Site-selective aromatic C-H λ3-iodanation with a cyclic iodine(iii) electrophile in solution and solid phases

Article abstract of DOI:10.1039/d0sc02737e

An efficient and site-selective aromatic C-H λ3-iodanation reaction is achieved using benziodoxole triflate (BXT) as an electrophile under room temperature conditions. The reaction tolerates a variety of electron-rich arenes and heteroarenes to afford the corresponding arylbenziodoxoles in moderate to good yields. The reaction can also be performed mechanochemically by grinding a mixture of solid arenes and BXT under solvent-free conditions. The arylbenziodoxoles can be used for various C-C and C-heteroatom bond formations, and are also amenable to further modification by electrophilic halogenation. DFT calculations suggested that the present reaction proceeds via a concerted λ3-iodanation-deprotonation transition state, where the triflate anion acts as an internal base. This journal is

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Site-selective aromatic C–H λ3-iodanation with cyclic iodine(III)
electrophile in solution and solid phases
Wei Ding,a Chen Wang,a,b Jie Ren Tan,a Chang Chin Ho,a Felix León,a Felipe García,*a and Naohiko
Received 00th January 20xx,
Accepted 00th January 20xx
Yoshikai*a
DOI: 10.1039/x0xx00000x
An efficient and site-selective aromatic C–H λ3-iodanation reaction is achieved using benziodoxole triflate (BXT) as
electrophile under room temperature conditions. The reaction tolerates a variety of electron-rich arenes and heteroarenes
to afford the corresponding arylbenziodoxoles in moderate to good yields. The reaction can also be performed
mechanochemically by grinding a mixture of solid arene and BXT under solvent-free conditions. The arylbenziodoxoles can
be used for various C–C and C–heteroatom bond formations, and are also amenable to further modification by electrophilic
halogenation. DFT calculations suggested that the present reaction proceeds via a concerted λ3-iodanation–deprotonation
transition state, where the triflate anion acts as an internal base.
aryl-λ3-iodane reagent such as MesI(OH)OTs with acidic
activator, or from (hetero)arenes, bulky aryl iodide, oxidant and
acid.8 However, diaryliodonium salts are potentially unstable
Introduction
Direct and site-selective C–H functionalization of arenes and
heteroarenes with a leaving group that can allow aryl–carbon
and aryl–heteroatom bond formations offers a highly attractive
strategy to access diverse (hetero)aromatic compounds.
Transition metal-catalyzed arene C–H borylations, which install
a boryl group as an electrofugal leaving group onto arenes, are
among the most powerful C–H functionalization methods of this
type.1 The installation of a nucleofugal leaving group onto
arenes can be equally attractive and complementary to the C–
H borylation. However, traditional electrophilic halogenation
reactions often suffer from drawbacks such as incomplete site
selectivity and harsh reaction conditions.2,3 As such, methods
for site-selective installation of synthetically versatile
nucleofuges other than halogens are highly desirable.4
for isolation and prolonged storage, and are often used without
isolation.8a-c In this context, aryl-λ3-iodane compounds bearing
a cyclic benziodoxol(on)e (BX) moiety could be a valuable
alternative or complement to diaryliodonium salts, as their non-
ionic nature and rigid structure would endow them with
enhanced stability for facile isolation and long-term storage as
well as opportunity to tolerate a wider range of reaction
conditions. The BX group has already had great success in the
development of reagents for transferring groups such as
trifluoromethyl, alkynyl, azido, and cyano groups.9 On the other
hand, access to analogous (hetero)aryl–BX reagents remains
relatively limited and their reactivity less explored. The direct
preparation of aryl–BXs from arenes and 2-iodobenzoic acid
was reported by Olofsson and Zhdankin (Scheme 1a).10
However, these compounds have not been utilized as aryl
transfer agents. Instead, they were reported to produce 2-
functionalized benzoic acids in the reaction with
nucleophiles.10b More recently, Waser developed indole- and
pyrrole-BX reagents via zinc-catalyzed BX transfer to indoles
and pyrroles with acetoxy benziodoxolone and demonstrated
their utility in C–H functionalization reactions (Scheme 1b),11,12
while the reaction required relatively high dilution and was not
extended to arenes.
Trivalent iodine (λ3-iodane) moieties represent a class of
useful nucleofuges in arene transformations. Thus, vast arrays
of aryl–carbon and aryl–heteroatom bond forming reactions
have been developed using diaryliodonium salts as electrophilic
aryl-transfer
agents.5 Particularly
attractive
among
diaryliodonium salts are unsymmetrical ones that allow
selective transfer of one of the aryl groups over the other,
“dummy” aryl group (e.g., mesityl).6,7 A direct C–H λ3-
iodanation approach has proved feasible for the synthesis of
such compounds from electron-rich (hetero)arenes and bulky
Herein, we report that Zhdankin’s benziodoxole triflate (BXT;
1) derived from α,α-bis(trifluoromethyl)-2-iodobenzyl alcohol13
undergoes C–H λ3-iodanation of (hetero)arenes with high site
selectivity (Scheme 1c). This BX transfer reaction tolerates
various electron-rich arenes and heteroarenes, allowing facile
preparation of the corresponding aryl–BX derivatives in
moderate to excellent yields under simple and mild conditions
aDivision of Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University, Singapore 637371,
Singapore. E-mail: nyoshikai@ntu.edu.sg
bZhejiang Key Laboratory of Alternative Technologies for Fine Chemicals Process,
Shaoxing University, Shaoxing 312000, China.
† Electronic Supplementary Information (ESI) available. CCDC 1981452. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/x0xx00000x
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without any catalyst or promoter. Moreover, the reaction can between 1 and 2a could be run under air to afford 3a in an
View Article Online
DOI: 10.1039/D0SC02737E
also be performed mechanochemically using solid arene and equally high yield (95%).
BXT under solvent-free conditions. The aryl–BX compounds
serve as aryl donors for a variety of C–C and C–heteroatom bond
Table 1 Effect of reaction conditionsa
formations, and also tolerate further modification by
electrophilic halogenation. Owing to the superior leaving group
ability of the BX group, iodinated aryl–BX compounds can be
used for chemoselective sequential cross-couplings.
Entry
1
2
3
4
5
Solvent
MeCN
CH2Cl2
toluene
chlorobenzene
DMF
Yield (%)b
94
83
65
69
0
6
Et2O
0
7
8c
9d
MeOH
MeCN
MeCN
0
84
86
a Unless otherwise noted, the reaction of 1 (0.10 mmol) and 2a (0.15 mmol) was
carried out in the solvent (0.25 mL) at room temperature. b Determined by 19F NMR
using 1,4-bis(trifluoromethyl)benzene as an internal standard. c 1 (0.10 mmol) and
2a (0.10 mmol) were used. d 1 (0.20 mmol) and 2a (0.10 mmol) were used.
With the optimized reaction conditions in hand, we
explored the scope of the λ3-iodanation reaction (Table 2). A
variety of monoalkoxyarenes took part in the reaction to afford
the desired aryl–BX products 3a–3e in high yields with exclusive
para-selectivity. 1,3-Disubstituted arenes such as m-xylene,
resorcinol
dimethyl
ether,
and
3-methoxytoluene
regioselectively afforded aryl–BX products 3f–3h with 1,2,4-
substitution pattern. The latter reacted exclusively at the para-
Scheme 1 Synthetic approaches to (hetero)arylbenziodoxol(on)es via C–H λ3-iodanation. position of the methoxy group. 1-Alkoxy-2-substituted benzene
derivatives,
including
dihydrobenzofuran
and
9,9-
dimethylxanthene, were functionalized at the para-position of
the alkoxy group, thus affording the products 3i–3o in moderate
to good yields, while elevated temperatures (60–80 °C) were
necessary for 1-methoxy-2-halobenzenes. 3-Methylbenzoxazol-
2(3H)-one reacted exclusively at the para-position of the
nitrogen atom, as unambiguously supported by X-ray
crystallographic analysis of the product 3p.16 Electron-rich
1,3,5-trisubstituted arenes such as mesitylene, 1-bromo-3,5-
dimethoxybenzene, 3,5-dimethylanisole, and N-methyl
metaxalone17 took part in the reaction to afford the products
3q–3t in good yields, where, for the latter three, the para-
position of the alkoxy group was selectively functionalized.
Other trisubstituted methoxyarenes with different substitution
patterns were also amenable to the present λ3-iodanation (see
the products 3u–3w). Electron-rich heteroarenes such as
thiophene and indole derivatives could be employed as
substrates for the present reaction, producing the products 3x–
3aa in good yields. The scalability of the present λ3-iodanation
reaction was demonstrated by gram-scale (3 mmol) synthesis of
3a and 3q, which could be achieved without a significant
decrease in the yield (86% and 77% yields, respectively). It
should be noted that the present method allows access to
unique aryl–BX compounds such as 3m and 3z that contain
Results and discussion
Pursuing our continuing interest in hypervalent iodine
chemistry14 and encouraged by our recent success in using 1 as
a λ3-iodane electrophile,15 the present study commenced with
the exploration of the reaction between anisole (2a, 1.5 equiv)
and 1 (Table 1). The reaction proceeded smoothly in MeCN at
room temperature, affording the aryl–BX product 3a with
exclusive para-selectivity in 94% yield, which could be purified
by routine chromatography and are stable to air and moisture
(entry 1). No decomposition was observed upon storage at
room temperature for at least one month. The reaction proved
highly solvent-dependent. Aromatic and chlorinated solvents
could be used albeit with a sizable decrease in the yield (entries
2-4). On the other hand, no product was observed in polar
coordinating (DMF), ethereal (Et2O), and protic (MeOH)
solvents (entries 5-7). The yield slightly dropped by using
equimolar mixture of 2a and 1 or using 1 as the excess reagent
(entries 8 and 9). Note that an analogous BXT reagent derived
from 2-iodobenzoic acid13 failed to promote the desired λ3-
iodanation of 2a. While the above and the following
experiments to explore the substrate scope were all set up in an
Ar-filled glove box, the reaction actually proved to be
unaffected by air and moisture. Thus, the model reaction
2 | J. Name., 2012, 00, 1-3
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iodonium and iodide moieties, which would offer opportunities alkenyl–BXs 3ab and 3ac in good yields (Scheme 2a).15c-e,18
View Article OTnlhinee
DOI: 10.1039/D0SC02737E
reaction of 1,1-di(p-tolyl)ethene (2ac) did not take place under
for selective and sequential functionalizations (vide infra).
the standard conditions but resulted in the decomposition of 1,
while the addition of Na2CO3 and the use of chlorobenzene as
the solvent allowed us to obtain the desired product 3ad in a
moderate yield (Scheme 2b). Other alkenes such as styrene, α-
methylstyrene, and vinylcyclohexane failed to participate in the
present C–H λ3-iodanation.
Table 2 Aromatic C–H λ3-iodanation with BXTa
R
I
O
R
1 (0.2 mmol)
CF3
CF3
H
MeCN, RT, 24 h
2a– 2aa (0.3 mmol)
3a– 3aa
Cl
EtO2C
O
RO
BX
BX
O
BX
3e, 75%
3a (R = Me), 92% (86%)b
3b (R = Et), 85%
3d, 73%c
3c (R = Bn), 91%
Me
OMe
BX
Me
2
Me
BX
MeO
MeO
BX
4
3f, 62%c
3g, 86%
3h, 81%
(C4:C2 = 21:1)
Scheme 2 C–H λ3-iodanation of 1,1-diarylethylenes.
R
3i (R = Me), 86%
3j (R = F), 76%d
O
BX 3k (R = Cl), 70%c
3l (R = Br), 68%d
3m (R = I), 65%c
BX
Recently, mechanochemistry has emerged as a powerful
tool in synthetic chemistry for attractive merits such as solvent-
free process, reduced reaction times, and ability to engage
poorly soluble solid compounds, and unique reactivity and
selectivity.19 Notably, mechanochemistry has proved to offer an
ideal means to accelerate the present λ3-iodanation under
solvent-free conditions. Thus, by simply subjecting a mixture of
arene (0.3 mmol) and 1 (0.2 mmol) to ball milling (30 Hz for 2
h), aryl–BX derivatives 3o, 3q, 3r, and 3u were obtained in good
yields (Scheme 3a). Note that, except for 3q, the starting arenes
of these aryl–BXs are solid compounds. Additionally, the
mechanochemical synthesis of 3r could be performed on a gram
scale using a slight excess of the arene 2r, yielding analytically
pure product without chromatographic purification (Scheme
3b).
MeO
3n, 74%
O
O
O
N
BX
BX
Me
3o, 77%
3p (X-ray)
3p, 70%
OMe
BX
Me
Me
2
Me
BX
MeO
BX
MeO
4
Me
Br
3r, 84%
Me
3q, 83% (77%)b
3s, 88%
(C4:C2 = 15:1)
Me
OMe
BX
Me
Br
OMe
BX
MeO
BX
O
O
MeO
O
N
Br
Me
3t, 77%
(from N-Me Metaxalone)
3u, 91%
3v, 64%
BX
OMe
3
Ph
Me
BX
R
BX
S
5
N
Piv
Br
3w, 75%
(C5:C3 = 10:1)
3aa, 70%
3x (R = H), 74%
3y (R = Br), 82%
3z (R = I), 89%
a
The reaction was performed on a 0.2 mmol scale according to the standard
conditions described in Table 1, entry 1. BX in the product formula refers to the
b
benziodoxole moiety. The yield for a 3 mmol-scale reaction is given in the
parentheses. c The reaction was performed at 60 °C. d The reaction was performed
e
at 80 °C. The reaction was performed with 2ac (0.2 mmol), 1 (0.3 mmol), and
Na2CO3 (0.4 mmol) in chlorobenzene (1.0 mL).
Scheme 3 Mechanochemical λ3-iodanation of arenes.
Besides arenes and heteroarenes, 1,1-diphenylethene (2ab)
and its para-fluoro-substituted derivative (2ac) reacted with
BXT under the standard conditions to afford the corresponding
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J. Name., 2013, 00, 1-3 | 3
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Some important limitations of the present λ3-iodanation trimethylsilylacetylene on the aryl–BX moiety over the aryl–
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should be noted. Less electron-rich, electron-neutral or iodide moiety to afford the monoalkynylDaOteI:d10p.1r0o3d9u/Dct0sSC10027a3n7dE
electron-poor arenes did not participate well in the reaction 12, respectively, which illustrated the superior leaving group
with 1 even at elevated temperatures (up to 80 °C), and were ability of the BX group in oxidative addition to Pd(0) (Scheme
largely recovered. However, the reaction of moderately 5b). Subsequent Sonogashira coupling of 10 and 12 with
electron-rich o-xylene, which was sluggish under the original phenylacetylene provided unsymmetrically dialkynylated
conditions (28% yield at 60 °C), could be promoted by the arenes 11 and 13, respectively. Finally, the compounds 3g and
addition of Sc(OTf)3 catalyst (20 mol%) and the use of CH2Cl2 as 3o could be regioselectively brominated or chlorinated without
the solvent to afford the corresponding aryl–BX product 3ae in affecting the BX group to afford the products 3v, 14, and 15 in
55% yield (Scheme 4a). Meanwhile, aryl–BXs bearing electron- good yields (Scheme 5c).3e The sequential installation of BX and
neutral phenyl (3af) or electron-deficient 4-bromophenyl (3ag) halogen may offer
a
means for chemoselective
or 4-cyanophenyl (3ah) group could be synthesized in good difunctionalization of aromatic compounds.
yield via silicon-to-iodine(III) or boron-to-iodine(III) aryl
transfer20,21 using the corresponding aryltrimethylsilane or
aryltrifluoroborate (Scheme 4b-c). Highly electron-rich arenes,
such as 1,2- and 1,4-dimethoxybenzenes and N,N-
dimethylaniline, failed to give the desired aryl–BX products with
1 and decomposed to α,α-bis(trifluoromethyl)-2-iodobenzyl
alcohol. This reduction of the I(III) reagent is likely caused by the
ability of these electron-rich arenes to undergo single electron
transfer.
Scheme 4 Preparation of aryl–BXs via Lewis acid-catalyzed C–H λ3-iodanation or aryl
transfer from aryl silicon or boron reagents.
The functionalized aryl–BX products obtained by the
present reaction could be used as versatile building blocks for
further transformations via selective transfer of the arene-
derived aryl groups (Scheme 5). As illustrated in Scheme 5a, the
benziodoxole moiety in 3a and 3q served as an excellent leaving
group in Pd-catalyzed Suzuki–Miyaura, Sonogashira, Stille
couplings, and Miyaura borylation,22 which afforded biaryl 4,
aryl alkyne 5, styrene 6, and aryl boronate 7, respectively, in
good yields. In addition, aryl–BX 3a was amenable to Cu-
catalyzed sulfonylation23 and cyanation,24 affording the
corresponding aryl sulfone 8 and aryl nitrile 9, respectively. 3-
Iodo-4-methoxyphenyl–BX 3m and 5-iodothien-2-yl–BX 3z
underwent site-selective Sonogashira coupling with
Scheme 5 Product transformations. Reaction conditions: a) Pd(PPh3)4, 4-MeOC6H4B(OH)2,
K2CO3, DMF/H2O, 100 °C, 8 h; b) PdCl2(PPh3)2, CuI, trimethylsilylacetylene, Et3N, DMF, rt,
12 h; c) PdCl2(PPh3)2, (CH2=CH)SnBu3, DMF, 60 °C, 12 h; d) Pd(OAc)2, PPh3, CuI, B2Pin2,
Cs2CO3, MeCN, rt, 24 h; e) CuI, L-proline sodium salt, PhSO2Na, DMSO, 90 °C, 24 h; f)
CuCN, L-proline, DMF, 90 °C, 24 h; g) PdCl2(PPh3)2, CuI, trimethylsilylacetylene, Et3N, DMF,
4 | J. Name., 2012, 00, 1-3
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0 °C, 12 h; h) PdCl2(PPh3)2, CuI, phenylacetylene, THF/Et3N, rt, 12 h; i) NBS, HFIP, 40 °C,
24 h; j) NCS, HFIP, 80 °C, 24 h; k) NBS, HFIP, rt, 4 h.
C–C and C–heteroatom bond formations as well as for
electrophilic aromatic substitution. Further studies on the use
View Article Online
DOI: 10.1039/D0SC02737E
of benziodoxole triflate and related compounds as iodane
transfer agents and the transformation of organo–BX
compounds are currently underway.
To gain insight into the mechanism of the C–H λ3-iodanation,
DFT calculations on the reaction between 1 and anisole (2a)
were performed (Figure 1; see the Supporting Information for
the computational detail). Prior to the iodanation event, the
triflate on 1 is slipped to the trans position of the aryl group (1
to 1’ via TS1), which allows 2a to bind to the cis position of the
aryl ligand (CP1).25 This is followed by a six-centered TS for
concerted λ3-iodanation/deprotonation of the para-position
(TS2p, ΔG‡ = 19.3 kcal mol–1) to give the product 3a and TfOH,
which is reminiscent of the concerted metalation–
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
deprotonation mechanism in aromatic C–H activation by This work was supported by the Singapore Ministry of Education
transition metal carboxylates.25,26 Note that λ3-iodanation (Academic Research Funds Tier 2 (MOE2016-T2-2-043) and Tier
without prior isomerization of 1 requires an unreasonably high 1 (RG114/18) to N.Y.). and Nanyang Technological University.
activation energy (37.3 kcal mol–1; Figure S4). The calculated F.G. and F.L acknowledge A*STAR (AME IRG A1783c0003) and a
endergonicity (2.1 kcal mol–1) might be a reflection of NTU start-up grant (M4080552) for financial support. We thank
computational artifact, which does not take the interaction Dr. Yongxin Li (Nanyang Technological University) for his
between TfOH and MeCN (in the solution-phase reaction) or the assistance with the X-ray crystallographic analysis
intermolecular hydrogen bonding between TfOH molecules (in
the solid-phase reaction) into account. Consistent with the
experiment, analogous transition states for the λ3-iodanation of
the ortho- and meta-positions were found to require higher
activation energies (20.5 kcal mol–1 and 27.5 kcal mol–1,
respectively; Figure S5).
Notes and references
1
(a) I. A. Mkhalid, J. H. Barnard, T. B. Marder, J. M. Murphy and
J. F. Hartwig, Chem. Rev., 2010, 110, 890-931; (b) J. F. Hartwig,
Acc. Chem. Res., 2012, 45, 864-873; (c) A. Ros, R. Fernandez
and J. M. Lassaletta, Chem. Soc. Rev., 2014, 43, 3229-3243; (d)
Y. Kuroda and Y. Nakao, Chem. Lett., 2019, 48, 1092-1100.
(a) G. A. Olah, Acc. Chem. Res., 1971, 4, 240-248; (b) R. Taylor,
Electrophilic Aromatic Substitution, John Wiley & Sons, New
York, 1990.
(a) F. Mo, J. M. Yan, D. Qiu, F. Li, Y. Zhang and J. Wang, Angew.
Chem. Int. Ed., 2010, 49, 2028-2032; (b) S. M. Maddox, C. J.
Nalbandian, D. E. Smith and J. L. Gustafson, Org. Lett., 2015,
17, 1042-1045; (c) R. C. Samanta and H. Yamamoto, Chem.
Eur. J., 2015, 21, 11976-11979; (d) X. Xiong, F. Tan and Y. Y.
Yeung, Org. Lett., 2017, 19, 4243-4246; (e) R. J. Tang, T.
Milcent and B. Crousse, J. Org. Chem., 2018, 83, 930-938.
F. Berger, M. B. Plutschack, J. Riegger, W. Yu, S. Speicher, M.
Ho, N. Frank and T. Ritter, Nature, 2019, 567, 223-228.
(a) N. R. Deprez and M. S. Sanford, Inorg. Chem., 2007, 46,
1924-1935; (b) E. A. Merritt and B. Olofsson, Angew. Chem.
Int. Ed., 2009, 48, 9052-9070; (c) A. Yoshimura and V. V.
Zhdankin, Chem. Rev. 2016, 116, 3328-3435.
O
CF3
O
2
3
ΔGMeCN (kcal mol– 1
)
S
O
1.27
1.37
3.24
H
2.25
CF3
I
O
O
S
CF3
CF3
O
MeO
O
I
O
TS2p
CF3
CF3
19.3
TS1 + 2a
11.5
11.9
8.5
CP1
4
5
OMe
1’ + 2a
2.1
3a + TfOH
OTf
OTf
0.0
I
O
I
O
CF3
CF3
CF3
CF3
1 + 2a
Figure 1 Gibbs free energy diagram for the para C–H λ3-iodanation of anisole (2a) with
BXT (1). The bond distances are in Å.
6
For selected examples, see: (a) Y. Kita, K. Morimoto, M. Ito, C.
Ogawa, A. Goto and T. Dohi, J. Am. Chem. Soc., 2009, 131,
1668-1669; (b) N. R. Deprez and M. S. Sanford, J. Am. Chem.
Soc., 2009, 131, 11234-11241; (c) T. Dohi, M. Ito, N. Yamaoka,
K. Morimoto, H. Fujioka and Y. Kita, Angew. Chem. Int. Ed.,
2010, 49, 3334-3337; (d) E. Cahard, H. P. Male, M. Tissot and
M. J. Gaunt, J. Am. Chem. Soc., 2015, 137, 7986-7989; (e) M.
S. McCammant, S. Thompson, A. F. Brooks, S. W. Krska, P. J. H.
Scott and M. S. Sanford, Org. Lett., 2017, 19, 3939-3942; (f) D.
H. Lukamto and M. J. Gaunt, J. Am. Chem. Soc., 2017, 139,
9160-9163; (g) J. Rae, J. Frey, S. Jerhaoui, S. Choppin, J.
Wencel-Delord and F. Colobert, ACS Catal., 2018, 8, 2805-
2809; (h) W. Shang, Z. D. Mou, H. Tang, X. Zhang, J. Liu, Z. Fu
and D. Niu, Angew. Chem. Int. Ed., 2018, 57, 314-318.
Conclusions
In summary, we have reported site-selective λ3-iodanation of
aromatic compounds with benziodoxole triflate under simple
and mild conditions. The reaction tolerates a variety of electron-
rich arenes and heteroarenes, affording arylbenziodoxole
derivatives in moderate to excellent yields. Mechanochemistry
has proved to offer further improvement, enabling expedient
and solvent-free reaction between solid reactants. The scope of
the arylbenziodoxole synthesis based on this metal-free C–H λ3-
iodanation may be complemented by the Lewis acid-assisted λ3-
iodanation or the aryl group transfer from the corresponding
silicon and boron compounds. The thus-synthesized
arylbenziodoxoles serve as versatile synthetic intermediates for
7
8
D. R. Stuart, Chem. Eur. J., 2017, 23, 15852-15863
(a) I. Sokolovs, D. Lubriks and E. Suna, J. Am. Chem. Soc., 2014,
136, 6920-6928; (b) B. Berzina, I. Sokolovs and E. Suna, ACS
Catal., 2015, 5, 7008-7014; (c) I. Sokolovs and E. Suna, J. Org.
Chem., 2016, 81, 371-379; (d) G. Laudadio, H. P. L. Gemoets,
V. Hessel and T. Noel, J. Org. Chem., 2017, 82, 11735-11741;
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Page 6 of 7
ARTICLE
(e) T. Dohi, T. Hayashi, S. Ueda, T. Shoji, K. Komiyama, H.
Journal Name
Neumann, E. J. Linstad, K. McCauley, J. Veness, J. J. Kempinger
View Article Online
Takeuchi and Y. Kita, Tetrahedron, 2019, 75, 3617-3627; (f) E.
and S. G. DiMagno, Eur. J. Org. Chem., 2015, 5919-5924.
Lindstedt, M. Reitti and B. Olofsson, J. Org. Chem., 2017, 82, 22 J. Ratniyom, N. Dechnarong, S. YotphaDnOaI:n1d0.S10. 3K9i/aDt0isSeCv0i,27E3u7rE.
11909-11914.
J. Org. Chem., 2014, 2014, 1381-1385.
9
(a) V. V. Zhdankin, Curr. Org. Synth., 2005, 2, 121-145; (b) J. P. 23 W. Zhu and D. Ma, J. Org. Chem., 2005, 70, 2696-2700.
Brand, D. F. Gonzalez, S. Nicolai and J. Waser, Chem. 24 D. Wang, L. Kuang, Z. Li and K. Ding, Synlett, 2008, 69-72.
Commun., 2011, 47, 102-115; (c) J. P. Brand and J. Waser, 25 S. Izquierdo, S. Essafi, I. Del Rosal, P. Vidossich, R. Pleixats, A.
Chem. Soc. Rev., 2012, 41, 4165-4179; (d) J. Charpentier, N.
Fruh and A. Togni, Chem. Rev., 2015, 115, 650-682; (e) Y. Li, D.
Vallribera, G. Ujaque, A. Lledos and A. Shafir, J. Am. Chem.
Soc., 2016, 138, 12747-12750.
P. Hari, M. V. Vita and J. Waser, Angew. Chem. Int. Ed., 2016, 26 (a) D. Lapointe and K. Fagnou, Chem. Lett., 2010, 39, 1118-
55, 4436-4454; (f) J. Waser, Synlett, 2016, 27, 2761-2773; (g)
D. P. Hari, P. Caramenti and J. Waser, Acc. Chem. Res., 2018,
51, 3212-3225.
1126; (b) L. Ackermann, Chem. Rev., 2011, 111, 1315-1345.
10 (a) E. A. Merritt and B. Olofsson, Eur. J. Org. Chem., 2011,
3690-3694; (b) M. S. Yusubov, R. Y. Yusubova, V. N. Nemykin
and V. V. Zhdankin, J. Org. Chem., 2013, 78, 3767-3773.
11 (a) P. Caramenti, S. Nicolai and J. Waser, Chem. Eur. J., 2017,
23, 14702-14706; (b) P. Caramenti and J. Waser, Helv. Chim.
Acta, 2017, 100, e1700221; (c) P. Caramenti, R. K. Nandi and
J. Waser, Chem. Eur. J., 2018, 24, 10049-10053; (d) E. Grenet,
A. Das, P. Caramenti and J. Waser, Beilstein J. Org. Chem.,
2018, 14, 1208-1214; (e) E. Grenet and J. Waser, Org. Lett.,
2018, 20, 1473-1476.
12 (a) K. Ishida, H. Togo and K. Moriyama, Chem. Asian J., 2016,
11, 3583-3588; (b) K. Morimoto, Y. Ohnishi, D. Koseki, A.
Nakamura, T. Dohi and Y. Kita, Org. Biomol. Chem., 2016, 14,
8947-8951.
13 V. V. Zhdankin, C. J. Kuehl, A. P. Krasutsky, J. T. Bolz and A. J.
Simonsen, J. Org. Chem., 1996, 61, 6547-6551.
14 (a) B. Lu, J. Wu and N. Yoshikai, J. Am. Chem. Soc., 2014, 136,
11598-11601; (b) J. L. Wu and N. Yoshikai, Angew. Chem. Int.
Ed., 2015, 54, 11107-11111; (c) J. Wu, X. Deng, H. Hirao and
N. Yoshikai, J. Am. Chem. Soc., 2016, 138, 9105-9108; (d) J.
Wu, K. Xu, H. Hirao and N. Yoshikai, Chem. Eur. J., 2017, 23,
1521-1525; (e) J. Wu, X. Deng and N. Yoshikai, Chem. Eur. J.,
2019, 25, 7839-7842.
15 (a) B. Wu, J. Wu and N. Yoshikai, Chem. Asian J., 2017, 12,
3123-3127. (b) W. Ding, J. Chai, C. Wang, J. Wu and N.
Yoshikai, J. Am. Chem. Soc., 2020, 142, 8619-8624.
16 CCDC 1981452 (3p) contains crystallographic data for this
paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
17 S. See and R. Ginzburg, Pharmacotherapy, 2012, 28, 207-213.
18 (a) T. Kitamura, T. Fukuoka and Y. Fujiwara, Synlett, 1996, 659-
660; (b) E. Stridfeldt, A. Seemann, M. J. Bouma, C. Dey, A.
Ertan and B. Olofsson, Chem. Eur. J., 2016, 22, 16066-16070;
(c) P. Caramenti, N. Declas, R. Tessier, M. D. Wodrich and J.
Waser, Chem. Sci., 2019, 10, 3223-3230.
19 (a) J. L. Do and T. Friscic, ACS Cent. Sci., 2017, 3, 13-19; (b) J.
G. Hernandez and C. Bolm, J. Org. Chem., 2017, 82, 4007-
4019; (c) J. Andersen and J. Mack, Green Chem., 2018, 20,
1435-1443; (d) J. L. Howard, Q. Cao and D. L. Browne, Chem.
Sci., 2018, 9, 3080-3094; (e) D. Tan and F. García, Chem. Soc.
Rev., 2019, 48, 2274-2292; (f) T. Friscic, C. Mottillo and H. M.
Titi, Angew. Chem. Int. Ed., 2020, 59, 1018-1029.
20 (a) G. F. Koser, R. H. Wettach and C. S. Smith, J. Org. Chem.,
1980, 45, 1543-1544; (b) M. Ochiai, K. Sumi, Y. Takaoka, M.
Kunishima, Y. Nagao, M. Shiro and E. Fujita, Tetrahedron,
1988, 44, 4095-4112; (c) P. J. Stang, V. V. Zhdankin, R.
Tykwinski and N. S. Zefirov, Tetrahedron Lett., 1991, 32, 7497-
7498; (d) P. J. Stang and V. V. Zhdankin, J. Am. Chem. Soc.,
1993, 115, 9808-9809.
21 (a) M. Ochiai, M. Toyonari, T. Nagaoka, D.-W. Chen and M.
Kida, Tetrahedron Lett., 1997, 38, 6709-6712; (b) M. A. Carroll,
V. W. Pike and D. A. Widdowson, Tetrahedron Lett., 2000, 41,
5393-5396; (c) M. Yoshida, K. Osafune and S. Hara, Synthesis,
2007, 1542-1546; (d) M. Bielawski, D. Aili and B. Olofsson, J.
Org. Chem., 2008, 73, 4602-4607; (e) L. Qin, B. Hu, K. D.
6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0SC02737E
Table of contents entry
A cyclic iodine(III) electrophile allows catalyst- and additive-free site-selective
functionalization of arenes and heteroarenes in solution or mechanochemical settings.