Synthesis of Functionalized Monoaryl-λ3-iodanes through Chemo- and Site-Selective ipso-Substitution Reactions

Article abstract of DOI:10.1002/chem.201805970

Monoaryl-λ³-iodanes are potentially attractive arylating agents. They are generally synthesized from aryl iodides via oxidation, which can cause functional group incompatibility, especially when polyfunctionalized derivatives are desired. This work describes the direct synthesis of monoaryl-λ³-iodanes through a chemoselective ipso-substitution reaction of arylgermanes and arylstannanes with iodine tris(trifluoroacetate). The generated iodanes were converted to iodonium ylides or used for further transformations in one pot. The presented method enables the preparation of polyfunctionalized monoaryl-λ³-iodanes.

Full text of DOI:10.1002/chem.201805970

A Journal of
Accepted Article
Title: Synthesis of Functionalized Monoaryl-λ³-iodanes via Chemo- and
Site-selective ipso-Substitution Reactions
Authors: Narumi Komami, Keitaro Matsuoka, Ayako Nakano, Masahiro
Kojima, Tatsuhiko Yoshino, and Shigeki Matsunaga
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To be cited as: Chem. Eur. J. 10.1002/chem.201805970
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Synthesis of Functionalized Monoaryl-3-iodanes via Chemo- and
Site-selective ipso-Substitution Reactions
Narumi Komami,† Keitaro Matsuoka,† Ayako Nakano, Masahiro Kojima, Tatsuhiko Yoshino,* and
Shigeki Matsunaga*
Abstract: Monoaryl-3-iodanes are potentially attractive arylating
agents. They are generally synthesized from aryl iodides via oxidation,
which can cause functional group incompatibility, especially when
polyfunctionalized derivatives are desired. Here we describe the direct
synthesis of monoaryl-3-iodanes via
a chemoselective ipso-
substitution reaction of arylgermanes and arylstannanes with iodine
tris(trifluoroacetate). The generated iodanes were converted to
iodonium ylides or used for further transformations in one pot. The
presented method enables the preparation of polyfunctionalized
monoaryl-3-iodanes.
Hypervalent iodine compounds are widely studied in organic
chemistry due to their unique reactivity and low toxicity.[1] Among
the various I(III/V/VII) compounds reported, monoaryl-λ3-iodane
(ArIL2) is one of the most popular classes of hypervalent iodines
in terms of the versatile applications in oxidation reactions.
Although these compounds are mainly used for oxidative
transformations in which the aryl group is not involved in the
products, some recent studies focused on their potential as
arylating agents.[2-7] An interesting feature of most arylation
reactions using a monoaryl-λ3-iodane is that the C-I bond of the
reagent is not cleaved, and a 2-iodoaryl group is introduced via
sigmatropic rearrangement (Scheme 1a, left side).[2,3]
Furthermore, monoaryl-λ3-iodanes are easily converted to
iodonium ylides, which also serve as arylating agents (Scheme
1a, right side).[5,6] The typical synthesis of monoaryl-3-iodanes
involves the introduction of I(I) to an aromatic ring and oxidation
to I(III) (Scheme 1b).[1,8-13] The oxidation step can cause functional
group incompatibility and limit the accessible structures. To
further expand the applications of monoaryl-3-iodanes as
arylating agents, we considered that the development of efficient
synthetic methods of monoaryl-3-iodanes containing multiple
functional groups is crucial.
Scheme 1. Synthesis of hypervalent iodine(III) reagents and their applications
as arylating agents.
1a.[16] Recently, Wirth and co-workers reported that I(OAc)3 1b or
ITT 1a reacts with several aromatic compounds to give
(dicarboxyiodo)arenes.[17] The scope of these reactions, however,
is limited to rather simple substrates, and the functional group
compatibility was not well elucidated. Moreover, the site
selectivity of these electrophilic substitution reactions depends on
the electronic nature of the substrates, and the introduction of the
-I(III)L2 moiety at the less electron-rich position is difficult in
principle.
Here we report the direct synthesis of monoaryl-3-iodanes by
chemo- and site-selective ipso-substitution reactions of stable
arylmetal species (Ar-M, M = Si, Ge, Sn) with ITT 1a.[19] Our
method provides direct access to monoaryl-3-iodanes containing
several oxidizable functional groups, and the generated iodanes
are converted to monoaryliodonium ylides or directly subjected to
further transformation reactions in one pot (Scheme 1d).
ipso-Substitution reactions of arylsilanes[20] and their Ge[21] and
Sn[22] analogues with halogen-based electrophiles are well-
established methods for selectively introducing a halogen atom at
the desired site. With this in mind, we began by seeking
appropriate arylmetal compounds for ipso-substitution using ITT
1a (Table 1).[23] To circumvent the decomposition of an I(III)
species and facilitate the analysis, the reaction mixtures were
treated with a basic aqueous solution of Meldrum's acid derivative
Direct introduction of the -I(III)L2 fragment to aromatic rings
using iodine tricarboxylates[14] has been described in a few reports
(Scheme 1c).[14-18] As early as 1974, Maletina and co-workers
reported electrophilic aromatic substitution using iodine
tris(trifluoroacetate) (ITT, 1a),[15] followed by a report by Kurosawa
and co-workers on the reactions between aryl ketones and ITT
[a]
N. Komami, K. Matsuoka, A. Nakano, Dr. M. Kojima, Dr. T. Yoshino,
Prof. Dr. S. Matsunaga
Faculty of Pharmaceutical Sciences
Hokkaido University
Kita-ku, Sapporo 060-0812, Japan
E-mail: tyoshino@pharm.hokudai.ac.jp;
smatsuna@pharm.hokudai.ac.jp
[†]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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Table 1. ipso-Substitution of Arylmetal Compounds with 1[a]
aromatic substitution reactions. We next examined other
arylmetal compounds under similar reaction conditions (entries 2–
4). Arylgermane 3a and arylstannane 4a exhibited higher
reactivity and selectivity than arylsilane 2a, providing 7a in good
yield (entries 2 and 3). In these cases, only 7a and a small amount
of 4-iodoanisole were detected, indicating improved ipso-
selectivity. The improvement with 3a and 4a would be due to the
stronger -effects of Ge and Sn compared with Si to stabilize a
cationic intermediate in the electrophilic aromatic ipso-substitution
reaction.[24] Arylboronate 5a was also examined as a substrate,
but only a complex mixture was observed (entry 4). On the other
hand, a reaction of arylgermane 3a with I(OAc)3 1b instead of ITT
1a afforded a similar yield (entry 5). Although similar results were
obtained in entries 2, 3, and 5, we decided to use arylgermanes
3[25] and ITT 1a (entry 2) as a standard combination for further
studies due to the toxicity of organotin compounds and higher
electrophilicity of ITT 1a, which would be benefitial for ipso-
substitution reactions using less reactive arylmetal substrates.
We applied the optimized protocol to various substrates
bearing functional groups, and the results are summarized in
Scheme 2. In all cases, the product was converted to the
corresponding iodonium ylide 7 for isolation and characterization.
Iodonium ylides of this type were not only stable and easy to
isolate, but also served as efficient precursors for 18F positron
emission tomography probes.[6] p-Substituted arylgermanes
underwent a selective ipso-substitution reaction to provide 7a–7f
regardless of the electronic properties and orientation toward
electrophilic aromatic substitution of the substituent (3a–3f).
When we use 3b, with an amide substituent, the reaction in
propionitrile instead of CH2Cl2 afforded cleaner conversion and
Reagent
(equiv)
Yield[b]
(%)
Entry
Arylmetal compounds (M)
1
2
2a (SiMe3)
3a (GeMe3)
1a (0.6 equiv)
1a (0.6 equiv)
42
82[c]
3
4
5
4a (SnBu3)
5a (BPin)
1a (0.6 equiv)
77
1a (0.6 equiv) complex mixture
3a (GeMe3)
1b (1.2 equiv)
77
[a] Reaction conditions: 1) 2a–5a (0.30 mmol) and reagent
1
[1a =
[I(OCOCF3)3]2(NO)(OCOCF3); 1b = I(OAc)3] in CH2Cl2 (3 mL) at –20 °C for 2 h;
2) aq. Na2CO3 (10% w/v, 0.9 mL) at rt for 1 h. [b] Determined by 1H NMR
analysis of crude mixtures using 1,1,2,2-tetrachloroethane as an internal
standard. [c] Isolated yield.
6 to convert the intermediate to a relatively stable iodonium ylide,
7a.[6] Arylsilane 2a reacted with ITT 1a in CH2Cl2 at –20 °C, and
the desired product 7a was obtained in 42% yield after ylide
formation (entry 1). Several byproducts, including trisubstituted
benzenes, were observed in the crude mixture, probably due to
the incomplete ipso-selectivity and competing electrophilic
Scheme 2. Substrate scope of iodonium ylide synthesis via ipso-substitution of arylgermanes 3 and arylstannanes 4. Reaction conditions: 1) 3 or 4 (0.30 mmol)
and ITT 1a (0.18 mmol) in CH2Cl2 (3 mL) at –20 °C for 2 h; 2) aq. Na2CO3 (10% w/v, 0.9 mL), rt, 1 h unless otherwise noted. [a] The reaction was run in propionitrile
(3 mL) at –60 °C for 18 h. [b] –60 °C.
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Scheme 3. One pot transformation of ArI(OCOCF3)2. See Supporting Information for detailed reaction conditions.
better yield (7b). Although arylgermanes with a m-methoxy or
an o-methoxy substituent did not selectively afford the desired
ipso-substitution product, the corresponding arylstannanes (4g,
4h) were appropriate substrates, affording 7g and 7h in high
yield. The results of 3e, 3f, 3i, 4g, and 4h clearly demonstrate
that ipso-selectivity of the arylmetals can override the intrinsic
site-selectivity of the standard electrophilic aromatic
substitution, and that our protocol effectively provides
substitution patterns that are difficult to achieve by direct
reactions of simple arenes and 1.[15-17] We successfully
obtained an iodonium ylide containing an aliphatic amine
moiety (7j) and an iodonium ylide containing an olefin
conjugated with aromatic rings (7k), demonstrating the
functional group compatibility of the developed conditions.
Arylgermanes containing an oxygen- and nitrogen-heterocycle
were also tolerated to afford iodonium ylides 7l–7o in good
yield. Furthermore, an arylgermane with a fibrate-like structure
(3p) and arylgermanes derived from tyrosine (3q) and estrone
(3r) provided iodonium ylides 7p–7r in 69%–85% yields,
validating the applicability of our protocol for the synthesis of
functionalized, biologically active molecules.
generated in situ from 3e and ITT 1a, providing 13 in 62% yield
(Scheme 3c).
In summary, chemoselective ipso-substitution reactions of
arylgermanes 3 or arylstannanes 4 using ITT 1a provided
monoaryl-3-iodanes, which were converted to iodonium ylides
7 or underwent further transformations in one pot. The
presented
method
enables
the
preparation
of
polyfunctionalized monoaryl-3-iodanes. The application to
late-stage diversification of functionalized molecules and
biological studies, including the synthesis of 18F PET probes,
are ongoing in our laboratory.
Acknowledgements
This work was supported in part by JSPS KAKENHI Grant
Number JP15H05802 in Precisely Designed Catalysts with
Customized Scaffolding.
Keywords: hypervalent iodine • iodonium ylide • ipso-
substitution • arylation • germanium
We next focused on one pot reactions of the generated
monoaryl-3-iodane(III) intermediates[26] to demonstrate the
synthetic utility of the developed method (Scheme 3).
Cyanomethylation reactions, reported by Huang, Wang, Peng,
and co-workers,[3h] proceeded smoothly by the direct addition
of -stannylnitrile 8 to the reaction mixture of arylgermanes 3
and ITT 1a to afford o-cyanomethyl iodoarenes 9 in good to
excellent yields (Scheme 3a). A separable isomeric mixture
was obtained from estrone derivative 3r. Next, biaryl synthesis
reported by Yorimitsu and co-workers[3g] was examined, and
11 was obtained in 53% yield from 3i, ITT 1a, and 2-naphthol
10 in one pot (Scheme 3b). An -arylation protocol developed
by Vallribera, Shafir, and co-workers[3c,f] was successfully
applied to cyanoketone 12 and an iodane(III) intermediate
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Entry for the Table of Contents
COMMUNICATION
Polyfunctionalized
iodanes were
chemoselective ipso-substitution of
monoaryl-3-
accessible by
Narumi Komami, Keitaro Matsuoka,
Ayako Nakano, Masahiro Kojima,
Tatsuhiko Yoshino,* and Shigeki
Matsunaga*
arylgermanes and arylstannanes with
iodine
tris(trifluoroacetate).
The
Page No. – Page No.
generated iodanes were converted to
iodonium ylides or directly used for
further transformation in one-pot. The
presented protocol is useful for the
Synthesis of Functionalized
Monoaryl-3-iodanes via Chemo- and
Site-selective ipso-Substitution
Reactions
synthesis
containing
groups.
of
I(III)
compounds
functional
oxidizable
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