Metal-free arylation of oxygen nucleophiles with diaryliodonium salts

Article abstract of DOI:10.1002/chem.201201645

Phenols and carboxylic acids are efficiently arylated with diaryliodonium salts. The reaction conditions are mild, metal free, and avoid the use of halogenated solvents, additives, and excess reagents. The products are obtained in good-to-excellent yields after short reaction times. Steric hindrance is very well tolerated, both in the nucleophile and diaryliodonium salt. The scope includes ortho- and halo-substituted products, which are difficult to obtain by metal-catalyzed protocols. Many functional groups are tolerated, including carbonyl groups, heteroatoms, and alkenes. Unsymmetric salts can be chemoselectively utilized to obtain products with hitherto unreported levels of steric congestion. The arylation has been extended to sulfonic acids, which can be converted to sulfonate esters by two different approaches. With recent advances in efficient synthetic procedures for diaryliodonium salts the reagents are now inexpensive and readily available. The iodoarene byproduct formed from the iodonium reagent can be recovered quantitatively and used to regenerate the diaryliodonium salt, which improves the atom economy. Copyright

Full text of DOI:10.1002/chem.201201645

FULL PAPER
DOI: 10.1002/chem.201201645
Metal-Free Arylation of Oxygen Nucleophiles with Diaryliodonium Salts
Nazli Jalalian, Tue B. Petersen, and Berit Olofsson*[a]
Abstract: Phenols and carboxylic acids
are efficiently arylated with diaryliodo-
nium salts. The reaction conditions are
mild, metal free, and avoid the use of
halogenated solvents, additives, and
excess reagents. The products are ob-
tained in good-to-excellent yields after
short reaction times. Steric hindrance is
very well tolerated, both in the nucleo-
phile and diaryliodonium salt. The
scope includes ortho- and halo-substi-
tuted products, which are difficult to
obtain by metal-catalyzed protocols.
Many functional groups are tolerated,
including carbonyl groups, heteroa-
toms, and alkenes. Unsymmetric salts
can be chemoselectively utilized to
obtain products with hitherto unreport-
ed levels of steric congestion. The ary-
lation has been extended to sulfonic
acids, which can be converted to sulfo-
nate esters by two different ap-
proaches. With recent advances in effi-
cient synthetic procedures for diarylio-
donium salts the reagents are now in-
expensive and readily available. The io-
doarene byproduct formed from the
iodonium reagent can be recovered
quantitatively and used to regenerate
the diaryliodonium salt, which im-
proves the atom economy.
Keywords: aryl esters · arylation ·
diaryl ethers · hypervalent iodine ·
synthetic methods
Introduction
but excess amounts of reagents are often needed.[4a–c,8] Pd-
catalyzed cross-couplings of phenols and aryl halides rely on
high reaction temperatures and expensive, non-commercial
ligands. High yields of a range of diaryl ethers are often ob-
tained, but heteroaromatic or ortho-substituted coupling
partners are often challenging substrates.[9,10] Iron/copper co-
catalyzed systems have recently been reported.[11]
Metal-free arylations of phenols include reactions with
benzyne intermediates[12] and SNAr additions[13] to electron-
poor aryl halides under mild conditions. However, the scope
is limited to aryl groups with certain electron-withdrawing
substituents.
Diaryl ethers and aryl esters are common subunits used in
the pharmaceutical and agrochemical industries.[1] Many nat-
ural products that contain the diaryl ether substructure have
received considerable attention, for example, vancomycin
and other glycopeptide antibiotics, as well as anti-HIV
agents, such as chloropeptin.[2] Heteroatom alkylation and
arylation constitutes the most common transformation in
the pharmaceutical industry,[3] which highlights the impor-
tance of efficient and selective arylation methodology for
heteroatom nucleophiles.
Indeed, a wide range of synthetic methods to access these
compound classes have been developed under both metal-
mediated and metal-free conditions.[4] Despite this, ortho-
substituted diaryl ethers and sterically hindered aryl esters
remain difficult to obtain for applications in life sciences
and the polymer industry.[4,5]
Diaryl ethers can be synthesized from phenols and aryl io-
dides under classical Ullmann conditions with stoichiometric
amounts of copper.[6] Catalytic versions of this transforma-
tion have been developed, but still require high catalyst
loadings, excess reagents, elevated temperatures, and long
reaction times.[1,4a–c,7] The copper-catalyzed coupling of phe-
nols and arylboronic acids proceeds at room temperature,
Aryl esters are generally formed by reaction of a phenol
with a suitably activated carboxylic acid derivative.[14] The
latter can be generated in situ but stoichiometric amounts of
multiple coupling reagents are typically needed.[15] Other
methods include arylations with benzyne intermediates[12] or
oxidative esterification with hypervalent iodine reagents.[16]
Alternatively, metal-catalyzed methods similar to those
employed in the synthesis of diaryl ethers can be utilized.[17]
Carboxylic acids can be coupled with arylboronic acids or si-
lanes in copper-mediated reactions at elevated tempera-
ture.[18,19] Aryl esters can also be synthesized from carboxylic
acids and phenols by iron-catalyzed oxidative activation.[20]
Pd-catalyzed oxidative coupling of phenols with aromatic al-
dehydes or benzylic alcohols[21] or carbonylative coupling
with aryl halides also deliver aryl esters.[22] Aryl acetates can
[a] N. Jalalian, Dr. T. B. Petersen, Prof. B. Olofsson
Department of Organic Chemistry
Arrhenius Laboratory
ꢀ
be synthesized by C H activation of arenes with internal di-
recting groups.[23]
As part of our long-term interest in the synthesis[24] and
application[25] of hypervalent iodine compounds as selective
and environmentally benign reagents,[16a,26] we have exam-
ined the arylation of oxygen nucleophiles with diaryliodoni-
um salts.[27] We have previously reported preliminary results
Stockholm University
10691 Stockholm (Sweden)
Fax : (+46)8-154908
E-mail: berit@organ.su.se
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201645.
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on the arylation of phenols[28] and carboxylic acids.[29]
Herein, we show the scope of these important transforma-
tions, together with the novel arylation of sulfonic acids.
Results and Discussion
Synthesis of diaryliodonium salts: Diaryliodonium salts have
become readily available and inexpensive electrophilic ary-
lation reagents since the development of efficient one-pot
routes to these hypervalent iodine compounds.[30] Their
properties allow both for metal-catalyzed[31] and metal-
free[32] reactions in many areas of application. The draw-
backs of organometallic chemistry, such as cost, toxicity, and
threshold values in pharmaceutical products, can be avoided
by development of metal-free arylation methodology for
various nucleophiles.
We have recently reported several general routes to diary-
liodonium salts with various anions by oxidation of aryl io-
dides with meta-chloroperbenzoic acid (mCPBA) in the
Figure 1. Diaryliodonium salts used in this study (EWG=electron-with-
drawing group, EDG=electron-donating group).
[34]
presence of arenes and a suitable acid (Scheme 1a).[33]
um triflates or tetrafluoroborates because salts with these
[39]
anions are soluble in less-polar solvents.
This was indeed
the case and our preliminary results on the arylation of phe-
nols under mild and racemization-free conditions were re-
cently reported. [28,40]
A number of aspects have since been investigated to
make the reaction even more general. Herein we present:
1) the use of diaryliodonium salts with different anions,
which allows for smooth synthesis of the required reagents
independent of substituents; 2) a broad scope of both cou-
pling partners; 3) the synthesis of very sterically hindered
diaryl ethers; 4) a large-scale reaction with isolation of the
iodoarene byproduct; 5) chemoselective arylation with un-
symmetric salts.
Scheme 1. One-pot routes to diaryliodonium salts (TfOH=trifluoro-
ACHTUNGTRENNUNGmethanesulfonic acid, TsOH=pACHTUNTGREN-NUNG toluenesulfonic acid).
The reaction can be extended to direct use of iodine and
arenes for certain symmetric (R1 =R2) diaryliodonium salts,
which avoids the need for expensive aryl iodides. The use of
arylboronic acids enables regiospecific synthesis of diarylio-
donium salts that are unobtainable from arenes (Sche-
Optimization: The arylation was optimized with phenol (1a)
and diphenyliodonium triflate (2a) to give diphenyl ether
(3a). A solvent screen at room temperature with NaH as
the base revealed that DMF, toluene, THF, and CH2Cl2 all
gave high conversion, whereas acetonitrile was less efficient.
THF was deemed most suitable for further optimizations.
Subsequently, sodium hydroxide and potassium- or sodium
tert-butoxide were found to be more efficient bases than
NaH (Table 1, entries 1–5).
Weaker bases, such as carbonates and potassium phos-
phate, gave limited conversion (Table 1, entries 6–8). The
cation of the base influences the reaction outcome to a
much smaller extent than in the arylation of carboxylic acids
(see below) and a difference between sodium and potassium
cations was observed only with the carbonate bases. A tem-
perature increase to 408C was sufficient to reduce the reac-
tion time to 15 min with both NaOH and tBuOK and a reac-
tion time of 2 h was sufficient to achieve full conversion at
room temperature (Table 1, entries 9–12).
[35]
me 1b).
A large number of diaryliodonium salts were used in the
arylation of phenols and carboxylic acids described herein
(Figure 1). Most of the salts were synthesized by the proce-
dures shown in Scheme 1, but some salts required a stepwise
approach (see the Supporting Information). Both sterically
hindered salts and electron-deficient salts are difficult to
synthesize in symmetric versions, therefore, a number of un-
symmetric salts (R1 ¼R2) were also employed in the study.
Synthesis of diaryl ethers by arylation of phenols: Beringer
reported the synthesis of diaryl ethers from phenols and dia-
[37]
ryliodonium halides in the 1950s.
The reaction required
prolonged reaction times and high temperatures in protic
solvents, which are detrimental to racemization-prone sub-
strates, such as a-amino acid substituted phenols, common
in natural products. [38]
We envisioned that a mild and general arylation protocol
could be developed with aprotic solvents and diaryliodoni-
A reaction without deprotonation time allotted prior to
addition of the salt gave lower yield of 3a, which indicated
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Metal-Free Arylation of Oxygen Nucleophiles
FULL PAPER
Table 1. Optimization of the phenylation of 1a.[a]
vided 3a in equally good yield (Table 2, entry 3), without
any side products formed from the bromide acting as a
nucleoACHTNUTRGNEpNUG hile (see below). To the contrary, tosylate 2d gave
only traces of product (Table 2, entry 4), despite full conver-
sion of 2d into iodobenzene. Addition of the radical scav-
enger DPE improved the yield with 2d to 88% (Table 2,
entry 5), which is opposite to the result obtained with DPE
in the reaction of 2a (Table 1, entry 14). The tosylate results
can be rationalized by radical-promoted salt decomposi-
tion,[41] although the reason for this remains unclear.
Electron-rich diaryliodonium salts are easily synthesized
as tosylate salts, whereas the triflate or tetrafluoroborate an-
alogues are more difficult to obtain.[33b] Conditions were
sought under which tosylate salts could be utilized for the
synthesis of diaryl ethers without need for DPE as an addi-
tive. Toluene has been reported to act as a radical trap in ar-
ylations of alkoxides with diaryliodonium salts.[41] When the
arylation of 1a with salt 2d was performed in toluene in-
stead of THF, 3a was obtained in 89% yield (Table 2,
entry 6).
Entry
Base
T [8C]
Time [h]
Yield[b] [%]
1
2
3
4
5
6
7
8
NaH
NaOH
KOH
RT
RT
RT
RT
RT
RT
RT
RT
40
40
40
RT
40
40
4
4
4
4
4
4
4
4
93
>99
>99
97
99
32
1
6
>99
>99
95
tBuOK
tBuONa
K2CO3
Na2CO3
K3PO4
NaOH
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
9
15 min
15 min
2
1
0.5
10
11
12
13[c]
14[d]
85
82
>99
15 min
[a] Base (1.1 equiv) and 1a (1.1 equiv) were stirred at 08C for 15 min
before addition of salt 2a (1 equiv). [b] Determined by GC with 1,4-dime-
thoxybenzene as an internal standard. [c] Base and 2a added at once.
[d] DPE (1 equiv) was added.
an unwanted reaction between the base and the salt
(Table 1, entry 13). Finally, 1,1-diphenylethylene (DPE) was
added as radical scavenger to determine if the reaction pro-
ceeded by a radical mechanism (Table 1, entry 14). No de-
crease in yield was observed, consequently, this is an unlike-
ly reaction pathway.
Scope of diaryl ethers: The reactions of substituted phenols
1 with triflate salt 2a or tetrafluoroborate salt 2b were sub-
sequently explored and diaryl ethers 3 were isolated in high
yields (Scheme 2). Phenols with electron-withdrawing sub-
stituents gave diaryl ethers 3b–d in slightly lower yields
than ethers 3e–h obtained from phenols with electron-
donating substituents. Halo-substituted diaryl ethers are
convenient building blocks for further transformations, such
as cross-coupling reactions. Chloro- and iodo-substituted
diaryl ethers 3i–l were obtained in excellent yields. This il-
lustrates the potential of the methodology developed be-
Investigation of the anion effect: Diaryliodonium salts can be
synthesized with various anions that originate from the acid
used in the synthesis or a ligand already present in pre-
formed iodineACHTUNGTRENNUNG(III) reagents. Triflate and tetrafluoroborate
salts are the most utilized in current applications because
these anions rarely have a negative impact on the reaction
outcome.[30a] Although anion exchanges can be performed to
obtain triflate or tetrafluoroborate salts from various other
anions, it is more practical to use the salt with the original
anion when this does not hamper the application.
Thus, the effect of the diaryliodonium salt anion was in-
vestigated in the phenylation of 1a. Tetrafluoroborate 2b
proved as efficient as triflate 2a and delivered ether 3a in
excellent yield (Table 2, entries 1 and 2). Bromide 2c pro-
Table 2. Investigation of the anion effect.[a]
Entry
Salt (X)
Yield[b] [%]
1
2
3
4
2a (OTf)
2b (BF4)
2c (Br)
2d (OTs)
2d (OTs)
2d (OTs)
99
>99
>99
<1
88
5[c]
6[d]
89
[a] NaOH (1.1 equiv) and 1a (1.1 equiv) were stirred at 08C for 15 min
before addition of salt 2 (1 equiv). [b] Determined by GC with 1,4-dime-
thoxybenzene as an internal standard. [c] DPE (1 equiv) was added as a
radical scavenger. [d] Toluene was used as the solvent.
Scheme 2. Phenylation of substituted phenols 1. [a] At room temperature.
[b] In toluene.
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B. Olofsson et al.
cause such products can be difficult to obtain by metal-cata-
lyzed arylations due to chemoselectivity problems.
widely used as flame-retardants and ether 4k exemplifies
the potential to synthesize this type of compounds under
mild conditions.
Both electron-deficient and electron-rich salts could be
employed, demonstrated by the synthesis of the CF3-substi-
tuted product 4m and the dimethoxy-substituted ether 4n.
Finally, quinolin-8-ol was converted to heteroaryl ether 4o
in excellent yield.
Ortho-substituted phenols are also difficult substrates in
metal-mediated arylations[1b,4a] These compounds are
smoothly arylated, demonstrated by the synthesis of ortho-
substituted diaryl ethers 3e–f and 3l. Even the bulky 1,1ꢁ-bi-
2-naphthol was an excellent substrate; the diarylated prod-
uct 3r was delivered as a precipitate without the need for
further purification.
Phenols that bore carbonyl substituents could also be em-
ployed and provided ethers 3m–o in good yields. The het-
erocycle 3-hydroxypyridine was smoothly phenylated to give
3p, which further demonstrates the functional group toler-
ance of the transformation. As expected, a vinyl substituent
was also compatible with the arylation and ether 3q was ob-
tained in excellent yield.
Bis(tert-butyl) salt 2i was employed in a large-scale reac-
tion with 1a (3.1 mmol) and delivered 4h in 98% yield with
quantitative
recovery
of
4-tert-butyliodobenzene
(Scheme 4). The recovered iodoarene can easily be oxidized
(Scheme 1a) to reform salt 2i to provide better atom econo-
my in large-scale reactions.
The reaction scope with symmetrical diaryliodonium salts
2e–n was subsequently explored (Scheme 3). Bis(ortho-
methyl) salts 2e–h delivered ethers 4a–f in excellent yields
Scheme 4. Large-scale arylation with recovery of the aryl iodide.
To demonstrate the mild conditions of this arylation pro-
tocol, the racemization-prone tyrosine derivative 5a and
aryl glycine derivative 5b were phenylated (Scheme 5).
Both a-amino acid derivatives delivered the corresponding
diaryl ethers, 6a and 6b, respectively, in excellent yields
without erosion of the enantiomeric excess (ee).[42]
Scheme 5. Arylation of a-amino acid derivatives 5a and 5b (Boc=tert-
butoxycarbonyl).
Scheme 3. Arylation with symmetric diaryliodonium salts. The aryl
moiety contributed to product 4 by 1 is shown to the left and that from 2
to the right.
Chemoselectivity with unsymmetric salts: The use of unsym-
metric diaryliodonium salts was subsequently investigated.
One of the benefits with unsymmetric salts is their ease of
preparation; many efficient routes to diaryliodonium salts
do not allow the synthesis of very electron-rich or electron-
poor symmetric salts, whereas the synthesis of unsymmetric
salts with one electron-poor and one electron-rich moiety is
facile. Likewise, the synthesis of sterically hindered symmet-
ric salts is cumbersome. Another benefit is seen with salts
made from expensive or non-commercial aryl moieties be-
cause the waste of an expensive aryl iodide moiety can be
avoided.
with both electron-deficient and electron-rich phenol part-
ners. Combination of steric hindrance in both the phenol
and the salt smoothly provided the highly substituted diaryl
ether 4g, with three ortho-substituents, in quantitative yield.
The introduction of tert-butyl substituents was straightfor-
ward both from the salt and from the phenol to give 4h and
4i, and even highly hindered 2,4-di-tert-butylphenol could
be employed to give diaryl ether 4j in good yield. Halo-sub-
stituted salts 2j–l were employed to arylate a range of phe-
nols and afforded ethers 4i–l with suitable handles for fur-
ther derivatization. Polybrominated diphenyl ethers are
The obvious drawback with unsymmetric salts is that che-
moselectivity issues must be controlled. Previous reports for
metal-free reactions follow the trends that electron-poor
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Metal-Free Arylation of Oxygen Nucleophiles
FULL PAPER
aryl groups are transferred more readily than electron-rich
aryl groups[43] and ortho-substituted aryl groups are transfer-
red in preference to other aryl groups. However, these two
effects often contradict one another, which makes the che-
moselectivity difficult to predict.[44]
or used directly with a concurrent change of solvent to tol-
uene, as in the synthesis of 4t and 4v. Contrary to reactions
in THF, tosylates give high yields of arylated products in tol-
uene because byproducts from radical pathways are avoided
(see above). The 4-iodoanisole can be recycled as a “dummy
ligand” in large-scale reactions (Scheme 4).
The chemoselectivity in the arylation of phenols was ini-
tially examined with p-tolyl
expected, the aryl moieties in this salt were not different
(phenyl) salt 2p (Scheme 6). As
All reactions were run without precautions to avoid air or
moisture, and a temperature of 408C was generally selected
for conveniently short reaction times. Room temperature re-
actions work equally well (synthesis of 3a, 3g, and 3m–n),
NaOH can be used instead of tBuOK, and toluene instead
of THF (synthesis of 3e, 4t, 4v). Oxidative dearomatization
of the phenol was not observed.[46]
Synthesis of aryl esters by arylation of carboxylic acids: The
arylation of sodium carboxylates with diaryliodonium hal-
ides or hydrogensulfates was briefly reported in the 1950s.
Excess reagents were employed and long reaction times
were required in protic solvents at reflux temperature.[47]
The former conditions are potentially problematic for a
number of functional groups, for example, enolizable car-
bonyl groups. One diaryliodonium salt has also been utilized
as a benzyne precursor in the synthesis of phenyl esters.[48]
We sought to develop a general and efficient synthesis of
aryl esters under mild conditions to avoid the drawbacks
and limitations of the previous reports. Based on the condi-
tions developed for phenols (see above), we envisioned that
diaryliodonium triflate or tetrafluoroborate salts in aprotic
solvents would be superior to the previous conditions. This
was indeed the case, and a preliminary report on the effi-
cient arylation of carboxylic acids was published in 2011.[29]
The scope of the reaction has since been investigated by
variation of both coupling partners. The chemoselectivity as-
pects when unsymmetric diaryliodonium salts are used have
been investigated in detail and a series of novel and sterical-
ly very congested aryl esters have been synthesized by che-
moselective arylation with unsymmetric salts.
Scheme 6. Chemoselective arylation with unsymmetric diaryliodonium
salts. The aryl moiety contributed to product 4 by 1 is shown to the left
and that from 2 to the right. [a] Tosylate salt used; reaction run in tol-
uene.
enough to allow complete control of the chemoselectivity
and ether 4p was obtained as a 3:1 mixture with the unde-
sired ether 4q. When the p-methoxyphenylACTHNUGRTENUNG(phenyl) salt 2v
was employed the selectivity was excellent and 4p was
formed in 94% yield.
A range of unsymmetric salts with one anisyl moiety were
subsequently investigated in the arylation of phenols 1. As
predicted, these salts transferred the other aryl moiety of
the salt to the phenol with excellent chemoselectivity for
both electron-rich and electron-poor phenols to give 4p–s.
The sterically hindered ether 4r was formed in 94% yield
from salt 2x; the complete chemoselectivity of this reaction
can be rationalized by electronic arguments and the ortho
effect.
Optimization: The conditions were optimized with benzoic
acid (7a) and triflate salt 2a; selected results are shown in
Table 3.[49] A solvent screening with different bases revealed
that the yield of phenyl benzoate (8a) was much higher in
toluene than in THF, acetonitrile, or DMF.
The preference to transfer the most electron-poor aryl
group was further demonstrated with salts 2y–z. Further-
more, pyridyl ether 4u was obtained from 2ad by this strat-
egy, and thereby avoided the difficult synthesis of symmetric
pyridyl salts.[45] Even the synthesis of ether 4v, with extraor-
dinary steric hindrance in the ortho positions, was straight-
forward from the triisopropylphenyl salt 2ab. Symmetric
bis(2,4,6-triisopropylphenyl)iodonium salts have never been
reported, presumably due to the great steric hindrance,
which further illustrates the benefit of unsymmetric diarylio-
donium salts in arylation reactions.
In contrast to the arylation of phenols, this reaction
proved strongly dependent on the cation of the base.
Sodium bases effected almost no conversion to 8a within
1 h at reflux temperature, whereas potassium and cesium
bases resulted in good yields (Table 3, entries 1–6). Contrary
to the arylation of phenols, this reaction was best performed
under anhydrous conditions (Table 3, entry 4 versus 5). The
diprotic base cesium carbonate (0.55 equiv) was sufficient to
obtain 8a in high yield (Table 3, entry 7), but the price dif-
ference between Cs2CO3 and tBuOK does not justify the use
of this base in general. The reaction slowed down at lower
temperatures, although cesium carbonate still enabled signif-
icant conversion at 708C (Table 3, entries 8 and 9).
Unsymmetric salts that contain an anisyl group are most
easily obtained as the tosylate salts.[33b] These salts can
either be anion exchanged to give the corresponding triflates
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Table 3. Optimization of the phenylation of 7a.[a]
Entry
Base
2 (X)
T [8C]
Time [h]
Yield [%][b]
1
2
3
4
NaOH
KOH
2a (OTf)
2a (OTf)
2a (OTf)
2a (OTf)
2a (OTf)
2a (OTf)
2a (OTf)
2a (OTf)
2a (OTf)
2b (BF4)
2c (Br)
reflux
reflux
reflux
reflux
reflux
reflux
reflux
70
1
1
1
1
1
0.5
1
16
16
1
<5
79
85
95
87
92
95
<3
63
97
19
19
90
K3PO4
tBuOK
tBuOK
Cs2CO3
Cs2CO3
tBuOK
Cs2CO3
tBuOK
tBuOK
tBuOK
tBuOK
5[c]
6
7[d]
8
9[d]
10
11[e]
12[f]
13
70
reflux
reflux
reflux
reflux
1
1
1
2c (Br)
2d (OTs)
Scheme 7. Arylation of carboxylic acids 7 with symmetric diaryliodonium
salts 2.
[a] Base (1.1 equiv) and benzoic acid (1.1 equiv) were mixed in anhy-
drous toluene at RT, 2 was added, and the mixture was heated to the
temperature stated. [b] Isolated yield. [c] Toluene not dried. [d] Base
(0.55 equiv) used. [e] PhBr was detected by GC. [f] DPE (1.0 equiv) was
used.
and hydroxy ester 8k was obtained as the only product.
Racemic N-Boc phenylglycine could also be arylated to give
amino acid derivative 8l in good yield. Unfortunately, aryla-
tion of the corresponding enantiopure acid resulted in prod-
uct (S)-8l with only 88% ee.[50]
The influence of the anion of the diaryliodonium salt was
subsequently investigated. As expected, tetrafluoroborate
2b works just as efficiently as triflate 2a (Table 3, entry 10).
On the other hand, bromide 2c gave poor results under a
range of conditions (Table 3, entry 11), which again contrasts
the results obtained with phenols (Table 2, entry 3). Addi-
tion of the radical trap DPE had no effect, which suggests
that radical side reactions are unlikely (Table 3, entry 12).
Instead, the formation of bromobenzene from intramolecu-
lar coupling with the bromide anion[44b] could explain the
modest yields. Formation of this byproduct is not detected
in the synthesis of diaryl ethers, which takes place at lower
temperatures (see above). Tosylate 2d furnished aryl ester
8a in high yield (Table 3, entry 13), which is in accordance
with the results obtained with phenols in toluene (Table 2,
entry 6).
Chemoselectivity with unsymmetric salts: The chemoselectiv-
ity aspects of the reaction with unsymmetric salts were ini-
tially screened by arylation of 7a with various aryl-
AHCTUNGTREG(NNUN phenyl)triflates and the ratio of phenylated versus arylated
product was observed by NMR spectroscopy of the crude
product. p-Tolyl salt 2p gave a 3:1 ratio in favor of phenyla-
tion (Table 4, entry 1), which is in agreement with the aryla-
tion of phenols (Scheme 6). The opposite selectivity was ob-
tained with o-methyl salt 2q (Table 4, entry 2) and mesityl
Table 4. Arylation of acids 7 with unsymmetric diaryliodonium salts 2.
Scope of aryl esters: A variety of aromatic carboxylic acids
were subsequently treated with triflate 2a or tetrafluorobo-
rate 2b to afford phenyl esters 8a–g (Scheme 7). As expect-
ed, the nucleophilicity of the carboxylic acid influenced the
outcome of the reaction, and 2,4-dimethoxybenzoate was
phenylated in better yield than 4-nitrobenzoate to give 8b
and 8c, respectively.
Sterically hindered acids were efficiently phenylated.
Even the very bulky triisopropyl-substituted product 8g was
formed in 90% yield. The reaction scope was further inves-
tigated with symmetric salts 2. Steric bulk in the ortho posi-
tions of the salt was well tolerated, demonstrated by aryla-
Entry
1
Salt 2
Product 9
Ratio 8a/9
2p
2q
2r
9a
9b
9c
3:1
2
3
1:3
1:7
tion of bisACHTUNGTRENNUNG(mesityl) salt 2h to give 8h. Both electron-poor
and electron-rich aryl moieties were easily transferred from
salts 2k and 2o.
Aliphatic carboxylic acids could also be employed, exem-
plified by the synthesis of 8j–l. In contrast to classical esteri-
fication protocols, a primary alcohol moiety was tolerated
4
5
2w
2s
9d
9e
16:1
1:2
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FULL PAPER
salt 2r resulted in a 7:1 selectivity in favor of the substituted
arylated product 9c (Table 4, entry 3).
problems. Thus, the isolated yields of the TRIP esters were
in some cases much lower than the NMR yields, even with
chemoselectivities that exceeded 10:1.
The electron-rich methoxy salt 2w was highly selective to-
wards phenylation (Table 4, entry 4), as previously noted for
the phenol reactions (Scheme 6). On the contrary, the elec-
tron-deficient salt 2s was rather unselective and delivered
9e with only 2:1 selectivity (Table 4, entry 5).
These results follow the literature precedent that the most
electron-deficient aryl moiety is generally transferred, al-
though ortho-substituted aryl groups can be transferred de-
spite being more electron-rich.[44] Only the arylations per-
formed with 2r and 2w were selective enough to be synthet-
ically useful (Table 3, entries 3 and 4), therefore the chemo-
selectivity scope was subsequently investigated with salts
that contained bulky ortho substituents and/or p-methoxy
substituents.
Far better results were obtained with TRIP salt 2ac,
which combines the two chemoselectivity effects of steric
and electronic differentiation between the aryl moieties.
When this salt was used, TRIP esters 9l–m, with unprece-
dented steric bulk, were synthesized in excellent yields and
with complete chemoselectivity (Scheme 9). These products
were only obtained in moderate yields with salt 2t due to
the aforementioned separation problems from the minor
isomer.
The synthesis of highly congested triisopropylphenyl
(TRIP) esters was investigated with the unsymmetric salt 2t.
Excellent chemoselectivity was observed with a range of
acids 7, which were arylated with the TRIP group to give
TRIP esters 9 f–k in high yields (Scheme 8). The phenylated
Scheme 9. Chemoselective arylation with unsymmetric diaryliodonium
salts. [a] Reaction with salt 2t, isolated yield of structure shown; chemo-
selectivity determined by crude NMR spectroscopy. [b] Yield with salt
2u.
The unsymmetric anisyl salts 2z–aa were also employed
and gave electron-deficient aryl esters 9n–p with complete
chemoselectivity. Ester 9p was also formed with total che-
moselectivity in reactions with the phenyl salt 2u, but in
lower yield.
Interestingly, the opposite chemoselectivity trends are ob-
served with unsymmetric diaryliodonium salts used in
metal-catalyzed reactions. Then the least bulky or more
electron-rich aryl group is generally transferred and the
TRIP group is often used as a dummy ligand to increase the
chemoselectivity towards transfer of the other aryl
moiety.[43]
Scheme 8. Arylation of carboxylic acids 7 with unsymmetric salt 2t.
[a] Chemoselectivity determined by crude NMR spectroscopy, isolated
yield of structure shown.
product was only observed with two substrates, and then
only in minute amounts (9g and 9k). The observed chemo-
selectivity follows the previously reported ortho effect,[44]
which was also noted in the arylation of phenols (see
above).
Notably, even reactions that combined high levels of
steric hindrance in both the acid 7 and the salt proceeded
smoothly to provide novel esters 9g–i, with only quaternary
carbons surrounding the ester moiety, in excellent yields.
Furthermore, a keto substituent was compatible with the ar-
ylation; ester 9k was obtained without any detectable by-
products formed from base-catalyzed condensation reac-
tions.
Despite the successful, chemoselective arylations per-
formed with salt 2t, the applicability of this salt is somewhat
limited by the similar polarity of the TRIP ester and any
minor amounts of phenyl ester, which caused purification
Arylation of sulfonic acids: Aryl sulfonate esters are gener-
ally synthesized by reacting a suitable alcohol with the ap-
propriate sulfonyl chloride, whereas the direct transforma-
tion of a sulfonic acid to the respective ester is difficult to
achieve.[51,52] We have briefly investigated the arylation of
sulfonic acids with diaryliodonium salts and found the reac-
tion to proceed well under our standard conditions, despite
the poor nucleophilicity of sulfonic acids relative to carbox-
ylic acids.
In the first approach, tosylate salt 2d was heated in tol-
uene in the absence of an external nucleophile and phenyl
tosylate 10a was formed in excellent yield within 1 h (Sche-
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B. Olofsson et al.
study with a range of O, N, and C nucleophiles and a wide
variety of unsymmetric salts has been initiated and will be
reported in due course.
With recent advances in efficient synthetic procedures for
diaryliodonium salts, these reagents are now inexpensive
and readily available. The stoichiometric amount of iodoar-
ene formed in the arylations can be recovered quantitative-
ly, demonstrated in a large-scale reaction. The recovered io-
doarene can be utilized to regenerate the diaryliodonium
salt, which improves the atom economy. The arylation meth-
odology presented should, therefore, be useful in a wide
range of applications.
Experimental Section
Scheme 10. Arylation of sulfonic acids.
Representative procedure for arylation of phenols 1: Phenol 1 (1.0 equiv,
0.34 mmol) was added to a suspension of tBuOK (1.1 equiv, 43 mg,
0.37 mmol) in THF (1.5 mL) at 08C and the reaction was stirred at 08C
for 15 min. Diaryliodonium salt 2 (1.2 equiv, 0.40 mmol) was added in
one portion and the reaction was stirred at RT, or in an oil bath preheat-
ed to 408C, until TLC indicated complete consumption of 1. The reaction
was quenched with H2O at 08C, the organic phase was separated, and the
aqueous phase was extracted with Et2O (3ꢂ10 mL). The combined or-
ganic phases were dried (Na2SO4) and concentrated in vacuo. The crude
material was purified by flash chromatography to give diaryl ether 4.
me 10a). The reaction was repeated with the chiral cam-
phorsulfonate salt 2ae to smoothly deliver phenyl ester 10b.
In the second approach, tolyl and phenyl sulfonic acids
were arylated with diaryliodonium triflate 2a or 2h to
afford 10a and 10c, respectively, in moderate yields (Sche-
me 10b). The lowered yields in the second approach could
partially be explained by the presence of water or indicate
that the ligand exchange (nucleophilic attack) on iodine is
the rate-determining step in this reaction.
Representative procedure for arylation of carboxylic acids 7: tBuOK
(62 mg, 1.1 equiv, 0.55 mmol) was added to a flame-dried round-bottom
flask equipped with a magnetic stirrer bar. NB: It is important to ensure
good mixing because the reaction mixture can be quite viscous. The flask
was fitted with a rubber septum and kept under a positive pressure of
argon. Dry toluene (3 mL) was introduced by syringe. The carboxylic
acid 7 (1.1 equiv, 0.55 mmol) and the diaryliodonium salt 2 (1.0 equiv,
0.50 mmol) were added sequentially each as solids. The flask was equip-
ped with a water-jacketed condenser and heated at reflux temperature
(oil bath temperature=1308C) for 1 h. The heating source was removed
and the reaction mixture was transferred to a separating funnel and dilut-
ed with Et2O. After washing with water and brine, the organic layer was
dried over anhydrous MgSO4 and concentrated in vacuo. The crude ma-
terial was purified by flash chromatography to yield aryl ester 8.
Conclusion
Efficient methodology for the electrophilic arylation of phe-
nols, carboxylic acids, and sulfonic acids with diaryliodonium
salts has been presented. The reaction conditions are mild,
metal free, and avoid the use of halogenated solvents, addi-
tives, or excess reagents. As expected, the reactivity of the
nucleophile influences the required reaction temperature;
phenols are arylated at room temperature, whereas carbox-
ylic acids and sulfonic acids need elevated temperatures.
The arylated products are obtained in good-to-excellent
yields after short reaction times. Steric hindrance is very
well tolerated, both in the nucleophile and the diaryliodoni-
um salt. The scope allows access to bulky ortho- and halo-
substituted products, which are difficult to obtain by metal-
catalyzed protocols. Many functional groups are tolerated,
including carbonyl groups, heteroatoms, and alkenes. The
potential of the diaryl ether methodology has been further
illustrated by arylation of two a-amino acid derivatives with-
out concomitant racemization.
Acknowledgements
This work was financially supported by the Swedish Research Council,
Carl Trygger Foundation, and the Swedish Foundation for International
Cooperation in Research and Higher Education (STINT).
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ilton, C. M. Bailey, R. A. Domaoal, L. Wang, K. S. Anderson, W. L.
Jorgensen, Bioorg. Med. Chem. Lett. 2006, 16, 5664–5667; and
h) D. M. B. Hickey, P. D. Leeson, R. Novelli, V. P. Shah, B. E. Bur-
pitt, L. P. Crawford, B. J. Davies, M. B. Mitchell, K. D. Pancholi, D.
Tuddenham, N. J. Lewis, C. OꢁFarrell, J. Chem. Soc. Perkin Trans. 1
1988, 3103–3111.
electron-donating ortho-substituents are not transferred, see
a) ref [43]; b) M. A. Carroll, R. A. Wood, Tetrahedron 2007, 63,
11349–11354; c) M. Ochiai, Y. Kitagawa, N. Takayama, Y. Takaoka,
M. Shiro, J. Am. Chem. Soc. 1999, 121, 9233–9234.
[45] P. J. Stang, B. Olenyuk, K. Chen, Synthesis 1995, 937–938.
[46] A. Ozanne-Beaudenon, S. Quideau, Angew. Chem. 2005, 117, 7227–
7231; Angew. Chem. Int. Ed. 2005, 44, 7065–7069.
[47] a) Ref [37] (arylation of sodium benzoate (5 equiv) with three differ-
ent salts in 40–85% yield); b) A. N. Nesmeyanov, L. G. Makarova,
T. P. Tolstaya, Tetrahedron 1957, 1, 145–157(no details given);
c) R. C. Fuson, R. L. Albright, J. Am. Chem. Soc. 1959, 81, 487–
490(Cu-catalyzed synthesis of 2-acetoxy-2ꢁ-iodobiphenyl).
[48] J. Xue, X. Huang, Synth. Commun. 2007, 37, 2179–2185.
[49] Published in ref [29], shown here for comparison. See the Support-
ing Information for the remaining results.
[50] A decrease of the reaction temperature to 1008C and use of cesium
carbonate did not change the outcome of the reaction.
[51] a) S. Caddick, J. D. Wilden, D. B. Judd, J. Am. Chem. Soc. 2004, 126,
1024–1025; b) N. Sakurai, T. Mukaiyama, Chem. Lett. 2007, 36,
928–929.
[39] The nucleophilicity of the phenoxide was expected to increase in an
aprotic solvent. The previous use of protic solvents is likely due to
the insolubility of diaryliodonium halides in aprotic media.
[40] Similar conditions were used in one arylation example, see M. W.
Justik, J. D. Protasiewicz, J. B. Updegraff, Tetrahedron Lett. 2009, 50,
6072–6075.
[41] J. J. Lubinkowski, C. Gimenez Arrieche, W. E. McEwen, J. Org.
Chem. 1980, 45, 2076–2079.
[42] Phenol 4b was arylated in CH2Cl2 because a byproduct lowered the
yield when the reaction was performed in THF.
[52] For arylations with iodonium salts, see: a) ref [49] (via aryne);
b) P. J. Stang, B. W. Surber, J. Am. Chem. Soc. 1985, 107, 1452–
1453(from alkynyl salt).
[43] C. H. Oh, J. S. Kim, H. H. Jung, J. Org. Chem. 1999, 64, 1338–1340.
[44] This so-called ortho effect varies with the nucleophile and is some-
times overriden by electronic properties so that aryl groups with
Received: May 9, 2012
Published online: && &&, 0000
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Metal-Free Arylation of Oxygen Nucleophiles
FULL PAPER
Arylation
N. Jalalian, T. B. Petersen,
B. Olofsson* .................. &&&& — &&&&
Metal-Free Arylation of Oxygen
Nucleophiles with Diaryliodonium
Salts
Believe the hype! Phenols, carboxylic
acids, and sulfonic acids are efficiently
arylated with diaryliodonium salts (see
scheme). The reaction conditions are
mild, metal free, and avoid the use of
halogenated solvents, additives, and
excess reagents. The products are
obtained in good to excellent yields in
short reaction times. Unsymmetric
salts can be chemoselectively utilized
to obtain products with hitherto unre-
ported levels of steric hindrance.
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!