Para-Selective Cu-Catalyzed C-H Aryloxylation of Electron-Rich Arenes and Heteroarenes

Article abstract of DOI:10.1021/acs.joc.5b02728

Cu-catalyzed reaction of phenols with electron-rich arene or heteroarene ligands of unsymmetrical diaryl-λ³-iodanes is a key step in the developed one-pot two-step method for intermolecular para-selective C-H aryloxylation of heteroarenes and arenes.

Full text of DOI:10.1021/acs.joc.5b02728

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Featured Article
Para-Selective Cu–catalyzed C–H Aryloxylation
of Electron-rich Arenes and Heteroarenes
Igors Sokolovs, and Edgars Suna
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02728 • Publication Date (Web): 23 Dec 2015
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ParaꢀSelective Cu–catalyzed C–H Aryloxylation of Electronꢀrich Arenes and
Heteroarenes
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Igors Sokolovs and Edgars Suna*
Latvian Institute of Organic Synthesis, Aizkraukles 21, LVꢀ1006, Riga, Latvia
edgars@osi.lv
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Abstract. Cuꢀcatalyzed reaction of phenols with electronꢀrich (hetero)arene ligands of
unsymmetrical diarylꢀλ3ꢀiodanes is a key step in the developed oneꢀpot twoꢀstep
method for intermolecular paraꢀselective C−H aryloxylation of heteroarenes and
arenes.
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Introduction
Synthetic methodologies employing hypervalent iodonium species have
recently become an important alternative to the transition metalꢀcatalyzed direct
Csp2–H activation methods for CꢀO bonds formation.1,2 Thus, a reaction of
diaryliodonium salts with various oxygen nucleophiles such as alcohols and phenols
under metalꢀfree conditions has been widely used for synthesis of arylꢀalkyl ethers
and diarylethers.3,4 The use of symmetrical diaryliodonium salts in the reaction with
oxygen nucleophiles generates one equivalent of aryl iodide sideꢀproduct together
with the desired ether (eq 1).The waste of aryl iodide nucleofuge becomes costꢀ
inefficient for diaryliodonium salts possessing structurally complex aryl moieties.
Therefore, unsymmetrical diaryliodonium salts comprising an elaborated aryl moiety
and structurally simple nontransferrable or “dummy” arene ligand are often used (eq
2). The nontransferrable aryl moieties should be relatively electronꢀrich and sterically
unhindered, because oxygen nucleophiles such as phenolates react either with the
most electronꢀdeficient of the two aryl moieties in the unsymmetrical iodonium salt
(electronic control) or with orthoꢀsubstituted aryl moiety (steric control or soꢀcalled
orthoꢀeffect).5,6 Such reactivity pattern, however, imparts an important limitation to
the transition metalꢀfree methodology: oxygen nucleophiles apparently do not react
with electronꢀrich aryl moieties of unsymmetrical diaryliodonium species.
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We have recently demonstrated that the selectivity of the reaction between
unsymmetrical diarylꢀλ3ꢀiodanes and nitrogen nucleophiles such as azides and amines
can be directed to the more electronꢀrich (hetero)arene moiety by a Cu(I) catalyst.7,8
We report herein that the most electronꢀrich of the two aryl ligands in unsymmetrical
diaryliodonium species react selectively with oxygen nucleophiles such as phenols in
the presence of Cu(I) species.9 This finding provided new opportunities for Csp2ꢀH
functionalization of arenes given that the unsymmetrical diarylꢀλ3ꢀiodanes can be
generated in situ directly from relatively electronꢀrich arenes and hypervalent
iodonium reagent such as ArI(OH)OTs.10 We envisioned that the electronꢀrich aryl
moiety of the in situ formed unsymmetrical diarylꢀλ3ꢀiodanes would subsequently
react with phenols in the presence of Cu(I) catalyst to afford diarylethers. Indeed, we
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found that the transformation of nonꢀprefunctionalized arenes to diarylethers can be
performed in sequential two step manner as described below. Furthermore, the
developed Csp2ꢀH aryloxylation approach features high paraꢀselectivity of C–O bond
formation, and, hence, it is a complementary methodology to transition metalꢀ
catalyzed Csp2–H to Csp2–O transformations which usually requires the presence of
an orthoꢀdirecting group in the arene.11
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Results and Discussion.
paraꢀMethoxyphenyl moietyꢀcontaining diarylꢀλ3ꢀiodane 2e12 was chosen as a
model for the development of Csp2–H aryloxylation method because paraꢀanisyl
moiety has been frequently used as a “dummy” ligand in the noncatalyzed reactions
of unsymmetrical diarylꢀλ3ꢀiodanes with oxygen nucleophiles.13 Indeed, phenol 3a
reacted preferentially with a mesityl ligand of the λ3ꢀiodane 2e to afford mesityl 4ꢀ
bromophenyl ether and iodoanisole 5 (entry 1, Table 1). The desired 4e was formed
only in less than 5% yield. In sharp contrast, addition of Cu(MeCN)4BF4 (10 mol%)
altered the selectivity of the reaction providing ether 4e as the major product
(4e:5=2:1, entry 2). Mesityl moiety apparently served as a nontransferable aryl
ligand14 in the Cu(I)ꢀcatalyzed reaction of λ3ꢀiodane 2e with 3a. As anticipated,
replacement of bulky mesityl ligand for a less sterically hindered phenyl group
(iodane 2e-Ph) resulted in a nonꢀselective reaction (entry 3). Disappointingly, the use
of sterically highly hindered triisopropylphenyl (TIPP) ligand as the nontransferable
aryl moiety15 (iodane2e-TIPP) resulted in undesired selectivity (4e:5=1:3, entry 4).
Therefore the mesityl group was chosen as the “dummy” ligand in all subsequent
experiments. Copper(I) iodide can be used as a catalyst at the expense of slightly
diminished yields of the target 4e (4e:5=1.4:1, entry 5). Interestingly, catalytic
efficiency of copper salts depended on the structure of anion: both Cu(I) and Cu(II)
triflates were inferior to Cu(MeCN)4BF4 (entries 6,7 vs. entry 2). The presence of
water (1 equiv) was found to be detrimental for the success of the reaction between
λ3ꢀiodane 2e and 3a (entry 8). Hence, moistureꢀfree conditions are critical to obtain
the desired product 4e in good yields. The presence of oxygen had relatively small
effect on the reaction outcome (entry 9 vs. entry 2).
Table 1. Reaction of λ3ꢀiodane 2e with phenol 3a.a
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Entry λ3ꢀiodane
Cu catalyst
None
time, hb 4e, %c 5, %c
1
168d
1.5
1.5
1.5
1.5
48
<5
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55e
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2e
2
3
2ef
2e-Phg
2e-TIPPh
2e
Cu(MeCN)4BF4
Cu(MeCN)4BF4
Cu(MeCN)4BF4
CuI
4
5
6
Cu(OTf)2
2e
7
CuOTf
48
2e
8i
9j
Cu(MeCN)4BF4
48
2e
Cu(MeCN)4BF4
1.5
2e
a Conditions: λ3ꢀiodane 2e (1 equiv), phenol 3a (1.2 equiv), iPrNEt2 (1.5 equiv), CH2Cl2 (0.1 M). b Full
conversion of 2e. c Determined by 1HꢀNMR using methyl 2ꢀiodobenzoate as an internal standard.
d 75% conversion of 2e. e Formed together with 20% of mesityl 4ꢀbromophenyl ether. f Ar=Mes.
g Ar=Ph. h Ar=TIPP (2,4,6ꢀtriisopropyl)phenyl. i In the presence of water (1 equiv). j Under air.
With the optimized conditions for the reaction between λ3ꢀiodane 2e and
phenol 3a in hand, the development of a oneꢀpot sequential synthesis of diarylethers
from nonꢀprefunctionalized arenes without isolation of the intermediate λ3ꢀiodane was
addressed. The λ3ꢀiodane 2e could be formed from anisole and MesI(OH)OTs (1.1
equiv) in 74% yield within 24 h in anhydrous CH2Cl2 at room temperature. Higher
yields of 2e were achieved in the presence of protic acids such as CF3COOH and
TsOH (82% and 91%, respectively).16 Subsequent reaction of the in situ formed 2e
with phenol 3a in the presence of iPrNEt2 (2.5 equiv) and Cu(MeCN)4BF4 (10 mol%)
afforded the desired diarylether 4e in 57% yield after 18 hours at room temperature.
The prolonged reaction time could be decreased substantially by capturing one
equivalent of water that is generated during the formation of λ3ꢀiodane 2e from
anisole and MesI(OH)OTs (compare entries 8 and 2, Table 1). This was achieved by
using trifluoroacetic acid anhydride (1 equiv) as an additive. The anhydride reacted
with water to form trifluoroacetic acid which, in turn, facilitated the formation of λ3
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iodane 2e in 70% yield within 3 hours at room temperature (entry 1, Table 2).
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Next, the scope of phenols suitable for the reaction with λ3ꢀiodane 2e was
examined (Table 2). Phenols with both electronꢀwithdrawing groups (entries
2,4,9,11,14) and electronꢀreleasing groups (entries 6, 8, 12) are suitable as
nucleophiles. Sterically hindered phenols (entries 8 and 9) afforded lower yields of
diarylethers. The C–H aryloxylation conditions are compatible with a variety of
functional groups in phenols such as halides (entry 1,9,16), nitro group (entry 2),
carboxylic ester (entries 4 and 5), amide (entry 11), benzylic alcohol (entry 13),
aldehyde (entry 14), alkene (entry 10) and NꢀBoc protecting group (entry 12).
Quinolinꢀ6ꢀol (entry 7) and hydroxypyridines (entries 15,16) could be also used as
nucleophiles.
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Table 2. Scope of phenols 3.a
entry
1
ArOH 3
yield, %b entry
ArOH 3
yield, %b
4e, 70
5e, 65
9
12e, 37
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13e, 64
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7e, 68
8e, 69
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17e, 75
18e, 67
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p
h
a Conditions: Arene 1e (1.0 equiv); (CF3CO)2O (1.0 equiv) and MesꢀI(OH)OTs (1.0 equiv) in CH2Cl2
(0.25 M) at room temperature for 30 min; then Cu(MeCN)4BF4 (10 mol%), phenol 3 (1.2 equiv) and
DIPEA (3.5 equiv) in CH2Cl2 (0.1 M) at rt for 3 h. b Average yield of two runs.
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All arenes that react with MesI(OH)OTs reagent in the presence of
trifluoroacetic anhydride and form relatively stable λ3ꢀiodanes are suitable as
substrates (Table 3). Toluene 1a (entry 1) represents a reactivity borderline: less
electronꢀrich arenes than toluene (for example benzene and aryl halides) did not react
with MesI(OH)OTs reagent. Time of the formation of λ3ꢀiodanes 2a–r correlated well
with electronic properties of the starting arenes 1a–r: the more electronꢀrich were
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arenes 1a–r, the shorter time was required to achieve complete conversion to λ3
ꢀ
iodanes 2a–r (compare entries 1, 3, 5 and 12 as well as entries 4 and 10, Table 3). The
strong electronꢀdonating effect of methoxy group (σp= –0.27)17 compensated for the
presence of deactivating electronꢀwithdrawing substituents such as bromine (entry 9)
and amide (entry 13). Relatively electronꢀrich heterocycles such as thiophene (entry
14), indoles (entries 15, 16) and pyrroles (entries 17, 18) also afforded the C–H
aryloxylation products.
Regioselectivity of the C−H aryloxylation is controlled at the stage of the
formation of the unsymmetrical diarylꢀλ3ꢀiodane intermediates 2a–r. Notably, all
monosubstituted arenes underwent highly regioselective paraꢀC–H aryloxylation and
the formation of isomeric orthoꢀsubstituted products was not observed. The C–O bond
formation in multiply substituted arenes proceeded selectively at the paraꢀposition to
the strongest electronꢀreleasing substituent (entries 9–11). In heterocycles the
regioselectivity of the C–O bond formation was consistent with that of electrophilic
aromatic substitution (SEAr) reactions: λ3ꢀiodanes were formed at the βꢀposition of
indoles (entries 15 and 16, Table 3), and at the αꢀposition of thiophenes (entry 14) and
pyrroles (entry 17). In 2,5ꢀdisubstituted pyrrole the C–H aryloxylation occurred at the
βꢀposition (entry 18).
The C−H aryloxylation conditions were compatible with the presence of
bromine (entries 9, 15, 16, 18) and even pinacolyl boronate moiety (entry 11) in
substrates which renders feasible their further functionalization. OꢀAllyl (entry 6), Oꢀ
benzyl (entry 7), Nꢀbenzyl (entry 18) and even relatively labile OꢀTBDMS (entry 8)
protecting groups are tolerated. (Hetero)arenes may contain a range of functional
groups such as secondary amides (entry 13), carboxylic esters (entries 15, 17, 18) and
nitrile (entry 16).
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Table 3. Substrate scope for the synthesis of diarylethers.a
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time, yield,
time, yield,
entry
1
arene 1
ArOH
entry
10
arene 1
ArOH
b
b
h
%
h
%
40
63
67
0.1
57
3a
3a
j
a
2
18
11
2
65c
3a
3a
b
k
l
3
4
3
72
51
12
13
0.25
0.5
55
28
3a
3a
3a
3a
c
0.5
d
m
5
6
0.5
0.5
70
73
14
15
0.5
0.5
50
71
3a
3a
3b
3b
e
n
f
o
7
8
9
0.5
0.5
18
78
68
65
16
17
18
18
0.25
0.5
53
49
43
3a
3a
3a
3b
3b
3b
g
p
q
h
i
r
a Conditions: (Hetero)arene 1 (1.0 equiv); (CF3CO)2O (1.0 equiv) and MesꢀI(OH)OTs (1.0 equiv) in
CH2Cl2 (0.25 M) at room temperature; then Cu(MeCN)4BF4 (10 mol%), phenol 3 (1.2 equiv) and
DIPEA (3.5 equiv) in CH2Cl2 (0.1 M) at rt for 3 h. b Average yield of two runs. c 80% purity according
to 1HꢀNMR; pure product (>95%) was obtained by crystallization.
An important mechanistic question pertains to possible involvement of
phenoxy diarylꢀλ3ꢀiodanes in the Cuꢀcatalyzed aryloxylation reaction. Putative
phenoxy diarylꢀλ3ꢀiodanes could form from tosyloxy diarylꢀλ3ꢀiodanes 2a–r and
phenols by exchange of tosyloxy ligand for phenoxy moiety. Subsequent Cuꢀ
catalyzed reductive elimination from phenoxy diarylꢀλ3ꢀiodanes would afford
diarylethers and iodoꢀmesitylene. To verify such a mechanistic scenario, preparation
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of phenoxy diarylꢀλ3ꢀiodanes in pure form was attempted. After a considerable work
it was found that relatively stable phenoxy diarylꢀλ3ꢀiodanes could be obtained from
the corresponding tosylates only if phenols possessing electronꢀwithdrawing
substituents were used. Thus, the reaction of sodium paraꢀnitrophenolate and
iodonium tosylate 2o afforded crystalline phenoxy diarylꢀλ3ꢀiodane 20, which could
be stored for more than a week at +4 oC without decomposition. The structure of 20
was confirmed by Xꢀray crystallographic analysis (Figure 1).18
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Figure 1. Xꢀray crystal structure of a 1:1 adduct of λ3ꢀiodane 20 and phenol 3b
(thermal displacement ellipsoids are drawn at the 50% probability level and hydrogen
atoms are omitted for clarity). Selected bond distances (Å) and angles (deg): I16−C3,
2.095(3); I16−C17, 2.102(3); I16−O7a, 2.578(2); I−O12, 2.748(2); C3−I16−C17,
95.0(1). See the Supporting Information for details.
In CH2Cl2 solution phenoxy diarylꢀλ3ꢀiodane 20 undergoes slow reductive
elimination to form 3ꢀiodoindole 21 and diarylether 22 (eq 3; 25% conversion after 3
h at rt; 100% conversion after 168 h at rt), and the formation of 4o was not observed.
Importantly, addition of Cu(MeCN)4BF4 (10 mol%) resulted in reversal of selectivity
favoring the formation of the desired ether 4o (4o:21=5:1) together with MesꢀI (eq 4).
Furthermore, the copper catalyst considerably decreased the reaction time (complete
conversion of 20 was observed already after 1.5 h). These results point toward an
involvement of phenoxy diarylꢀλ3ꢀiodane intermediates such as 20 in catalytic cycle
of the Cuꢀcatalyzed CꢀH aryloxylation.
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A control experiment has been carried out to determine the oxidation state of
catalytically active copper species in the CꢀH aryloxylation reaction. Accordingly,
neocuproine (2 equiv with respect to Cu(MeCN)4BF4) was added to the λ3ꢀiodane 20
and Cu(I) catalyst (eq 5). Neocuproine is a highly specific chelating agent for Cu(I)
ions, which forms a stable bright orangeꢀcolored complex of formula
CuI(neocuproine)2.19 The addition of neocuproine considerably decelerated the
reaction and only 15% conversion of λ3ꢀiodane 20 was observed after 6 hours as
opposed to the complete conversion of 20 within 1.5 h without the added neocuproine
(eq 5 vs. eq 4).20 Furthermore, 3ꢀiodoindole 21 and ether 22 were the only products
observed in the reaction mixture and the desired 4o was not formed. Evidently, the
addition of neocuproine completely inhibited the Cu(I)ꢀcatalyzed reaction and λ3
ꢀ
iodane 20 underwent slow noncatalyzed conversion to 21 and 22. Based on these
results a CuI/CuIII catalytic cycle for the reaction between λ3ꢀiodanes 2 and phenols 3
is plausible. Accordingly, an initially formed Cu(I)ꢀphenolate would undergo
oxidative addition of the λ3ꢀiodane 2 to form the Cu(III) intermediate. Product
forming reductive elimination would afford diarylether and regenerate a catalytically
active Cu(I) species.
Conclusions.
In summary, electronꢀrich (hetero)arene ligands of unsymmetrical diarylꢀλ3
iodanes undergo reaction with phenolates in the presence of Cu(I) catalyst. Such
reactivity mode of unsymmetrical diarylꢀλ3ꢀiodanes with phenolates cannot be
ꢀ
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achieved under metalꢀfree conditions where electronically poor arene ligands react
preferentially. Hence, the Cu(I)ꢀcatalyzed synthesis of diarylethers from
unsymmetrical diarylꢀλ3ꢀiodanes is a complementary method to the metalꢀfree
conditions. The Cu(I)ꢀcatalyzed reaction between unsymmetrical diarylꢀλ3ꢀiodanes
and phenolates was used also as a key step in the development of a oneꢀpot twoꢀstep
sequential catalytic CꢀH aryloxylation method. The CꢀH aryloxylation method
comprised an initial formation of unsymmetrical diarylꢀλ3ꢀiodanes directly from nonꢀ
prefunctionalized electron rich (hetero)arenes and MesI(OH)OTs reagent. Subsequent
Cu(I)ꢀcatalyzed reaction of the in situ formed unsymmetrical diarylꢀλ3ꢀiodanes with
phenolates provided the desired diarylethers. The developed CꢀH aryloxylation
method features high paraꢀselectivity of C−H aryloxylation of a wide range of
relatively electronrich arenes. The para regioselectivity is controlled at the stage of
the formation of the unsymmetrical diarylꢀλ3ꢀiodane intermediates. Regioselectivity of
C−H aryloxylation in heteroarenes in general is consistent with that of electrophilic
aromatic substitution (SEAr) reactions. Given the mild reaction conditions (room
temperature) and excellent functional group compatibility, the developed C–H
aryloxylation is especially suitable for lateꢀstage paraꢀselective functionalization of
pharmaceutically relevant (hetero)arenes.
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Experimental Section.
General Information.
Unless otherwise noted, all chemicals were used as obtained from commercial sources
and all reactions were performed under argon atmosphere. Analytical thinꢀlayer
chromatography (TLC) was performed on precoated silica gel Fꢀ254 plates. Nuclear
magnetic resonance spectra were recorded on NMR spectrometers at the following
frequencies: 1H, 400 or 300 MHz; 13C{1H}, 101 or 75 MHz. Chemical shifts are
reported in parts per million (ppm) relative to TMS or with the residual solvent peak
as an internal reference. Infrared (IR) spectra were recorded with KBr pellet, and
wavenumbers were given in cm−1. High resolution mass spectra (HRMS) were
recorded on an TOF MS instrument using the ESI technique.
Preparation of unsymmetrical diaryl-λ3-iodanes.
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(4-Methoxyphenyl){[(4-methylphenyl)sulfonyl]oxy}(2,4,6-trimethylphenyl)-λ3
iodane (2e). To a wellꢀstirred suspension of MesI(OH)OTs (2.17 g, 5.00 mmol,
-
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1.0 equiv) and TsOH●H2O (951 mg, 5.00 mmol, 1.0 equiv) in CH2Cl2 (30 mL) was
added dropwise neat anisole 1e (543 µL, 5.00 mmol, 1.00 equiv) and the resulting
yellow solution was stirred at room temperature. The progress of the reaction was
monitored by TLC (disappearance of the MesI(OH)OTs spot, Rf = 0.49, 20:80:5
MeOH/CH2Cl2/AcOH) and complete conversion of the starting material was
observed within 1 hour. The solution was concentrated to ca. 2/3 of the original
volume and Et2O was added (50 mL). Formed precipitate was filtered, washed with
Et2O (10 mL) and dried in vacuo to afford 2e as a white powder (2.50 g, 95% yield).
Pure material was obtained by crystallization from CH2Cl2/diethyl ether: mp 180 oC
dec. 1H NMR (300 MHz, DMSOꢀd6, ppm) δ 7.95 – 7.89 (2H, m), 7.49 – 7.44 (2H, m),
7.19 (2H, s), 7.12 – 7.08 (2H, m), 7.06 – 7.00 (2H, m), 3.78 (3H, s), 2.60 (6H, s), 2.28
(6H, s). 1H NMR spectrum was in agreement with that reported in the literature.21
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(4-Methoxyphenyl){[(4-methylphenyl)sulfonyl]oxy}[2,4,6-tris(1-
methylethyl)phenyl]-λ3-iodane (2e-TIPP). Iodane 2e-TIPP (2.33 g, 77% yield) was
synthesized from TIPPꢀI(OH)OTs22 (2.59 g, 5.00 mmol, 1.0 equiv), TsOH●H2O (951
mg, 5.00 mmol, 1.0 equiv) and anisole 1e (543 µL, 5.00 mmol, 1.00 equiv) as
described for iodane 2e. Pure material was obtained by crystallization from
CH2Cl2/diethyl ether: mp 168 oC dec. 1H NMR (300 MHz, DMSOꢀd6, ppm) δ 7.91 –
7.84 (2H, m), 7.49 – 7.44 (2H, m), 7.28 (2H, s), 7.14 – 7.05 (4H, m), 3.78 (3H, s),
3.49 – 3.38 (2H, m), 3.03 – 2.89 (1H, m), 2.28 (3H, s), 1.26 – 1.17 (18H, m). 1H
NMR spectrum was in agreement with that reported in the literature.13d
(4-Methoxyphenyl){[(4-methylphenyl)sulfonyl]oxy}phenyl-λ3-iodane (2e-Ph).
Iodane 2e-Ph (2.3 g, 95% yield) was synthesized from PhI(OAc)2 (1.61 g, 5.00 mmol,
1.0 equiv), TsOH●H2O (1.24 g, 6.5 mmol, 1.3 equiv) and anisole 1e (543 µL, 5.0
mmol, 1.00 equiv) as described for iodane 2e. Pure material was obtained by
crystallization from CH2Cl2/diethyl ether: mp 160 oC dec. 1H NMR (300 MHz,
DMSOꢀd6, ppm) δ 8.23 – 8.13 (4H, m), 7.68 – 7.61 (1H, m), 7.55 – 7.44 (4H, m),
7.14 – 7.04 (4H, m), 3.79 (3H, s), 2.28 (3H, s). 1H NMR spectrum was in agreement
with that reported in the literature.10a
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Ethyl 5-bromo-1-methyl-3-[(4-nitrophenoxy)(2,4,6-trimethylphenyl)-λ3-iodanyl]-
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1H-indole-2-carboxylate 1:1 adduct with 4-nitrophenol (20). A solution of ethyl 5ꢀ
bromoꢀ3ꢀ(mesityl(tosyloxy)ꢀλ3ꢀiodanyl)ꢀ1ꢀmethylꢀ1Hꢀindoleꢀ2ꢀcarboxylate8a (2.0 g,
2.86 mmol, 1.0 equiv.) in CH2Cl2 (50 mL) was extracted twice with a solution of 4ꢀ
nitrophenol (598 mg, 4.30 mmol, 1.5 equiv.) and NaOH (172 mg, 4.30 mmol, 1.5
equiv) in water (50 mL). Organic layer was dried over Na2SO4, concentered in vacuo
and Et2O (50 mL) was added to the yellow residue. Formed precipitate was filtered,
washed with Et2O (10 mL) and dried in vacuo to afford λ3ꢀiodane 20 as a yellow
powder (1.53 g, 67% yield). Pure material was obtained by crystallization from
CH2Cl2/diethyl ether: mp 124 oC dec. IR (film, cmꢀ1) 1717 (C=O).1H NMR (400
MHz, CDCl3, ppm) δ 11.25 – 10.50 (1H, br s), 7.99 – 7.94 (4H, m), 7.41 (1H, dd, J =
9.0, 1.8 Hz), 7.30 (1H, d, J = 9.0 Hz), 7.05 (2H, s), 6.61 – 6.57 (4H, m), 5.96 (1H, d, J
= 1.8 Hz), 4.58 (2H, q, J = 7.1 Hz), 4.08 (3H, s), 2.56 (6H, s), 2.35 (3H, s), 1.50 (3H,
t, J=7.1 Hz).13C{1H} NMR (101 MHz, CDCl3, ppm) δ 169.71, 169.68, 161.8, 144.9,
143.1, 138.9, 137.9, 129.99, 129.97, 129.0, 127.2, 126.6, 122.3, 119.8, 117.4, 116.5,
113.2, 64.0, 33.6, 27.3, 21.2, 14.5.HRMSꢀESI (m/z) calcd for C21H22NO2BrI [Mꢀ
OC6H4NO2*HOC6H4NO2]+ 525.9879, found 525.9878.
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Preparation of Cu(MeCN)4BF4
[Cu(MeCN)4]BF4 was synthesized in accordance with literature procedure.23 Thus, to
a blueꢀcolored suspension of Cu(BF4)2●6H2O (2.00 g, 5.79 mmol) in anhydrous
MeCN (50 mL) was added copper powder (1.47 g, 23.17 mmol). The resulting
suspension was heated under reflux for 4 h under argon atmosphere and then hotꢀ
filtered. The pale blue filtrate was then cooled to –20 oC whereupon a white solid
crystalline material was formed. The white solid was collected by filtration and
washed with Et2O (15 mL). Pure material was obtained by recrystallization from hot
MeCN. Yield: 1.73 g (95%).
General Procedure for Sequential One-Pot Two-Step Synthesis of Diarylethers
To a solution of MesI(OTs)OH (217 mg, 0.50 mmol, 1.0 equiv) in anhydrous CH2Cl2
(1 mL) under argon atmosphere was added a solution of arene 1 (0.50 mmol, 1.0
equiv) in anhydrous CH2Cl2 (1 mL). Neat TFAA (71 ꢁL, 0.50 mmol, 1.0 equiv) was
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then added dropwise (slowly, within 2ꢀ3 minutes; too fast addition of TFAA leads to
the formation of sideꢀproducts). The resulting solution (color range – pale yellow to
dark brown) was stirred at room temperature under argon atmosphere and the progress
of the reaction was monitored by TLC (disappearance of the starting I (III) reagent
spot; mobile phase 20:80:5 MeOH/DCM/AcOH). Immediately upon disappearance of
MesI(OTs)OH reagent (see Table 3 for appropriate time), the reaction mixture was
transferred via cannula to another flask which contained preꢀweighed solid
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[Cu(MeCN)4]+BF4 (16 mg, 0.05 mmol, 10 mol%) and a magnetic stirꢀbar, and the
ꢀ
source flask was rinsed with CH2Cl2 (1 mL). To the resulting wellꢀstirred suspension
was immediately (!) added a solution of phenol (0.6 mmol, 1.2 equiv) in anhydrous
CH2Cl2 (2 mL), followed with neat DIPEA (305 ꢁL 1.75 mmol, 3.5 equiv)
(Important! Decomposition of the formed λ3ꢀiodane begins if the addition of Cu
catalyst and/or DIPEA is delayed). The resulting solution was stirred at room
temperature under argon atmosphere and the progress of the reaction was monitored
by TLC (mobile phase MeOH/CH2Cl2/AcOH=20:80:5; the intermediate λ3ꢀiodanes
have Rf=0.4–0.6). In the most cases the reaction was completed in 3 hours. The
solution was poured into a mixture of water (50 mL) and aqueous saturated ammonia
solution (20 mL) and extracted with CH2Cl2(3x30 mL). Combined organic extracts
were dried over Na2SO4, filtered and concentrated. The residue was purified by
column chromatography on silica gel.
1-Bromo-4-(4-methoxyphenoxy)benzene (4e).24 Following the general procedure
anisole 1e (54 µL, 0.50 mmol) was converted into 4e. Purification of the crude
product by column chromatography (Biotage M+12) using gradient elution from
100% light petroleum ether to 15% EtOAc in light petroleum ether afforded product
as a pale yellow powder (100 mg in the 1st run and 95 mg in the 2nd run, 72% and
68% yield, respectively); analytical TLC on silica gel, 1:10 EtOAc/petroleum ether,
Rf=0.35. Pure material was obtained by crystallization from diethyl ether /petroleum
ether: mp 87–88 oC. 1H NMR (300MHz, CDCl3, ppm) δ 7.42 – 7.35 (2H, m), 7.00 –
6.94 (2H, m), 6.92 – 6.86 (2H, m), 6.85 – 6.78 (2H, m), 3.81 (3H, s).
1-Methoxy-4-(4-nitrophenoxy)benzene (5e).25 Following the general procedure
anisole 1e (54 µL, 0.50 mmol) was converted into 5e. Purification of the crude
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product by column chromatography (Biotage M+12) using gradient elution from
100% light petroleum ether to 15% EtOAc in light petroleum ether afforded product
as a white powder (75 mg in the 1st run and 85 mg in the 2nd run, 61% and 69% yield,
respectively); analytical TLC on silica gel, 1:10 EtOAc/petroleum ether, Rf=0.29.
Pure material was obtained by crystallization from diethyl ether /petroleum ether: mp
113ꢀ114 oC. 1H NMR (300 MHz, CDCl3, ppm) δ 8.21 – 8.15 (2H, m), 7.06ꢀ7.00 (2H,
m), 6.99ꢀ6.92 (4H, m), 3.84 (3H, s).
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1-Methoxy-4-phenoxybenzene (6e).25 Following the general procedure anisole 1e
(54 µL, 0.50 mmol) was converted into 6e. Purification of the crude product by
column chromatography (Biotage M+12) using gradient elution from 100% light
petroleum ether to 15% EtOAc in light petroleum ether afforded product as a
colorless oil (75 mg in the 1st run and 70 mg in the 2nd run, 75% and 70% yield,
respectively); analytical TLC on silica gel, 1:10 EtOAc/petroleum ether, Rf=0.46. 1H
NMR (300 MHz, CDCl3, ppm) δ 7.33 – 7.27 (2H, m), 7.07 – 7.01 (1H, m), 7.01 –
6.96 (2H, m), 6.96 – 6.91 (2H, m), 6.91 – 6.85 (2H, m), 3.81 (3H, s).
Ethyl 4-(4-methoxyphenoxy)benzoate (7e).26 Following the general procedure
anisole 1e (54 µL, 0.50 mmol) was converted into 7e. Purification of the crude
product by column chromatography (Biotage M+12) using gradient elution from
100% light petroleum ether to 15% EtOAc in light petroleum ether afforded product
as a colorless oil (95 mg in the 1st run and 90 mg in the 2nd run, 70% and 66% yield,
respectively); analytical TLC on silica gel, 1:10 EtOAc/petroleum ether, Rf=0.29. 1H
NMR (300 MHz, CDCl3, ppm) δ 8.02 – 7.95 (2H, m), 7.05 – 6.98 (2H, m), 6.96 –
6.89 (4H, m), 4.35 (2H, q, J = 7.1 Hz), 3.82 (3H, s), 1.38 (3H, t, J = 7.1 Hz).
Methyl [4-(4-methoxyphenoxy)phenyl]acetate (8e).27 Following the general
procedure anisole 1e (54 µL, 0.50 mmol) was converted into 8e. Purification of the
crude product by column chromatography (Biotage M+12) using gradient elution
from 100% light petroleum ether to 15% EtOAc in light petroleum ether afforded
product as a colorless oil (91 mg in the 1st run and 95 mg in the 2nd run, 67% and 70%
yield, respectively); analytical TLC on silica gel, 1:10 EtOAc/petroleum ether,
Rf=0.21. 1H NMR (300 MHz, CDCl3, ppm) δ 7.24 – 7.17 (2H, m), 7.01 – 6.94 (2H,
m), 6.93 – 6.84 (4H, m), 3.81 (3H, s), 3.70 (3H, s), 3.59 (2H, s).
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5-(4-Methoxyphenoxy)-1,3-benzodioxole (9e).28 Following the general procedure
anisole 1e (54 µL, 0.50 mmol) was converted into 9e. Purification of the crude
product by column chromatography (Biotage M+12) using gradient elution from
100% light petroleum ether to 15% EtOAc in light petroleum ether afforded product
as a colorless oil (70 mg in the 1st run and 75 mg in the 2nd run, 57% and 61% yield,
respectively); analytical TLC on silica gel, 1:10 EtOAc/petroleum ether, Rf=0.33. 1H
NMR (300 MHz, CDCl3, ppm) δ 6.96 – 6.91 (2H, m), 6.88 – 6.84 (2H, m), 6.72 (1H,
d, J = 8.4 Hz), 6.53 (1H, d, J = 2.4 Hz), 6.42 (1H, dd, J = 8.4, 2.4 Hz), 5.95 (2H, s),
3.79 (3H, s).
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6-(4-Methoxyphenoxy)quinoline (10e). Following the general procedure anisole 1e
(54 µL, 0.50 mmol) was converted into 10e. Purification of the crude product by
column chromatography (Biotage M+12) using gradient elution from 5% diethyl ether
/ light petroleum ether to 35% diethyl ether in light petroleum ether afforded product
as a grey powder (60 mg in the 1st run and 65 mg in the 2nd run, 48% and 52% yield,
respectively); analytical TLC on silica gel, 1:3 diethyl ether /petroleum ether, Rf=0.21.
Pure material was obtained by crystallization from diethyl ether /petroleum ether: mp
46–47 oC. 1H NMR (400 MHz, CDCl3, ppm) δ 8.80 (1H, dd, J = 4.2, 1.7 Hz), 8.06
(1H, d, J = 9.2 Hz), 7.97 – 7.94 (1H, m), 7.47 (1H, dd, J = 9.2, 2.7 Hz), 7.33 (1H, dd,
J = 8.3, 4.2 Hz), 7.09 (1H, d, J = 2.7 Hz), 7.08 – 7.04 (2H, m), 6.96 – 6.91 (2H, m),
3.83 (3H, s).13C{1H} NMR (101 MHz, CDCl3, ppm) δ 157.0, 156.5, 149.6, 148.9,
145.0, 135.1, 131.4, 129.2, 122.7, 121.6, 121.5, 115.2, 111.2, 55.8. HRMSꢀESI (m/z)
calcd for C16H14NO2 [M+H]+ 252.1025, found 252.1025.
2-(4-Methoxyphenoxy)-1,3-dimethylbenzene (11e).29 Following the general
procedure anisole 1e (54 µL, 0.50 mmol) was converted into 11e. Purification of the
crude product by column chromatography (Biotage M+12) using gradient elution
from 100% light petroleum ether to 15% EtOAc in light petroleum ether afforded
product as a white powder (68 mg in the 1st run and 63 mg in the 2nd run, 60% and
55% yield, respectively); analytical TLC on silica gel, 1:10 EtOAc/petroleum ether,
Rf=0.50. Pure material was obtained by crystallization from petroleum ether: mp 43–
45 oC. 1H NMR (300 MHz, CDCl3, ppm) 7.11 – 7.00 (3H, m), 6.82 – 6.76 (2H, m),
6.71 – 6.65 (2H, m), 3.76 (3H, s), 2.13 (6H, s).
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1,3-Difluoro-2-(4-methoxyphenoxy)benzene (12e). Following the general procedure
anisole 1e (54 µL, 0.50 mmol) was converted into 12e. Purification of the crude
product by column chromatography (Biotage M+12) using gradient elution from
100% light petroleum ether to 15% EtOAc in light petroleum ether afforded product
as a colorless oil (45 mg in the 1st run and 41 mg in the 2nd run, 38% and 35% yield,
respectively); analytical TLC on silica gel, 1:10 EtOAc/petroleum ether, Rf=0.38.1H
NMR (400 MHz, CDCl3, ppm) δ 7.12 (1H, ddt, J = 9.2, 7.7, 5.8 Hz), 7.03 – 6.95 (2H,
m), 6.93 – 6.88 (2H, m), 6.85 – 6.80 (2H, m), 3.77 (3H, s).13C{1H} NMR (101 MHz,
CDCl3, ppm) δ 156.6 (dd, J = 251.1, 4.6 Hz), 155.4, 152.1, 132.4 (t, J = 14.8 Hz),
124.9 (t, J = 9.1 Hz), 116.5, 114.8, 112.6 (dd, J = 16.7, 5.6 Hz), 55.8. Anal. Calcd. for
C13H10O2F2: C, 66.10; H, 4.27. Found: C, 66.44; H, 4.49.
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1-(4-Methoxyphenoxy)-2-prop-2-en-1-ylbenzene (13e).29 Following the general
procedure anisole 1e (54 µL, 0.50 mmol) was converted into 13e. Purification of the
crude product by column chromatography (Biotage M+12) using gradient elution
from 100% light petroleum ether to 15% EtOAc in light petroleum ether afforded
product as a colorless oil (78 mg in the 1st run and 75 mg in the 2nd run, 65% and 63%
yield, respectively); analytical TLC on silica gel, 1:10 EtOAc/petroleum ether,
Rf=0.50. 1H NMR (300 MHz, CDCl3, ppm) δ 7.24 (1H, dd, J = 7.4, 1.8 Hz), 7.14 (1H,
ddd, J = 8.0, 7.5, 1.8 Hz), 7.03 (1H, ddd, J = 7.5, 7.4, 1.1 Hz), 6.93 – 6.84 (4H, m),
6.79 (1H, dd, J = 8.0, 1.1 Hz), 6.00 (1H, ddt, J = 16.9, 10.2, 6.6 Hz), 5.12 – 5.03 (2H,
m), 3.80 (3H, s), 3.45 (2H, d, J = 6.6 Hz).
N,N
-Diethyl-2-(4-methoxyphenoxy)benzamide (14e).30 Following the general
procedure anisole 1e (54 µL, 0.50 mmol) was converted into 14e. Purification of the
crude product by column chromatography (Biotage M+12) using gradient elution
from 100% CH2Cl2 to 15% diethyl ether in CH2Cl2 afforded product as a white
powder (79 mg in the 1st run and 70 mg in the 2nd run, 53% and 47% yield,
respectively); analytical TLC on silica gel, 1:10 diethyl ether/CH2Cl2, Rf=0.32. Pure
material was obtained by crystallization from diethyl ether/petroleum ether: mp 62–
o
63 C. 1H NMR (300 MHz, DMSOꢀd6, ppm) δ 7.36 – 7.25 (2H, m), 7.12 (1H, td, J =
7.4, 0.9 Hz), 6.99 – 6.92 (4H, m), 6.78 (1H, dd, J = 8.3, 0.7 Hz), 3.74 (3H, s), 3.54 –
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3.33 (2H, m), 3.18 (2H, q, J = 7.0 Hz), 1.07 (3H, t, J = 7.1 Hz), 1.01 (3H, t, J = 7.1
Hz).
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tert-Butyl [4-(4-methoxyphenoxy)phenyl]carbamate (15e). Following the general
procedure anisole 1e (54 µL, 0.50 mmol) was converted into 15e. Purification of the
crude product by column chromatography (Biotage M+12) using gradient elution
from 10% EtOAc in light petroleum ether to 35% EtOAc in light petroleum ether
afforded product as a white powder (99 mg in the 1st run and 112 mg in the 2nd run,
63% and 71% yield, respectively); analytical TLC on silica gel, 1:10 EtOAc/light
petroleum ether, Rf=0.17. Pure material was obtained by crystallization from diethyl
ether/petroleum ether: mp 124–125 oC. 1H NMR (400 MHz, CDCl3, ppm) δ 7.33 –
7.26 (2H, m), 6.96 – 6.91 (2H, m), 6.92 – 6.88 (2H, m), 6.88 – 6.83 (2H, m), 6.44
(1H, s), 3.79 (3H, s), 1.51 (9H, s). 13C{1H} NMR (101 MHz, CDCl3, ppm) δ 155.7,
154.0, 153.1, 151.0, 133.4, 120.5, 120.2, 118.8, 114.9, 80.6, 55.8, 28.5. Anal. Calcd.
for C18H21NO4: C, 68.55; H, 6.71; N, 4.44. Found: C, 68.57; H, 6.72; N, 4.37.
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[3-(4-Methoxyphenoxy)phenyl]methanol (16e).31 Following the general procedure
anisole 1e (54 µL, 0.50 mmol) was converted into 16e. Purification of the crude
product by column chromatography (Biotage M+12) using gradient elution from 5%
diethyl ether in light petroleum ether to 35% diethyl ether in light petroleum ether
afforded product as a pale yellow oil (64 mg in the 1st run and 60 mg in the 2nd run,
56% and 52% yield, respectively); analytical TLC on silica gel, 1:3 diethyl
ether/petroleum ether, Rf=0.33. 1H NMR (300 MHz, CDCl3, ppm) δ 7.32 – 7.26 (1H,
m), 7.06 – 7.02 (1H, m), 7.01 – 6.93 (3H, m), 6.92 – 6.84 (3H, m), 4.65 (2H, d, J =
5.6 Hz), 3.81 (3H, s), 1.64 (1H, t, J = 5.6 Hz).
4-(4-Methoxyphenoxy)benzaldehyde (17e).32 Following the general procedure
anisole 1e (54 µL, 0.50 mmol) was converted into 17e. Purification of the crude
product by column chromatography (Biotage M+12) using gradient elution from 10%
EtOAc in light petroleum ether to 35% EtOAc in light petroleum ether afforded
product as a pale yellow powder (82 mg in the 1st run and 88 mg in the 2nd run, 72%
and 77% yield, respectively); analytical TLC on silica gel, 1:10 EtOAc/light
petroleum ether, Rf=0.17. Pure material was obtained by crystallization from diethyl
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ether/petroleum ether: mp 60–61 oC. 1H NMR (300 MHz, CDCl3, ppm) δ 9.91 (1H,
s), 7.85 – 7.79 (2H, m), 7.06 – 6.98 (4H, m), 6.97 – 6.90 (2H, m), 3.83 (3H, s).
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2-(4-Methoxyphenoxy)pyridine (18e).27 Following the general procedure anisole 1e
(54 µL, 0.50 mmol) was converted into 18e. Purification of the crude product by
column chromatography (Biotage M+12) using gradient elution from 10% diethyl
ether in CH2Cl2 to 60% diethyl ether in CH2Cl2M afforded product as a grey powder
(69 mg in the 1st run and 65 mg in the 2nd run, 69% and 65% yield, respectively);
analytical TLC on silica gel, 1:1 diethyl ether/ CH2Cl2, Rf=0.29. Pure material was
obtained by crystallization from diethyl ether/petroleum ether: mp 111–112 oC. 1H
NMR (300 MHz, CDCl3, ppm) δ 7.37 (1H, ddd, J = 9.2, 6.6, 2.1 Hz), 7.33 – 7.27 (3H,
m), 7.02 – 6.96 (2H, m), 6.67 – 6.61 (1H, m), 6.21 (1H, td, J = 6.7, 1.3 Hz), 3.84 (3H,
s).
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3-Chloro-5-(4-methoxyphenoxy)pyridine (19e). Following the general procedure
anisole 1e (54 µL, 0.50 mmol) was converted into 19e. Purification of the crude
product by column chromatography (Biotage M+12) using gradient elution from 10%
EtOAc in light petroleum ether to 35% EtOAc in light petroleum ether afforded
product as a white powder (60 mg in the 1st run and 65 mg in the 2nd run, 51% and
55% yield, respectively); analytical TLC on silica gel, 1:10 EtOAc/light petroleum
ether, Rf=0.25. Pure material was obtained by crystallization from diethyl
ether/petroleum ether: mp 54–55 oC. 1H NMR (400 MHz, DMSOꢀd6, ppm) δ 8.35
(1H, d, J = 2.0 Hz), 8.27 (1H, d, J = 2.5 Hz), 7.42 (1H, dd, J = 2.5, 2.3 Hz), 7.14 –
7.11 (2H, m), 7.02 – 6.99 (2H, m), 3.77 (3H, s). 13C{1H} NMR (101 MHz, DMSOꢀd6,
ppm) δ 156.4, 155.0, 148.0, 142.0, 138.1, 131.2, 123.7, 121.1, 115.4, 55.4. HRMSꢀ
ESI (m/z) calcd for C12H11NO2Cl [M+H]+ 236.0478, found 236.0483.
1-Bromo-4-(4-methylphenoxy)benzene (4a).33 Following the general procedure
toluene 1a (53 µL, 0.50 mmol) was converted into 4a. Purification of the crude
product by column chromatography (Biotage M+12) using light petroleum ether as a
mobile phase afforded product as a white powder (87 mg in the 1st run and 78 mg in
the 2nd run, 66% and 59% yield, respectively); analytical TLC on silica gel, light
petroleum ether, Rf=0.38. Pure material was obtained by crystallization from
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petroleum ether: mp 65–66 oC. 1H NMR (300 MHz, CDCl3, ppm) δ 7.44 – 7.37 (2H,
m), 7.18 – 7.12 (2H, m), 6.94 – 6.88 (2H, m), 6.88 – 6.82 (2H, m), 2.34 (3H, s).
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4-(4-Bromophenoxy)-1,2-dimethylbenzene (4b). Following the general procedure oꢀ
xylene 1b (60 µL, 0.50 mmol) was converted into 4b. Purification of the crude
product by column chromatography (Biotage M+12) using light petroleum ether as a
mobile phase afforded product as a colorless oil (96 mg in the 1st run and 90 mg in the
2nd run, 69% and 65% yield, respectively); analytical TLC on silica gel, light
petroleum ether, Rf=0.32. 1H NMR (400 MHz, CDCl3, ppm) δ 7.43 – 7.38 (2H, m),
7.10 (1H, d, J = 8.2 Hz), 6.88 – 6.83 (2H, m), 6.81 (1H, d, J = 2.6 Hz), 6.75 (1H, dd, J
= 8.2, 2.6 Hz), 2.25 – 2.24 (6H, m). 13C{1H} NMR (101 MHz, CDCl3, ppm) δ 157.3,
154.5, 138.5, 132.7, 132.3, 130.9, 120.7, 120.0, 116.7, 115.1, 20.1, 19.2. Anal. Calcd.
for C14H13OBr: C, 60.67; H, 4.73. Found: C, 60.62; H, 4.76.
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1-(4-Bromophenoxy)-2,4-dimethylbenzene(4c). Following the general procedure mꢀ
xylene 1c (62 µL, 0.50 mmol) was converted into 4c. Purification of the crude product
by column chromatography (Biotage M+12) using light petroleum ether as a mobile
phase afforded product as a colorless oil (103 mg in the 1st run and 96 mg in the 2nd
run, 74% and 69% yield, respectively); analytical TLC on silica gel, light petroleum
ether, Rf=0.42. 1H NMR (400 MHz, CDCl3, ppm) δ 7.39 – 7.35 (2H, m), 7.08 – 7.06
(1H, m), 7.01 – 6.97 (1H, m), 6.84 – 6.80 (1H, m), 6.78 – 6.73 (2H, m), 2.33 (3H, s),
2.16 (3H, s). 13C{1H} NMR (101 MHz, CDCl3, ppm) δ 157.7, 151.6, 134.3, 132.6,
132.4, 130.1, 128.0, 120.4, 118.5, 114.3, 20.9, 16.2. Anal. Calcd. for C14H13OBr: C,
60.67; H, 4.73. Found: C, 61.03; H, 4.81.
4-Bromophenyl 5,6,7,8-tetrahydronaphthalen-2-yl ether (4d). Following the
general procedure tetraline 1d (68 µL, 0.50 mmol) was converted into 4d. Purification
of the crude product by column chromatography (Biotage M+12) using light
petroleum ether as a mobile phase afforded product as a colorless oil (70 mg in the 1st
run and 83 mg in the 2nd run, 46% and 55% yield, respectively); analytical TLC on
silica gel, light petroleum ether, Rf=0.29. 1H NMR (400 MHz, CDCl3, ppm) δ 7.42 –
7.38 (2H, m), 7.04 (1H, d, J = 8.2 Hz), 6.89 – 6.84 (2H, m), 6.75 (1H, dd, J=8.2, 2.6
Hz), 6.72 (1H, d, J = 2.6 Hz), 2.78 – 2.71 (1H, m), 1.82 – 1.77 (4H, m). 13C{1H}
NMR (101 MHz, CDCl3, ppm) δ 157.3, 154.2 139.0, 132.9, 132.7, 130.5, 120.1,
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119.6, 116.8, 115.1, 29.7, 28.9, 23.4, 23.1. Anal. Calcd. for C16H15OBr: C, 63.38; H,
4.99. Found: C, 63.42; H, 4.97.
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1-Bromo-4-[4-(prop-2-en-1-yloxy)phenoxy]benzene (4f).34 Following the general
procedure Oꢀallyl ether 1f (68 µL, 0.50 mmol) was converted into 4f. Purification of
the crude product by column chromatography (Biotage M+12) using gradient elution
from 5% EtOAc in light petroleum ether to 25% EtOAc in light petroleum ether
afforded product as a white powder (109 mg in the 1st run and 111 mg in the 2nd run,
72% and 73% yield, respectively); analytical TLC on silica gel, 1:10 EtOAc/light
petroleum ether, Rf=0.42. Pure material was obtained by crystallization from
petroleum ether: mp 58–59 oC. 1H NMR (300 MHz, CDCl3, ppm) δ 7.43 – 7.35 (2H,
m), 6.99 – 6.87 (4H, m), 6.86 – 6.78 (2H, m), 6.06 (1H, ddt, J = 17.2, 10.5, 5.3 Hz),
5.42 (1H, dq, J = 17.3, 1.6 Hz), 5.30 (1H, dq, J = 10.5, 1.4 Hz), 4.53 (2H, dt, J = 5.3,
1.5 Hz).
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1-(Benzyloxy)-4-(4-bromophenoxy)benzene (4g).35 Following the general procedure
Oꢀbenzyl ether 1g (92 mg, 0.50 mmol) was converted into 4g. Purification of the
crude product by column chromatography (Biotage M+12) using gradient elution
from 5% EtOAc in light petroleum ether to 25% EtOAc in light petroleum ether
afforded product as a white powder (135 mg in the 1st run and 140 mg in the 2nd run,
76% and 79% yield, respectively); analytical TLC on silica gel, 1:10 EtOAc/light
petroleum ether, Rf=0.35. Pure material was obtained by crystallization from
petroleum ether: mp 109–110 oC.1H NMR (300 MHz, CDCl3, ppm) δ 7.46 – 7.33
(7H, m), 6.96 (4H, s), 6.86 – 6.80 (2H, m), 5.06 (2H, s).
[4‐(4‐Bromophenoxy)phenoxy](tert‐butyl)dimethylsilane (4h). Following the
general procedure OꢀTBDMS phenol 1h36 (105 mg, 0.50 mmol) was converted into
4h. Purification of the crude product by column chromatography (Biotage M+12)
using gradient elution from 100% light petroleum ether to 10% EtOAc in light
petroleum ether afforded product as a colorless oil (125 mg in the 1st run and 131 mg
in the 2nd run, 66% and 69% yield, respectively); analytical TLC on silica gel, light
petroleum ether, Rf=0.25.1H NMR (400 MHz, CDCl3, ppm) δ 7.41 – 7.37 (2H, m),
6.91 – 6.87 (2H, m), 6.84 – 6.80 (4H, m), 0.99 (9H, s), 0.21 (6H, s). 13C{1H} NMR
(101 MHz, CDCl3, ppm) δ 157.8, 152.2, 150.3, 132.6, 121.2, 120.8, 119.5, 114.9,
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25.8, 18.3, ꢀ4.3. Anal. Calcd. for C18H23O2BrSi: C, 56.99; H, 6.11. Found: C, 56.98;
H, 6.10.
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2-Bromo-4-(4-bromophenoxy)-1-methoxybenzene (4i). Following the general
procedure 2ꢀbromoanisole 1i (62 µL, 0.50 mmol) was converted into 4i. Purification
of the crude product by column chromatography (Biotage M+12) using gradient
elution from 100% light petroleum ether to 10% EtOAc in light petroleum ether
afforded product as a white powder (125 mg in the 1st run and 109 mg in the 2nd run,
70% and 61% yield, respectively); analytical TLC on silica gel, 1:10 EtOAc/light
petroleum ether, Rf=0.50. Pure material was obtained by crystallization from diethyl
ether/petroleum ether: mp 69–70 oC.1H NMR (400 MHz, CDCl3, ppm) δ 7.44 – 7.39
(2H, m), 7.25 (1H, d, J = 2.8 Hz), 6.96 (1H, dd, J = 8.9, 2.8 Hz), 6.88 (1H, d, J = 8.9
Hz), 6.86 – 6.81 (2H, m), 3.89 (3H, s).13C{1H} NMR (101 MHz, CDCl3, ppm) δ
157.2, 152.8, 150.2, 132.8, 124.9, 119.7, 119.5, 115.6, 112.7, 112.2, 56.8. Anal.
Calcd. for C13H10O2Br2: C, 43.61; H, 2.82. Found: C, 43.54; H, 2.72.
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5-(4-Bromophenoxy)-2,3-dihydro-1-benzofuran (4j). Following the general
procedure dihydrobenzofuran 1j (56 µL, 0.50 mmol) was converted into 4j.
Purification of the crude product by column chromatography (Biotage M+12) using
gradient elution from 100% light petroleum ether to 10% EtOAc in light petroleum
ether afforded product as a white powder (70 mg in the 1st run and 95 mg in the 2nd
run, 48% and 65% yield, respectively); analytical TLC on silica gel, 1:10 EtOAc/light
petroleum ether, Rf=0.42. Pure material was obtained by crystallization from diethyl
ether/petroleum ether: mp 54–55 oC. 1H NMR (400 MHz, CDCl3, ppm) δ 7.40 – 7.36
(2H, m), 6.90 – 6.87 (1H, m), 6.83 – 6.79 (2H, m), 6.79 – 6.76 (1H, m), 6.74 (1H, d,
J=8.5 Hz), 4.59 (2H, t, J = 8.7 Hz), 3.20 (2H, t, J = 8.7 Hz). 13C{1H} NMR (101
MHz, CDCl3, ppm) δ 158.3, 156.8, 149.7, 132.6, 128.7, 119.7, 119.1, 117.3, 114.6,
109.8, 71.7, 30.2. Anal. Calcd. for C14H11O2Br: C, 57.76; H, 3.81. Found: C, 57.59;
H, 3.72.
2‐[5‐(4‐Bromophenoxy)‐2‐methoxyphenyl]‐4,4,5,5‐tetramethyl‐1,3,2‐dioxa
borolane (4k). Following the general procedure pinacolyl boronate 1k37 (117 mg,
0.50 mmol) was converted into 4k. Purification of the crude product by column
chromatography (Biotage M+12) using gradient elution from 5% EtOAc in light
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petroleum ether to 25% EtOAc in light petroleum ether afforded product as a white
powder (142 mg in the 1st run and 122 mg in the 2nd run, 70% and 60% yield,
respectively); analytical TLC on silica gel, 1:10 EtOAc/light petroleum ether,
Rf=0.10. Pure material was obtained by crystallization from diethyl ether/petroleum
ether: mp 133–134 oC.1H NMR (400 MHz, CDCl3, ppm) δ 7.40 – 7.33 (3H, m), 7.05
(1H, dd, J = 8.9, 3.1 Hz), 6.84 (1H, d, J = 8.9 Hz), 6.82 – 6.77 (2H, m), 3.83 (3H, s),
1.34 (12H, s). 13C{1H} NMR (101 MHz, CDCl3, ppm) δ 161.0, 158.2, 149.0, 132.6,
128.2, 124.1, 119.0, 114.5, 112.0, 83.9, 56.6, 25.0. Anal. Calcd. for C19H22O4BBr: C,
56.33; H, 5.47. Found: C, 56.37; H, 5.45.
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1-(4-Bromophenoxy)-2,4-dimethoxybenzene (4l). Following the general procedure
resorcinol dimethyl ether 1l (65 µL, 0.50 mmol) was converted into 4l. Purification of
the crude product by column chromatography (Biotage M+12) using gradient elution
from 100% light petroleum ether to 20% EtOAc in light petroleum ether afforded
product as a colorless oil (80 mg in the 1st run and 88 mg in the 2nd run, 52% and 57%
yield, respectively); analytical TLC on silica gel, 1:10 EtOAc/light petroleum ether,
Rf=0.33.1H NMR (400 MHz, CDCl3, ppm) δ 7.37 – 7.32 (2H, m), 6.95 (1H, d, J = 8.7
Hz), 6.78 – 6.74 (2H, m), 6.58 (1H, d, J = 2.8 Hz), 6.46 (1H, dd, J = 8.7, 2.8 Hz), 3.82
(3H, s), 3.77 (3H, s). 13C{1H} NMR (101 MHz, CDCl3, ppm) δ 158.3, 157.8, 152.6,
137.8, 132.4, 122.6, 117.8, 114.1, 104.4, 100.8, 56.1, 55.8. Anal. Calcd. for
C14H13O3Br: C, 54.39; H, 4.24. Found: C, 54.24; H, 4.18.
2-(4-Bromophenoxy)-3,5-dimethoxy-N-methylbenzamide (4m). Following the
general procedure 3,5ꢀdimethoxyꢀNꢀmethylbenzamide (1m)8a (97 mg, 0.50 mmol)
was converted into 4m. Purification of the crude product by column chromatography
(Biotage M+12) using gradient elution from 100% CH2Cl2 to 10% diethyl ether in
CH2Cl2 afforded product as a white powder (51 mg in the 1st run and 49 mg in the 2nd
run, 28% and 27% yield, respectively); analytical TLC on silica gel, 1:10 diethyl
ether/CH2Cl2, Rf=0.31. Pure material was obtained by crystallization from diethyl
ether/petroleum ether: mp 116–117 oC. IR (film, cmꢀ1) 3324 (NꢀH), 1638 (C=O).1H
NMR (400 MHz, CDCl3, ppm) δ 7.38 – 7.32 (2H, m), 7.23 (1H, d, J = 3.0 Hz), 7.21 –
7.15 (1H, m), 6.74 – 6.69 (2H, m), 6.65 (1H, d, J = 3.0 Hz), 3.86 (3H, s), 3.68 (3H, s),
2.88 (3H, d, J = 4.9 Hz). 13C{1H} NMR (101 MHz, CDCl3, ppm) δ 165.2, 157.6,
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157.1, 153.0, 135.1, 132.7, 128.6, 117.0, 115.1, 104.8, 104.2, 56.3, 55.9, 27.0.
HRMSꢀESI (m/z) calcd for C16H17NO4Br [M+H]+ 366.0341, found 366.0354.
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3-Methyl-2-(4-nitrophenoxy)thiophene (4n). Following the general procedure
methylthiophene 1n (48 µL, 0.50 mmol) was converted into 4n. Purification of the
crude product by column chromatography (Biotage M+12) using gradient elution
from 100% light petroleum ether to 15% EtOAc in light petroleum ether afforded
product as a pale yellow powder (59 mg in the 1st run and 59 mg in the 2nd run, 50%
and 50% yield, respectively); analytical TLC on silica gel, 1:10 EtOAc/light
petroleum ether, Rf=0.32. Pure material was obtained by crystallization from diethyl
ether/petroleum ether: mp 69–70 oC.1H NMR (400 MHz, CDCl3, ppm) δ 8.23 – 8.19
(2H, m), 7.08 – 7.03 (2H, m), 6.90 (1H, d, J=5.9 Hz), 6.77 (1H, d, J=5.9 Hz), 2.02
(3H, s). 13C{1H} NMR (101 MHz, CDCl3, ppm) δ 163.8, 150.4, 143.1, 128.1, 126.1,
125.6, 117.5, 115.9, 11.8. HRMSꢀESI (m/z) calcd for C11H10NO3S [M+H]+ 236.0381,
found 236.0388.
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Ethyl 5-bromo-1-methyl-3-(4-nitrophenoxy)-1H-indole-2-carboxylate (4o).
Following the general procedure indole 1o8a (141 mg, 0.50 mmol) was converted into
4o. Purification of the crude product by column chromatography (Biotage M+12)
using gradient elution from 5% EtOAc in light petroleum ether to 25% EtOAc in light
petroleum ether afforded product as a pale yellow powder (140 mg in the 1st run and
155 mg in the 2nd run, 67% and 74% yield, respectively); analytical TLC on silica gel,
1:10 EtOAc/light petroleum ether, Rf=0.17. Pure material was obtained by
crystallization from diethyl ether/petroleum ether: mp 151–152 oC. IR (film, cmꢀ1)
1717 (C=O). 1H NMR (400 MHz, CDCl3, ppm) δ 8.22 – 8.16 (2H, m), 7.61 (1H, dd, J
= 1.9, 0.4 Hz), 7.48 (1H, dd, J = 9.0, 1.9 Hz), 7.33 (1H, dd, J = 9.0, 0.4 Hz), 7.03 –
6.97 (2H, m), 4.20 (2H, q, J = 7.1 Hz), 4.07 (3H, s), 1.05 (3H, t, J = 7.1 Hz). 13C{1H}
NMR (101 MHz, CDCl3, ppm) δ 164.1, 160.7, 142.7, 135.9, 135.3, 129.5, 126.0,
121.6, 120.7, 119.2, 115.5, 114.5, 112.3, 61.1, 32.2, 14.0. Anal. Calcd. for
C18H15N2O5Br: C, 51.57; H, 3.61; N, 6.68. Found: C, 51.36; H, 3.52; N, 6.55.
5-Bromo-1-methyl-3-(4-nitrophenoxy)-1H-indole-2-carbonitrile (4p). Following
the general procedure 2ꢀcyanoindole 1p38 (118 mg, 0.50 mmol) was converted into
4p. Purification of the crude product by column chromatography (Biotage M+12)
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using gradient elution from 15% EtOAc in light petroleum ether to 45% EtOAc in
light petroleum ether afforded product as a pale yellow powder (100 mg in the 1st run
and 95 mg in the 2nd run, 54% and 51% yield, respectively); analytical TLC on silica
gel, 1:5 EtOAc/light petroleum ether, Rf=0.16. Pure material was obtained by
crystallization from EtOAc/petroleum ether: mp 202–203 oC. IR (film, cmꢀ1) 2220
(C≡N). 1H NMR (400 MHz, CDCl3, ppm) δ 8.25 – 8.22 (2H, m), 7.53 (1H, dd, J =
8.9, 1.9 Hz), 7.48 (1H, dd, J = 1.9, 0.6 Hz), 7.29 (1H, dd, J = 9.0, 0.5 Hz), 7.12 – 7.09
(2H, m), 3.90 (3H, s). 13C{1H} NMR (101 MHz, CDCl3, ppm) δ 162.4, 143.6, 139.6,
135.0, 130.4, 126.3, 121.7, 119.6, 116.3, 115.3, 112.4, 110.7, 103.1, 32.1. Anal.
Calcd. for C16H10N3O3Br: C, 51.64; H, 2.71; N, 11.29. Found: C, 51.55; H, 2.72; N,
10.96.
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Methyl 1-methyl-5-(4-nitrophenoxy)-1H-pyrrole-2-carboxylate (4q). Following
the general procedure methyl 1Hꢀpyrrole 1q (70 mg, 0.50 mmol) was converted into
4q. Purification of the crude product by column chromatography (Biotage M+12)
using gradient elution from 10% EtOAc in light petroleum ether to 30% EtOAc in
light petroleum ether afforded product as a pale yellow powder (68 mg in the 1st run
and 68 mg in the 2nd run, 49% and 49% yield, respectively); analytical TLC on silica
gel, 1:10 EtOAc/light petroleum ether, Rf=0.16. Pure material was obtained by
crystallization from diethyl ether /petroleum ether: mp 135–136 oC. IR (film, cmꢀ1)
1716 (C=O). 1H NMR (400 MHz, CDCl3, ppm) δ 8.19 – 8.15 (2H, m), 7.09 – 7.05
(2H, m), 6.69 – 6.67 (2H, m), 3.94 (3H, s), 3.82 (3H, s). 13C{1H} NMR (101 MHz,
CDCl3, ppm) δ 164.3, 161.3, 142.6, 139.1, 126.0, 120.7, 119.7, 116.0, 109.1, 51.5,
37.2. HRMSꢀESI (m/z) calcd for C13H13N2O5 [M+H]+ 277.0824, found 277.0819.
Methyl 1-(2-bromobenzyl)-2,5-dimethyl-4-(4-nitrophenoxy)-1H-pyrrole-3-
carboxylate (4r). Following the general procedure 1Hꢀpyrrole 1r39 (161 mg,
0.50 mmol) was converted into 4r. Purification of the crude product by column
chromatography (Biotage M+12) using gradient elution from 10% EtOAc in light
petroleum ether to 30% EtOAc in light petroleum ether afforded product as a pale
yellow powder (92 mg in the 1st run and 106 mg in the 2nd run, 40% and 46% yield,
respectively); analytical TLC on silica gel, 1:10 EtOAc/light petroleum ether,
Rf=0.16. Pure material was obtained by crystallization from diethyl ether/petroleum
ether: mp 159–160 oC. IR (film, cmꢀ1) 1700 (C=O). 1H NMR (400 MHz, CDCl3, ppm)
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δ 8.21 – 8.16 (2H, m), 7.61 (1H, dd, J = 7.8, 1.3 Hz), 7.26 (1H, td, J = 7.6, 1.2 Hz),
7.19 (1H, td, J = 7.7, 1.7 Hz), 7.02 – 6.97 (2H, m), 6.37 – 6.33 (1H, m), 5.08 (2H, s),
3.57 (3H, s), 2.46 (3H, s), 1.96 (3H, s). 13C{1H} NMR (101 MHz, CDCl3, ppm) δ
164.9, 164.3, 142.2, 135.53, 135.47, 134.3, 133.1, 129.5, 128.4, 126.4, 125.9, 121.7,
119.1, 115.3, 104.6, 50.9, 47.7, 11.3, 8.2. HRMSꢀESI (m/z) calcd for C21H20N2O5Br
[M+H]+ 459.0556, found 459.0551.
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Associated Content
Author Information
Corresponding Author
*Eꢀmail: edgars@osi.lv
Notes
The authors declare no competing financial interest.
Acknowledgments
This work was supported by Latvian Science Council Grant 274/2012. We thank Dr.
S. Belyakov for Xꢀray crystallographic analysis.
Supporting Information
1H and 13C spectra, Xꢀray crystallographic data for λ3ꢀiodane 20 (CIF). This material
is available free of charge via the Internet at http://pubs.acs.org.
References
1. Recent reviews on chemistry of hypervalent iodine(III): (a) Yusubov, M. S.;
Maskaev, A. V.; Zhdankin, V. V. ARKIVOC 2011, 1, 370–409. (b) Merritt, E.A.;
Olofsson, B. Angew. Chem. Int. Ed. 2009, 48, 9052–9070. (c) Zhdankin, V. V.;
Stang, P. J. Chem. Rev. 2008, 108, 5299–5358.
2. Suna, E. Chem. Heterocycl. Comp. 2012, 48, 44–48.
3. For pioneering works, see: (a) Beringer, F. M.; Brierley, A.; Drexler, M.; Gindler,
E. M.; Lumpkin, C. C. J. Am. Chem. Soc. 1953, 75, 2708–2712. (b) Crowder, J.
R.; Glover, E. E.; Grundon, M. F.; Kaempfen, H. X. J. Chem. Soc. 1963, 4578–
4585.
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7
8
9
4. For selected recent examples, see: (a) Sundalam, S. K.; Stuart, D. R. J. Org.
Chem. 2015, 80, 6456–6466. (b) Chan, L.; McNally, A.; Toh, Q. Y.; Mendoza, A.;
Gaunt, M. J. Chem. Sci. 2015, 6, 1277–1281. (c) Matsuzaki, K.; Okuyama, K.;
Tokunaga, E.; Saito, N.; Shiro, M.; Shibata, N. Org. Lett. 2015, 17, 3038–3041.
(d) Ghosh, R.; Lindstedt, E.; Jalalian, N.; Olofsson, B. ChemistryOpen 2014, 3,
54–57. (e) Lindstedt, E.; Ghosh, R.; Olofsson, B. Org. Lett. 2013, 15, 6070–6073.
(f) Kakinuma, Y.; Moriyama, K.; Togo, H. Synthesis, 2013, 45, 183–188. (g)
Jalalian, N.; Petersen, T. B.; Olofsson, B. Chem.ꢀEur. J. 2012, 18, 14140–14149.
(h) Jalalian, N.; Ishikawa, E. E.; Silva, L. F.; Olofsson, B. Org. Lett. 2011, 13,
1552–1555.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5. Malmgren, J.; Santoro, S.; Jalalian, N.; Himo, F.; Olofsson, B. Chem.– Eur.
J. 2013, 19, 10334–10342.
6. Wang, B.; Graskemper, J. W.; Qin, L.; DiMagno, S. G. Angew. Chem. Int.
Ed. 2010, 49, 4079–4083.
7. Lubriks, D.; Sokolovs, I.; Suna, E. J. Am. Chem. Soc. 2012, 134, 15436–15442.
8. (a) Sokolovs, I.; Lubriks, D.; Suna, E. J. Am. Chem. Soc. 2014, 136, 6920–6928.
(b) Berzina, B.; Sokolovs, I.; Suna, E. ACS Catal. 2015, 5, 7008–7014.
9. Cu(II)ꢀcatalyzed synthesis of phenol from unsymmetrical diaryliodane (1
example) has been recently reported: Kuriyama, M.; Hamaguchi, N.; Onomura, O.
Chem.ꢀEur. J. 2012, 18, 1591–1594.
10. (a) Dohi, T.; Ito, M.; Morimoto, K.; Minamitsuji, Y.;Takenaga, N.; Kita, Y.
Chem. Commun. 2007, 4152–4154. (b) Dohi, T.;Yamaoka, N.; Kita, Y.
Tetrahedron 2010, 66, 5775–5785 and references cited therein.
11. For selected recent examples of C−H oxygenations of arenes, see: (a) Roane, J.;
Daugulis, O. Org. Lett. 2013, 15, 5842–5845. (b) Wang, Y.; Gulevich, A. V.;
Gevorgyan, V. Chem.ꢀEur. J. 2013, 19, 15836−15840. (c) Suess, A. M.; Ertem,
M. Z.; Cramer, C. J.; Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 9797–9804. (d)
Hao, X.; Chen, L.; Ren, B.; Li, L.; Yang, X.; Gong, J.; Niu, J.; Song, M. Org.
Lett. 2014, 16, 1104–1107. (e) Sun, S.ꢀZ.; Shang, M.; Wang, H.ꢀL.; Lin, H.ꢀX.;
Dai, H.ꢀX.; Yu, J.ꢀQ. J. Org. Chem. 2015, 80, 8843–8848. (f) Sarkar, D.;
Gulevich, A. V.; Melkonyan, F. S.; Gevorgyan, V. ACS Catal. 2015, 5,
6792−6801 and references cited therein.
12. Prepared from anisole and MesI(OH)OTs in the presence of TsOH or CF3COOH
as described in ref. 8a.
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13. (a) Matsuzaki, K.; Okuyama, K.; Tokunaga, E.; Saito, N.; Shiro, M.; Shibata, N.
Org. Lett. 2015, 17, 3038–3041. (b) Kakinuma, Y.; Moriyama, K.; Togo, H.
Synthesis 2013, 45, 183–188. (c) Malmgren, J.; Santoro, S.; Jalalian, N.; Himo, F.;
Olofsson, B. Chem.–Eur. J. 2013, 19, 10334–10342. (d) Jalalian, N.; Petersen, T.
B.; Olofsson, B. Chem.–Eur. J. 2012, 18, 14140–14149.
10
11
12
13
14
15
16
17
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60
14. (a) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593–1597.(b) Zhu, S.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2012, 134, 10815–10818. c) Bigot, A.;
Williamson, A. E.; Gaunt, M. J. J. Am. Chem. Soc. 2011, 133, 13778–13781.
15. Replacement of nontransferable mesityl ligand for 2,4,6ꢀtriisopropylphenyl (TIPP)
group in unsymmetrical diarylꢀλ3ꢀiodane helped to improve selectivity in Cu(II)ꢀ
catalyzed arylations:a) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem.
Soc. 2008, 130, 8172–8174. For related recent nonꢀcatalyzed arylations with
TIPP–containing unsymmetrical diarylꢀλ3ꢀiodanes, see: b) Matsuzaki,
K.;Okuyama, K.; Tokunaga, E.; Shiro, M.; Shibata, N. Chemistry Open 2014, 3,
233–237.
16. It has been shown that strong acids such as TsOH facilitate the formation of
diarylꢀλ3ꢀiodanes from arenes: (a) Kitamura, T.; Matsuyuki, J.; Taniguchi, H.
Synthesis 1994, 147–148. (b) Shah, A.; Pike, V. W.; Widdowson, D. A. J. Chem.
Soc., Perkin Trans. 1 1997, 2463–2466. (c) Zhu, M.; Jalalian, N.; Olofsson, B.
Synlett 2008, 592–596.
17. Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165–195.
18. To the best of our knowledge, the Xꢀray structure ofdiaryl(phenoxy)ꢀλ3ꢀiodanes
has never been reported in the literature.
19. Davies, G.; Loose, D. J. Inorg. Chem. 1976, 15, 694–700.
20. Similar results were observed using structurally related cuproin. Cuproin has been
used as a specific inhibitor of Cu(I)ꢀcatalyzed reactions; see: (a) Caserio, M. C.;
Glusker, D. L.; Roberts, J. D. J. Am. Chem. Soc. 1959, 81, 336−342. (b) Lockhart,
T. P. J. Am. Chem. Soc. 1983, 105, 1940–1946.
21. Ichiishi, N.; Brooks, A. F.; Topczewski, J. J.; Rodnick, M. E.; Sanford, M. S.;
Scott, P. J. H. Org. Lett. 2014, 16, 3224–3227.
22. Merritt, E. A.; Carneiro, V. M. T.; Silva Jr, L. F.; Olofsson, B. J. Org.
Chem. 2010, 75, 7416–7419.
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9
23. (a) Fortin, D.; Drouin, M.; Turcotte, M.; Harvey, P. D. J. Am. Chem. Soc. 1997,
119, 531–541. (b) Kubas, G. J. Inorg. Synth. 1979, 19, 90–92.
24. Liu, X.; Fu, H.; Jiang, Y.; Zhao, Y. Synlett 2008, 221–224.
25. Gueell, I.; Ribas, X. Eur. J. Org. Chem. 2014, 3188–3195.
26. Raders, S. M.; Verkade, J. G. Tetrahedron Lett. 2008, 49, 3507–3511.
27. Breyholz, H.ꢀJ.; Schaefers, M.; Wagner, S.; Hoeltke, C.; Faust, A.; Rabeneck, H.;
Levkau, B.; Schober, O.; Kopka, K. J. Med. Chem. 2005, 48, 3400–3409.
28. Liu, X.; Zhang, S. Synlett 2011, 268–272.
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57
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59
60
29. Sambiagio, C.; Munday, R. H.; Marsden, S. P.; Blacker, A. J.; McGowan, P. C.
Chem. Eur. J. 2014, 20, 17606–17615.
30. Kalinin, A. V.; Bower, J. F.; Riebel, P.; Snieckus, V. J. Org. Chem. 1999, 64,
2986–2987.
31. Frlan, R.; Gobec, S.; Kikelj, D. Tetrahedron 2007, 63, 10698–10708.
32. Kundu, D.; Tripathy, M.; Maity, P.; Ranu, B. C. Chem. Eur. J. 2015, 21, 8727–
8732.
33. Musolino, B. J.; Kabalka, G. W. Heterocycles 2015, 90, 271–297.
34. Cinque, G. M.; Szajnman, S. H.; Zhong, L.; Docampo, R.; Schvartzapel, A. J.;
Rodriguez, J. B.; Gros, E. G. J. Med. Chem. 1998, 41, 1540–1554.
35. Lee, M.; Ikejiri, M.; Chang, M.; Fridman, R.; Mobashery, S. WO 2006125208 A1,
2006. Chem. Abstr. 2006, 146, 7815.
36. Baker, M. S.; Phillips, S. T. J. Am. Chem. Soc. 2011, 133, 5170–5173.
37. Broutin, P.ꢀE.; Čerňa, I.; Campaniello, M.; Leroux, F.; Colobert, F. Org.
Lett. 2004, 6, 4419–4422.
38. Mutule, I.; Suna, E.; Olofsson, K.; Pelcman, B. J. Org. Chem. 2009, 74, 7195–
7198.
39. Lubriks, D.; Sokolovs, I.; Suna, E. Org. Lett. 2011, 13, 4324–4327.
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