61 3 Electrophilic Arylation of Arenes 3.1 General Aspects Most arene arylations belong to one of the reaction types sketched in Scheme 3.1. In the first step, an arene is metallated by the insertion of a metal into a C–H or C–X bond. The second step can proceed either via the formation of a diarylmetal intermediate which undergoes reductive elimination or by aromatic nucleophilic substitution. In many of the examples presented below, radicals are formed as intermediates. Only few examples of the arylation of unsubstituted arenes with aryl halides had been reported until recently [1]. The oldest examples are copper-catalyzed, Ullmann-type reactions of aryl halides (mostly iodides) with other arenes or het- eroarenes. Usually, though, the Ullmann reaction [2, 3] converts aryl halides into homodimers. Yields of heterodimers are, therefore, often low. Further disadvan- tages of the Ullmann reaction are the required stoichiometric amounts of copper and the high reaction temperature. Typical side reactions of the Ullmann reaction include halogen exchange, reductive dehalogenation, and nucleophilic aromatic substitutions. In recent decades, a number of more convenient alternatives to the classic Ullmann conditions have been developed [4]. The improvements include the use of only catalytic amounts of transition metals, lower reaction temperatures, and a better functional group tolerance. 3.2 Arylations with Aryl Halides 3.2.1 Via Cationic Intermediates Most aryl halides are not electrophilic enough to arylate electron-rich arenes in the absence of catalysts. Even in the presence of strong Lewis acids, aryl halides usually remain unchanged. Only highly electrophilic heteroarenes, such as 2,4,6-trichlorotriazine (cyanuric chloride), or arenes capable of 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
61
3Electrophilic Arylation of Arenes
3.1General Aspects
Most arene arylations belong to one of the reaction types sketched in Scheme 3.1.In the first step, an arene is metallated by the insertion of a metal into a C–H orC–X bond. The second step can proceed either via the formation of a diarylmetalintermediate which undergoes reductive elimination or by aromatic nucleophilicsubstitution. In many of the examples presented below, radicals are formed asintermediates.
Only few examples of the arylation of unsubstituted arenes with aryl halideshad been reported until recently [1]. The oldest examples are copper-catalyzed,Ullmann-type reactions of aryl halides (mostly iodides) with other arenes or het-eroarenes. Usually, though, the Ullmann reaction [2, 3] converts aryl halides intohomodimers. Yields of heterodimers are, therefore, often low. Further disadvan-tages of the Ullmann reaction are the required stoichiometric amounts of copperand the high reaction temperature. Typical side reactions of the Ullmann reactioninclude halogen exchange, reductive dehalogenation, and nucleophilic aromaticsubstitutions.
In recent decades, a number of more convenient alternatives to the classicUllmann conditions have been developed [4]. The improvements include the useof only catalytic amounts of transition metals, lower reaction temperatures, and abetter functional group tolerance.
3.2Arylations with Aryl Halides
3.2.1Via Cationic Intermediates
Most aryl halides are not electrophilic enough to arylate electron-rich arenesin the absence of catalysts. Even in the presence of strong Lewis acids, arylhalides usually remain unchanged. Only highly electrophilic heteroarenes,such as 2,4,6-trichlorotriazine (cyanuric chloride), or arenes capable of
Scheme 3.1 Mechanisms of biaryl formation. M, metal; X, hydrogen or leaving group; DG,directing group.
forming stabilized cations by halogen abstraction or protonation (e.g., 9,10-dichloroanthracene and thiophene) arylate other arenes in the presence of AlCl3(Scheme 3.2).
N
N
N
Cl Cl
Cl
2.5 eq AlCl30.9 eq m-xylene
1,2-dichlorobenzene85 °C, 4 h, then
1.4 eq m-xylene
35 °C, 6 h N
N
N
Cl
1 eq resorcine
80 °C, 3 hN
N
N
OH
OH
61%
EP 0779280
Scheme 3.2 Arylation of cyanuric chloride [5]. Further examples: [6].
Because the complete abstraction of halides from arenes to generate aryl cationsis unfavorable (because no effective charge delocalization is possible in arylcations), most transition-metal-free arylations with aryl halides will proceed viaan addition–elimination mechanism. In acid-catalyzed arylations, the aryl halidecan be protonated to yield a more reactive intermediate, which will, however, notnecessarily react at the halogen-bearing carbon atom (Scheme 3.3). Nor will it reactforcibly with the most stable or representative resonance formula because this willalso be the least reactive one. The complexity of such reactions is further increasedby reactions of the protonated with the unprotonated aryl halide (Scheme 3.3,last equation).
3.2 Arylations with Aryl Halides 63
S ClCl
3 eq benzene
1 eq AlCl3, CH2Cl25–40 °C, 2 h
SCl62%
S ClH
S ClH
Ph
− H H
− HCl
+ C6H6
Cl Cl+S ClCl
HH
+ H
88bcsj3779
S ClCl
11 eq benzene
1 eq AlCl3−5 to 20 °C, 1.7 h
SCl
77%
Cl
81cl399
S Cl
Amberlyst 15
120 °C, 4 h+
OMe
SOMe
SOMeS
O
17%
10%
S Cl
S
O
20%
S ClS
6%
54% conversion+
+ +
S ClH
S ClH
79bcsj1126
+
+
+
+
+
+
Scheme 3.3 Acid-mediated arylations of 2-chlorothiophenes [7–9].
3.2.2Via Radicals
Most arylations with aryl halides proceed either via metal–halogen exchange orby the formation of aryl radicals. The latter can be generated in several ways,for instance, by treatment of aryl halides with tertiary alkanolates (Scheme 3.4).The best results are usually obtained with two arenes of unlike electron density,and with a large excess of the ‘‘radical accepting’’ arene (to prevent homodimerformation). Examples of uncatalyzed reactions of this type and alcoholate-mediatedarylations catalyzed by transition metals have been reported (Scheme 3.4). Radical-based mechanisms have also been proposed for copper-catalyzed, Ullmann-typearylations with aryl halides [10].
64 3 Electrophilic Arylation of Arenes
+ONa
+ONa
+Hal
Ar-Hal Ar-Hal
Ar Ar
H
ONaAr
H
+
Ar
SET
N
N
40 eq
+
S
I
1 eq
1.5 eq KOtBu
50 °C, 5 min
71% N
N
S08ol4673
NC
Cl
120 eq benzene
2 eq NaOtBu
0.1 eq ligand
155 °C, 6 h
75%
NC
ligand:
N N
Ph Ph
10ja15537
−+
−
+80%
I
1 eq
1 eq
+S
2 eq
2 eq
2 eq LiOtBu, 0.1 eq CuI
0.1 eq phenanthroline
DMPU, 125 °C, 12 h
2 eq LiOtBu, 0.1 eq CuI
0.1 eq phenanthroline
DMPU, 125 °C, 1 h
91%Cl
I
SCl
F3C
N
O
PhN
O
Ph
F3C08ja15185
08ja15185
+
−
+
−
Scheme 3.4 Transition-metal-catalyzed arylations with aryl halides mediated by strongbases [11–15]. Further examples: [16].
3.2 Arylations with Aryl Halides 65
N I
100 eq benzene
2 eq KOtBu10% ligand, 5% Fe(OAc)2
80 °C, 20 hN
85%
ligand:
N N
Ph Ph
10ja1514
Ph2N
Br
90 eq C6H6, 15% FeCl330% (MeNHCH2)2
4 eq LiN(SiMe3)2
80 °C, 48 h
Ph2N72%
10ang2004
Scheme 3.4 (Continued)
Because radicals are less sensitive than charged intermediates to variationsof electron density in the reacting partner, their regioselectivity is usually low.Accordingly, mixtures of regioisomers are often obtained during arylations witharyl radicals (Scheme 3.5).
Reactions performed in the presence of a large excess of a strong base can easilyyield unexpected products. If weakly acidic compounds are deprotonated, they oftenbecome strong reducing reagents, and will be oxidized by even weak oxidants. Airand other potential oxidants (ketones, polyhaloalkanes, or nitro compounds) shouldbe meticulously excluded from the reaction mixture. Moreover, strong bases canlead to aryne formation and thereby to mixtures of regioisomers.
Aryl radicals can also be generated by thermolysis of benzoylperoxides(Scheme 3.6). This reaction is of little scope, because acylperoxides are also acylatingreagents and can oxidize many functional groups (amines, thioethers, sulfoxides,olefins, ketones, arenes, etc.). Moreover, the outcome of these reactions variesstrongly depending on the substitution pattern at the arene [21, 22]. Many peroxides,including diacylperoxides, are explosive, and can detonate spontaneously.
Radicals are short-lived intermediates, and often require high concentrations ofa radical acceptor to give satisfactory yields. Processes that compete with the mainreaction include radical dimerization (homocoupling), reduction (e.g., H-transferfrom the solvent or other hydrogen donors), or reaction with oxygen to form peroxylradicals. Radicals can also induce the oligomerization of alkenes or alkynes.
3.2.3Via Transition-Metal Chelates
Arenes substituted with a coordinating functional group can be metallated undermild conditions and without strong bases by chelate formation. Arylruthenium
66 3 Electrophilic Arylation of Arenes
N
40 eq
1 eq PhI1.5 eq KOtBu
50 °C, 5 min
N63%
36 : 21 : 43
Ph N N
+ +
Ph
Ph
08ol4673
I+
OMe
1 eq 40 eq
5% [Cp*IrHCl]23.3 eq KOtBu
80 °C, 30 hOMe OMe OMe
Ph
Ph
Ph
+ +
55%
72 : 16 : 1204cc1926
OH
O
Br
20% Pd(PPh3)4
3 eq KOtBuDMA, 95 °C, 2 d
OH
O O
+
87% 2-5%
HO97joc2
N Br
+
Cl
2 eq (Me3Si)3SiH
2 eq AIBN
80 °C, 24 h
1 eq solvent
N N+
Cl
Cl93 : 7
84%
00ol3933
N
MeO2C
O
NBoc
I
1.1 eq Bu3SnH
AIBN, PhMe
02tet1453
112 °C, 1 h
MeO2C
N
N
O
Boc
26%
+
N
MeO2C
O
NBoc
N
MeO2C
O
NBoc
13% 5%
+
Scheme 3.5 Formation of regioisomers during arylations with aryl radicals [11, 17–20].
3.2 Arylations with Aryl Halides 67
O
O
O
OCl
Cl
ClCl
cat. 1,3-dinitrobenzene
C6H6, 80 °C, 40 h
OH
O
Cl
Cl
95% 78–81%
Cl
Cl
+
oscv(5)51
O
O
O
O
+ N
5% Pd(OAc)2
MeCN/AcOH 1:1
100 °C, 2 h N
81%(70% conversion)
09ol3174
O
O
O
OMeO
OMe
+
2 eq
N
10% Pd(OAc)2
MeCN
160 °C, 10 min
1 eq
2 eq 1 eq
N
O90%
09ol3174 O
OMe
Scheme 3.6 Generation and reactions of aryl radicals from diacylperoxides [23, 24].
and -palladium chelates generated this way can react with aryl halides to yieldbiaryls after reductive elimination and regeneration of the catalyst (Scheme 3.7).
3.2.4By Transition-Metal Catalysis
A number of arylation reactions with aryl halides have been reported that areassumed to proceed by metallation of an unsubstituted arene without chelate forma-tion. Though not strictly necessary, oxidants are sometimes added to these reactions.The regioselectivity can be low and difficult to predict (Scheme 3.8), but the prin-ciples governing the regioselectivity (or lack of it) are slowly being understood [33].Moreover, products of homocoupling are occasionally obtained as byproducts.
One typical side reaction of transition-metal-catalyzed arylations with aryl halidesis the homocoupling of the aryl halide. This reaction can occur under amazingly
mild conditions [46–48] (Scheme 3.9). To prevent homocoupling, in most of theexamples given above one of the reactants must be used in a large excess.
3.3Arylations with Diazonium Salts
A further simple way to generate aryl radicals is the treatment of arenediazoniumsalts with aqueous base (Gomberg–Bachmann reaction). Thereby, diazo anhydrides(Ar–N=N–O–N=N–Ar) are formed that undergo thermal homolysis to yield arylradicals. In the presence of a large excess of another arene, arylation occurs, andunsymmetric biaryls result (Scheme 3.10). Alternatively, aryl radicals may also begenerated by the photolysis of arenediazonium salts [51].
Not all aryl- or heteroarylamines can be converted to diazonium salts.Electron-deficient heteroarenediazonium salts (e.g., those prepared from 2- or4-aminopyridines or 2-aminopyrimidines) undergo fast aromatic nucleophilicsubstitution of nitrogen, and are often hydrolyzed to hydroxyarenes. Diazoniumsalts prepared from 2-(primary alkyl)anilines are base-labile, and readily cyclize toindazoles [60]. The diazotization of electron-rich anilines can occasionally lead to
70 3 Electrophilic Arylation of Arenes
NO2
Cl10% ligand, 5% [Rh(cod)Cl]2
benzene, 70 °C, 24 hNO2
73%
ligand:
NN N
PPh2
07ang3135
CHO
Br
5% Pd(OAc)2
0.51 eq Ag2CO3
100 eq benzene, 125 °C, 20 h
CHO
74%
10ja14412
N
HN
SPh
O O
0.5% Pd(OAc)2
1.2 eq PhI, 2% PPh3
2 eq CsOAc
DMA, 125 °C, 48 h
N
HN
SPh
O OPh +
34% 22%
04ol2897
N
S+ Br Cl
1.0 eq 1.5 eq
5% catalyst
1.5 eq K2CO3, DMA
140 °C, 24 h
N
S
Cl65%
catalyst:
Pd
N
HO
OH
Cl 2
12ejoc669
N OTs
OTs
+
F
F
F
F
5% Pd(TFA)2
10% P(2-biphenylyl)Cy2
1.2 eq K3PO4
1.2 eq 1-AdaCO2H
tBuOH, 90 °C, 12 h
N
OTs
F
F
F
F55%
11ol4374
Scheme 3.8 Transition-metal-catalyzed arylation of unsubstituted arenes with aryl halidesor tosylates [34–41]. Further examples: [33, 42–45].
3.3 Arylations with Diazonium Salts 71
N
CN
N
F
5% Pd(OAc)2
10% PBuAda2HBF4
1 eq Ag2CO3, 3 eq Cs2CO3
0.5 eq 2,2-dimethylhexanoic acid
toluene, 120 °C, 24 h+
BrN
F
74%
5% Pd(OAc)2
10% PCy3HBF4, 3 eq K2CO3
0.3 eq 2,2-dimethylhexanoic acid
toluene, 120 °C, 24 h+
Br 27%
1.0 eq 1.5 eq
1.5 eq1.0 eq N
CN
11ja16338
11ja16338
N
+
Br OMe
5% Pd(OAc)2
15% phenanthroline
3 eq Cs2CO3
140 °C, 68 h
solvent 1 eq
1 eq1 eq
70%
N
OMe
11ja19090
NO2
NO2O2N
+
I
N
0.5 eq Cu2O
quinoline
180 °C, 1 hNO2
NO2O2N
N
24%83joc4649
Scheme 3.8 (Continued)
BrNC
5% Pd(OAc)2
3 eq NEt3DMF, iPrOH, 115 °C, 23 h
57%
NCCN
98thl2559
Cl
NC
3% Pd(OAc)2
0.5 eq glucose
3 eq Bu4NOH
H2O, 60 °C, 6 h
NC
CN
+NC
15%80%10joc3908
Scheme 3.9 Homocoupling of aryl halides [49, 50].
72 3 Electrophilic Arylation of Arenes
ArN2X
H2O
ArN
N
−
ON
NAr
Ar + N2N
ArNO+
Ar
H
Ar
+ NArN
HO
HO
Cl
N2Cl
+
NH2
F
1 eq 13 eq
NaOH, H2O
75−95 °C, 25 min
NH2
F
Cl
68%12cej11555
H2N
F
CN
92 eq C6H6
1.5 eq isoamylnitrite
10 °C, 1 h, then 90 °C, 22 h
64%
F
CN
US 4539397
CO2MeH2N
OH
+
Cl
N2Cl
5 eq1 eq
2 eq TiCl3H2O, HCl
20 °C, 0.5 h
CO2MeH2N
OHCl
57%10cej2547
O2N
N2BF4
2 eq KOAc
5% 18-crown-6
C6H6, 20 °C, 1.5 h
O2N
85%
84joc1594
Scheme 3.10 Arylations with aryl radicals generated from diazonium salts [52–58]. Furtherexamples: [59].
3.4 Arylations with Other Functionalized Arenes 73
NN O
O
NC
+
OMe
MeO
1 eq 30 eq
1 eq MnO2
160 °C
44%
NC
MeO
OMe
12joc1520
NHO 4 eq PhN2BF4, 10% Pd(OAc)2
2.5% Ru(bpy)3-hexahydrate
MeOH, light, 20 °C, 4 h
NHO
50%
11ja18566
HN
H2N
F
F
F
+
NH2
1 eq 20 eq
5 eq MnO2
MeCN, 20 °C, 3 h
NH2
F
F
F
F
F
F
H2N
+
59% 16%
HN
ClH3N+
OMe
1 eq 20 eq
5 eq MnO2
5 eq NaHCO3
MeCN, 20 °C, 3 h
OMe
Cl Cl
MeO
+
25% 5%
Cl
Cl
+
OMe
4%
12joc10699
12joc10699
Scheme 3.10 (Continued)
aromatic nitrosation or nitration [61]. Some heteroaryl radicals rearrange to morestable radicals faster than adding to arenes (Scheme 3.11).
3.4Arylations with Other Functionalized Arenes
Benzoic and heteroaromatic acids are further precursors for aryl radicals ormetallated arenes, and can be used for the arylation of aromatic C–H bonds(Scheme 3.12). Benzoyl radicals, formed by the oxidation of benzoic acid salts,decarboxylate so quickly to aryl radicals that no byproducts resulting from thebenzoyl radicals are usually observed.
Arylpalladium complexes generated by metallation of aromatic C–H groupsthrough chelate formation readily undergo homocoupling reactions. To achieve
74 3 Electrophilic Arylation of Arenes
N
O
NH2
N
O
Br
NH
O
O
10 eq KBr
HBr (48% in H2O)
7 eq NaNO2
H2O, 5 °C, 1 h+
66% 7%
10cpb685
N
N NN
NH2
+O
NO
1 eq 8 eq
10% TsOH, PhMe
120 °C, 18 h
NN
ON
NPh
Me
NN
ON
NPh
+
N
N NN
NN
NC− HCN
NN
NC
Me
+
NN
NCPhMe
PhMeRONO
Ph N O
12% 7%
82ja4013
+ −
Scheme 3.11 Decomposition pathways of 2-pyridine and 4-pyrimidinediazonium salts[62, 63].
CO2H
OMeMeO
+
F
F
F
F
F1 eq 15 eq
15% Pd(TFA)2
45% PCy3, 3.5 eq Ag2CO3
1.5 eq K3PO4, MS 3 Å
DMSO, dioxane, 140 °C, 22 h
OMeMeO
F
F
F
F
F75%
11joc882
O CO2H
0.2 eq AgOAc
3 eq K2S2O8
d3-MeCN
130 °C (MW), 1 h
O O D
76% 8%
+12ol2650
S
N
CO2H
Ph +
O
N
Ph
CO2Et
1.5 eq 1.0 eq
10% Pd(OAc)2
5% (Cy2PCH2)2
3 eq CuCO3, MS 4 Å
dioxane/DMSO 9 : 1, 140 °C, 16 h
S
NPh
O
N
Ph
CO2Et +
O
N
Ph
CO2Et
O
N
Ph
EtO2C
11%53%
10ang2768
Scheme 3.12 Arylations with arenecarboxylic acids [64–66]. Further examples: [67].
3.4 Arylations with Other Functionalized Arenes 75
+
HN
O
N
B(OH)2
10% [Pd(MeCN)4](BF4)2
3 eq benzoquinone
AcOEt, 20 °C, 20 h
1.0 eq 1.5 eq
HN
O
N94%
10ja4978
N+
(HO)2B
20% Fe(C2O4)-2H2O
20% ligand, air
130 °C, 10 h
75 eq 1 eq
N83%
10ol2694
ligand:
N
NH HNHN
N
N
+
(HO)2B
1.1 eq1.0 eq
20% Fe(acac)2
3 eq K2S2O8, 1 eq TFA, air
CH2Cl2/H2O 1 : 1, 20 °C, 12 h
N
N
+
72% 10%
13joc2639
Scheme 3.13 Palladium- and iron-catalyzed arylation of aromatic C–H groups with boronicacids [68–70].
N
+Ph
+
IPh
−
+ −
+ −
OTf
1.5 eq tBuONa
110 °C, 8 h
58%N N NPh
Ph
Ph
+ +
52 : 38 : 10
12joc766
NPh
Ph
+Ph
IPh
OTf
1.0 eq
1 eq 2 eq
1.3 eq
1.0 eq 1.3 eq
dtbpy, DCE
90 °C, 3 d
NPh
Ph
+
NPh
Ph
Ph Ph Ph
59%
82 : 18
11ang458
O
+Ph
IPh
OTf
20% Cu(OTf)2
DCE, 70 °C, 3 d
75%
O
Ph11ang458
N
N N
N
O
O
+ BrS
O
NaO
5% Pd(PhCN)2Cl22 eq Cu(OAc)2
dioxane/DMSO 9 : 1
110 °C, 24 h N
N N
N
O
O
Br91%
11cej12415
Scheme 3.14 Arylation of arenes with arene iodonium salts and sulfinates [71–73].
76 3 Electrophilic Arylation of Arenes
N
Raney-Ni
air, 116 °C, 48 h
N
Napprox 10%conversion
main product
+
N
N
N
minor products
+NH
N
N
131 °C, 22 h
2 Br
Diquat
BrBr
oscv(5)102
06syn146 > 90%
N Cl
2.5 eq NaCN
1.2 eq NaOH
EtOH, 79 °C, 0.5 h
NCl
N
Cl
Paraquat
93%
US 6087504
N
CO2Etcat Pd/C
130 °C, 16 torr, 6 d
35% N N
CO2EtEtO2C
97joc3013
N
N1% CuCl, 2% ligand
p-xylene, 140 °C, 20 h
N
N
N
N
95%
ligand:
NNaO11cc12876
SBr
HO3% PdCl2(PhCN)2
2 eq AgNO3, 2 eq KFDMSO, 60 °C
SBr
HO
S Br
OH
70%06ja10930
Scheme 3.15 Oxidative homodimerization of arenes [75–81].
heterocouplings, the challenge is to find oxidants that will not react with thenucleophilic coupling partner or with the metallated arene but just convert Pd(0)to Pd(II). One such oxidant is benzoquinone, a suitable reagent for oxidativeSuzuki couplings. Although benzoquinone can undergo Heck reaction with aryl-palladium complexes, coupling with the boronic acid is faster. Similar arylationswith arylboronic acids have been achieved with iron catalysis and air as oxidant(Scheme 3.13).
3.4 Arylations with Other Functionalized Arenes 77
OH
Me2NOH
Me2N
+
1 eq 1 eq
1 eq 1 eq
1 eq 1 eq
20% FeCl3-6H2O
2 eq tBuOOH
PhH, air, 0 °C, 1.5 h
60%
11joc10229
MeO
+
MeO
S
CN
S
CN
10% CuI/phen
1.3 eq I2, 1 eq pyridine
3.5 eq K3PO4
1,2-dichlorobenzene
130 °C, 5 d
72%
11ja13577
S
N N
OEtO2C CO2Et
+
20% Cu(OAc)2
1 eq pyridine
1.5 eq Ag2CO3, O2
xylene, 140 °C, 24 h
S
N N
OEtO2C CO2Et S
N N
SEtO2C CO2Et O
N N
OEtO2C CO2Et
+ +
63% 21% <5%
12joc7677
F
F
F
F
MeO
+
NO2
1 eq solvent
10% Pd(OAc)2, 2 eq Cu(OAc)2
0.75 eq Na2CO3,1.5 eq PivOH
DMA, 110 °C, 24 h
33%
F
F
F
F
MeO
NO2
F
F
F
F
MeO
NO2
+
71 : 29
10ja16377
O
HO
5% Pd(OAc)2
1.5 eq Ag2O, 2.5 eq K2CO3
TFA, 140 °C, 24 h
O
HO
84%
12ol4850
Scheme 3.16 Oxidative heterodimerization of arenes [82, 84–90]. Further examples:[91–96].
78 3 Electrophilic Arylation of Arenes
O N
O
F
+
O N
O
F
Cl
ClCl
Cl
1 eq 40 eq
10% Pd(OAc)2
3 eq Na2S2O8, 5 eq TFA
70 °C, 68 h
84%10ja5837
S
N
+
S
N
SO
S
N
SO
SO
+
SO
10% [Cp*RhCl2]22.8 eq Cu(OAc)2
DMA, 140 °C, 24 h
38% 28%
1 eq 3 eq
13ol1290
N
O
40 eq benzene
10% Pd(OAc)2, 2.2 eq Ag2CO3
130 °C, 16 h
N
O
Ph+
N
O
PhPh79%
75 : 2508ja9254
Scheme 3.16 (Continued)
A number of other aromatic electrophiles have been used for the preparationof biaryls from unsubstituted arenes. These include aryl iodonium salts, sul-fonyl chlorides, and sulfinates (Scheme 3.14). Few examples of such reactionshave been reported, and little is known about their scope and functional grouptolerance.
3.5Arylations with Unsubstituted Arenes
Oxidative dimerizations of arenes offer an attractive approach to large, symmetricmolecules. Important syntheses of this type include couplings of phenols tosymmetric 2,2′- or 4,4′-dihydroxybiphenyls (e.g., for the synthesis of binaphthol [74])and the oxidative dimerization of pyridine to 2,2′-bipyridine, the key intermediatefor the herbicide diquat (Scheme 3.15).
Scheme 3.17 Oxidative dimerization of metallated arenes [97, 98].
The oxidative coupling of two different arenes is a more difficult reaction,prone to yielding regioisomeric mixtures of homo and heterodimers [82]. Carefulselection of the reacting partners and reaction conditions, though, can sometimeslead to high-yielding biaryl syntheses (Scheme 3.16). Common side reactionsinclude oxidative transformations of functional groups, oxidation to quinones, aswell as hydroxylation, amidation, sulfenylation, and halogenation of the arenes. Inthe presence of oxygen and copper salts, N,N-dimethylformamide (DMF) can beoxidized to cyanide [83], which can lead to the cyanation of arenes or the poisoningof transition-metal catalysts.
Acidic arenes can be metallated and dimerized by oxidants to yield symmetricbiaryls (Scheme 3.17). Potential side reactions include reaction of the metallatedarene with the oxidant and aromatic nucleophilic substitutions.
Mixtures of oxidants, and flammable organic solvents, and strong bases candecompose violently, and are usually too dangerous for large-scale preparations.Reactions such as those shown in Scheme 3.17 should better be conducted in lessflammable solvents and with solid or liquid oxidants that allow a more precise andcontrolled dosing.
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