A counteranion triggered arylation strategy using diaryliodonium fluorides

Article abstract of DOI:10.1039/c4sc02856b

A mild and transition metal-free counteranion triggered arylation strategy has been developed using diaryliodonium fluorides. The fluoride counteranion within the hypervalent iodonium species displays unusual reactivity that activates a phenolic O-H bond leading to electrophilic O-arylation. A wide range of phenols and diaryliodonium salts are compatible with this transformation under remarkably mild conditions. Furthermore, we pre-empt the wider implications of this strategy by demonstrating the compatibility of the arylation tactic with latent carbon nucleophiles.

Full text of DOI:10.1039/c4sc02856b

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A counteranion triggered arylation strategy using
diaryliodonium fluorides†
Cite this: DOI: 10.1039/c4sc02856b
*
L. Chan, A. McNally, Q. Y. Toh, A. Mendoza and M. J. Gaunt
A mild and transition metal-free counteranion triggered arylation strategy has been developed using
diaryliodonium fluorides. The fluoride counteranion within the hypervalent iodonium species displays
unusual reactivity that activates a phenolic O–H bond leading to electrophilic O-arylation. A wide range
of phenols and diaryliodonium salts are compatible with this transformation under remarkably mild
conditions. Furthermore, we pre-empt the wider implications of this strategy by demonstrating the
compatibility of the arylation tactic with latent carbon nucleophiles.
Received 17th September 2014
Accepted 12th November 2014
DOI: 10.1039/c4sc02856b
www.rsc.org/chemicalscience
Counterion effects can signicantly inuence the course of a
In 1991, Koser reported that the reaction between silyl enol
chemical reaction and the ability to control and manipulate ethers and diphenyliodonium uoride formed a-phenyl
these non-covalent interactions represents a non-classical ketones.6 The reaction does not require any external reagents
approach to develop new chemical transformations.1 Of the and is proposed to proceed through an initial salt metathesis
many types of counteranion species, uorides are a unique class that results in Si–F bond formation and an iodonium enolate
of anions that exist in a dichotomy between high stability, due (Scheme 1b).7 Subsequent O- to C-rearrangement and aryl
to the electronegativity of the uorine nucleus, and high reac- transfer forms the C–Caryl bond. Despite the apparent simplicity
tivity arising from enhanced basicity and nucleophilicity.2 of this process, there have been very few reports employing
Furthermore, reactions can be initiated based on the ability of diaryliodonium uorides in this manner.8 Based on this
uorides to form very strong bonds to molecules containing mechanistic pathway, where the formation of a strong Si–F
acidic hydrogen motifs and other atoms such as boron and bond is a key driving force, we were intrigued whether the
silicon.3
creation of other strong bonds to uorine could be used to
Our group has a long-standing interest in exploiting the design useful transformations. Examining bond enthalpy data
reactivity of diaryliodonium salts.4 These hypervalent iodine reveals that forming a H–F bond is highly favourable and should
reagents display a T-shaped arrangement of aryl groups about t this criteria (H–F 135 kcal molꢀ1 vs. Si–F 138 kcal molꢀ1).9 We
an iodine(III) atom that can be paired with a variety of coun- envisioned that the uoride counteranion could function as a
teranions. In both metal-mediated and metal-free reactions of base and activate a less reactive nucleophile towards electro-
iodine(III) salts, the counteranion has been shown to have a philic arylation (Scheme 1c).
dramatic effect on the reactivity and selectivity of a given reac-
In order to test this hypothesis, we selected the O-arylation of
tion pathway.5 Despite the existence of detailed solid state phenols as a model reaction. Olofsson and others have shown
structures, a correlation between the reactivity of diary- that this reaction is feasible using diaryliodonium salts
liodonium salts and the nature of their counteranion has been providing that the reaction media is sufficiently basic to form
difficult to establish.6 Despite this knowledge gap, the generally reactive phenoxide ions.10 These oxy-anions are capable of
accepted principle is that the counteranion functions as a direct attack at the iodine(III) centre (Scheme 1a) and a ligand
leaving group for electrophilic aryl species (Scheme 1a). Over transfer completes the phenol arylation process. Instead, we
the last 6 years, observations made in our laboratories led us to speculated that the uoride group within diaryliodonium uo-
speculate that the counteranions within diaryliodonium salts ride may be able to activate the O–H bond through formation of
may sometimes function as more than just a leaving group. As a a stable H–F bond, rendering the phenol more nucleophilic and
result, we became interested in bespoke reagents that may build allowing it to undergo simultaneous attack onto the iodine(III)
in an additional layer of reactivity into the counteranion unit of centre, as shown in Scheme 1c.11 An advantage of such an
these salts, thereby enabling new transformations.
activation strategy is that it would obviate the need for a strongly
basic reaction media that may preclude some transformations
with sensitive functionality. Herein, we describe the successful
realization of this design principle and report an electrophilic
arylation strategy with diaryliodonium uorides for phenols as
well as carbon pronucleophiles. The uoride counteranion
Department of Chemistry, University of Cambridge, Lenseld Road, Cambridge CB2
1EW, UK. E-mail: mjg32@cam.ac.uk; Tel: +44 1223 336318
† Electronic supplementary information (ESI) available: Experimental data for all
new compounds and procedures. See DOI: 10.1039/c4sc02856b
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Scheme 1 Outline of the counteranion triggered arylation strategy.
activates the nucleophile resulting in a transition metal free
arylation process that proceeds under remarkably mild condi-
tions (Scheme 1d).12
Table 1 Reaction optimisationa
Our initial experiments to validate the concept of the uoride
counteranion-triggered reactivity are shown in Table 1. A
control reaction between phenol and diphenyliodonium triate
(2a) in dichloromethane at room temperature resulted in no
reaction (entry 1), presumably due to the limited capacity of the
phenolic oxygen to act as a nucleophile. However, when
diphenyliodonium uoride was used, we observed formation of
diphenyl ether in 18% yield (entry 2). Despite the low yield of
this initial reaction, we were encouraged by the fact that the
product was formed under these conditions, thereby conrm-
ing that our initial hypothesis was valid. We believed that the
low yield could be accounted for by the accumulation of HF that
might prevent the reaction from proceeding to completion; we
observed no further product formation or starting material
consumption aer reaction for one hour. Addition of a mild
base to neutralise the HF generated should therefore allow the
Entry
X
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
OTf (2a)
F (2b)
F
F
F
F
F
F
—
—
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
MeCN
THF
MeOH
CH2Cl2
0
18
95
32
84
47
92
42
90
50
15
0
NaHCO3
KHCO3
Na2CO3
K2CO3
Cs2CO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
9
10
11
F
F
F
reaction to proceed. A screen of mild bases (entries 3–7) 12
OTf (2a)
revealed that the addition of solid sodium bicarbonate to the
reaction mixture led to improvements in both starting material
a
1 equiv. of 1a, 1.2 equiv. 2, 2.4 equiv. base, 0.05 M concentration. b GC
yield with triphenylmethane as the internal standard.
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consumption and product formation giving a yield of 95% aer with electron-withdrawing substituents worked equally well as
reaction for 30 minutes in dichloromethane solution (entry 3). those with electron-donating substituents. Interestingly, 3e was
A survey of the reaction parameters showed that although formed selectively without observation of arylation at the
reaction in dichloromethane proved the most efficient, a range benzylic alcohol, giving the desired product in good yield.
of polar and non-polar solvents also worked, in some cases Ortho-substituted phenols proceeded smoothly under the
giving comparable yields. Signicantly, no reaction was standard reaction conditions (3f–i, k) as exemplied by the
observed where diphenyliodonium triate was employed even successful arylation of the hindered 1,10-bi-2-naphthol (3m) in
in the presence of sodium bicarbonate (entry 12), further con- excellent yield. A substrate displaying an electron rich hetero-
rming the unique reactivity of the diaryliodonium uoride cycle also gave the desired diaryl ether 3n in almost quantitative
system.
yield demonstrating the preferential reactivity of the phenol
With an optimal set of reaction conditions in hand, we next over other nucleophilic moieties.13 Phenols containing Lewis
examined the scope of the new process using a range of basic heterocycles, such as hydroxypyridines and quinolines,
substituted phenols (Table 2). At 40 ꢁC, the reaction time varied were also compatible with this transformation, giving moderate
from 20 minutes to 6 hours across the different substrates and to good yields (3o–r).
good to excellent isolated yields were obtained (3a–r). Phenols
Although the synthesis of diaryliodonium uorides is rela-
tively trivial using standard literature procedures,7,8 we ques-
tioned whether we could directly generate the uoride
counterparts in situ from more readily available diaryliodonium
triates (and tetrauoroborates) and an external uoride addi-
tive in the reaction. This would enable the transfer of a wide
range of aryl groups from the more readily available, and
commercial diaryliodonium triates. Therefore, we tested
whether our O-arylation process could be initiated by the in situ
combination of diphenyliodonium triate and one equivalent
of tetrabutyl ammonium uoride (TBAF). We were pleased to
nd that a range of substituted diaryliodonium salts worked
Table 2 Scope of phenyl componenta
Table 3 Scope of aryl transfera
a
1 equiv. of 1, 1.2 equiv. 2, 1.2 equiv. TBAF$3H2O, 2.4 equiv. NaHCO3,
a
b
1 equiv. of 1, 1.2 equiv. 2b, 2.4 equiv. NaHCO3, 0.05 M concentration. 0.05 M concentration. Reaction with [(4-NO2–C6H4)–I–(C6H5)]OTf. All
Yields are quoted aer isolation and purication via silica gel yields are quoted aer isolation and purication via silica gel
chromatography.
chromatography.
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well in the reaction to give a range of diaryl ethers in good to
excellent yield (Table 3). Neither electron-rich nor electron-
decient salts posed a problem. Steric hinderance imparted
from the ortho-substituent in the corresponding diary-
liodonium salts did not pose any difficulties. In line with the
previously observed selectivity of electronically unsymmetric
diaryliodonium salts (4-NO2–C6H4 vs. C6H5) under transition
metal free conditions, exclusive transfer of the electron-de-
cient aryl group was observed to form 3c.7,8,14
Under our previously reported copper-catalyzed arylation
tactic, we had shown that estrone underwent ortho-arylation of
the resident phenolic functionality (Scheme 2a).15 When we
tested estrone under the reactions conditions using dipheny-
liodonium uoride we observed exclusive O-arylation of the
steroid 10 in excellent yield (Scheme 2b), thereby demonstrating
the orthogonal reactivity of the diaryliodonium uorides
compared to other more conventional iodonium species.
L-Tyrosine derivatives and small peptides containing this
amino acid were also responsive to the new arylation process.
Protected tyrosine derivative 7 was submitted to the standard
reaction conditions and an excellent yield of the arylated
product 8 was obtained aer only 30 minutes without loss of
enantiomeric purity (Scheme 3a). A tripeptide 9 also worked
well and phenol motif undergoes arylation without interference
from other functionalities to form the product 10 in 84% yield
(the reaction proceeded in under 2 hours and even at reaction
concentrations as low as 1 mM, Scheme 3b). Taken together,
these results offer the potential for bioorothogonal arylative
functionalization strategies.16
Scheme 3 Phenylation of tyrosine derivative and a tripeptide.
using the boron containing pronucleophiles by exploiting the
strength of the B–F bonds (Scheme 4b). Under similar condi-
tions, a metal-free cross coupling to form biphenyl 15 could be
affected through the combination with triphenyl borane 14 and
diphenyliodonium uoride using no additional reagents other
than reaction solvent. Similarly, the combination of diary-
liodonium triate and TBAF with the triphenyl borane provided
the unsymmetrical biaryl 16 in good yield. While we acknowl-
edge the latter transformations to form biaryls are inefficient in
terms of ‘aryl economy’, the underpinning mechanistic pathway
provides an interesting conceptual strategy to the formation of
this fundamental carbon framework.
Finally, we assessed the broader potential of the diary-
liodonium uorides in other systems. Considering the pKa of
the average phenol in water is around 10, we investigated acidic
carbon centred pronucleophiles with pKa's in the same range as
phenols (Scheme 4a). We found that the latently nucleophilic a-
cyano, a-phenyl esters (11) underwent C-phenylation in excel-
lent yield under identical reaction conditions to the phenol
system to form the all carbon quaternary centred ester 12.17
Additionally, the diaryliodonium triate – TBAF combination
also enabled the transfer of substituted aryl derivatives (to 13) in
good yields. To further explore the reactivity of the counter-
anion effect, we were also able to demonstrate related reactions
Scheme 2 Chemoselective phenylations of estrone.
Scheme 4 a-Arylation of carbonyl compounds.
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In summary, we have developed a counteranion controlled
strategy for transition metal free electrophilic arylation with
diaryliodonium uorides. The activation process is demon-
strated via the arylation of phenols to form diaryl ethers under
ambient conditions. This transformation is tolerant to a wide
range of functional groups on both the phenol building blocks
and diaryliodonium reagents. We believe that the reaction is
initiated by hydrogen bonding between the uoride counterion
and the phenolic O–H, which enhances the nucleophilicity of
the phenol and triggers the attack at the iodine(III) centre dis-
placing the uoride as a leaving group. Subsequent ligand
coupling from the iodine atom generates the aryl ether. During
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products. Current studies are focused on these lead results and
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Acknowledgements
We gratefully acknowledge the EPSRC (EP/I002065), the Marie
Curie Foundation (A.Mc., A.M.), the CRUK Molecular Medicine
and Chemical Biology Training Programme (L.C.), and the
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