Competing Pathways in O-Arylations with Diaryliodonium Salts: Mechanistic Insights

Article abstract of DOI:10.1002/chem.201703057

A mechanistic study of arylations of aliphatic alcohols and hydroxide with diaryliodonium salts, to give alkyl aryl ethers and diaryl ethers, has been performed using experimental techniques and DFT calculations. Aryne intermediates have been trapped, and additives to avoid by-product formation originating from arynes have been found. An alcohol oxidation pathway was observed in parallel to arylation; this is suggested to proceed by an intramolecular mechanism. Product formation pathways via ligand coupling and arynes have been compared, and 4-coordinated transition states were found to be favored in reactions with alcohols. Furthermore, a novel, direct nucleophilic substitution pathway has been identified in reactions with electron-deficient diaryliodonium salts.

Full text of DOI:10.1002/chem.201703057

A Journal of
Accepted Article
Title: Competing Pathways in O-Arylations with Diaryliodonium Salts -
Mechanistic Insights
Authors: Elin Stridfeldt, Erik Lindstedt, Marcus Reitti, Jan Blid, Per-Ola
Norrby, and Berit Olofsson
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201703057
Link to VoR: http://dx.doi.org/10.1002/chem.201703057
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Competing Pathways in O-Arylations with Diaryliodonium Salts -
Mechanistic Insights
Elin Stridfeldt,[a]‡ Erik Lindstedt,[a]‡ Marcus Reitti,[a]‡ Jan Blid,[a] Per-Ola Norrby[b] and Berit Olofsson*[a]
Abstract: A mechanistic study of arylations of aliphatic alcohols and
hydroxide with diaryliodonium salts, to give alkyl aryl ethers and
a) Ligand coupling:
‡
ligand
diaryl ethers, has been performed using experimental techniques
and DFT calculations. Aryne intermediates have been trapped, and
additives to avoid by-product formation originating from arynes have
been found. An alcohol oxidation pathway was observed in parallel
to arylation; this is suggested to proceed by an intramolecular
mechanism. Product formation pathways via ligand coupling and
arynes have been compared, and 4-coordinated transition states
were found to be favored in reactions with alcohols. Furthermore, a
novel, direct nucleophilic substitution pathway has been identified in
reactions with electron-deficient diaryliodonium salts.
Ar
I
Nu
Ar
I
Nu
coupling
Ar
I
X
Nu
Ar Nu
Ar
Ar
- ArI
Ar
- X
b) Aryne formation:
R
for R = SiMe3:
Bu4NF, CH2Cl2, RT
X
O
+
I
O
for R = H:
LiHMDS, PhMe, 13 °C
Ar
+ ArI
Scheme 1. Mechanistic pathways in metal-free arylations.
Aryl transfer via SET reactions is preferred under certain
conditions, which has been investigated in detail by Kita and co-
workers.[5] Less studied pathways include radical reactions and
aryne formation, which have been suggested to explain by-
product formation in certain reactions with iodonium salts.[6]
While aryne intermediates have been applied in cycloadditions
employing ortho-silylated diaryliodonium salts or strongly basic
conditions (Scheme 1b), the mechanism for aryne formation
from diaryliodonium salts remains unexplored.[7]
Introduction
The interest in hypervalent iodine chemistry has dramatically
increased over the past decade, and a plethora of novel
transformations has appeared under both metal-free and metal-
catalyzed conditions.[1] Apart from being excellent oxidants,
hypervalent iodine reagents can be used in carbon ligand
transfer to
a variety of nucleophiles. Several interesting
Our research group has gained considerable experience in
metal-free arylations with these reagents using O-, N- and C-
centered nucleophiles.[8] While most of these have been
efficiently arylated by the ligand coupling pathway, several
intriguing indications on alternative reaction pathways have been
observed, e.g. by formation of regioisomeric products and
oxidized byproducts. Mechanistic insights to these fascinating
observations would aid further developments with diaryliodonium
salts and other iodine(III) reagents, and we thus initiated an
investigation on competing pathways in O-arylations using both
experimental techniques and DFT calculations. Herein we report
evidence for aryne intermediates as the origin of several
products, as well as the use of amine additives to suppress their
formation. A mechanism has been outlined to explain the
unexpected oxidation of alcohols to carbonyl compounds with
diaryliodonium salts, which are generally not used as oxidants.
Furthermore, a novel, direct nucleophilic substitution pathway
has been identified for reactions with electron-deficient iodonium
salts.
mechanistic studies have recently been reported on reactions
with iodine(III) reagents, giving new insights in some of the key
aspects of these reactions.[2] The knowledge gained from these
experimental and theoretical studies will certainly be highly
important for further developments in the field.
Diaryliodonium salts (diaryl- λ3-iodanes) are increasingly
applied in organic synthesis as efficient electrophilic arylation
reagents with
a
wide range of nucleophiles.[3] Their
straightforward synthesis using one-pot reactions, combined
with high bench-stability and low toxicity, has made them
desirable in a growing number of transformations. In metal-free
reactions with nucleophiles, the generally accepted mechanism
for these reagents proceeds via a ligand exchange to T-shaped
Nu-I intermediates that subsequently react via a ligand coupling
mechanism to provide the arylated nucleophile and the corre-
sponding iodoarene in a regiospecific fashion (Scheme 1a).[4]
[a]
Dr. E. Stridfeldt, Dr. E. Lindstedt, M. Reitti, Dr. J. Blid and Prof. B.
Olofsson
The mechanistic investigations were focused on O-arylations
of hydroxide and aliphatic alcohols,[9] as the synthesis of aryl
ethers is an important quest due to their abundance in natural
products and pharmaceutically active compounds.[10] Already
sixty years ago, diaryliodonium salts were used to arylate
alkoxides in moderate yields and with poor scope,[11] and the
reactions were later observed to suffer from severe by-product
formation.[6a] We recently developed an efficient and general
synthesis of diaryl ethers by arylation of phenols (Scheme 2a).[9d,
Department of Organic Chemistry, Arrhenius Laboratory
Stockholm University, SE-106 91 Stockholm (Sweden)
E-mail: berit.olofsson@su.se
Homepage: http://www.organ.su.se/bo/
Prof. P.-O. Norrby
Pharmaceutical Sciences
[b]
‡
AstraZeneca Gothenburg, SE-431 83 Mölndal (Sweden)
These authors contributed equally.
9e]
Supporting information for this article is given via a link at the end of
the document.
Double arylation of sodium hydroxide with strongly electron-
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10.1002/chem.201703057
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withdrawing salt 1a yielded diaryl ether 2a (Scheme 2b),[9d] and
mild conditions were reported for the arylation of aliphatic
alcohols 3 to aryl ethers 4 (Scheme 2c).[9c, 9d] Contrary to the
phenol arylation, the reactions with aliphatic alcohols proved
sensitive to steric hindrance, and were most efficient for primary
alcohols and electron-deficient aryl groups. Unexpected
oxidation of the alcohol substrate to the corresponding
aldehyde/ketone or carboxylic acid was observed (Scheme 2d),
as well as formation of regioisomeric product mixtures in
arylations with electron-donating iodonium salts.
a)
b)
OTf
OTf
I
O
O
NaOH (2 equiv)
CH2Cl2, RT, 22 h
+
I
1b
2b (p/p)+ 2c (p/m) + 2d (m/m)
5
I
O
NaOH (2 equiv)
CH2Cl2, RT, 22 h
O
+
O
+
1b
(5 equiv)
2b 11%
6a 11%
c)
H2O
OH
OH
OH
HO
H
2b
OH
1b
I
OTf
- ArI
- OTf
a)
2c
2d
OH
OH
OH
O
Ar1
1b
Ar2
I
X
H2O
tBuOK, THF, RT, 2 h or
R1
R1
1b
Ar2
NaOH, H2O, 50 °C, 3 h
1
2
d)
e)
up to 99% yield
b)
OTf
MeO
I
Ph
I
OTf
NaOH (2 equiv)
O
MeO
OH
furan (5 equiv)
O
1a
NaOH, H2O
RT, 15 h
O
+
CH2Cl2, RT, 22 h
MeO
OMe
O2N
1c
1a
O2N
NO2
2e not detected
6b 34%
1a
2a 52%
OMe
OTf
NO2
c)
Ar1
I
X
NaOH, H2O, 50 °C, 3 h
or
O
I
NaOH (2 equiv)
furan (5 equiv)
Ar2
R
OH
O
R
Ar2
R
tBuONa, toluene, RT, 30-90 min
+
O
4
3
1
CH2Cl2, RT, 22 h
up to 94% yield
O2N
NO2
d)
2a 62%
Ar
6c R = H traces
6d R = NO2 traces
OH
O
NO2
O
Ar
I
X
base
R
Ar
1
R
R
Scheme 3. Aryne trapping and mechanistic proposal.
Scheme 2. Synthesis of aryl ethers and oxidation.
coupling (cf Scheme 1a) would furnish diaryl ethers 2b and 2c.
The formation of 2d could originate from the attack of a
phenoxide on the aryne, which could also lead to 2c. The clean
formation of 2b in the presence of furan can be rationalized by
efficient trapping of the arynes, shutting down the aryne pathway
to aryl ether products, leaving ligand coupling as the only
pathway leading to diaryl ether.
The substituents on the diaryliodonium salt 1 proved to
strongly influence the outcome in reactions with hydroxide. With
strongly electron-donating methoxy substituents on the iodonium
salt (1c), only the aryne pathway operated and Diels-Alder
adduct 6b was the sole product (Scheme 3d), To the contrary,
electron-deficient nitro salt 1a gave diaryl ether 2a as the main
product with only traces of 6c-d (Scheme 3e).
The formation of by-products 5, with iodine incorporated in
the ortho-position, was intriguing. While ortho-iodinated diaryl
ethers recently have been obtained from phenols with other
iodine(III) reagents,[15] their synthesis from diaryliodonium salts
has not been reported. To simplify the analysis, diphenyl-
iodonium triflate (1d) was employed in the investigations into the
formation of this product. Treatment of sodium hydroxide with
salt 1d resulted in formation of an inseparable mixture of diaryl
ethers 2f and 5a (Table 1, entry 1). The product ratio was
increased, at the cost of sharply reduced yield of 2f, when only 1
equiv NaOH was used (entry 2) The addition of furan as aryne
trap delivered ether 2f in diminished yield, together with the
cycloaddition product 6c (entry 3). By-product 5a was only
obtained in trace amount, indicating that 5a forms via an aryne
Results and Discussion
Arylation of Hydroxide
Based on the conditions in Scheme 2b, a small screening with
other diaryliodonium salts 1 was performed. The reactions
generally required elevated temperature to proceed in water,
whereas room temperature proved sufficient for reactions in
dichloromethane.[12] Surprisingly, a mixture of regioisomeric
diaryl ethers 2, as well as iodo-substituted by-products 5 was
obtained with salts 1 lacking strong EWG substituents in both
solvents, as exemplified with di(4-tolyl)iodonium triflate (1b) in
Scheme 3a. As the ligand coupling mechanism is regiospecific,
the formation of regioisomeric products 2b-d indicated that
another mechanism was operating.
Aryne intermediates are known to react with nucleophiles
with poor regioselectivity in the absence of strong directing
groups,[13] and aryne formation was hence hypothesized to
explain the observed regioisomeric mixture of 2. This was
supported by a trapping experiment with excess furan, giving
Diels-Alder adduct 6a together with diaryl ether 2b as a single
regioisomer (Scheme 3b). Furthermore, the ortho-iodo products
5 were no longer formed. Scheme 3c depicts a plausible aryne
mechanism leading to diaryl ethers 2b-d, where deprotonation at
the ortho-position with elimination of the iodoarene gives the
aryne. Unselective reaction with hydroxide would yield two regio-
isomeric anionic intermediates that are quickly protonated to the
phenols. Subsequent arylation of the phenol[9e, 14] by ligand
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pathway, whereas 2f forms both via ligand coupling and via
arynes.
Previous arylations of phenols in water did not suffer from
by-product formation (cf Scheme 2a),[9d] indicating that the
arylation of hydroxide proceeds via arynes, followed by
regiospecific phenoxide arylation by ligand coupling. Phenolic
products were not detected in either solvent, supporting the
hypothesis that arylation of phenol intermediates is fast
compared to arylation of hydroxide.
The competition between ligand coupling and aryne
formation in arylations of hydroxide with diaryliodonium salts 1a,
1c, and 1d was studied by DFT calculations using two different
functionals (B3LYP-D3, M06-2X) commonly used for
hypervalent iodine reactions.[2a, 8b, 15c, 18] We started to investigate
the reaction between 1d and hydroxide in CH2Cl2 (Figure 1).[19]
Ligand exchange in iodine(III) compounds is considered to be
facile,[2h, 4e, 20] and formation of intermediate 1d-OH was followed
by a large decrease in energy (-69 kJ/mol), as expected by the
different pKa of TfOH and H2O. Reactions via 4-coordinated
Other aryne scavengers were also considered, as furan did
not completely suppress the formation of 5a. Amines were
deemed suitable as they readily react with arynes,[16] but are
difficult to arylate with diaryliodonium salts under metal-free
conditions.[17] Piperidine was thus added in sub-stoichiometric
amounts, which indeed inhibited the formation of 5a (entry 4).
Likewise, addition of piperidine to the reaction of tolyl salt 1b
with hydroxide resulted in facile isolation of diaryl ether 2b
without concomitant formation of 2c, 2d and 5.[12] In both cases,
the formed N-arylated trap 7 was easily separated from 2,
making this additive useful in avoiding by-products resulting from
arynes at the expense of lower isolated yield of 2.
Table 1. Trapping of benzyne.
O
Ph
Ph
I
OTf
additive
O
+
NaOH
+
Ph
Ph
Ph
CH2Cl2, RT, 22 h
or
H2O, 80 °C, 22 h
complexes have rarely been investigated in iodine(III)
I
2e, 4e, 21]
reactions,[2b,
but were deemed interesting due to the
1d (1 equiv)
(2 equiv)
2f
5a
stoichiometry of this transformation. Indeed, addition of a second
hydroxide led to the more stable, 4-coordinated iodonium
complex 1d-(OH)2 (-73 kJ/mol), whereas the mixed 4-
coordinated complex 1d-(OH)OTf was higher in energy.[22]
Also complex 1d-(OH)OH, with a hydroxide coordinated to
the ortho-protons of 1d-OH, is higher in energy. Due to the fast
equilibrium between these three intermediates, the transition
state energies are calculated with respect to 1d-(OH)2 according
to the Curtin-Hammett principle.[23] The possible transitions
states for deprotonation and elimination to the aryne are lower in
energy than the ligand coupling transition states. External
deprotonation (TS1-1d, +33 kJ/mol) is favored over internal 3-
coordinated (TS2-1d) 4-coordinated deprotonation (TS3-1d) or
direct deprotonation of 1d, as depicted in Scheme 3b. The 3-
coordinated ligand coupling (TS4-1d) and the 4-coordinated
ligand coupling (TS5-1d) are significantly higher in energy. While
the experimental results also show a preference for aryne
formation, the calculated energy differences between the aryne
formation and the ligand coupling are higher than expected with
this diaryliodonium salt.
The results with methoxy-substituted salt 1c are similar to
those with 1d, with three intermediates in fast equilibrium,
although the 3-coordinated 1c-OH is slightly more stable than
1c-(OH)2 (Figure 2a). The transition states energies for the aryne
pathway are lowest in energy, and the external deprotonation via
TS1-1c (+36 kJ/mol) is again slightly favored over the internal
deprotonation via TS2-1c (+46 kJ/mol). The 4-coordinated
deprotonation (TS3-1c), the 3-coordinated ligand coupling (TS4-
1c) and the 4-coordinated ligand coupling (TS5-1c), are all much
higher in energy, in agreement with the experimental results
where coupling product 2e was not detected (Scheme 3d).
The reaction of nitro salt 1a with hydroxide shows a rather
different energy profile, with a clear preference for the 4-
coordinated intermediate 1a-(OH)2 over the 3-coordinated 1a-
OH (Figure 2b). Surprisingly, the obtained transition state
energies did not match the experimental results, where
formation of product 2a is strongly favored (Scheme 3e). Instead,
the external deprotonation via TS1-1a (+30 kJ/mol) is slightly
2f
5a
Other
Entry
Conditions
Additive (equiv)
(%)[a]
(%)[a]
products[a]
1
CH2Cl2 rt
CH2Cl2 rt
CH2Cl2 rt
-
40
25
3
-
-
2[b,c]
3
-
13
furan (5)
23
2
O
6c 20%
N
7a 26%
-
Ph
4
CH2Cl2 rt
piperidine (0.5)
27
0
5
H2O 80 °C
H2O 80 °C
-
56
17
3
0
6[c]
piperidine (1.2)
7a 4%
[a] Isolated yields. [b]
trimethoxybenzene (TMB) as internal standard.
1
equiv NaOH. [c] 1H NMR yields with 1,3,5-
The product distribution was also investigated in other
solvents. Reactions in water required elevated temperature to
proceed, but resulted in increased yield of 2f (entry 5).
Interestingly, by-product 5a was only formed in trace amounts
under these conditions. The addition of piperidine considerably
suppressed formation of 2f (entry 6).
When salt 1d was treated with NaOD in deuterated water,
diphenyl ether 2f-D was isolated as the only deuterated diaryl
ether according to NMR and GC-MS (Scheme 4).[12] Deuterium-
free product 2f was not detected, and by-product 5a was formed
in 4%, corresponding well to the reaction using NaOH (Table 1,
entry 5). The labeling outcome is consistent with one of the two
arylations taking place mainly via the aryne pathway in water.[12]
D
H
O
O
I
Ph
I
OTf
NaOD, D2O
80 °C, 22 h
Ph
+
Ph
HH
1d
2f-D 55%
5a 4%
Scheme 4. Deuterium labeling experiment.
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TS5-1d
(74)
H
1d
(73)
O
H
O
I
OH
I
TS4-1d
Ph
OTf
Ph
TS5-1d
(65)
TS3-1d
Ph
I
TS4-1d
OH
H
Ph
(62)
OH
H
I
OH
TS2-1d
(49)
Ph
TS3-1d
I
Ph
OH
I
TS2-1d
TS1-1d
(33)
H
H
HO
TS1-1d
1d-(OH)OH
(19)
1d-OH
(4)
1d-(OH)2
via TS1-3
(0)
OH
I
I
I
H2O
OH
OH
I
δ+
(-50)
δ+
H
Ph
I
Ph
OH
H
OH
Ph
Ph
via TS4-5
OH
1d-(OH)OH
1d-OH
1d-(OH)2
(-322)
Figure 1. Free energy surface for the reaction between 1d and hydroxide in CH2Cl2 using B3LYP-D3. Dissociated OH and OTf are omitted for clarity. Energies
are given in kJ/mol.
favored over the 4-coordinated ligand coupling (TS5-1a, +38
kJ/mol). While the barriers between the pathways are more
similar than for 1c and 1d, aryne formation is still favored
according to these calculations.
This unexpected finding inspired us to search for alternative
mechanisms with salt 1a, and a direct C-attack of the hydroxide
on the iodonium salt 1a, without prior coordination to the iodine,
indeed proved to have a very low barrier. TS6-1a (rO-I = 3.2 Å) is
only 6 kJ/mol higher in energy than 1a, which explains the
product distribution seen in Scheme 3e. This is not a normal
nucleophilic aromatic substitution (SNAr), as no Meisenheimer
complex could be identified. Instead, TS6-1a directly leads to the
by a branching point that is not connected to the actual free
energy transition state. Such situations can be addressed, for
example by dynamic simulations with randomized approach
vectors,[27] but such calculations are currently beyond the scope
of our computational resources. We are satisfied that our
calculations have revealed that both reaction paths are plausible,
and the experiments clearly show that the preference is for
attack on the ipso carbon. All attempts to find this type of TS for
salt 1c and 1d were unsuccessful as they both showed
preference for coordination to the iodine.[12]
Based on the experimental and theoretical results, we
propose that the formation of diaryl ethers 2 from hydroxide
takes place via three competing mechanisms. Ethers 2 are
partly formed via the traditional ligand coupling mechanism that
is depicted in Scheme 5a, where ligand exchange to 1d-OH
followed by regiospecific ligand coupling (LC). The intermediate
phenol (A) quickly undergoes another arylation by LC.
Diaryliodonium salts lacking strong EWG substituents partly
react via the aryne mechanism shown in Scheme 5b, and this
pathway dominates with electron-donating salts such as 1c. In
this pathway, a hydroxide deprotonates intermediate 1d-OH,
(rather than salt 1d directly, cf Scheme 3c), with concomitant
elimination of iodobenzene to give benzyne B, which is attacked
by a hydroxide to form anionic intermediate C.
phenol in
a concerted nucleophilic aromatic substitution
(CSNAr),[24] similar to previous reports for vinyliodonium salts and
ethynylbenziodoxolones.[2c, 25]
To fully compare this pathway to the alternative paths in
Figure 2, we would need to calculate the barrier to attack of
hydroxide directly on iodine, leading to 1a(OH)OTf. We have
been unable to locate this transition state; the energy change on
approach is monotonous, indicating that this is a diffusion-
controlled reaction. Harvey and coworkers have estimated that
the free energy barrier corresponding to diffusion control is ca.
20 kJ/mol.[26] Since this is higher than the free energy barrier
calculated for TS6-1a, we postulate that both reactions are
under diffusion control, with the reaction preference determined
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OH
TS6-1a
a)
b)
(106)
ΔG = 6
I
OTf
1a
(100)
Ph
O2N
OTf
TS6-1a
TS5-1c
(82)
MeO
I
OTf
O2N
I
TS4-1c
(67)
OMe
TS4-1a
1c
OH
I
(64)
TS2-1a
(57)
(63)
TS3-1c
(58)
O2N
OTf
TS3-1a
(47)
TS5-1a
(38)
TS1-1a
(30)
TS2-1c
(46)
1a-(OH)OTf
TS1-1c
(36)
(39)
1a-(OH)OH
(27)
1a-OH
1c-(OH)OH
(20)
(14)
1c-(OH)2 (1)
1c-OH (0)
1a-(OH)2
(0)
OH
OH
OH
I
H
H
H
O
H
O
R
1a R = NO2, Ar = Ph
2c R = OMe, Ar = p-Anisyl
R
I
R
I
OH
R
I
R
I
OH
Ar
H
Ar
Ar
Ar
Ar
HO
TS1
TS2
TS3
TS4
TS5
Figure 2. Free energy surface for the reaction between 1a or 1c and hydroxide in CH2Cl2. OH and OTf are omitted for clarity. Energies are given in kJ/mol.
A solvent-mediated proton shift delivers phenoxide (D)
followed by facile O-arylation via LC to yield diaryl ether 2f.
Contrary to the ligand coupling, the intermediate and TS for the
aryne pathway involves two hydroxides, which is in line with the
observed product ratio variation with the stoichiometry of the
reaction (cf Table 1, entries 1-2). The competition between these
pathways is solvent dependent, and reactions in CH2Cl2 proceed
via both mechanisms whereas product formation in water takes
place mainly via arynes.[28] Reactions with strongly electron-
deficient salts result in regiospecific product formation, which
could either proceed via ligand coupling, or via a low energy,
direct substitution mechanism. This pathway was only found for
nitro salt 1a (Scheme 5c), explaining the facile reactions with
this salt.
The observed diaryl ether by-products could be formed via
several aryne pathways from intermediate C, as illustrated in
Scheme 5d. Aryne-derived intermediates similar to C have been
reported to attack the iodine of iodobenzene.[29] Should C react
with PhI, which is produced in the aryne formation step, the
hypervalent iodine (ate) complex E could fragment to iodophenol
F and a high-energy phenyl carbanion. F could then be arylated
by LC to give 5a. However, the addition of another iodoarene did
not alter the ratio between 2f and 5a,[12] and as a high energy
intermediate would be formed, this pathway seems unlikely.
Alternatively, C could attack the much better electrophile 1d
to give the T-shaped triaryl intermediate G.[30] Ligand coupling
from G would deliver phenol H and iodobenzene, as depicted in
pathway II.
Subsequent arylation of H by LC would yield ether 8, which has
indeed been detected in minor amounts by GC-MS. The other
possible ligand coupling from triaryl intermediate G would give
iodophenol F and biphenyl (pathway III). Subsequent arylation of
F with 1d by a ligand coupling would give 5a. As only a trace
amount of biphenyl has been detected, this cannot be the major
pathway to 5a.
To account for the observed formation of iodo ethers 5, we
instead propose the novel mechanism depicted in pathway IV.
Triaryl intermediate G is in fast equilibrium with the other T-
shaped intermediate G’, having the phenolic moiety in the
equatorial position. In this conformation, a facile collapse of G’
into benzene and the zwitterionic intermediate I is plausible.
Such iodonium phenolates are well known to undergo
intramolecular rearrangement leading to ortho-iodo substituted
diaryl ethers like 5a under mild conditions.[31] The suppressed
formation of 5a in water compared to CH2Cl2 (Table 1, entries 1,
5) is explained by the facile proton shift from C to D in aqueous
media, leading to product 2f rather than 5a.[32]
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a) Double ligand coupling (LC):
Table 2. Arylation of 1-pentanol.
‡
H
O
OTf
OH
1d
base
tBuONa
(1.2 equiv),
additive
OH
O
I
Ph
Ph
I
I
Ph
PhOH
A
Ph
OTf
I
O
LC
- OTf
- PhI
LC
2f
Ph
OH
+
Ph
Ph
1d
1d-OH
toluene
RT, 3 h
1d
LC
4a (para)
4b (meta)
3a
1b
b) Aryne formation leading to diaryl ethers:
OH
(1.2 equiv)
OH
O
HO
I
Other productsa
H
OH
H2O
4a
+
4b
Ratio
4a:4b
Entry
Additive (equiv)
δ+
- PhI
OH
δ+
H
1d
1d-OH
- H2O
(%)[a]
H
- OTf
OH
B
C
D
c) Diaryl ethers via direct substitution:
1
-
51
80:20
nd
-
OTf
‡
OTf
I
OH
2[b]
3
furan (5)
36
6a 9%
Ph
OH
Ph
I
O
OH
1a
- PhI
- OTf
N
piperidine (0.5)
27
100:0
O2N
NO2
LC
2a
1a
NO2
NO2
7b (m) + 7c (p) 31%
O2N
d) By-product formation:
4c
5
piperidine (1.2)
NaHMDS (1.2)
0
-
-
-
OH
OH
I)
Ph
Ph
OH
O
I
I
I
1d
LC
Ph
Ph
52b
80:20
- Ph
I
C
E
F
5a
8
Ph
I
OTf
[a] Isolated yields. [b] 1H NMR yield with TMB as internal standard. [c] No
tBuONa was added. nd = not determined due to overlapping peaks, mainly
4a.
Ph
OH
II)
- OTf
OH
Ph
O
- PhI
1d
I
Ph
LC
LC
Ph
Ph
G
H
F
Similar types of by-products, derived from aryne
intermediates, were detected in arylations of both secondary and
tertiary alcohols with electron-donating diaryliodonium salts.
Furthermore, primary and secondary alcohols suffered from
partial oxidation of the alcohol to the corresponding
aldehyde/ketone or carboxylic acid.[9d] Diaryliodonium salts are
generally poor oxidants, in contrast to iodine(III) reagents with
two heteroaromatic ligands,[1b] and McEwen and co-workers
suggested a radical pathway to explain the observed oxidation
products in this type of transformation.[6a]
III)
LC
OH
I
1d
Ph Ph
5a
IV)
LC
traces
OH
O
O
I
aryl
migration
Ph
Ph
I
I
- PhH
Ph
5a
G’
I
Ph
Scheme 5. Proposed mechanisms for reactions with hydroxide.
We envisioned that the oxidation could either proceed via
radicals, arynes or the T-shaped intermediate, which is formed
Arylation of Aliphatic Alcohols
prior to the ligand coupling. The oxidation was especially
The competition between ligand coupling and aryne formation
was also found when primary aliphatic alcohols were arylated
with electron-donating diaryliodonium salts. This is exemplified
by the arylation of 1-pentanol (3a) with p-tolyl salt 1b under our
reported conditions,[9c] which resulted in a regioisomeric mixture
of ethers 4a-b (Table 2, entry 1). Contrary to reactions with
hydroxide, only traces of iodo-substituted by-products were
formed. The product ratio between 4a and 4b indicates that
ligand coupling and aryne intermediates yield ethers in a 60:40
ratio. Diels-Alder adduct 6a was indeed formed upon addition of
furan to the reaction mixture, supporting the presence of arynes
(entry 2).[12] As by-product 4b could still be detected, the reaction
was examined with amine additives to suppress the by-product
formation.
The use of piperidine changed the reaction outcome, and
ether 4a was isolated as the only regioisomer (entry 3). Other
amines were also screened, but piperidine proved best.[12] When
piperidine was employed as both base and aryne trap, no ether
was formed (entry 4).[33] The use of the stronger base NaHMDS,
which gives an amine after the initial deprotonation and might
act as an internal trap, unfortunately delivered a regioisomeric
mixture of the product (entry 5).
9d]
prominent with benzylic and allylic alcohols,[9c,
and the
reaction was hence investigated using secondary benzylic
alcohol 3b (Table 3). Ketone 9 was indeed formed as major
product in the attempts to arylate 3b with salt 1d, delivering
ether 4c in poor yield under the reaction conditions optimized for
primary[9c] and tertiary alcohols[9a] (entries 1 and 3). Only traces
of an ortho-iodo by-product was identified, and the Diels-Alder
adduct 6d could barely be detected (<5%) upon addition of
furan.[12] Addition of piperidine to the reaction only slightly
changed the reaction outcome, (entries 2 and 4), indicating that
arynes are not the main pathway in the oxidation mechanism.
In Stuart’s recent methodology to arylate primary and
secondary aliphatic alcohols, benzyl alcohol was arylated using
aryl(mesityl)iodonium salts with only trace formation of
benzaldehyde.[9b] However, submission of 3b to these conditions,
with either salt 1d or unsymmetric Ph(Mes)IBr, delivered the
oxidized product 9 as a major product and ether 4c as a minor
product
(entries
5-6).
Furthermore,
the
arylation
chemoselectivity was only 2:1 in favor of phenyl over mesityl,
illustrating the need for electron- deficient aryl groups when
using the mesityl as dummy group.
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10.1002/chem.201703057
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Table 3. Phenylation and oxidation of alcohol 3b.[a]
a)
tBuONa
(1.2 equiv)
OH
I
OTf
Ph
O
OH
O
O
O
Ph
I
OTf
base
Ar =
Ph
+
Ar
toluene
RT, 1.5 h
Ph
solvent
RT, 1-3 h
Ar
9 39%
Ar
Ar
Ar
Ar
4c
3b
1e
4d 41%
3b
1d
9
(1.2 equiv)
Entry
Base
Solvent
Additive (equiv)
9 (%)[b]
4c
b)
(%)[b]
21
14
9
Ar =
Ph
1e (1.2 equiv)
tBuONa (1.2 equiv)
OH
D
O
O
+
1
tBuONa
tBuONa
NaHMDS
NaHMDS
NaH
toluene
toluene
pentane
pentane
TBME
TBME
THF
-
60
54
35
30
53
65
31
39
43
toluene
RT, 1.5 h
Ar
Ar
Ar
D
2
piperidine (1.2)
4d-D 59%
9 24%
3b-D
3
-
c)
1e (1.2 equiv)
tBuONa
(1.2 equiv)
3b
O
OH
(0.5 equiv)
O
4
piperidine (1.2)
5
+
+
Ar
Ar
Ar
toluene
RT, 1.5 h
5[c]
6[c,d]
7
-
30
11
10
21
24
3b-D
H/D
H/D
(0.5 equiv)
4d : 4d-D
50%, 1:1
9
3b : 3b-D
14%, 3:5
32%
NaH
-
tBuONa
tBuONa
tBuONa
-
Scheme 6. Arylations with ortho-blocked salt 1e.
8
THF
DPE (1.2)
Having ruled out both arynes and radicals as oxidation
promoters, we envisioned two possible mechanisms for the
oxidation (Scheme 7). Both pathways go via the T-shaped
intermediate J, which forms from the deprotonated alcohol and
salt 1d. The benzylic proton could either be transferred to the
phenyl ring in an intramolecular, concerted fashion to release 9,
iodobenzene and benzene (Scheme 7a), similar to mechanisms
involving iodine(V) reagents.[34]
9
THF
TEMPO (1.2)
[a] Reaction conditions: see the Supporting Information. [b] 1H NMR yields
using TMB as internal standard. [c] 3b in excess, 50 °C for 1 h, isolated yields.
[d] Ph(Mes)IBr was used instead of 1d, chemoselectivity Ph:Mes 2:1.
The effect of radical traps was examined in THF, as traps in
toluene had no effect.[9c, 12] While the yield of ether 4c increased
in the presence of 1,1-diphenylethylene (DPE) or TEMPO
(entries 7-9), the oxidation product 9 formed in similar amounts
This indicates that the oxidation does not take place via radicals,
while radical pathways leading to other by-products could play a
role in THF.
Reactions between alcohol 3b and ortho-blocked dimesityl
salt 1e resulted in considerably higher arylation yields than with
salts having ortho-protons (Scheme 6a). This could be
rationalized by facilitated ligand coupling due to the ortho-effect
and aryne formation being impossible with 1e.[9a] Importantly, the
oxidation to ketone 9 still competed with the ether formation, and
the combined yield of ether 4d and 9 corresponds well to
reactions with salt 1d.
a) intramolecular mechanism
OH
Ph2IOTf (1d)
Ar
H
H
O
I
O
+
+
PhI
Ar
H
Ar
base
Ph
3b
J
9
b) intermolecular mechansim
base
base
Ph
H
H
H
O
PhI
O
+
+
I
base-H
Ar
Ph
J
9
K
The deuterated substrate 3b-D was arylated to ether 4d-D in
higher yield, with less of ketone 9 compared to reactions with 3b
(Scheme 6b). Deuterated mesitylene was detected by GC-MS. A
reaction containing both alcohols 3b and 3b-D gave a good
average yield of ethers 4d and 4d-D in a 1:1 ratio, whereas the
unreacted starting materials contained more of 3b-D (Scheme
6c). The yield of 9 was affected in a similar fashion.
Scheme 7. Plausible oxidation mechanisms.
Alternatively, intermediate J could be deprotonated by an
external base, releasing 9, iodobenzene and benzene carbanion
K, which is quickly protonated to benzene (Scheme 7b).
Assuming that both coupling and oxidation occurs from common
intermediate J, the results in Scheme 6 clearly show that the
proton transfer is subject to a primary kinetic isotope effect,
which also implies that the deprotonation is rate limiting for the
oxidation. As no increase in deuterium content of 4d was
observed, the intermediate must be in rapid equilibrium with free
alcohol/alkoxide.
To distinguish between these mechanisms, excess base
was added to the reaction of alcohol 3b with mesityl salt 1e. This
neither affected the yield nor the ratio of 4d and 9. The amount
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10.1002/chem.201703057
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of oxidized product 9 also remained the same upon dilution of
the reaction. The reaction mixtures were heterogeneous in
toluene, but comparable ratios were obtained in homogenous
solution (toluene:DMF).[12] This indicates that the two processes
are of the same order. As the ligand coupling mechanism is
considered to be a concerted process (see Scheme 1a), the
oxidation should proceed via the intramolecular pathway shown
in Scheme 7a.
Further investigations were conducted using DFT. The
arylation of 1-phenylethoxide with mesityl salt 1e was
investigated, to avoid alternative pathways via arynes. The 4-
coordinated intermediate 1e-(OR)2 was found to be considerably
lower in energy than the 3-coordinated 1e-OR (Figure 3a).
Likewise, the TS corresponding to the 4-coordinated coupling
(TS7-1e) is strongly favored over any other TS corresponding to
coupling or oxidation (TS8-1e to TS11-1e). The internal
oxidation (TS9-1e) is much more favorable compared to the
external pathway (TS11-1e). The same trends were observed
using both the B3LYP-D3 and the M06-2X functional.[12]
energy penalty of around 7.9 kJ/mol for the reactions that are
bimolecular with respect to the alkoxide.[23],[35] Taking this into
account, the energy for the 4-coordinated TSs and intermediates
increase and hence the gap between ligand coupling and
oxidation (TS7-1e vs. TS9-1e) decreases to 10 kJ/mol using
B3LYP-D3 (Figure 3b). This difference indicates a selectivity of
>10:1 in favor of coupling, which is not experimentally observed.
The deviations between the experimental results (Scheme 6)
and the DFT investigations could be the caused by the chosen
DFT method being insufficiently accurate in the current context.
Discrepancies between DFT and experimental results are not
uncommon. In particular, continuum solvation models can be
unreliable for anions.[36] In the current case, the relative energies
of small anions (like hydroxide) and distributed anions (like
square planar iodine(III) complexes) would be expected to be
unreliable. Calculations with explicit water molecules around the
nucleophile could provide more reliable energies,[37] but were
beyond our computational capacity. Within a set of similar
compounds, errors will cancel to a large extent, but between
sets, we have relied on experimental results to judge which of
several manifolds that best describe the studied transformations.
Considering that the experimental conditions (0.1 M) diverge
from the standard state conditions (1 M), this accounts for an
a)
b)
1e
(128)
1e
(120)
Mes
I
OTf
Mes
Mes
I
OTf
Mes
TS11-1e
TS11-1e
(98)
(98)
TS10-1e (79)
TS9-1e (75)
TS8-1e (71)
TS10-1e (71)
TS8-1e (71)
TS9-1e (66)
TS7-1e (56)
TS7-1e (56)
1e-OR
(26)
Ph
Ph
1e-OR
(19)
O
O
I
I
O
Ph
Mes
Mes
1e-(OR)2
1e-(OR)2
(0)
(0)
1e-OR
1e-(OR)2
Ph
Ph
O
Ph
H
Ph
O
Ph
O
H
H
Ph
O
I
O
I
O
O
I
O
I
I
Ph
Ph
Mes
Mes
Mes
Mes
Mes
TS7-1e
TS8-1e
TS9-1e
TS10-1e
TS11-1e
Figure 3. (a) Free energy surface for the reaction between 1e and 1-phenylethoxide in toluene using the B3LYP-D3 functional (b) Free energy surface with an
applied standard state correction. Free alkoxides and triflates are omitted for clarity. Energies are given in kJ/mol.
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Based on the combination of experimental and theoretical
results, we believe that 4-coordinated intermediates and
transition states are favored in reactions with alcohols and
diaryliodonium salts to give aryl ethers (Scheme 8). The ligand
coupling pathway proceeds regiospecifically via intermediate 1d-
(OR)2 (Scheme 8a). Arynes were formed in reactions with
diaryliodonium salts lacking EWG substituents. This pathway
also yields aryl ethers, albeit with poor regioselectivity when
substituted salts are employed. In another competing reaction
pathway, the alcohol is oxidized to the corresponding ketone or
aldehyde via an intramolecular mechanism (Scheme 8b). The
computational barriers for the 4- and 3-coordinated TSs are
similar. Still, we suggest that the oxidation mainly proceeds via
the 4-coordinated TS, since the experimental results show that
oxidation and ligand coupling are of the same order. This side
reaction is most prominent with allylic and benzylic alcohols.
Experimental Section
Arylation of hydroxide: Sodium hydroxide (1.6 mmol, 2 equiv) was
added to a 10-20 mL or 2-5 mL microwave vial and CH2Cl2 or deionized
H2O (3 mL) was added. The indicated additive was added followed by
immediate addition of diaryliodonium salt 1 (0.8 mmol, 1 equiv). The
reagents were rinsed down from the walls of the vial with solvent (1 mL).
The vial was capped and stirred at RT for 22 h, or stirred in a pre-heated
oil bath at 80 °C for 22 h. The reaction mixture was quenched with sat.
NH4Cl and then extracted with CH2Cl2 (x3). The combined organic
phases were dried over MgSO4, filtrated and the solvent removed in
vacuo. The crude mixture was then submitted to column chromatography.
Arylation of alcohols: A dry 10 mL Schlenk tube was evacuated and
backfilled with argon three times. tBuONa (58 mg, 0.6 mmol, 1.2 equiv)
was added, followed by anhydrous toluene (1.5 mL). The mixture was
cooled to 0 °C and 1-pentanol (54 µL, 0.5 mmol, 1 equiv) was added and
rinsed down using toluene (0.5 mL). After stirring at RT for 15 min the
mixture was cooled to 0 °C and additive (0.3-5.0 equiv) was added
followed by salt 1 (0.6 mmol, 1.2 equiv). After rinsing down using toluene
(0.5 mL) the mixture was left to stir at RT for 3 hours. The reaction was
quenched using sat. NH4Cl, extracted with CH2Cl2 (3x10 mL), dried over
MgSO4, filtered and concentrated in vacuo. The crude was then
submitted to flash column chromatography to obtain the product.
a) Aryl ethers via ligand coupling:
‡
R
OTf
OR
O
OR
- PhI
- OTf
O
Ph
I
Ph
I
OR
R
Ph
Ph
I
OR
- OTf
Ph
Ph
Ph
1d-(OR)2
b) Oxidation of alcohols:
‡
R
- PhI
- PhH
OH
H
1d
base
1d-OR
H
O
O
R
R
O
- OTf
I
O
1d-(OR)2
-
R
Ph
R
Computational Methods
Scheme 8. Mechanistic summary with alcohols.
Geometry optimizations and energy calculations were carried out with the
Becke Three-Parameter Lee-Yang-Parr functional[38] with the dispersion
correction by Grimme[39] (B3LYP-D3) or the Minnesota functional, M06-
40]
2X,[12,
as implemented by Gaussian09. The SDD basis set with an
Conclusions
applied effective core potential (MWB46) was used for iodine,[41] Pople’s
triple-zeta basis set with added polarization and diffuse functions (6-
311+G(d,p))[42] were used for N, O, F, Cl and Na atoms while the triple-
zeta basis set with added polarization (6-311G(d,p))[42b, 42c] were used for
A mechanistic investigation of O-arylations of hydroxide and
aliphatic alcohols with diaryliodonium salts under metal-free
conditions has been performed to understand the pathways that
compete with ligand coupling. The study involved both
experimental techniques and DFT calculations to understand the
different reaction outcomes depending on the electronic
properties of the diaryliodonium salt. Trapping experiments with
furan were consistent with the formation of aryne intermediates
under mild conditions. Piperidine proved to be a more efficient
trap to avoid by-products, which demonstrates an important
proof of principle. While the aryne formation presently cannot be
avoided in arylation of hydroxide and aliphatic alcohols with
electron-donating salts, the use of piperidine enables the
synthesis and easy isolation of aryl ethers as single
regioisomers in moderate isolated yields.
The oxidation of alcohols by diaryliodonium salts was found
to proceed via a novel cyclic transition state, ruling out the
involvement of arynes and radicals. Small differences in
substrate and reagent structures were found to have large
impacts on the reaction outcome with competing pathways via
arynes, ligand coupling and oxidation. Furthermore, a direct
substitution mechanism was found for arylations with nitrophenyl
salt 1a, explaining the facile synthesis of aryl ethers with this salt.
We believe that the mechanistic insights presented herein, as
well as the piperidine trap technique, can be utilized to develop
novel reactions with iodine(III) reagents and to overcome the
present limitations with these reagents.
the H, C and S atoms. Several iodine(III) reactions have recently been
8b, 15c, 18]
studied by DFT using similar setups.[2a,
The systems were
studied in both CH2Cl2 and H2O using the polarizable continuum model
(PCM, Surface=SES, Radii=UFF),[43] and the results in H2O are given in
the SI. Structures were optimized with the applied solvation model and
true transition states were verified via frequency analysis and the
presence of one, and only one, imaginary frequency.
Acknowledgements
The Swedish Research Council (621-2011-3608 and 2015-04404) is
kindly acknowledged for financial support. This research was conducted
using the resources of High Performance Computing Center North
(HPC2N, SNIC 2016/3-66). Dr. R. Ghosh is gratefully acknowledged for
initial results.
Keywords: aryl ethers • arynes • hypervalent iodine •
mechanistic study • oxidation
ORCID
Berit Olofsson: 0000-0001-7975-4582
Per-Ola Norrby: 0000-0002-2419-0705
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10.1002/chem.201703057
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This article is protected by copyright. All rights reserved.

10.1002/chem.201703057
Chemistry - A European Journal
FULL PAPER
FULL PAPER
Elin Stridfeldt, Erik Lindstedt, Marcus
Reitti, Jan Blid, Per-Ola Norrby, Berit
Olofsson*
Page No. – Page No.
Competing Pathways in O-Arylations
with Diaryliodonium Salts -
Mechanistic Insights
The arylation of aliphatic alcohols and hydroxide with diaryliodonium salts, to give
alkyl aryl ethers and diaryl ethers, has been studied using experimental techniques
and DFT calculations. Aryne formation and alcohol oxidation pathways were
observed in parallel to arylation, and additives to avoid by-product formation
originating from arynes have been found. A novel, direct nucleophilic substitution
pathway has been identified in reactions with electron-deficient diaryliodonium salts.
This article is protected by copyright. All rights reserved.