedel–Craftsalkylations [32].
OH
+CO2EtEtO2C
Br
OH
+ CO2EtEtO2C
Br
neat, 100 °C82%
01bcsj179
CO2Me
OH
+
O
Cl
ClCl
Cl
Cl
Cl
1.1 eq1.0 eq
DMF, CCl420 °C, 24 h
CO2Me
OH
Cl
34%
US 2011306621
TfO+
0.2 eq AuCl30.6 eq AgOTf
DCE120 °C, 1 h
35% conversion
04ja13596
+
Cl
12% 20%
Scheme 1.7 Halogenation of arenes by alkyl halides and by AuCl3 [30, 33, 34].
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 undergoacid-catalyzed oxidative dimerization (Scholl reaction) [35]. This reaction occursparticularly easily with electron-rich arenes, such as phenols and anilines.
1.2Problematic Arenes
1.2.1Electron-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 rear-rangement and polymerization before attacking the arene. If no alternative reactionpathways are available for the carbocation, though, high-yielding Friedel–Craftsalkylations of electron-deficient arenes can be achieved (Scheme 1.8).
O
+ OH
H2SO4
90 °C, 1.2 h
O O O
+ +
25% conversionof benzophenone
0.6% 19% 3.2%
+dialkylatedproducts
2.4%
1 eq 2 eq91joc7160
HO2C
CO2H
+O
O
O
H2SO4 (27% SO3)
135 °C, 6 h
HO2C
O
O
65%
0.85 eq1.00 eqEP 1118614
NO2
+ OCl Cl
2.4 eq 1.0 eq
H2SO4
50 °C, 1 week
35%
NO2Cl
US 2758137
Scheme 1.8 Friedel–Crafts alkylation of electron-deficient arenes [36–38].
8 1 Electrophilic Alkylation of Arenes
Electron-deficient arenes can be alkylated by olefins or alkyl halides via inter-mediate arene metallation. Chelate formation is usually required and crucial forthe regioselectivity of transition-metal-catalyzed reactions (Scheme 1.9). The Ru-and Rh-catalyzed ortho-alkylation of acetophenones and acetophenone-imines byalkenes can even proceed at room temperature [39]. With sterically demanding alkylhalides, Ru complexes can mediate meta-alkylations [24]. When conducted in thepresence of oxidants, these reactions can yield styrenes instead of alkylbenzenes[40–42] (see also Section 2.3).
Cl
Oethylene (30 bar), PhMe
10% RuH2(H2)2(PCy3)2
23 °C, 24 h
Cl
O
+
Cl
O
89% 7%
01asc192
NO
+
Cl
OMe
O
2.5% [RuCl2(p-cymene)]230% 1-AdaCO2H
2 eq K2CO3
PhMe, 100 °C, 20 h
1.0 eq 1.5 eq
NOOMe
O
61%
09ol4966
N Ph
+
2% RhCl(PPh3)3
PhMe, 150 °C, 2 hthen hydrolysis
O
95%
02cej485
N
N
20% Pd(OAc)21 eq Cu(OAc)2
10 eq TFA
DCE, 110 °C, 48 h+
S
CF3BF4
1.0 eq 1.5 eq
N
N
CF353%
10ja3648
Scheme 1.9 Ru-, Rh-, and Pd-catalyzed, chelate-mediated alkylation of electron-deficientarenes [43–46].
The metals used as catalysts for this ortho-alkylation of acetophenones insertnot 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 ofthe catalyst [47]. Another potential side reaction of the alkylations described above
1.2 Problematic Arenes 9
OMeO
+ Si(OEt)3
1 eq 2 eq
2.5% [RuCl2(p-cym)]215% PPh3
30% NaHCO3
PhMe, 140 °C, 60 h
OMeO
Si(OEt)3
+
O
20% 25%
(EtO)3Si
09ja7887
ONH
+O
BO
Ph
1.0 eq 1.2 eq
4% RuH2(CO)(PPh3)3
PhMe, 111 °C, 20 h
OPh
87%
ON
+O
BO
Ph
1.0 eq 2.0 eq
OPh
+ SiMe3
as above
99%SiMe3
2.0 eq
07ja6098
Scheme 1.10 Ru-catalyzed ortho-alkylation and -arylation of acetophenones [50, 51]. Furtherexamples: [52, 53].
is aromatic hydroxylation, which can readily occur if oxidants are present in thereaction mixture [48, 49].
Some heteroarenes, such as pyridine N-oxides, thiazoles, or imidazoles, arestrongly C–H acidic, and can be metallated catalytically even without chelateformation. In the examples in Scheme 1.11, the intermediates are, in fact, metalcarbene complexes.
Under forcing conditions, fluoro- or nitrobenzenes can also be metallated with-out chelate formation, and trapped in situ with a number of electrophiles, includingaldehydes and ketones (Scheme 1.12). Owing to the competing Cannizzaro reactionand the potential cleavage of ketones by strong nucleophiles (e.g., Haller–Bauerreaction), these reactions may require a large excess of electrophile andcareful optimization.
Electron-deficient arenes and heteroarenes, such as pyridinium salts, can reactwith carbon-centered, electron-rich radicals. These can be generated from alkanes,alkyl halides, carboxylic acids, and some diacylperoxides [58] (Scheme 1.13), orby oxidation of boranes [59]. The regioselectivity of such alkylations is, however,often poor.
1.2.2Phenols
Phenols are inherently problematic nucleophiles in Friedel–Crafts type chemistrybecause the free hydroxyl group can deactivate Lewis acids and because phenols
10 1 Electrophilic Alkylation of Arenes
N
O
+O
O
2% [Rh(cod)Cl]25% Ph2PCH2CH2PPh2
0.25 eq CsOAc, PhMe
120 °C, 24 h
1 eq 5 eq
N
O
O
O
O
O
86%
N
N+
O
O
2% [Rh(cod)Cl]25% Ph2PCH2CH2PPh2
0.25 eq CsOAc, PhMe
120 °C, 12 h
2 eq
72%
1 eq
N
N
O
O
12ang3677
12ang3677
NO
Ph
+S
O
solvent1 eq
10% PdCl2(MeCN)2
2 eq Bu4NOAc
2 eq ZnO, 2 eq NBu3
air, 120 °C, 36 h
N
Ph
75%
12asc1890
S+ Br
13% ligand
5% FeCl3TMPMgCl−LiCl
THF, 20 °C, 6 h
74% S
1.0 eq1.8 eq
ligand:
HN
NH10ol4277
Scheme 1.11 Metallation and alkylation of C–H acidic heteroarenes [54–56].
MeO
F
F
F
F
+
1 eq 3 eq
Cl
O1.5 eq t-BuOLi
DMF, 20 °C, 2 h
93%MeO
F
F
F
F
OH
Cl
SCl +
O
3 eq1 eq
1.5 eq t-BuOLi
DMF, 105 °C, 20 h
41%SCl
OH
09joc8309
09joc8309
Scheme 1.12 Metallation and alkylation of C–H acidic arenes [57].
1.2 Problematic Arenes 11
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, andreact preferentially with soft nucleophiles, such as arenes or olefins. PhenolO-alkylation under acidic conditions is observed only with hard alkylating reagents(diazomethane, dimethyl carbonate, methanol, methyl esters, alkoxyphosphoniumsalts (Mitsunobu reaction), or acetals). O-Alkylated phenols sometimes rearrangeto C-alkylated phenols in the presence of acids [66] (Scheme 1.14).
At high temperatures, phenols and aluminum phenolates are C-alkylated byolefins (Scheme 1.15). This reaction proceeds less readily and has a narrower scope
O
O
OH
OH
OH
HO
O
O
OH
OH
OH
HO
O
O
OH
OH
OH
HO
O
O
O
t-BuOH, 82 °C60% conversion
02tet1751
+
51% 6%
O
CO2H
+
1 eq 9 eq
10% Ru3(CO)12
5% dppb, 2 eq (t-BuO)2
air, 135 °C, 12 h
CO2H
65%
dppb: 1,4-bis(diphenylphosphino)butane
N
9 eq C6H12, 10% Ru3(CO)12
5% dppb, 2 eq (t-BuO)2
135 °C, 12 h NN+
70% 10%
11ol4977
11ol4977
N
+I
1 eq 3 eq
3 eq H2O2 (30% in H2O)
1 eq H2SO4, DMSO
0.2 eq FeSO4-7H2O
20 °C, 20 min
N84%
89joc5224
Scheme 1.13 Alkylation of arenes with radicals [59–64]. Further examples: [65].
12 1 Electrophilic Alkylation of Arenes
+
N
N
CO2HHO2C
CO2H
1 eq 10 eq
0.6 eq AgNO3
10 eq NH4S2O8
excess 10% aq H2SO4
80 °C24%
N
N
N
NN
N
WO 2008048967
N
N
OH
+
KF3B
1 eq 1 eq
2.5 eq Mn(OAc)3
1 eq TFA
AcOH/H2O 1 : 1
50 °C, 18 h
59%N
N
OH
11ol1852
N
+
N
I
Boc
1 eq 2 eq
0.9 eq FeSO4
6 eq H2O2 (30% in H2O)
2 eq H2SO4, DMSO
40 °C, 3 h
50%
N
N
Boc
09joc6354
Scheme 1.13 (Continued)
than the corresponding reaction of aluminum anilides (see next section). Althoughortho-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 ofimportant alkylphenols are prepared by high-temperature alkylations with olefinsin the presence of heterogeneous catalysts [73, 75].
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 Rhcomplexes [79] to yield chromanes (Scheme 1.16).
Phenols are tautomers of cyclohexadienones, and may react as such. In particu-lar, 1- or 2-naphthols, 1,3-dihydroxybenzenes, and 1,3,5-trihydroxybenzenes showstrong cyclohexenone character. Phenols and arylethers react with arenes in thepresence 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 onthe amount of acid used and the basicity of the phenol, either conjugate arylationof an enone or arylation of a dication can occur (Scheme 1.17). Moreover, 4,4-disubstituted cyclohexenones, which also may be formed, undergo acid-mediatedrearrangement to 3,4-disubstituted cyclohexanones. Phenols substituted with leav-ing groups (halides, hydroxyl groups) can undergo elimination after the arylationand yield 3- or 4-arylphenols.
1.2 Problematic Arenes 13
10sl261
O
SMe
NH
NO2
+
EtOH
79 °C, 12 h
88%
O NH
NO2
HO
11tet8146HO
OH
MeO
+ HOPh
1% [PhH(PCy3)(CO)RuH]BF4
10% cyclopentene
PhMe, 100 °C, 8 h
92%
Ph
OH
MeO12ja7325
1.0 eq 1.2 eq
OH
MeO
+
OMe OMeO
OH
OH
1 eq2 eq
0.2 eq Me3SiOTf
CH2Cl225 °C, 1 h
O
OH
OHOH
OMeMeO
98%
98joc2307
HS
+
NO2
CHO3 eq1 eq
0.01 eq [Ir(cod)Cl]20.04 eq SnCl4
90 °C, 1 h
NO2
HS SH
74%
07joc3100
SH
1.1 eq
HO Ph +
0.1 eq CuBr2
0.2 eq Fe
DCE, 84 °C, 20 h
72%
SH
Ph
1.0 eq
Scheme 1.14 C-Alkylation of phenols and thiophenols under acidic conditions [67–71].
1.2.3Anilines
Regardless of being N-protonated by acids, anilines can be alkylated at carbon andat nitrogen under acidic reaction conditions. Suitable alkylating reagents includealcohols, ethers, alkenes, aldehydes, ketones, and alkyl halides.
Despite the electron-withdrawing effect of ammonium groups, Friedel–Craftsalkylations of anilines usually proceed with ortho and para selectivity, and more
14 1 Electrophilic Alkylation of Arenes
OH
+
4% Al(OPh)3
320 °C, 60 bar, 10 hOH
+
OH
24% 8%
OH
+
4% Al(OPh)3
240 °C, 38 bar, 2 hOH
61%
56joc712
56joc712
OH
Ph
Al, 220 °C, 1.5 h
then cyclohexene
180 °C, 11 h
OH
PhPd/C
340 °C, 4 h
OH
Ph Ph
62%(two steps)
JP 2009269868
Scheme 1.15 Alkylation of aluminum phenolates with alkenes [76, 77].
OH
+
0.5% TfOH
DCE, 20 °C, 2 h
1.0 eq 1.5 eq
63%
O
11joc9353
OHO
+HO
HO
1.0 eq 1.2 eq
1% RuH(PhH)(PCy3)(CO)BF4
3 eq cyclopentene
PhMe, 100 °C, 12 h
43%
12ja7325
Scheme 1.16 Formation of chromanes from phenols [68, 80].
readily than Friedel–Crafts alkylations of the corresponding benzenes. Thus,although aniline hydrochloride can be para-tritylated in acetic acid (first examplein Scheme 1.18), benzene does not react with the trityl cation.
The precise outcome of the reaction of anilines with alkylating reagents canbe difficult to predict. Stoichiometric amounts of strong acids usually favor C-alkylations. At high temperatures or in the presence of acids, N-alkylanilinesmay be dealkylated and act as alkylating agents themselves [91–93]. Occasionally,mixtures of N- and C-alkylated products are obtained (Scheme 1.19).
If anilines are treated with aldehydes or ketones in the presence of acids atroom temperature, reversible aminal, imine, or enamine formation usually occurs.Upon heating, irreversible alkylation at carbon can take place. Thus, if aniline is
1.2 Problematic Arenes 15
OH
AlCl3
OAlCl3
O
ArH
OAlCl3
Ar
H
− H
O
Ar
+ H
OAlCl3
ArH − H
OAlCl3
Ar
O
Ar
OH1.5 eq AlBr3
1.5 eq C6H6
70 °C, 5 h
O
Ph
12%
+
O
Ph
Ph34%
73zok2158
73zok2158
OH 1.5 eq AlCl3excess C6H620 °C, 52 h
O
Ph
75%
OHAlCl3, C6H6
20 °C, 16 h
O
Ph
90%
OHAlCl3, C6H6
80 °C, 1 h
OH
75%
Cl
Ph
04cc1754
04cc1754
Scheme 1.17 Acid-mediated arylation of phenols [84, 85].
treated with formaldehyde at a low temperature, only aminals, benzylamines, orTroger’s base are formed. At higher temperatures, though, diarylmethanes arethe main products (Scheme 1.20). Hydride transfer from aldehydes or anilines tointermediate iminium salts causes the formation of N-alkylanilines as byproducts.
16 1 Electrophilic Alkylation of Arenes
OH
+
5% cat*, 10% NH4BF4
DCE, 60 °C, 3 h
NMe2
NMe2
Cl
Cl
46%
83% ee
cat*:
0.5 {Cp*RuCl}4 + S S
Ph
Ph
Ph
Ph
Ph
Ph
07ang6488
NH2
S
CF3
NO2+
1 eq 1 eq
DMF, 80 °C, 6 h
78%
NH2
+
NH2
CF3
CF384 : 16TfO 09ejoc1390
N+
F3CO2S
F3CO2S
SO2CF3
SO2CF3 MeCN, 80 °C N
F3CO2S
F3CO2SH
87%
13ang1530
+
NH3Cl AcOH
118 °C, 3 h
then NaOH
70%
OH
PhPhPh
NH2
Ph PhPh2.1 eq1.0 eq oscv(4)47
H2N
10 eq
O
1 eq
0.6 eq MsOH
175 °C, 24 h+
H2N NH2
85%
EP 0203828
NH2
+
1 eq 1 eq
0.2 eq F3CSO3H
160 °C, 16 h
53%
NH2
05ol5135
Scheme 1.18 Examples of C-alkylations of anilines [27, 86–90].
1.2 Problematic Arenes 17
+O
Al2O3
330 °CNH2
N
83−90%
oscv(4)7952 eq 1 eq
NH
+ ClBr
5 eq1 eq
150−160 °C, 20 h
N77−81%
oscv(3)504
H2N
2 eq
+
NN
1 eq
0.05 eq BF3OEt2135 °C, 24 h
NH
58 : 42
83%H2N
+
Tf2N
06thl6775
H2N
2 eq
+
1 eq
OH
montmorilloniteheptane
80 °C, 24 h
88% NH
86 : 10 : 4
H2N
+
H2N
+
07joc6006
Scheme 1.19 Examples of C- and N-alkylations of anilines [94–97]. Further examples:[98, 99].
H2N
2 eq (HCHO)nCF3CO2H
20 °C, 48 h
78%N
N
Tröger’s base07ejoc3905
H2N
HCHO, H2O
<70 °C
NH
NH
SiO2, Al2O3
90 °C
H2N
NH
zeolites
125 °C
H2N NH2
04cc2008, WO 2010072504
H2N
O2N
2 eq
1 eq (HCHO)n25% HClheat, 5 h
90%H2N
O2N
NH2
NO2
07cej9515
Scheme 1.20 Formation of diarylmethanes from anilines and formaldehyde [100–103].
18 1 Electrophilic Alkylation of Arenes
One side reaction often observed during the preparation of diarylmethanes fromanilines is the formation of triarylmethane dyes. A suitable oxidant is air, andthe oxidation can be catalyzed by vanadates (Scheme 1.21). Even if oxygen isrigorously excluded, small amounts of these dyes will result from oxidation by theintermediate iminium salts.
Anilines can be selectively ortho-alkylated with olefins under basic reactionconditions. This requires conversion of the aniline into an aluminum anilide bytreatment with Al/AlCl3 (Scheme 1.22). This interesting reaction is, however, oflittle scope, and not well suited to alkylate phenols [76].
H2N
10 eq
1.4 eq HCl (25%)1.0 eq HCHO (35%)
130 °C, 3 h
H2N NH2
0.002 eq (NaVO3)4air, 110 °C, 3 h
H2N NH2
NH
Pararosaniline
EP 0909794
Scheme 1.21 Formation of triarylmethane dyes from diarylmethanes [104].
NH2
4−7% (PhNH)3Al
ethylene, 40−60 bar
330 °C, 7 h
>99% conversion
NH2 NH2
+
1.2% 89%56joc711
NH2
+
0.07 eq Et3Al2Cl3262 °C, 17 h
1.0 eq 0.7 eq
56% conversionof aniline
NH2
68%WO 2009029383
NH2
HN
0.25% RhCl3-3H2O
0.5% PPh3
ethylene (100 bar)
200 °C, 3 dN
+
2.5%7.5%
79ja490
Scheme 1.22 Alkylation of anilines with olefins [105–107]. Further examples: [108].
1.3 Problematic Electrophiles 19
1.2.4Azoles
Azoles with a free NH group can be alkylated at nitrogen or at carbon. The outcomeof such reactions is barely predictable, in particular for substrates containing arenes(e.g., indoles, benzimidazoles, etc.). Azoles may also be alkylated after stoichio-metric metallation, which enhances the scope of regioselectivities even further.N-Alkylation is favored by hard electrophiles (e.g., methylating reagents), whilesoft electrophiles (e.g., olefins) lead sometimes to clean C-alkylations. Illustrativeexamples of the alkylation of non-metallated azoles are given in Scheme 1.23.
N
NH
N
HN
1.1 eq 1N NaOHEtOH, 79 °C, 1 h, then
0.7 eq PhCH2Br79 °C, 24 h
N
NH
N
HN Ph
+N
NH
N
N
Ph
16% 23%
+N
N N
N
Ph
Ph 17%
EP 0301456
NH
N
+
2.5% [RhCl(coe)2]27.5% PCy3
5% lutidine-HClTHF, 150 °C, 15 h
80%coe: cis-cyclooctene
NH
N
04joc7329
NH
+
4% PdCl2(MeCN)2
2 eq norbornene
2 eq K2CO3
DMA, H2O, 70 °C
65% NH
CO2EtBr CO2Et
12ja14563
Scheme 1.23 Alkylation of azoles [109–111].
1.3Problematic Electrophiles
1.3.1Methylations
Because Friedel–Crafts alkylations require the formation of free carbocations orcarbocation-like intermediates, methylations do not proceed readily. Phenols can
20 1 Electrophilic Alkylation of Arenes
OHMeOH, Al2O3
530 °C, gas phase
65−67%
oscv(4)520
mixture ofisomers
0.25 eq AlCl3excess MeCl
100 °C, 100 h
52%
+
16%
+
18%
mixture ofisomers
mixture ofisomers
oscv(2)248
17% MeCl, 9% B(OTf)3
CH2Cl2, 25 °C, 1 h
17 : 58 : 25
+ +11%
88ja2560
N +Ph O
O Ph
1 eq 2 eq
5% Pd(OAc)2
130 °C, 12 hN N+
60% 20%
08ja2900
Scheme 1.24 Methylation of arenes with methanol, methyl chloride, and methyl radicals[112–115].
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 acomplex of catalyst with the methylating reagent is more likely to be the reactiveintermediate [112].
1.3.2Olefins
Upon reaction with an arene under acidic reaction conditions, unsymmetric olefinscan yield two different products: the one resulting from the more stable carbocation(the Markovnikov product), or the one resulting from the less stable but morereactive carbocation (the anti-Markovnikov product). As with other acid-mediatedadditions to alkenes, arenes are usually alkylated by the predominant, more stablecarbocation. This can also be the case for transition-metal-catalyzed alkylations[116]. Catalysts have been developed, however, that enable the preparation of linearalkylarenes from terminal olefins [117, 118] (Scheme 1.3).
1.3 Problematic Electrophiles 21
Olefins substituted with electron-withdrawing groups (Michael acceptors) alky-late 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).
Cl
SNH
O O% SbF5
HF, −20 °C, 10 min
Cl
SNH
O O
F+
Cl
SNH
O O
13%55%64%
71%17%0%
% SbF5
3.8%8.4%27%10ol868
+
NO2
30 eq 1 eq
10 eq F3CSO3H
−40 °C, 1 min NHO OH
O O+
92%
57 : 43
89joc733
Scheme 1.25 Aromatic alkylations with olefins [120, 121].
A typical side reaction of acid-mediated alkylations with olefins is the oligomer-ization of the alkene. Styrenes and acrylates polymerize particularly easily. This cansometimes be avoided by keeping the concentration of alkene low, because olefinsrequire a minimum concentration to polymerize. In the presence of oxidants ortransition metals, the reaction of arenes with olefins can yield styrenes instead ofalkylarenes (Section 2.3).
1.3.3Allylic Electrophiles
The reaction of arenes with allylic electrophiles often yields mixtures of isomericproducts. It is not always the dominant (more stable but less reactive) resonanceformula that controls regioselectivity; steric effects also influence the course of thereaction (Scheme 1.26). The results may always be rationalized somehow, but thepredictive value of such rationalizations is limited.
In the presence of acids, allylic electrophiles are synthetic equivalents of the1,3-propylene dication. Accordingly, one potential side reaction is the cyclizationof the product to yield indanes. Such cyclizations can sometimes be avoided by alarge excess of arene. If Pd-based catalysts are used, Heck-type vinylations (insteadof allylic substitution) are a further side reaction to be expected (Scheme 1.27).
22 1 Electrophilic Alkylation of Arenes
OF3C
O
37 eq benzene7 eq TFA80 °C, 8 h
1.5 mmol
++
78% 3% 1%84joc4309
F
F
F
F
F
+ OO
O
2 eq 1 eq
5% Pd(OAc)2
10% PPh3, 5% CuI-phen
1.2 eq Cs2CO3
PhMe, 120 °C, 12 h
48%
F
F
F
F
F
F
F
F
F
F
+
85 : 15
11ang5918
NPh
O
+
Ph
OPO(OEt)2
1.0 eq1.2 eq
10% CuCl
1 eq LiOtBu
THF, 40 °C, 10 h
92%NPh
O
Ph
12ang4122
Scheme 1.26 Examples of the alkylation of arenes with allylic electrophiles [122–124]. Fur-ther examples: [125, 126].
+ Br
1 eq 1 eq
1 eq AlCl3CH2Cl2
20 °C, 12 h
36%
EP 0826654
+Cl
1.0 eq 1.1 eq
0.05 eq Cu(OTf)2CH2Cl2
60 °C, 16 h
78%
11asc1055
F
F
F
F
F
+ AcO
3 eq
1 eq
5% Pd(OAc)22 eq AgOAc
5% DMSO in THF110 °C, 20 h
78%
F
F
F
F
F
OAc
F
F
F
F
F OAc
F
F
F
F
F
OAc
+ +
86 : 9 : 5
12ol74
Scheme 1.27 Cyclizations and Heck reaction of allylic electrophiles [126–128].
1.3 Problematic Electrophiles 23
Acrylates are a further type of 1,3-dielectrophile that can cause the formation ofbicyclic products upon acid-mediated reaction with arenes (Scheme 1.28).
CO2H
1 eq
+
5 eq
17 eq F3CSO3H
20 °C, 4 h
O
+
O35% 12%
CO2H
1 eq
+
5 eq
17 eq F3CSO3H
75 °C, 24 h
O93%
CF3
CO2H
1 eq
+
5 eq
17 eq F3CSO3H
20 °C, 4 h
O
CF3
90%
CF3
CO2H
1 eq
+
5 eq
17 eq F3CSO3H
45 °C, 7 h
68%
CF3
CO2H
10joc2219
10joc2219
10joc2219
10joc2219
Scheme 1.28 Acid-mediated reactions of acrylic acids with arenes [129].
1.3.4Epoxides
Arenes are usually alkylated by epoxides at the carbon atom that forms themore stable carbocation. Alkyl-, aryl-, or alkenylepoxides will therefore mostlyyield primary alcohols, while epoxides substituted with electron-withdrawinggroups will mostly yield secondary alcohols. Epichlorohydrin and glycidyl ethersalso tend to yield secondary alcohols upon acid-mediated reaction with arenes(Scheme 1.29).
Epoxides are reactive intermediates and may lead to product mixtures ifthe reaction conditions are not carefully chosen. Typical side reactions includerearrangement of the oxiranes to aldehydes or ketones, dimerization or oligomer-ization of the oxirane, and alkylation of the arene by the newly formed alcohol(Scheme 1.30).
24 1 Electrophilic Alkylation of Arenes
NH
+Cl
O
montmorillonite
SbCl320 °C, 0.3 h
70%NH
OH
Cl
09thl916
O
O
2.5% AuCl3/3 AgOTf
DCE, 83 °C, 4 h
65%
O
OH
04ja5964
HN
HN
HNS
Tol
OO
(racemic)
N
STol
O
O
+
0.1 eq InCl3CH2Cl2
20 °C, 6.5 h
74%
1.0 eq 1.4 eq02thl1565
Scheme 1.29 Examples of the alkylation of arenes with epoxides and aziridines [130–132].Further examples: [133].
O PhMe, 0.4 eq SnCl40 °C, 1.5 h
OH
Tol
ortho/para 28 : 72
+ +
OO
O
43% 33% 13%
83joc592
O+
CF3CO2H
CF3SO3H
20 °C, 3 h
44%
78 : 19 : 3
+ +
03catl1
O
Cl
CO2Me
Oct
C6H6, AlCl320 °C, 1 h
77%Oct
Cl
HO Ph
CO2Me
Oct: C8H17
Oct
Cl
HO Ph
CO2Me
81 : 19
+
O
Cl
CO2Me
Oct
AlCl3O
CO2MeOct
Cl
AlCl3
03tet1781
Scheme 1.30 Side reactions during the alkylation of arenes by epoxides [134–136].
1.3 Problematic Electrophiles 25
1.3.5𝛂-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 halideto produce a (destabilized) carbocation is difficult, and only a few examples ofacid-catalyzed arene alkylations with such electrophiles have been reported [137,138] (Scheme 1.31). Nucleophilic substitutions at such alkyl halides, however, canproceed with ease. Initial addition of the nucleophile to the carbonyl group is apossible reason for the enhanced reactivity of these electrophiles [139].
+
O
Cl
7.5 eq 1 eq
2 eq AlCl380 °C, 5 h
32%
O
40ja1622
CO2Me
OS
O O
4 eq C6H6, 2 eq AlCl380 °C, 6 h
80%
CO2Me
85joc3945
OCO2HO
O
S
O O
+
1 eq
3 eq AlCl345 °C, 16 h
then NaOH
then HCl
83%
EP 0665212solvent
+ CO2HCl
2% KBr, 0.4% Fe2O3
200−218 °C, 20 h
1 eq3 eq
CO2H
70% (crude)
34% (purified)
50ja4302
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 sidereaction to be expected when alkylating arenes with α-haloketones and relatedelectrophiles (Scheme 1.32). Moreover, α-haloketones may also act as halogenatingreagents or oxidants [144], and can dimerize or trimerize in the presence of bases.
Ketones and esters may also be converted to radicals, which can then add toarenes or heteroarenes. The most common strategies to generate these radicalsinclude 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
26 1 Electrophilic Alkylation of Arenes
+ CNCl
2% KBr, 0.4% Fe2O3
177−220 °C, 20 h
1 eq3 eq
CN
42%
51joc239
NH2
F
+ CNCl
1 eq 2 eq
1.1 eq AlCl31.1 eq BCl3
CH2Cl2, 40 °C, 14 h
57%NH2
F
O
Cl
12oprd1832
but:
OH
+
O
Cl
4 eq 1 eq
7 eq MeSO3H
CH2Cl2, −10 °C
OH
HO
Cl
>78%
WO 9811043
OMe
+
O
Cl
H2SO4
0 °C, 5 h
OMe
MeO
78%
54jcs3360
Scheme 1.32 Arene alkylation or acylation with α-chloroketones and -nitriles [145–148].
only, the arene cannot usually be used as solvent, because it would not allow therequired UV light to reach the haloester (second example in Scheme 1.33).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 cyclopropanatealkenes, alkynes, and even arenes. For this reason, diazocarbonyl compounds (ordiazoalkanes [6]) are only rarely used as electrophilic alkylating reagents for arenes.
The arylation of α-haloketones and related electrophiles via vicarious nucleophilicsubstitution is discussed in Section 8.2.3.
1.3.6Nitroalkanes
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 reactionis complicated by numerous potential side reactions. Nitro groups can act ascarbon electrophiles without loss of the nitro group. Moreover, in the presence
1.3 Problematic Electrophiles 27
N+ CO2EtI
1 eq20 eq
12 eq H2O2 (35%)
0.6 eq FeSO4−7H2O
DMSO, 20 °C
NCO2Et
55%
92joc6817
+ CO2EtCl
hν (254 nm)25 °C
1 eq solvent
CO2Et+ CO2Et
EtO2C
78% 1%
69bcsj794
Mn(OAc)3
1 eq
+
excess
+
O
excess
AcOH, 56 °C
O O+
O+
O
Obyproduct
14 : 20 : 66
51% yield
+84joc1603
Scheme 1.33 Arylation of α-haloesters and ketones via radicals [149–151].
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 atoxygen. Examples have also been reported of electrophilic aromatic aminationswith nitro groups (last example, Scheme 1.35).
In the presence of dehydrating reagents, primary nitroalkanes (RCH2NO2) canbe converted to nitrile oxides, which are highly reactive and readily dimerize,polymerize, rearrange to isocyanates, react with nucleophiles, or undergo 1,3-dipolar cycloadditions.
1.3.7Ketones
Upon catalysis by acids, simple dialkylketones react cleanly with only electron-richarenes, 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 andoligomerization of the resulting olefin are also occasionally observed. If the alcohol
28 1 Electrophilic Alkylation of Arenes
NO
O
Ph +
CO2Me
PhN2
2% Cu(OTf)2
CH2Cl2, 20 °C, 12 h
NO
O
Ph
Ph
CO2Me
85%
10ejoc6719
N
CO2Me
Ph
Ph
PhO
N2
O
2.7% Rh2(OAc)4
DCE, 84 °C, 9 h
N
CO2MePh
O
Ph
Ph
O
+N
CO2Me
Ph
Ph
Ph
N
CO2Me
Ph
PhO
O
+N
CO2Me
Ph
O
O
Ph
Ph+
12% 22% 18% 16%
95tet8829
Scheme 1.34 Reaction of α-diazoesters with arenes [152, 153].
is the desired product, a mildly acidic catalyst and carefully optimized conditionswill often be required.
Isopropenylbenzene, for instance, cannot be directly prepared from acetone andbenzene (for recent research, see [159]) because the readily formed cumyl cationreacts with benzene [160]. The direct preparation of isopropenylbenzene fromacetone would be valuable because, during the production of phenol from cumenehydroperoxide, one equivalent of acetone is formed, which cannot currently beused directly for the preparation of cumene. Processes have been developed inwhich acetone is hydrogenated to isopropanol, which is then converted to propeneand used to alkylate benzene (Scheme 1.36). The direct alkylation of benzenewith isopropyl alcohol is possible [161, 162], but most catalysts for Friedel–Craftsalkylations are deactivated by water, and isopropylations with propene are thereforemore convenient than isopropylations with isopropanol.
Only ketones substituted with electron-withdrawing groups, such as trifluo-romethylketones, 1,2-diketones, or α-ketocarboxylic esters, react with unactivatedarenes. Fluorenones are also quite reactive because O-protonated fluorenones areantiaromatic. The initially formed alcohols do not form carbocations readily andcan often be isolated (Scheme 1.37).
Potential side reactions of the Friedel–Crafts alkylation with ketones is theformation of diarylmethanes, the oligomerization of the products, and aldol con-densation of the starting ketone. Moreover, in the presence of oxidants, ketonesmay be α-arylated via intermediate radical formation [151]. If Friedel–Crafts alky-lations with ketones are conducted in the presence of hydride donors, a reductivealkylation of arenes can occur (Scheme 1.38).
1.3 Problematic Electrophiles 29
MeO
MeO
SPh
NO2
O2 eq SnCl4
CH2Cl2, 20 °C, 3 h
86%
MeO
MeO SPh
O
87joc4133
CO2Me
NO2
10 eq F3CSO3H
CHCl3, 50 °C, 0.5 h CO2Me
NO
85%
CO2Me
NO2
10 eq F3CSO3H
CHCl3, 50 °C, 0.5 h
55%MeO
ON
O
CO2Me
07ja1724
07ja1724
Br
O
NO2
50 eq C6H6
10 eq F3CSO3H
CH2Cl2, 0 °C, 20 min
Br
O
NOH Br
O
NOH
OH+ +
66% 13% 11%
09syn4129
NH
SMe
NO2
POCl3, MeCN
80 °C, 4 h
50%N SMe
N Cl
05ol2169
Scheme 1.35 Reactions of nitroalkanes with arenes [154–157]. Further examples: [158].
Strongly C–H acidic ketones, such as β-ketoesters, are readily palladated atcarbon. The resulting intermediates can undergo β-hydride elimination to yieldα,β-unsaturated ketones. The latter are Michael acceptors, capable of alkylatingelectron-rich arenes (Scheme 1.39).
Occasionally, benzylic electrophiles are attacked by nucleophiles not at thebenzylic position but at the arene (e.g., first equation in Scheme 1.37). Exampleshave been reported of the electrophilic arylation of unsubstituted arenes withtetralones and related aryl ketones (Scheme 1.40).
30 1 Electrophilic Alkylation of Arenes
+
acidiccatalyst
cumene
air
OOH
OH
+
O
phenol(high demand)
acetone(low demand)
H2
catalystOH
+
O
or
OH
Scheme 1.36 Preparation of phenol and acetone from benzene.
NCF3
O
excess C6H6
22 eq CF3SO3H
25 °C, 2 h
79%N
CF3
HO
C6H6
CF3SO3H
60 °C86%
NCF3
Ph
10ja3266
F3C CF3
O O
excess C6H6
22 eq CF3SO3H
25 °C, 2 h
F3C CF3
Ph Ph83%
but:
O OC6H6
CF3SO3Hno reaction
10ja3266
10ja3266
N
O
O
TFA (0.9 M)20 °C
NO
HO
+ NO
HO
N O
11ol5536
Scheme 1.37 Alkylation of arenes and heteroarenes by ketones [163–167].
1.3 Problematic Electrophiles 31
EtO
+CO2Et
O
1.0 eq 1.1 eq
1.0 eq TiCl4CH2Cl2, 0 °C, 4 h
EtO
OH
CO2Et
+
EtO
CO2Et
OEt
+
EtO
CO2Et CO2Et
OEtOEt
15% 60% 11%
EtO
+CO2Et
O
1.0 eq 1.1 eq
1.0 eq TiCl42.5 eq Al2O3, CH2Cl2
−15 °C, 8 h
EtO
OH
CO2Et
85%
06asc898
06asc898
NH
+
O
1 eq 1 eq
0.5 eq TFACH2Cl2, 20 °C, 18 h
N
NH
79%
11ol5846
NH
+
AcOH, 2N H3PO480 °C, 13 h
40%
1.0 eq
NO
CO2Et
1.5 eq
N
CO2EtNH75joc2525
Scheme 1.37 (Continued)
+
O
excess
Me2SiClH
5% InCl3110 °C, 3 h
99%
99tet1017
Scheme 1.38 Reductive aromatic alkylation with ketones [168].
32 1 Electrophilic Alkylation of Arenes
O
CO2Et
1.5 eq
+
OMe
MeO OMe
1.0 eq
0.5 eq ( PhO)2PO(OH)
10% Pd(OAc)2
AcOH, DCE, 25 °C, 24 h
OMe
MeO OMe
CO2EtO
OMe
MeO OMe
CO2EtO
+
87% 3%
O
CO2Et
PdOAc
O
CO2Et
12cej12590
Scheme 1.39 Dehydrogenation as side reaction of the Pd-catalyzed arylation of ketones[169].
O6 eq AlCl3
C6H6, 25 °C, 48 h
O
56% 10%
7% 5%
+ +
+
90joc4036
Scheme 1.40 Arylation of benzene with tetralone [83].
1.3.8Alcohols
Alcohols are widely used electrophiles for Friedel–Crafts alkylations. Alcohols areoften more reactive than alkyl halides, but require more acid to alkylate arenes.Primary, non-benzylic alcohols are rarely used as alkylating reagents, owing to theirfast rearrangement to more stable secondary or tertiary cations.
As is the case with other electrophiles, alcohols that do not readily form carbo-cations are not well suited for arene alkylation. No examples for cationic arenealkylations with 2,2,2-trihaloethanols or cyanohydrins, for instance, could be found.Only a few examples have been reported of alkylations with α-hydroxycarboxylicacids or α-hydroxyketones, and most of these examples were alcohols withcarbocation-stabilizing α-substituents (e.g., benzylic alcohols).
Under strongly basic conditions, indole can be alkylated at C-3 with glycolicacid, but this reaction proceeds by oxidation of the alcohol to an intermediatealdehyde (Scheme 1.41). A similar alkylation of fluorene with alcohols at thebenzylic methylene group has also been reported [170, 171].
1.3 Problematic Electrophiles 33
NH
+
1 eq
F3C
NN
CO2H
NHAc
AcO
Ac2O, AcOH
20 °C, 1.5 h
NH
F3C
NN
CO2H
NHAc
25%
2 eq 12joc8581
NH
+ CO2HHO
1.0 eq 1.1 eq
1.4 eq KOH
H2O, 250 °C,18 h
then HCl
NH
CO2H
87−93%
CO2KON
H
CO2K
OH
N
CO2K
− H2+ H2 + HCl
oscv(5)654
NH
O
OOH
OH
+
AcOH, 2N H3PO4
reflux, 0.5 h
NH
O
50%
1.0 eq 0.7 eq WO 2008095835
Scheme 1.41 Alkylation of indoles with alcohols and esters [172–174].
OH
NPh
20 eq PhMe2 eq AlCl3
CH2Cl2, 60 °C, 24 h NPh
85%
10cej50
NOH
S
PPA, 160 °C, 6 h N
S
56%
06jmc760
NH
+ OHHO
19 eq1 eq
25% Ba(OH)2−8H2O
250 °C, 20 h
NH
OH
70%
US 3197479
Scheme 1.42 Alkylation of arenes with 2-aminoalcohols and ethylene glycol [175–177].
34 1 Electrophilic Alkylation of Arenes
Alcohols or esters thereof, which upon dehydratization yield Michael acceptors,react as soft electrophiles, and are well suited for the alkylation of electron-richarenes (first equation, Scheme 1.41).
2-Amino- and 2-alkoxyethanols are further types of alcohol that do not readilyalkylate arenes under acidic conditions. Oxygen and nitrogen are more electro-negative than carbon, and the corresponding carbocations are destabilized by aninductive effect. Moreover, the acids will protonate amines and ethers, and thusfurther slow down the formation of the required dications. Otherwise, only activatedalcohols (e.g., benzylic or allylic alcohols) or intramolecular alkylations proceed inacceptable yields (Scheme 1.42).
2. Xu, X., Xu, X., Li, H., Xie, X., and Li,Y. (2010) Iron-catalyzed, microwave-promoted, one-pot synthesis of9-substituted xanthenes by a cascadebenzylation-cyclization process. Org.Lett., 12, 100–103.
3. Chung, K.H., Kim, J.N., and Ryu,E.K. (1994) Friedel–Crafts alkylationreactions of benzene with amide bondcontaining compounds. TetrahedronLett., 35, 2913–2914.
4. Bonvino, V., Casini, G., Ferappi, M.,Cingolani, G.M., and Pietroni, B.R.(1981) Nitro compounds as alkylatingreagents in Friedel–Crafts condi-tions: reaction of 2-nitropropane withbenzene. Tetrahedron, 37, 615–620.
5. Margosian, D., Speier, J., andKovacic, P. (1981) Formation of(1-adamantylcarbinyl)arenes from 3-azidohomoadamantane–aluminumchloride–aromatic substrates. J. Org.Chem., 46, 1346–1350.
6. Zhao, X., Wu, G., Zhang, Y., andWang, J. (2011) Copper-catalyzed directbenzylation or allylation of 1,3-azoleswith N-tosylhydrazones. J. Am. Chem.Soc., 133, 3296–3299.
7. Klumpp, D.A., Aguirre, S.L., Sanchez,G.V. Jr., and de Leon, S.J. (2001) Reac-tions of amino alcohols in superacid:the direct observation of dicationicintermediates and their application insynthesis. Org. Lett., 3, 2781–2784.
8. Ohwada, T., Kasuga, M., and Shudo, K.(1990) Direct observation of an inter-mediate in the oxygen atom rearrange-ment of 2-cyclopropylnitrobenzenein a strong acid. J. Org. Chem., 55,2717–2719.
9. Katritzky, A.R., Lopez Rodriguez,M.L., Keay, J.G., and King, R.W.(1985) Nucleophilic displacementwith heterocycles as leaving groups.Part 16. Reactions of secondary alkylprimary amines with 5,6,8,9-tetrahydro-7-phenyldibenzo[c,h]xanthyliumtrifluoromethanesulfonate to giveintermediates solvolysing without rear-rangement. J. Chem. Soc., Perkin Trans.2, 165–169.
10. Imm, S., Bahn, S., Tillack, A., Mevius,K., Neubert, L., and Beller, M. (2010)Selective ruthenium-catalyzed alkylationof indoles by using amines. Chem. Eur.J., 16, 2705–2709.
11. Quast, H., Nudling, W., Klemm, G.,Kirschfeld, A., Neuhaus, P., Sander,W., Hrovat, D.A., and Borden, W.T.(2008) A perimidine-derived non-Kekule triplet diradical. J. Org. Chem.,73, 4956–4961.
12. Mazik, M. and Sonnenberg, C. (2010)Isopropylamino and isobutylaminogroups as recognition sites for carbohy-drates: acyclic receptors with enhancedbinding affinity toward β-galactosides.J. Org. Chem., 75, 6416–6423.
13. Wallace, K.J., Hanes, R., Anslyn,E., Morey, J., Kilway, K.V., andSiegel, J. (2005) Preparation of
References 35
1,3,5-tris(aminomethyl)-2,4,6-triethylbenzene from two versatile1,3,5-tri(halosubstituted) 2,4,6-triethylbenzene derivatives. Synthesis,2080–2083.
14. Saulnier, G., Dodier, M., Frennesson,D.B., Langley, D.R., and Vyas, D.M.(2009) Nucleophilic capture of theimino-quinone methide type intermedi-ates generated from 2-aminothiazol-5-ylcarbinols. Org. Lett., 11, 5154–5157.
15. Piao, C., Zhao, Y., Han, X., andLiu, Q. (2008) AlCl3-mediated directcarbon–carbon bond-forming reac-tion of α-hydroxyketene-S,S-acetalswith arenes and synthesis of 3,4-disubstituted dihydrocoumarin deriva-tives. J. Org. Chem., 73, 2264–2269.
16. O’Keefe, B.M., Mans, D.M., Kaelin,D.E., and Martin, S.F. (2010) Total syn-thesis of isokidamycin. J. Am. Chem.Soc., 132, 15528–15530.
17. Izumi, K., Kabaki, M., Uenaka, M., andShimizu, S. (2007) One-step synthesisof 5-(4-fluorobenzyl)-2-furyl methylketone: a key intermediate of HIV-integrase inhibitor S-1360. Org. ProcessRes. Dev., 11, 1059–1061.
18. Piccolo, O., Azzena, U., Melloni, G.,Delogu, G., and Valoti, E. (1991) Stere-ospecific Friedel–Crafts alkylation ofaromatic compounds: synthesis of opti-cally active 2- and 3-arylalkanoic esters.J. Org. Chem., 56, 183–187.
19. Klumpp, D.A., Garza, M., Jones, A.,and Mendoza, S. (1999) Synthesisof aryl-substituted piperidines bysuperacid activation of piperidones. J.Org. Chem., 64, 6702–6705.
20. Hofmann, M., Hampel, N., Kanzian,T., and Mayr, H. (2004) Electrophilicalkylations in neutral aqueous or alco-holic solutions. Angew. Chem. Int. Ed.,43, 5402–5405.
21. Liu, C. and Widenhoefer, R.A. (2006)Scope and mechanism of the PdII-catalyzed arylation/carboalkoxylation ofunactivated olefins with indoles. Chem.Eur. J., 12, 2371–2382.
22. Zhao, Y. and Chen, G. (2011)Palladium-catalyzed alkylation ofortho-C(sp2)–H bonds of benzylamidesubstrates with alkyl halides. Org. Lett.,13, 4850–4853.
23. Ackermann, L., Novak, P., Vicente, R.,and Hofmann, N. (2009) Ruthenium-catalyzed regioselective direct alkylationof arenes with unactivated alkyl halidesthrough C–H bond cleavage. Angew.Chem. Int. Ed., 48, 6045–6048.
24. Hofmann, N. and Ackermann, L.(2013) Meta-selective C–H bond alky-lation with secondary alkyl halides. J.Am. Chem. Soc., 135, 5877–5884.
25. Tsai, A.S., Brasse, M., Bergman, R.G.,and Ellman, J.A. (2011) Rh(III)-catalyzed oxidative coupling ofunactivated alkenes via C–H activation.Org. Lett., 13, 540–542.
26. Yu, D., Lee, S., Sum, Y.N., andZhang, Y. (2012) Selective for-mation of formamidines or 7-aminomethylbenzoxazoles fromunprecedented couplings betweenbenzoxazoles and amines. Adv. Synth.Catal., 354, 1672–1678.
27. Matsuzawa, H., Miyake, Y., andNishibayashi, Y. (2007) Ruthenium-catalyzed enantioselective propargy-lation of aromatic compounds withpropargylic alcohols via allenylideneintermediates. Angew. Chem. Int. Ed.,46, 6488–6491.
28. Mertins, K., Iovel, I., Kischel, J., Zapf,A., and Beller, M. (2005) Transition-metal-catalyzed benzylation of arenesand heteroarenes. Angew. Chem. Int.Ed., 44, 238–242.
29. Olah, G.A. and Kuhn, S.J. (1964)Selective Friedel–Crafts reactions. I.Boron halide catalyzed haloalkylationof benzene and alkylbenzenes withfluorohaloalkanes. J. Org. Chem., 29,2317–2320.
30. Shi, Z. and Chuan, H. (2004) Directfunctionalization of arenes by pri-mary alcohol sulfonate esters catalyzedby gold(III). J. Am. Chem. Soc., 126,13596–13597.
31. Mayr, H., Lang, G., and Ofial, A.R.(2002) Reactions of carbocations withunsaturated hydrocarbons: electrophilicalkylation or hydride abstraction? J.Am. Chem. Soc., 124, 4076–4083.
32. Serres, C. and Fields, E.K. (1963) Syn-thesis of 2,2-diarylpropanes by hydridetransfer. J. Org. Chem., 28, 1624–1627.
36 1 Electrophilic Alkylation of Arenes
33. Coumbarides, G.S., Dingjan, M.,Eames, J., and Weerasooriya, N. (2001)Investigations into the brominationof substituted phenols using diethylbromomalonate and diethyl dibromo-malonate. Bull. Chem. Soc. Jpn., 74,179–180.
34. Kinoyama, I., Miyazaki, T.,Koganemaru, Y., Shiraishi, N.,Kawamoto, Y., and Washio, T. (2011)Acylguanidine derivatives. US Patent2011306621.
35. Pradhan, A., Dechambenoit, P., Bock,H., and Durola, F. (2013) Twisted poly-cyclic arenes by intramolecular Schollreactions of C3-symmetric precursors.J. Org. Chem., 78, 2266–2274.
36. Shen, Y., Liu, H., Wu, M., Du,W., Chen, Y., and Li, N. (1991)Friedel–Crafts alkylation of benzenessubstituted with meta-directing groups.J. Org. Chem., 56, 7160–7162.
37. Dall’Asta, L., Casazza, U., andCotticelli, G. (2001) Process for thepreparation of 5-carboxyphthalide. EPPatent 1118614.
38. Buc, S.R. (1956) Preparation of meta-nitrobenzyl chlorides. US Patent2758137.
39. Grellier, M., Vendier, L., Chaudret, B.,Albinati, A., Rizzato, S., Mason, S.,and Sabo-Etienne, S. (2005) Synthe-sis, neutron structure, and reactivityof the bis(dihydrogen) complexRuH2(𝜂2-H2)2(PCyp3)2 stabilized bytwo tricyclopentylphosphines. J. Am.Chem. Soc., 127, 17592–17593.
40. Mochida, S., Hirano, K., Satoh, T., andMiura, M. (2011) Rhodium-catalyzedregioselective olefination directed bya carboxylic group. J. Org. Chem., 76,3024–3033.
41. Park, S.H., Kim, J.Y., and Chang, S.(2011) Rhodium-catalyzed selective ole-fination of arene esters via C–H bondactivation. Org. Lett., 13, 2372–2375.
42. Rakshit, S., Grohmann, C., Besset, T.,and Glorius, F. (2011) Rh(III)-catalyzeddirected C–H olefination using an oxi-dizing directing group: mild, efficient,and versatile. J. Am. Chem. Soc., 133,2350–2353.
43. Busch, S. and Leitner, W. (2001)Ruthenium-catalysed Murai-type cou-plings at room temperature. Adv.Synth. Catal., 343, 192–195.
44. Ackermann, L. and Novak, P. (2009)Regioselective ruthenium-catalyzeddirect benzylations of arenes throughC–H bond cleavages. Org. Lett., 11,4966–4969.
45. Jun, C., Moon, C.W., Hong, J., Lim,S., Chung, K., and Kim, Y. (2002)Chelation-assisted RhI-catalyzed ortho-alkylation of aromatic ketimines, orketones with olefins. Chem. Eur. J., 8,485–492.
46. Wang, X., Truesdale, L., and Yu,J. (2010) Pd(II)-catalyzed ortho-trifluoromethylation of arenes usingTFA as a promoter. J. Am. Chem. Soc.,132, 3648–3649.
47. Ueno, S., Kochi, T., Chatani, N., andKakiuchi, F. (2009) Unique effectof coordination of an alkene moietyin products on ruthenium-catalyzedchemoselective C–H alkenylation. Org.Lett., 11, 855–858.
48. Yang, Y., Lin, Y., and Rao, Y. (2012)Ruthenium(II)-catalyzed synthesis ofhydroxylated arenes with ester as aneffective directing group. Org. Lett., 14,2874–2877.
49. Yadav, M.R., Rit, R.K., and Sahoo, A.K.(2012) Sulfoximines: a reusable direct-ing group for chemo- and regioselectiveortho C–H oxidation of arenes. Chem.Eur. J., 18, 5541–5545.
50. Martinez, R., Simon, M., Chevalier, R.,Pautigny, C., Genet, J.-P., and Darses,S. (2009) C–C bond formation viaC–H bond activation using an in situ-generated ruthenium catalyst. J. Am.Chem. Soc., 131, 7887–7895.
51. Ueno, S., Chatani, N., and Kakiuchi,F. (2007) Ruthenium-catalyzed C–Cbond formation via the cleavage of anunreactive aryl C–N bond in anilinederivatives with organoboronates. J.Am. Chem. Soc., 129, 6098–6099.
52. Sonoda, M., Kakiuchi, F., Chatani,N., and Murai, S. (1997) Ruthenium-catalyzed addition of C–H bonds inaromatic ketones to olefins. The effect
References 37
of various substituents at the aro-matic ring. Bull. Chem. Soc. Jpn., 70,3117–3128.
53. Ueno, S., Mizushima, E., Chatani, N.,and Kakiuchi, F. (2006) Direct obser-vation of the oxidative addition of thearyl C–O bond to a ruthenium com-plex and elucidation of the relativereactivity between aryl C–O and arylC–H bonds. J. Am. Chem. Soc., 128,16516–16517.
54. Ryu, J., Cho, S.H., and Chang, S.(2012) A versatile rhodium(I) catalystsystem for the addition of heteroarenesto both alkenes and alkynes by a C–Hbond activation. Angew. Chem. Int. Ed.,51, 3677–3681.
55. Yao, B., Song, R., Liu, Y., Xie, Y., Li,J., Wang, M., Tang, R., Zhang, X., andDeng, C. (2012) Palladium-catalyzedC–H oxidation of isoquinoline N-oxides: selective alkylation with dialkylsulfoxides and halogenation with dihalosulfoxides. Adv. Synth. Catal., 354,1890–1896.
56. Tran, L.D. and Daugulis, O. (2010)Iron-catalyzed heterocycle and arenedeprotonative alkylation. Org. Lett., 12,4277–4279.
57. Popov, I., Do, H., and Daugulis, O.(2009) In situ generation and trap-ping of aryllithium and arylpotassiumspecies by halogen, sulfur, and car-bon electrophiles. J. Org. Chem., 74,8309–8313.
58. Linhardt, R.J., Montgomery, B.L.E.,Osby, J., and Sherbine, J. (1982)Mechanism for diacyl peroxide decom-position. J. Org. Chem., 47, 2242–2251.
59. Molander, G.A., Colombel, V., andBraz, V.A. (2011) Direct alkylation ofheteroaryls using potassium alkyl- andalkoxymethyltrifluoroborates. Org. Lett.,13, 1852–1855.
60. Glazunov, V.P., Tchizhova, A.Y.,Pokhilo, N.D., Anufriev, V.P., andElyakov, G.B. (2002) First directobservation of tautomerism of mono-hydroxynaphthazarins. Tetrahedron, 58,1751–1757.
61. Guo, X. and Li, C.-J. (2011)Ruthenium-catalyzed para-selectiveoxidative cross-coupling of arenes andcycloalkanes. Org. Lett., 13, 4977–4979.
62. Minisci, F., Vismara, E., and Fontana,F. (1989) Homolytic alkylation ofprotonated heteroaromatic bases byalkyl iodides, hydrogen peroxide, anddimethyl sulfoxide. J. Org. Chem., 54,5224–5227.
63. Miller, B.L., Palde, P.B., and Gareiss,P.C. (2008) Tripodal cyclohexanederivatives and their use as car-bohydrate receptors., WO Patent2008048967.
64. Duncton, M.A.J., Estiarte, M.A.,Johnson, R.J., Cox, M., O’Mahony,D.J.R., Edwards, W.T., and Kelly, M.G.(2009) Preparation of heteroaryloxe-tanes and heteroarylazetidines by useof a Minisci reaction. J. Org. Chem., 74,6354–6357.
65. Yoshida, M., Amemiya, H., Kobayashi,M., Sawada, H., Hagii, H., andAoshima, K. (1985) Perfluoropropy-lation of aromatic compounds withbis(heptafluorobutyryl) peroxide. J.Chem. Soc., Chem. Commun, 234–236.
66. Firth, B.E. and Rosen, T.J. (1985)Preparation of ortho-alkylated phenols.US Patent 4538008.
67. Rao, H.S.P., Geetha, K., andKamalraj, M. (2011) Synthesis of 4-(2-hydroxyaryl)-3-nitro-4H-chromenes.Tetrahedron, 67, 8146–8154.
68. Lee, D.-H., Kwon, K.-H., and Yi, C.S.(2012) Dehydrative C–H alkylation andalkenylation of phenols with alcohols:expedient synthesis for substitutedphenols and benzofurans. J. Am. Chem.Soc., 134, 7325–7328.
69. Toshima, K., Matsuo, G., Ishizuka,T., Ushiki, Y., Nakata, M., andMatsumura, S. (1998) Aryl andallyl C-glycosidation methods usingunprotected sugars. J. Org. Chem., 63,2307–2313.
70. Podder, S., Choudhury, J., Roy, U.K.,and Roy, S. (2007) Dual-reagent cata-lysis within Ir–Sn domain: highlyselective alkylation of arenes and hete-roarenes with aromatic aldehydes. J.Org. Chem., 72, 3100–3103.
71. Zhang, C., Gao, X., Zhang, J., andPeng, X. (2010) Fe/CuBr2-catalyzedbenzylation of arenes and thiopheneswith benzyl alcohols. Synlett, 261–265.
38 1 Electrophilic Alkylation of Arenes
72. Firth, B.E. (1981) Preparation of 2,4,6-triisopropylphenol. US Patent 4275248.
73. Klemm, L.H. and Taylor, D.R. (1980)Alumina-catalyzed reactions of hydrox-yarenes and hydroaromatic ketones. 9.Reaction of phenol with l-propanol. J.Org. Chem., 45, 4320–4326.
74. Kealy, T.J. and Coffman, D.D. (1961)Thermal addition reactions of mono-cyclic phenols with ethylene. J. Org.Chem., 26, 987–992.
75. Zhao, C., Camaioni, D.M., and Lercher,J.A. (2012) Selective catalytic hydroalky-lation and deoxygenation of substitutedphenols to bicycloalkanes. J. Catal.,288, 92–103.
76. Kolka, J., Napolitano, J.P., and Ecke,G.G. (1956) The ortho-alkylation ofphenols. J. Org. Chem., 21, 712–713.
77. Nakagawa, Y. and Sato, T. (2009)Preparation of 2,6-diphenylphenols. JPPatent 2009269868.
78. Youn, S.W. and Eom, J.I. (2006) Ag(I)-catalyzed sequential C–C and C–Obond formations between phenols anddienes with atom economy. J. Org.Chem., 71, 6705–6707.
79. Ancel, J.E., Bienayme, H., andMeilland, P. (1996) Procede despreparations de phenols substitues.EP Patent 0742194.
80. Dang, T.T., Boeck, F., andHintermann, L. (2011) HiddenBrønsted acid catalysis: pathways ofaccidental or deliberate generation oftriflic acid from metal triflates. J. Org.Chem., 76, 9353–9361.
81. Repinskaya, I.B., Barkhutova, D.D.,Makarova, Z.S., Alekseeva, A.V., andKoptyug, V.A. (1985) Condensationof phenols and their derivatives witharomatic compounds in the presence ofacidic agents. VII. Comparison of thecondensation of phenols with aromaticcompounds in HF–SbF5 and in thepresence of aluminum halides. Zh.Org. Khim., 21, 836–845 (translation:759–767).
82. Repinskaya, I.B. and Koptyug, V.A.(1980) Condensation of substi-tuted resorcinols with benzene andchlorobenzene. Zh. Org. Khim., 16,1508–1514 (translation: 1298–1303).
83. El-Zohry, M.F. and El-Khawaga, A.M.(1990) Nonconventional Friedel–Craftschemistry. 1. Reaction of α-tetraloneand anthrone with arenes underFriedel–Crafts conditions. J. Org.Chem., 55, 4036–4039.
84. Koptyug, V.A. and Golounin, A.V.(1973) Reaction of phenols with Lewisacids VIII. Reaction of phenol and itsmethylated derivatives with benzeneand aluminum halides. Zh. Org. Khim.,9, 2158–2163 (translation: 2172–2176).
85. Koltunov, K.Y., Walspurger, S.,and Sommer, J. (2004) Superelec-trophilic activation of polyfunctionalorganic compounds using zeolites andother solid acids. Chem. Commun.,1754–1755.
86. Witten, B. and Reid, E.E. (1963) p-Aminotetraphenylmethane. Org. Synth.,Coll. Vol. 4, 47–48.
87. Schultz, W.J., Portelli, G.B., and Tane,J.P. (1986) Epoxy resin curing agent,curing process and composition con-taining it. EP Patent 0203828.
88. Cherian, A.E., Domski, G.J., Rose, J.M.,Lobkovsky, E.B., and Coates, G.W.(2005) Acid-catalyzed ortho-alkylationof anilines with styrenes: an improvedroute to chiral anilines with bulkysubstituents. Org. Lett., 7, 5135–5137.
89. Mace, Y., Raymondeau, B., Pradet,C., Blazejewski, J.-C., and Magnier,E. (2009) Benchmark and solvent-free preparation of sulfonium saltbased electrophilic trifluoromethylat-ing reagents. Eur. J. Org. Chem., 2009,1390–1397.
90. Yanai, H., Yoshino, T., Fujita, M.,Fukaya, H., Kotani, A., Kusu, F., andTaguchi, T. (2013) Synthesis, character-ization, and applications of zwitterionscontaining a carbanion moiety. Angew.Chem. Int. Ed., 52, 1560–1563.
91. Hickinbottom, W.J. (1933) The elimi-nation of tertiary alkyl groups fromalkylanilines by hydrolysis. J. Chem.Soc., 1070–1073.
92. Pillai, R.B.C. (1999) Isomerisationof N-isopropylaniline and N-n-propylaniline over zeolites. J. IndianChem. Soc., 76, 157–158.
93. Beyer, H., Gerencserne, A., Palkovics,I., Gemes, I., Ratosi, E., Sebestyen,
References 39
B., Horvath, J., Czagler, I., Perger, J.,Hegedus, I., Aranyi, P., Torkos, L.,Hodossy, L., Borbeli, G., and Halasz,I. (1992) Process for the Preparationof Ring-Alkylated Anilines by Iso-merization of N-alkylanilines OverAcidic Zeolites as Catalysts. Ger. Offen.4023652.
95. Glass, D.B. and Weissberger, A. (1955)Julolidine. Org. Synth., Coll. Vol. 3,504–505.
96. Lapis, A.A.M., DaSilveira Neto, B.A.,Scholten, J.D., Nachtigall, F.M.,Eberlin, M.N., and Dupont, J. (2006)Intermolecular hydroamination andhydroarylation reactions of alkenesin ionic liquids. Tetrahedron Lett., 47,6775–6779.
97. Motokura, K., Nakagiri, N., Mizugaki,T., Ebitani, K., and Kaneda, K. (2007)Nucleophilic substitution reactions ofalcohols with use of montmorillonitecatalysts as solid Brønsted acids. J. Org.Chem., 72, 6006–6015.
98. Tsuji, Y., Huh, K.-T., Ohsugi, Y., andWatanabe, Y. (1985) Ruthenium com-plex catalyzed N-heterocyclization.Syntheses of N-substituted piperidines,morpholines, and piperazines fromamines and 1,5-diols. J. Org. Chem., 50,1365–1370.
99. Wei, H., Qian, G., Xia, Y., Li, K., Li,Y., and Li, W. (2007) BiCl3-catalyzedhydroamination of norbornene witharomatic amines. Eur. J. Org. Chem.,2007, 4471–4474.
100. Didier, D. and Sergeyev,S. (2007) Bromination andiodination of 6H,12H-5,11-methanodibenzo[b,f ][1,5]diazocine:a convenient entry to unsymmetricalanalogs of Troger’s base. Eur. J. Org.Chem., 2007, 3905–3910.
101. Corma, A., Botella, P., and Mitchell,C. (2004) Replacing HCl by solid acidsin industrial processes: synthesis ofdiamino diphenyl methane (DADPM)for producing polyurethanes. Chem.Commun., 2008–2010.
102. Mitchell, C.J., Corma Canos, A., Carr,R.H., and Botella Asuncion, P. (2010)Process for production of methylene-bridged polyphenyl polyamines. WOPatent 2010072504.
103. Chauvin, A.-S., Comby, S., Song,B., Vandevyver, C.D.B., Thomas,F., and Bunzli, J.-C.G. (2007) Apolyoxyethylene-substituted bimetal-lic europium helicate for luminescentstaining of living cells. Chem. Eur. J.,13, 9515–9526.
104. Ellis, G.D., Dimarcello, B.J., andBradshaw, D.J. (1999) Preparationof a dye for coloring protein-basedfibers and cellulose-based materialsfrom the oxidation byproducts of themanufacture of a triphenylmethanedye. EP Patent 0909794.
105. Ecke, G.G., Napolitano, J.P., and Kolka,A.J. (1956) The ortho-alkylation ofaromatic amines. J. Org. Chem., 21,711–712.
106. Chockalingam, K. (2009) Preparation of2-(1,3-dimethylbutyl)aniline and otherbranched alkyl-substituted anilines. WOPatent 2009029383.
107. Diamond, S.E., Szalkiewicz, A., andMares, F. (1979) Reactions of anilinewith olefins catalyzed by group 8 metalcomplexes: N-alkylation and heterocy-cle formation. J. Am. Chem. Soc., 101,490–491.
108. Ecke, G.G., Napolitano, J.P., Filbey,A.H., and Kolka, A.J. (1957) Ortho-alkylation of aromatic amines. J. Org.Chem., 22, 639–642.
110. Tan, K.L., Park, S., Ellman, J.A., andBergman, R.G. (2004) Intermolecularcoupling of alkenes to heterocycles viaC–H bond activation. J. Org. Chem.,69, 7329–7335.
111. Jiao, L., Herdtweck, E., and Bach,T. (2012) Pd(II)-catalyzed regiose-lective 2-alkylation of indoles via anorbornene-mediated C–H activation:mechanism and applications. J. Am.Chem. Soc., 134, 14563–14572.
112. Olah, G.A., Farooq, O., Farnia,S.M.F., and Olah, J.A. (1988)
40 1 Electrophilic Alkylation of Arenes
Boron, aluminum, and galliumtris(trifluoromethanesulfonate) (triflate):effective new Friedel–Crafts catalysts. J.Am. Chem. Soc., 110, 2560–2565.
118. Matsumoto, T., Taube, D.J., Periana,R.A., Taube, H., and Yoshida, H.(2000) Anti-Markovnikov olefin aryla-tion catalyzed by an iridium complex. J.Am. Chem. Soc., 122, 7414–7415.
119. Sun, Z.-M., Zhang, J., Manan, R.S.,and Zhao, P. (2010) Rh(I)-catalyzedolefin hydroarylation with electron-deficient perfluoroarenes. J. Am. Chem.Soc., 132, 6935–6937.
120. Liu, F., Martin-Mingot, A.,Jouannetaud, M., Zunino, F., andThibaudeau, S. (2010) Superelec-trophilic activation in superacidHF/SbF5 and synthesis of benzofusedsultams. Org. Lett., 12, 868–871.
121. Okabe, K., Ohwada, T., Ohta, T., andShudo, K. (1989) Novel electrophilicspecies equivalent to α-keto cations.Reactions of O,O-diprotonated nitroolefins with benzenes yield arylmethylketones. J. Org. Chem., 54, 733–734.
122. Fujiwara, Y., Kuromaru, H., andTaniguchi, H. (1984) Trifluoroaceticacid catalyzed allylic phenylation ofα-methylallyl acetate, α-methylallyltrifluoroacetate, and α-methylallyl alco-hol with benzene. J. Org. Chem., 49,4309–4310.
123. Fan, S., Chen, F., and Zhang, X. (2011)Direct palladium-catalyzed intermolecu-lar allylation of highly electron-deficientpolyfluoroarenes. Angew. Chem. Int.Ed., 50, 5918–5923.
124. Makida, Y., Ohmiya, H., andSawamura, M. (2012) Regio- and stere-ocontrolled introduction of secondaryalkyl groups to electron-deficient arenesthrough copper-catalyzed allylic alky-lation. Angew. Chem. Int. Ed., 51,4122–4127.
125. Yao, T., Hirano, K., Satoh, T., andMiura, M. (2011) Stereospecificcopper-catalyzed C–H allylation ofelectron-deficient arenes with allylphosphates. Angew. Chem. Int. Ed., 50,2990–2994.
126. Zhang, Y., Chen, L., and Lu, T. (2011)A copper(II) triflate-catalyzed tandemFriedel–Crafts alkylation/cyclizationprocess towards dihydroindenes. Adv.Synth. Catal., 353, 1055–1060.
127. Muller, H., Trubenbach, P., Rieger,B., Wagner, J.M., and Dietrich, U.(1998) Verfahren zur Herstellung vonIndenderivaten. EP Patent 0826654.
128. Li, Z., Zhang, Y., and Liu, Z.-Q. (2012)Pd-catalyzed olefination of perfluoro-arenes with allyl esters. Org. Lett., 14,74–77.
129. Prakash, G.K.S., Paknia, F., Vaghoo,H., Rasul, G., Mathew, T., and Olah,G.A. (2010) Preparation of trifluoro-methylated dihydrocoumarins,indanones, and arylpropanoic acidsby tandem superacidic activation of2-(trifluoromethyl)acrylic acid witharenes. J. Org. Chem., 75, 2219–2226.
130. Liu, Y.-H., Liu, Q.-S., and Zhang, Z.-H. (2009) An efficient Friedel–Craftsalkylation of nitrogen heterocyclescatalyzed by antimony trichlo-ride/montmorillonite K-10. TetrahedronLett., 50, 916–921.
131. Shi, Z. and He, C. (2004) An Au-catalyzed cyclialkylation of electron-richarenes with epoxides to prepare 3-chromanols. J. Am. Chem. Soc., 126,5964–5965.
132. Yadav, J.S., Reddy, B.V.S., Abraham, S.,and Sabitha, G. (2002) InCl3-catalyzedregioselective opening of aziridines
References 41
with heteroaromatics. Tetrahedron Lett.,43, 1565–1567.
133. Thirupathi, B., Srinivas, R., Prasad,A.N., Kumar, J.K.P., and Reddy, B.M.(2010) Green progression for synthesisof regioselective β-amino alcohols andchemoselective alkylated indoles. Org.Process Res. Dev., 14, 1457–1463.
139. Itoh, S., Yoshimura, N., Sato, M., andYamataka, H. (2011) Computationalstudy on the reaction pathway of α-bromoacetophenones with hydroxideion: possible path bifurcation in theaddition/substitution mechanism. J.Org. Chem., 76, 8294–8299.
140. Mason, J.P. and Terry, L.I. (1940)Preparation of phenylacetone. J. Am.Chem. Soc., 62, 1622.
141. Piccolo, O., Spreafico, F., Visentin, G.,and Valoti, E. (1985) Alkylation of aro-matic compounds with optically activelactic acid derivatives: synthesis ofoptically pure 2-arylpropionic acid andesters. J. Org. Chem., 50, 3945–3946.
142. Stelzer, U. (1995) Verfahren zurHerstellung von substituiertenPhenylessigsaurederivaten und Zwi-schenprodukten. EP Patent 0665212.
143. Ogata, Y. and Ishiguro, J. (1950) Prepa-ration of α-naphthaleneacetic acid bythe condensation of naphthalene withchloroacetic acid. J. Am. Chem. Soc., 72,4302.
144. Kawai, D., Kawasumi, K., Miyahara,T., Hirashita, T., and Araki, S. (2009)Cyclopropanation of electron-deficientalkenes with activated dibromomethy-lene compounds mediated by lithiumiodide or tetrabutylammonium salts.Tetrahedron, 65, 10390–10394.
145. Ogata, Y., Ishiguro, J., and Kitamura,Y. (1951) Condensation of naph-thalenes with α-halo fatty acids andrelated reactions. J. Org. Chem., 21,239–242.
147. Clement, K., Tasset, E.L., and Walker,L.L. (1998) Process for the preparationof stilbene diols. WO Patent 9811043.
148. Zaheer, S.H., Singh, B., Bhushan,B., Bhargava, P.M., Kacker, I.K.,Ramachandran, K., Sastri, V.D.N.,and Rao, N.S. (1954) Reactions ofα-halogeno-ketones with aromaticcompounds. Part I. Reactions ofchloroacetone and 3-chlorobutanonewith phenol and its ethers. J. Chem.Soc., 3360–3362.
149. Baciocchi, E., Muraglia, E., and Sleiter,G. (1992) Homolytic substitutionreactions of electron-rich pentatomicheteroaromatics by electrophiliccarbon-centered radicals. Synthesisof α-heteroarylacetic acids. J. Org.Chem., 57, 6817–6820.
150. Ogata, Y., Itoh, T., and Izawa, Y. (1969)Photochemical ethoxycarbonylmethyla-tion of benzene with ethyl haloacetates.Bull. Chem. Soc. Jpn., 42, 794–797.
151. Kurz, M.E., Baru, V., and Nguyen,P.-N. (1984) Aromatic acetonylationpromoted by manganese(III) andcerium(IV) salts. J. Org. Chem., 49,1603–1607.
152. Tayama, E., Yanaki, T., Iwamoto, H.,and Hasegawa, E. (2010) Copper(II)triflate catalyzed intermolecular aro-matic substitution of N,N-disubstituted
42 1 Electrophilic Alkylation of Arenes
anilines with diazo esters. Eur. J. Org.Chem., 2010, 6719–6721.
153. Zaragoza, F. (1995) Remarkable sub-stituent effects on the chemoselectivityof rhodium(II) carbenoids derivedfrom N-(2-diazo-3-oxobutyryl)-L-phenylalanine esters. Tetrahedron,51, 8829–8834.
154. Ono, N., Kamimura, A., Sasatani, H.,and Kaji, A. (1987) Lewis acid inducednucleophilic substitution reactions ofβ-nitro sulfides via episulfonium ions.J. Org. Chem., 52, 4133–4135.
155. Nakamura, S., Sugimoto, H., andOhwada, T. (2007) Formation of 4H-1,2-benzoxazines by intramolecularcyclization of nitroalkanes. Scope ofaromatic oxygen-functionalization reac-tion involving a nitro oxygen atom andmechanistic insights. J. Am. Chem.Soc., 129, 1724–1732.
156. Takamoto, M., Kurouchi, H., Otani,Y., and Ohwada, T. (2009) Phenylationreaction of α-acylnitromethanes to give1,2-diketone monooximes: involve-ment of carbon electrophile at theposition α to the nitro group. Synthesis,4129–4136.
157. Venkatesh, C., Singh, B., Mahata,P.K., Ila, H., and Junjappa, H. (2005)Heteroannulation of nitroketene N,S-arylaminoacetals with POCl3: a novelhighly regioselective synthesis ofunsymmetrical 2,3-substituted quinoxa-lines. Org. Lett., 7, 2169–2172.
158. Yao, C.-F., Kao, K.-H., Liu, J.-T., Chu,C.-M., Wang, Y., Chen, W.-C., Lin, Y.-M., Lin, W.-W., Yan, M.-C., Liu, J.-Y.,Chuang, M.-C., and Shiue, J.-L. (1998)Generation of nitroalkanes, hydroxi-moyl halides and nitrile oxides fromthe reactions of β-nitrostyrenes withGrignard or organolithium reagents.Tetrahedron, 54, 791–822.
159. Shutkina, O.V., Ponomareva, O.A., andIvanova, I.I. (2013) Catalytic synthesisof cumene from benzene and acetone.Pet. Chem., 53, 20–26.
160. Zimmerman, H.E. and Zweig, A.(1961) Carbanion rearrangements. II. J.Am. Chem. Soc., 83, 1196–1213.
161. Girotti, G., Rivetti, F., Ramello, S.,and Carnelli, L. (2003) Alkylation ofbenzene with isopropanol on β-zeolite:
influence of physical state and waterconcentration on catalyst performances.J. Mol. Catal. A, 204–205, 571–579.
162. Ohkubo, T., Aoki, S., Ishibashi, M.,Imai, M., Fujita, T., and Fujiwara, K.(2012) Process for producing alkylatedaromatic compounds and processfor producing phenols. US Patent2012004471.
163. O’Connor, M.J., Boblak, K.N., Topinka,M.J., Kindelin, P.J., Briski, J.M.,Zheng, C., and Klumpp, D.A. (2010)Superelectrophiles and the effects oftrifluoromethyl substituents. J. Am.Chem. Soc., 132, 3266–3267.
164. Gorokhovik, I., Neuville, L., and Zhu,J. (2011) Trifluoroacetic acid-promotedsynthesis of 3-hydroxy, 3-amino andspirooxindoles from α-keto-N-anilides.Org. Lett., 13, 5536–5539.
165. Si, Y.-G., Chen, J., Li, F., Li, J.-H.,Qin, Y.-J., and Jiang, B. (2006) Highlyregioselective Friedel–Crafts reactionsof electron-rich aromatic compoundswith pyruvate catalyzed by Lewis acid-base: efficient synthesis of pesticidecycloprothrin. Adv. Synth. Catal., 348,898–904.
171. Fleckenstein, C.A., Kadyrov, R., andPlenio, H. (2008) Efficient large-scalesynthesis of 9-alkylfluorenyl phos-phines for Pd-catalyzed cross-coupling
References 43
reactions. Org. Process Res. Dev., 12,475–479.
172. Murai, Y., Masuda, K., Sakihama,Y., Hashidoko, Y., Hatanaka, Y.,and Hashimoto, M. (2012) Com-prehensive synthesis of photore-active (3-trifluoromethyl)diazirinylindole derivatives from 5- and 6-trifluoroacetylindoles for photoaffinitylabeling. J. Org. Chem., 77, 8581–8587.
174. Weinbrenner, S., Dunkern, T., Marx,D., Schmidt, B., Stengel, T., Flockerzi,D., Kautz, U., Hauser, D., Diefenbach,J., Christiaans, J.A.M., and Menge,W.M.P.B. (2008) 6-Benzyl-2,3,4,7-tetrahydroindolo[2,3-c]quinolinecompounds useful as PDE5 inhibitors.WO Patent 2008095835.
175. Davoust, M., Kitching, J.A., Fleming,M.J., and Lautens, M. (2010)Diastereoselective benzylic arylationof tetralins. Chem. Eur. J., 16, 50–54.
176. Hoefgen, B., Decker, M., Mohr,P., Schramm, A.M., Rostom,S.A.F., El-Subbagh, H., Schweikert,P.M., Rudolf, D.R., Kassack,M.U., and Lehmann, J. (2006)Dopamine/serotonin receptor li-gands. 10: SAR studies on azecine-type dopamine receptor ligands byfunctional screening at human clonedD1, D2L, and D5 receptors with amicroplate reader based calcium assaylead to a novel potent D1/D5 selectiveantagonist. J. Med. Chem., 49, 760–769.
177. Johnson, H.E. (1965) Process for pro-ducing 3-substituted indoles. US Patent3197479.
![37c - UNT Digital Library/67531/metadc278942/m2/1/high_re… · 3.4. 1, 2-dihydroxycalix [4] arenes 32 3.5. 1,3 -dihydroxycalix [ 4 ] arenes 39 3.6. Monohydroxycalix [ 4 ] arenes](https://static.documents.pub/doc/80x56/605fa4de98198e4305318ec0/37c-unt-digital-library-67531metadc278942m21highre-34-1-2-dihydroxycalix.jpg)
