Aryl(TMP)iodonium Tosylate Reagents as a Strategic Entry Point to Diverse Aryl Intermediates: Selective Access to Arynes

Article abstract of DOI:10.1021/acs.orglett.1c01534

Arenes are broadly found motifs in societally important molecules. Access to diverse arene chemical space is critically important, and the ability to do so from common reagents is highly desirable. Aryl(TMP)iodonium tosylates provide one such access point

Full text of DOI:10.1021/acs.orglett.1c01534

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Letter
Aryl(TMP)iodonium Tosylate Reagents as a Strategic Entry Point to
Diverse Aryl Intermediates: Selective Access to Arynes
Aleksandra Nilova, Bryan Metze, and David R. Stuart*
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ABSTRACT: Arenes are broadly found motifs in societally important
molecules. Access to diverse arene chemical space is critically important,
and the ability to do so from common reagents is highly desirable.
Aryl(TMP)iodonium tosylates provide one such access point to arene
chemical space via diverse aryl intermediates. Here we demonstrate that
controlling reaction pathways selectively leads to arynes with a broad
scope of arenes and arynophiles (24 examples, 70% average yield) and
efficient access to biologically active compounds.
ccess to diverse chemical space is central to medicinal
chemistry and drug discovery. Arenes are a key motif in
Scheme 1. Current State-of-the-Art and Mechanistic
Knowledge in Aryne Formation from Diaryliodonium Salts
A
such efforts,1 and aryl halides provide a primary entry point
into the arene chemical space. Notwithstanding the wide range
of metal-catalyzed reactions that involve oxidative addition,2
other reaction pathways that involve a direct reaction with
nucleophiles (SNAr) or the generation of aryl radicals and
arynes often either are limited in scope or require forcing
conditions. Diaryliodonium salts are highly activated aryl
pseudo halides that typically react under more mild conditions
than traditional aryl halides.3 They are also known to
participate in metal-catalyzed reactions as well as metal-free
reactions with nucleophiles, in single-electron transfer (SET)
reduction to access aryl radicals, and as aryne precursors, all
with a relatively broad scope.3 However, two key challenges
remain to fully realize the potential of diaryliodonium salts as
strategic reagents to access a range of reactive intermediates.
(1) Precise control over competing reaction pathways is not
currently possible in all cases, especially between the direct
reaction with nucleophiles and aryne formation.4 (2) Unsym-
metrical diaryliodonium salts reduce waste, yet a suitable
auxiliary has not emerged to facilitate chemoselective aryl
transfer in all of the previously mentioned reactions.5
some cases, the mesityl group undergoes competitive aryl
transfer via ipso substitution.5,11 Evidence of the challenges
surrounding chemoselectivity have been documented by
Olofsson and coworkers during their mechanistic study of
Although the first observation of arynes via the ortho
deprotonation of symmetrical diaryliodonium salts occurred in
the 1970s,6,7 the development of methods with synthetically
useful yields has only recently emerged with aryl(Mes)-
iodonium salts (Mes = 2,4,6-trimethylphenyl; Scheme 1a).8
These recent advances aside, some limitations exist. From a
practical standpoint, the aryl scope is often rather narrow; that
is, strongly electron-donating and strongly electron-with-
drawing substituents are largely absent, especially in the para
position8,9 and with tert-butoxide as the base.10 Moreover, in
Received: May 5, 2021
Published: May 25, 2021
https://doi.org/10.1021/acs.orglett.1c01534
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4813−4817
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hydroxide arylation (Scheme 1b).4 Trace or low (34%) yields
of aryne adduct are observed when a para-nitro or para-
methoxy substituent is present on the aryliodonium,
respectively (Scheme 1b).
Table 1. Effects of Substituents, Auxiliary, and Base on
Reaction Outcome
a
Herein we address the limitations of aryl(Mes)iodonium
salts as aryne precursors by employing aryl(TMP)iodonium
salts (TMP = 2,4,6-trimethoxyphenyl; Scheme 1c). Impor-
tantly, aryl(TMP)iodonium salts are also effective as aryl
transfer reagents in direct reactions with nucleophiles, as aryl
radical precursors, and in metal-catalyzed reactions.12−14
Therefore, in addition to being easily synthesized,15 stable,16
free-flowing powders, aryl(TMP)iodonium salts are idealized
reagents that provide a practicing chemist broad access to the
chemical space via four distinct reactive intermediates;17 here
we demonstrate their first use as aryne precursors. Specifically,
we show that pairing an appropriate base with aryl substituent
effects and position is key to avoiding other reaction pathways,
namely, direct ipso substitution of the transferring aryl group
or auxiliary, and achieving the desired aryne formation. We
demonstrate the broad scope of both aryl(TMP)iodonium
salts and arynophiles and highlight that this approach increases
both the yield and efficiency in synthesizing a bioactive
compound. Finally, we demonstrate a relative reactivity scale
for substituted aryl(TMP)iodonium salts and reveal the subtle
reactivity difference related to the identity of base.
b
entry
R group
aux
base
yield 3a−g (%)
c
c
c
c
c
c
c
c
d
1
2
3
4
5
6
7
8
4-NO2 (1a)
4-CO2Me (1b)
4-Cl (1c)
Mes
Mes
Mes
Mes
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
LiHMDS
LiHMDS
LiHMDS
NaOtBu
NaOtBu
27; 25
17; 16
e
77
37; 19
13; 87
12; 45
f
4-OMe (1d)
4-NO2 (1a)
4-CO2Me (1b)
4-Cl (1c)
4-OMe (1d)
4-NO2 (1a)
4-CO2Me (1b)
4-CO2Me (1b)
3-NO2 (1e)
3-CO2Me (1f)
3-CO2Me (1f)
3-OMe (1g)
d
TMP
TMP
TMP
TMP
TMP
TMP
Mes
TMP
TMP
TMP
TMP
e
82
60
57
76
56
84
24
69
86
g
g
g
9
10
11
12
13
14
15
c
c
g
LiHMDS
NaOtBu
On the basis of ease-of-use and greenness, we prefer sodium
tert-butoxide among the bases known to generate arynes from
aryl(Mes)iodonium salts.8,10 Therefore, we used sodium tert-
butoxide in reactions with a series of salts having different
electronic effects (1a−g) and auxiliaries (Mes and TMP). The
arynes were trapped with furan 2a as cycloadducts 3a−g
(Table 1). Additionally, we analyzed the crude reactions for
side products from competitive pathways such as ipso
substitution. The use of Mes as an auxiliary on salts 1a−d
confirms the narrow aryl scope often observed in these
reactions and underscores a key limitation of the Mes auxiliary
(Table 1, entries 1−4). Specifically, low yields (<40%) of 3 are
observed for the electron-deficient and electron-rich salts
(Table 1, entries 1, 2, and 4), and high yield (77%) is observed
for the relatively electron-neutral 1c (Table 1, entry 3).
Moreover, in the low-yielding reactions, ipso substitution was a
significant competing pathway. C−O coupling products 4a and
4b were observed in 25 and 16% yield, respectively (Table 1,
entries 1 and 2). The case of 1d demonstrates an even greater
limitation of the Mes auxiliary as it undergoes competitive C−
O coupling with tert-butoxide (Table 1, entry 4). Under
identical conditions, switching to the TMP auxiliary reveals a
partial solution to the limitations of the Mes auxiliary (Table 1,
entries 5−8). The yield of cycloadducts 3a and 3b remains low
(13 and 12%, respectively), but interestingly, the yield of ipso-
substitution products is dramatically improved, which is
consistent with the use of TMP as a general auxiliary for the
direct reaction with nucleophiles.12 The yields of 3c and 3d are
both improved when TMP is used as the auxiliary (Table 1, cf.
entries 3 and 7; cf. entries 4 and 8). The result with 1d is
particularly striking, as the TMP group remains inert during
the reaction. The low yields of 3a and 3b are primarily a result
of the competitive nucleophilicity of tert-butoxide, and so we
assessed the reaction of 1a and 1b (with the TMP auxiliary)
with LiHMDS as the base (Table 1, entries 9 and 10). With
this change, we observed markedly increased yields of 3a and
3b (Table 1, entries 9 and 10). Additionally, when we tested
the reaction of 1b-Mes with LiHMDS as the base, a lower yield
c
a
Conditions: 1a−g (1 equiv), 2a (5 equiv), base (see below), solvent
b
(see below), r.t., 1 h. Yields are obtained from crude 1H NMR
spectra with 2,4-dichlorobenzaldehyde as the internal standard.
c
d
e
NaOtBu (1.5 equiv), TBME. NMR yield of 4a. NMR yield of
f
g
4b. NMR yield of 4c. LiHMDS (1.1 equiv), toluene.
was observed, which is consistent with our previous
observations8a,9 and further highlights the advantage of the
TMP auxiliary (Table 1, entry 11). Finally, we surveyed a
series of meta-substituted iodonium salts 1e−g with both
NaOtBu and LiHMDS (Table 1, entries 12−15). Contrary to
the situation with para substitution, salt 1e generates aryne in
high yield with NaOtBu (Table 1, cf. entries 5 and 12). Again,
in the case of ester-substituted 1f, the use of LiHMDS is the
key to a high yield (Table 1, entries 13 and 14). Finally, meta-
methoxy-substituted 1g results in a high yield of aryne adduct
when NaOtBu is used as the base (Table 1, entry 15). Taken
together, these results support the wider generality of TMP as
an auxiliary over Mes in aryne formation and other
reactions.12−14 Specifically, the greater electron richness of
the TMP versus Mes auxiliary and the smaller size of the
methoxy versus methyl groups18 are the most likely
contributing factors to the relative inertness of TMP to
competing ipso-substitution pathways.
The scope with respect to aryl(TMP)iodonium tosylates is
wide-ranging with respect to functional groups and substituent
position. The bold bonds in 3 show the position of the
previous C−I bond in 1 (Scheme 2). In alignment with our
observations above, LiHMDS was used as the base for
electron-withdrawing para substituents (3a,b,h), and moderate
to high yields of aryne adducts were observed (Scheme 2).
Additionally, LiHMDS was used for meta-ester 3f and meta-
nitro 3p, resulting in high yields (Scheme 2). NaOt-Bu was
used as the base for most meta substituents, and a high yield of
aryne adduct was observed in all cases (3e,j,k, Scheme 2).
Polysubstituted aryl(TMP)iodonium salts lead to several
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using 1k as the aryne precursor (Scheme 2). Nitrone is an
efficient aryne trap resulting in a 94% yield of 5a (Scheme 2).21
Insertion into the C−N bond of cyclic urea (5b),22 the N−O
bond of pyridine N-oxide (5c),23 and the N−Cl bond of N-
chloroazepane (5d)24 all proceeded in synthetically useful yield
(38−68% yield, Scheme 2).25
We demonstrate the efficiency of our protocol through the
short synthesis of 5e, which is a key intermediate in the
synthesis of ALK and c-Met inhibitor 6 (Scheme 3).26 In the
Scheme 2. Scope of Aryl(TMP)iodonium Salts and
Arynophiles
Scheme 3. Application of Aryl(TMP)iodonium Tosylate to
the Synthesis of a Biologically Active Compound
a
1
Yield determined by H NMR spectroscopy.
patent literature, 5e is obtained in six pots (>80 h) from 2,6-
dinitrotoluene in an overall yield of 3% (Scheme 3).26
Recognizing that compound 5e could be accessed from an
in-situ-generated nitro-substituted aryne, we assessed the
feasibility of synthesizing 5e from aryl(TMP)iodonium salt
1e (Scheme 3). We obtained an 1H NMR yield of 77% for 5e
starting from 1e and 2,5-dimethylimidazolidinone (DMI) and
using NaOtBu as the base (Scheme 3). With the feasibility
confirmed, we performed a one-pot sequence beginning with
3-nitroiodobenzene and telescoping the synthesis of 1e and 5e
(Scheme 3). When performed in this way, 5e was obtained in
55% yield from 3-nitroiodobenzene in <2 h, which represents a
marked increase in the yield and reaction time efficiency.27
On the basis of the differences in reactivity observed for
para- and meta-substituted aryl(TMP)iodonium salts with
NaOtBu and LiHMDS as bases (Table 1), we sought to expand
this study to include ortho-substituted analogues and
determine a scale of relative reactivity via one-pot competition
experiments (Scheme 4). Compounds 1k (meta-) and 1x
(ortho-) lead to the same aryne and aryne adduct 3k;
therefore, each substrate competed against 1c, and the ratio of
products 3c:3k (or 3x) was used as a measure of the relative
reactivity. The relative reactivity scale obtained from these
experiments is meta (1k) > para (1c) > ortho (1x), and the
magnitude of this relative scale is greater when NaOtBu is used
as the base (Scheme 4). The greater reactivity of 1k over 1c
aligns with the closer proximity of the inductively withdrawing
chloro substituent. However, both 1c and 1x have an ortho-
iodonium group and a meta-chloro group relative to the site of
deprotonation; therefore, based on inductive electronic effects,
a
Conditions: 2a (2.75 mmol, 5.5 equiv), LiHMDS (0.5 mmol, 1
b
equiv), toluene (2 mL), r.t., 1 h. Conditions: 2a (2.75 mmol, 5.5
equiv), NaOt-Bu (1.5 to 3 equiv.; see the SI for variation), TBME
(2.5 mL), r.t., 1 h. 8% yield of 3b isolated as a side product. 1 mmol
of 1k used. Conditions: 2b (0.55 mmol, 1.1 equiv), NaOt-Bu (0.75
c
d
e
f
mmol, 1.5 equiv), TBME (2.5 mL), 0 °C, 1 h. Conditions: 2c−f (1−
5.5 equiv; see the SI for variation), NaOt-Bu (1−5 equiv.; see the SI
g
for variation), TBME (2.5 mL), r.t., 1−3 h. Isolated as a mixture of
regioisomers (11:1); major isomer shown.
medicinally relevant densely functionalized benzenoid sub-
stitution patterns (Scheme 2).19 Substitution at the meta and
para positions relative to the iodonium lead to 1,2,3,4-
substituted oxabicyclic arenes in high yield (3l−3o, Scheme
2). Additionally, aryl(TMP)iodonium salts with substitution at
the meta and ortho′ positions resulted in the distinct 1,2,3,4-
substituted oxabicyclic arene products 3p and 3q (Scheme 2).
Aryne adducts with 1,2,3,5- and 1,2,3,4,5-substitution were also
obtained in high yield using this approach (3r and 3s, Scheme
2). The yield was relatively insensitive to the scale, as a similar
but slightly higher yield of 3k was observed on the 1 mmol
scale of 1k (Scheme 2, cf. 78 vs 89%). Select salts were
annulated with benzylazide to give the heterocyclic products
3t−3w in moderate to high yield, which demonstrates the
compatibility of methoxy, trifluoromethoxy, fluoro, and
trifluoromethyl substituents (Scheme 2).20 Additionally,
several other arynophiles were compatible with this method
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a
Author Contributions
Scheme 4. Relative Reactivity of 1c,k,x
Conceptualization of the project was done by A.N. and D.R.S.
A.N. optimized the reaction and conducted initial studies on
the base and substituent effects. A.N. and B.M. conducted the
experimental investigation of the scope and data curation.
Writing of the manuscript was performed by D.R.S. with input
from A.N. and B.M.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Partial financial support of this work was provided by Portland
State University (Faculty Enhancement Award to D.R.S.) and
the National Science Foundation (mechanistic studies, CHE
1856705). The National Science Foundation provided
instrumentation funding for the BioAnalytical Mass Spectrom-
etry Facility at PSU (MRI 1828573). We thank Prof. Sophie
Rousseaux (University of Toronto) for insightful comments
during the preparation and revision of this manuscript.
a
1
Relative ratios determined from H NMR spectra; see the SI.
they should have similar reactivities. Yet 1c is more reactive to
deprotonation than 1x with both bases (Scheme 4), which
suggests the impact of steric effects, and perhaps iodonium
conformation,8a on the relative reactivity of deprotonation and
warrants further study.
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sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01534.
Experimental procedures, characterization data, and
copies of 1H, 13C{1H}, and 19F{1H} NMR spectra
(PDF)
FAIR data, including the primary NMR FID files, for
compounds 1a−d-Mes, 1f,h,m,o,p,s,u, 3a,b,e,f,h−w, and
5a−e (ZIP)
AUTHOR INFORMATION
Corresponding Author
■
David R. Stuart − Department of Chemistry, Portland State
University, Portland, Oregon 97201, United States;
orcid.org/0000-0003-3519-9067; Email: dstuart@
pdx.edu
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Direct arylation of tertiary amines via aryne intermediates using
diaryliodonium salts. Tetrahedron Lett. 2018, 59, 1737−1741.
Authors
Aleksandra Nilova − Department of Chemistry, Portland State
University, Portland, Oregon 97201, United States; Present
Address: Department of Chemistry, University of Florida,
Gainsville, Florida 32611, United States
Bryan Metze − Department of Chemistry, Portland State
University, Portland, Oregon 97201, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01534
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