Trimethoxyphenyl (TMP) as a Useful Auxiliary for in situ Formation and Reaction of Aryl(TMP)iodonium Salts: Synthesis of Diaryl Ethers

Article abstract of DOI:10.1002/adsc.201901187

Herein, we describe a synthetic approach for arylation that exploits the in situ formation and reaction of an unsymmetrical diaryliodonium salt. In this way, aryl iodides are used as reagents in a metal-free reaction with phenols, and a trimethoxyphenyl (TMP) group is used as a “dummy” group to facilitate transfer of a wide range of aryl moieties. The scope of aryl electrophiles and phenol nucleophiles is broad (>30 examples) and the yields are high (52–95%, 80% avg.). One-pot coupling reactions avoid the synthesis of diaryliodonium salts and provide opportunities for sequential reactions and novel chemoselectivity. (Figure presented.).

Full text of DOI:10.1002/adsc.201901187

Title: Trimethoxyphenyl (TMP) as a Useful Auxiliary for in situ
Formation and Reaction of Aryl(TMP)iodonium Salts: Synthesis
of Diaryl Ethers
Authors: Rory Gallagher, Souradeep Basu, and David R. Stuart
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10.1002/adsc.201901187
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Trimethoxyphenyl (TMP) as a Useful Auxiliary for in situ
Formation and Reaction of Aryl(TMP)iodonium Salts:
Synthesis of Diaryl Ethers
Rory T. Gallagher,a Souradeep Basu,a and David R. Stuarta*
a
Department of Chemistry, Portland State University, Portland Oregon, 97201, United States
Email: dstuart@pdx.edu
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
aryl group of aryl(TMP)iodonium salts,[6] and use of
Abstract. Herein, we describe a synthetic approach for
arylation that exploits the in situ formation and reaction of these reagents has continued to emerge over a range of
mechanistically distinct reactions.[7-9] We have an
an unsymmetrical diaryliodonium salt. In this way, aryl
iodides are used as reagents in a metal-free reaction. A
trimethoxyphenyl (TMP) group is used as a “dummy” group
to transfer a wide range of aryl moieties. The scope of aryl
electrophiles and phenol nucleophiles is broad (>30
examples) and the yields are high (52-95%, 80% avg.). One-
pot coupling reactions avoid the synthesis of diaryliodonium
salts and provide opportunities for sequential reactions and
novel chemoselectivity.
ongoing interest in the development of reactions to
synthesize[10,11] and use[7b-d] aryl(TMP)iodonium salts,
and herein we describe a methods to generate and use
them in situ for phenol arylation.
Keywords: C-O cross-coupling; telescoping; hypervalent
iodine; diaryliodonium; diaryl ether
Aromatic rings abound in pharmaceuticals,
agrochemicals, and novel materials. Consequently,
synthetic chemists have devoted significant resources
to devising innovative and practical arylation
strategies. Aryl electrophiles bearing leaving groups
feature prominently and both metal-free[1] and metal-
catalyzed[2] reactions of aryl (pseudo)halides with
nucleophiles are well established (Scheme 1a).
Diaryliodonium salts contain an aryliodonium leaving
group that facilitates mechanistic advantages over
traditional halides: facile oxidative addition to first-
row metals (i.e., copper) and increased scope in metal-
free reactions (Scheme 1b).[3] However, despite these
advantages, the need to synthesize diaryliodonium
salts is often viewed as a drawback. A potential
solution is to form the diaryliodonium in situ and
exploit the aforementioned advantages of the
iodonium leaving group while using more readily
abundant starting materials (Scheme 1c).[4]
Unsymmetric diaryliodonium salts are desired over
symmetric ones, especially for the transfer of even
moderately complex aryl moieties, and many auxiliary
aryl groups have been described and aryl transfer
selectivity reviewed.[5] Of note, in 2013, Olofsson and
co-workers reported a chemoselectivity study and
found that the 2,4,6-trimethoxyphenyl (TMP) group is
useful for promoting exclusive transfer of the other
Scheme 1. General arylation strategies.
Diaryl ethers are important motifs in
pharmaceuticals and agrochemicals and have been
synthesized by the strategies presented in Scheme 1a
and 1b. The use of both symmetrical and
unsymmetrical diaryliodonium salts to synthesize
diaryl ethers is precedented, as early as 1953, and is
particularly relevant to this work.[6,10a,12] To the best of
our knowledge there is no report on the synthesis of
diaryl ethers from aryl iodides with in situ formation
of a diaryliodonium salt. Herein, we use the synthesis
of diaryl ethers as a platform to demonstrate an
arylation strategy using aryl iodides and exploiting an
1
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10.1002/adsc.201901187
Advanced Synthesis & Catalysis
in situ generated aryl(TMP)iodonium salt. Moreover,
we highlight the functional group compatibility with
sequential reactions and novel chemoselectivity.
to the phenol (Table 1, entry 3). This result is
consistent with that previously observed by Togo and
co-workers,[12h] and underscores that anisyl is an
inferior auxiliary to TMP in this case. Additionally,
variation of the counter anion of 1a to either OTf or
BF4 revealed that triflate may be a suitable
replacement, though tetrafluoroborate resulted in
lower yield (Table 1, entry 4 and 5). We found that
reducing the equivalents of K2CO3 only marginally
affected the yield of 3aa (88%; Table 1, entry 6).
However, a screen of other bases that have been used
to couple diaryliodonium salts and phenols resulted in
generally lower yields (Table 1, entry 7 and 8). The
solvents THF and MeCN also provided high yield of
3aa, and may be useful alternatives to toluene (Table
1, entry 10 and 11). Finally, we found that moderate
heating at 55 °C provided higher yield than 21 or 80 °C
(Table 1, entry 12 and 13).
At the outset of our investigation we found that
there were relatively few examples of diaryl ether
synthesis from aryl(TMP)iodonium salts; in fact, there
were only four scope examples in total found in three
published papers.[6,10a,12l] Therefore, we viewed this as
an opportunity to optimize the second step of our
telescoped reaction and identify reaction conditions
that are specifically suited to the coupling of
aryl(TMP)iodonium salts and phenols (Table 1). Our
survey of reaction conditions included the structure of
the aryl(TMP)iodonium salt (1a), the identity of base
and solvent, the reaction temperature and time. The
conditions that we refer to hereafter as “standard
conditions” include 1.1 molar equivalents of phenol
coupling partner, 3 equivalents of K2CO3 as base,
toluene as solvent, 55 °C as reaction temperature, for
1
2 hours, and result in 99% H NMR yield and 91%
Table 2. Scope of aryl(TMP)iodonium salts.a)
isolated yield of 3aa (Table 1, entry 1). We found that
using the symmetrical variant of 1a ([di-(4-
tolyl)]iodonium tosylate) resulted in notably lower
yield (76%) under identical conditions (Table 1, entry
2). Moreover, anisyl as an auxiliary resulted in lower
yield and ~ 8: 1 selectivity for transfer of tolyl vs anisyl
Table 1. Influence of reaction conditions on coupling.a)
Entry Deviation from standard conditions
Yieldb)
1
2
none
99%(91%)c)
76%
[di-(4-tolyl)]iodonium tosylate
instead of 1a
(4-tolyl)(4ʹ-anisyl)iodonium
tosylate instead of 1a
3
83%d)
4
5
OTf as counter anion of 1a
94%
70%
88%
79%
29%
97%
93%
85%
96%
25%
BF4 as counter anion of 1a
1 equiv. of K2CO3
6
7
KOt-Bu instead of K2CO3
NaHCO3/TBAF instead of K2CO3
NaOH instead of K2CO3
THF instead of toluene
MeCN instead of toluene
80 °C as reaction temp.
21 °C as reaction temp.
8
9
10
11
12
13e)
a)
Reaction conditions: 1a (0.1 mmol, 1 equiv.), 2a (0.11
mmol, 1.1 equiv.), K2CO3 (0.3 mmol, 3 equiv.), toluene (0.5
mL), 55 °C, 2 h; see table for deviations. b) Yield determined
by 1H NMR spectroscopy with 2,4-dichlorobenzaldehyde as
internal standard. c) Isolated yield. d) 11% of 3ja detected. e)
24 hour reaction time.
a)
Reaction conditions: 1 (0.5 mmol, 1 equiv.), 2a (0.55
mmol, 1.1 equiv.), K2CO3 (1.5 mmol, 3 equiv.), toluene (2.5
mL), 55 °C, 2 h. See the SI for specific deviations in
conditions. b)Yields from ref. [12f]. c)Yields from ref. [12j].
d)Yields from ref [12h]. e)Yields from ref [12e]
2
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10.1002/adsc.201901187
Advanced Synthesis & Catalysis
Tables 2 and 3 contain representative examples of
standard electrophile to assess the scope of phenols in
this reaction. Electron rich (2b, 2h, 2j) and electron
deficient (2c-g) phenols are compatible, which
includes aldehyde groups (3qf) and N-H bonds (3qh).
Several other notable examples are provided in Table
diaryl ethers that may be prepared from
aryl(TMP)iodonium tosylates and phenols under the
standard conditions described above. The substrate
scope is generally tolerant of both electronic and steric
effects on both the aryl electrophile and phenol
nucleophile (Table 2 and 3). The high yields observed
for p-, m-, o-tolyl and p-, m-, o-chlorophenyl series
highlight the tolerance for steric and electronic effects
on the aryl electrophile (3aa-fa, Table 1). Other
electron donating (Ph, 3ga) and electron withdrawing
(F, NO2; 3ha, 3ia, and 3la) substituents are also
compatible in this coupling reaction. Notably, even
very electron rich rings are transferred preferentially
over the TMP group. Compound 3ja is synthesized in
85% yield by preferential transfer of p-anisole over
TMP. Although the selectivity of aryl group transfer
for starting material 1j is high, this electron rich
substrate required longer reaction time (24 hours) than
other substrates in Table 2. The use of unsymmetrical
aryl(TMP)iodonium salts also facilitates the transfer of
elaborate aryl groups (3ma and 3na), sterically
congested aryl groups (3oa), and heterocyclic aryl
groups (3pa; Table 2). Notably, the yields obtained
here are similar to those previously reported.[12e,f,h,j]
3.
The sterically encumbered phenol, 2,6-
dimethylphenol 2i couples with 1q to produce 3qi in
82% yield (Table 3). Additionally, aryl iodides are
well tolerated on the phenol coupling partners (3ql)
which is distinct from metal-catalyzed reactions and
may be used for further functionalization. Finally,
elaborate phenols (estrone, 2k and -tocopherol, 2m)
are well-tolerated and undergo O-arylation in
moderate yield (68%, 3qk, and 61%, 3qm,
respectively).
We have also demonstrated that the use of
aryl(TMP)iodonium tosylates is compatible with a
combination of both sterically encumbered aryl
electrophile and phenol nucleophile. The symmetrical,
and
highly
sterically
congested,
2,2ʹ,6,6ʹ-
tetramethyldiphenyl ether (2ri) has only been
described in the literature on one other occasion,[13]
and in ~2% yield by GCMS (Scheme 2). The coupling
of 1r and 2i proceeded in 52% isolated yield under our
standard conditions to deliver 3ri (Scheme 2).
Table 3. Scope of phenols.a)
Scheme 2. Access to sterically hindered diaryl ethers.
In line with our overall goal to capitalize on
aryl(TMP)iodonium salts as reaction intermediates,
we have developed a method to telescope three
reactions together: 1) aryl iodide oxidation, 2)
installation of the TMP auxiliary, and 3) C-O coupling.
The result is a direct coupling of aryl iodides with
phenols that takes place under relatively mild
temperature (55 °C), short reaction time (< 3 hours),
and without a metal catalyst. We have previously
telescoped the first two reactions together (aryl iodide
oxidation and installation of TMP auxiliary),[10a,c] but
to the best of our knowledge this is the first example
wherein the synthesis of aryl(TMP)iodonium salts
from aryl iodides and subsequent reactions are
combined in a single pot. During development we
found that the C-O coupling reaction was relatively
insensitive to the solvent (MeCN) and the by-products
(H2O and m-ClC6H4COOH) of the first two reactions.
Indeed, MeCN was found to be a suitable solvent for
this reaction, albeit in slightly lower yield than toluene
as solvent (Table 1, compare entries 1 and 11). We
a)
Reaction conditions: 1q (0.5 mmol, 1 equiv.), 2 (0.55
mmol, 1.1 equiv.), K2CO3 (1.5 mmol, 3 equiv.), toluene (2.5
mL), 55 °C, 2 h. See SI for specific deviations from standard
conditions.
Steric and electronic effects are also well-tolerated
on the phenol coupling partner (Table 3).
Aryl(TMP)iodonium tosylate 1q was used as the
3
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10.1002/adsc.201901187
Advanced Synthesis & Catalysis
also found that increasing the stoichiometry of base (4
equiv.) was necessary to neutralize the carboxylic acid
produced from m-CPBA, but we did not observe any
competitive C-O coupling with the carboxylate
nucleophile. Four examples of this strategy are shown
in Table 4. The first three examples replicate products
pot 3(ql)n was obtained in 56% isolated yield with
36% of unreacted 3ql also isolated (88% based on
recovered start material).
that
were
synthesized
directly
from
aryl(TMP)iodonium salts (3qf, 3qc, 3ql) and are
formed in synthetically useful yields (60-85%) directly
from the aryl iodides (Table 4). On average, the yields
of diaryl ethers (3qf, 3qc, 3ql) formed from aryl
iodides are lower than those from aryl(TMP)iodonium
salts (74% vs. 83%, respectively), but the telescoped
approach reduces both solvent volume and time
Scheme 3. Sequential coupling reactions. a) Aryl iodide (0.5
mmol, 1 equiv.), m-CPBA (0.5 mmol, 1 equiv.), TsOH•H2O
associated
with
purification
of
the
b)
aryl(TMP)iodonium salt. The fourth example yields a
more structurally elaborate and functionalized diaryl
ether in 68% yield (Table 4, 3tl) and highlights not
only the importance of an unsymmetrical
aryl(TMP)iodonium intermediate, but also the
compatibility of this approach for iodo-functional
handles on the phenol nucleophile.[12m]
(0.5 mmol, 1 equiv.), MeCN (0.5 mL), 55 °C, 30 min.
TMP-H (0.5 mmol, 1 equiv.), 10 min. c) 2l (0.55 mmol, 1.1
equiv.), K2CO3 (2 mmol, 4 equiv.), toluene (2.5 mL), 55 °C,
2 h. d)4-methoxyphenol 2n used as the phenol.
Finally, we show in Scheme 4 that this reaction is
highly chemoselective for aryl iodides even in the
presence of more electrophilic groups. Classic
nucleophilic substitution (SNAr) of halogenated
pyridines occur fastest at the 2- and 4-positions
relative to the 3-position.[14] Indeed, several examples
of SNAr on 2-chloro-5-iodopyridine with O-
nucleophiles show a high preference for substitution of
the 2-chloro over the 5-iodo moiety.[15] Diaryl ethers
containing a pyridyl group have been investigated for
their antibacterial activity,[16] and copper-mediated
coupling was used to form the diaryl ether C-O bond
(Scheme 4). In the case of 2-chloro-5-iodopyridine the
reaction is relatively unselective, low-yielding, and
required high temperature and long reaction times.
Our telescoping approach is selective for the iodo
group, occurs under much more mild temperature, and
in shorter reaction time (Scheme 4).[17]
Table 4. Telescoped reactions.a)
a) Reaction conditions: 1. Aryl iodide (0.5 mmol, 1 equiv.),
m-CPBA (0.5 mmol, 1 equiv.), TsOH•H2O (0.5 mmol, 1
equiv.), MeCN (0.5 mL), 55 °C, 30 min.; 2. TMP-H (0.5
mmol, 1 equiv.), 10 min.; 3. 2 (0.55 mmol, 1.1 equiv.),
K2CO3 (2 mmol, 4 equiv.), toluene (2.5 mL), 55 °C, 2 h.
In an additional example, we demonstrate how the
compatibility of iodo functional handles on the
nucleophile can be used for sequential reactions to
synthesized polyaryl ethers (Scheme 3). In this way
product 3ql was produced in 85% yield and in a second
Scheme 4. Chemoselective coupling of 2-chloro-5-
iodopyridine.
4
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10.1002/adsc.201901187
Advanced Synthesis & Catalysis
In conclusion, we have developed a mild and
[3] P. Villo, B. Olofsson, Arylations Promoted by
Hypervalent Iodine Reagents. Patai’s Chemistry of
Functional Groups: The Chemistry of Hypervalent
Halogen Compounds. Ed. B. Olofsson, I. Merek, Z.
Rappoport 2018 DOI: 10.1002/9780470682531.pat0950.
b) B. Olofsson, Top. Curr. Chem. 2016, 373, 135-166.
c) E. A. Merritt, B. Olofsson, Angew. Chem. Int. Ed.
2009, 48, 9052-9070.
efficient method to synthesize diaryl ethers from aryl
iodides and phenols that takes advantage of
aryl(TMP)iodonium salts as
a
key reaction
intermediate. This method does not require a metal
catalyst and has broad substrate scope. We are further
evaluating this chemistry in the context of
functionalizing biomolecules and as a broader
arylation strategy.
[4] From aryl iodides (metal-free), see: a) M. Reitti, P. Villo,
B. Olofsson, Angew. Chem. Int. Ed. 2016, 55, 8928-8932.
From iodosoarenes (metal-free), see: b) T. Dohi, D.
Koseki, K. Sumida, K. Okada, S. Mizuno, A. Kato, K.
Morimoto, Y. Kita, Adv. Synth. Catal. 2017, 359, 3503-
3508. From simple arenes (copper catalyzed), see: c) B.
Berzina, I. Sokolovs, E. Suna, ACS Catalysis 2015, 5,
7008-7014. d) I. Sokolovs, E. Suna, J. Org. Chem. 2016,
81, 371-379 e) M. S. McCammant, S. Thompson, A. F.
Brookes, S. W. Krska, P. J. H. Scott, M. S. Sanford, Org.
Lett. 2017, 19, 3939-3942.
Experimental Section
Synthesis of diaryl ethers from aryl(TMP)iodonium
tosylate and phenols.
Aryl(TMP)iodonium tosylate (0.5 mmol,
potassium carbonate (1.5 mmol, equiv.), phenol
1 equiv.),
3
(0.55mmol, 1.1 equiv.), and toluene (2.5 mL) were added to
an 8 mL vial, equipped with a magnetic stir bar and sealed
with a cap. The reaction was placed in a preheated
aluminum block set to 55 °C and stirred vigorously for 2
hours. The reaction was removed from heat and partitioned
between dichloromethane and saturated aqueous
ammonium chloride. The organic phase was evaporated
under reduced pressure and the residue purified using flash
column chromatography.
[5] D. Stuart, Chem. Eur. J. 2017, 23, 15852-15863.\
[6] J. Malmgren, S. Santoro, N. Jalalian, F. Himo, B.
Olofsson, Chem. Eur. J. 2013, 19, 10334-10342.
[7] For recent examples in metal-free reactions, see: a) Y.-
D. Kwon, J. Son, J.-H. Chun, J. Org. Chem. 2019, 84,
3678-3686. b) S. Basu, A. H. Sandtorv, D. R. Stuart,
Beilstein J. Org. Chem. 2018, 14, 1034-1038. c) T. L.
Seidl, D. R. Stuart, J. Org. Chem. 2017, 82, 11765-
11771. d) A. H. Sandtorv, D. R. Stuart, Angew. Chem.
Int. Ed. 2016, 55, 15812-15815.
Synthesis of diaryl ethers from aryl iodides and phenols
via telescoped reactions.
Aryl iodide (0.5 mmol, 1 equiv.) and acetonitrile (0.5 mL)
were added to an 8 mL vial equipped with a magnetic stir
bar. p-Toluenesulfonic acid (0.55 mmol, 1.1 equiv.) was
added in one portion, followed by one portion of m-CPBA
(0.55 mmols, 1.1 equiv.). The vial was sealed with a cap
and transferred to a preheated aluminum block set to 55 °C
and stirred vigorously for 30 minutes. Trimethoxybenze
(0.5 mmols, 1 equiv.) was added in one portion and stirring
was continued at 55 °C for 10 minutes. Toluene (2.5 mL)
was added to the vial, followed by potassium carbonate (2.0
mmol, 4 equiv.) and phenol (0.55 mmol, 1.1 equiv.). The
reaction was stirred at 55 °C for 2 hours. The reaction was
[8] For a recent example in metal-catalyzed reaction, see: D.
Koseki, E, Aoto, T. Shoji, K. Watanabe, Y. In, Y. Kita,
T. Dohi, Tetrahedron Lett. 2019, 60, 1281-1286.
[9] For recent examples in aryl radical reactions, see: a) T.
Dohi, S. Ueda, A. Hirai, Y. Kojima, K. Morimoto, Y.
Kita, Heterocycles 2017, 95, 1272-1284. b) D. Sun, K.
Yin, R. Zhang, Chem. Commun. 2018, 54, 1335-1338.
removed
from
heat
and
partitioned
between
dichloromethane and saturated aqueous ammonium
chloride. The resulting organic solution was evaporated
under reduced pressure and purified using flash column
chromatography.
[10] For our work in the area, see: a) T. L. Seidl, S. K.
Sundalam, B. McCullough, D. R. Stuart, J. Org. Chem.
2016, 81, 1998-2009. b) V. Carreras, A. H. Sandtorv, D.
R. Stuart, J. Org. Chem. 2017, 82, 1279-1284. c) T. L.
Seidl, A. Moment, C. Orella, T. Vickery, D. R. Stuart,
Org. Synth. 2019, 96, 137-149.
Acknowledgements
DRS acknowledges the mentorship and continued support of Prof.
Eric Jacobsen, to whom this paper is dedicated on the occasion of
his 60th birthday. Portland State University is acknowledged for
funding. We thank Aleksandra Nilova, Karley Maier, and Dario
Durastanti for assistance in acquiring HRMS data.
[11] For others’ work in the area, see ref. 6 and: a) J.-H.
Chun, V. W. Pike, J. Org. Chem. 2012, 77, 1931. b) J.-
H. Chun, V. W. Pike, Org. Biomol. Chem. 2013, 11,
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P. Shah, B. E. Burpitt, L. P. Crawford, B. J. Davies, M.
B. Mitchell, K. D. Pancholi, D. Tuddenham, N. J. Lewis,
C. O’Farrell, J. Chem. Soc. Perkin Trans. 1 1988, 3103.
d) T. Dohi, N. Yamaoka, Y. Kita, Tetrahedron 2010, 66,
5775. e) T. Dohi, N. Yamaoka, I. Itami, Y. Kita, Aust. J.
Chem. 2011, 64, 529. f) A. Pradal, P. Faudot dit Bel, P.
Y. Toullec, V. Michelet, Synthesis 2012, 44, 2463. g) R.
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Gonda, Z. Novak, Chem. Eur. J. 2015, 21, 16801. i) E.
Lindstedt, M. Reitti, B. Olofsson, J. Org. Chem. 2017,
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10.1002/adsc.201901187
Advanced Synthesis & Catalysis
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Metal-Free Cross-Coupling of Aryl Iodides and
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Adv. Synth. Catal. Year, Volume, Page – Page
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