Direct C-H substitution reaction of anilides using hypervalent iodine and their regioselective issues

Article abstract of DOI:10.1016/j.tetlet.2017.08.079

The direct C-H substitution reactions of anilides using hypervalent iodine proceeded to afford azide, chloro, bromo, and fluoro derivatives, and their regioselectivity were described. In the specific reaction conditions, the unique regioisomers were obtai

Full text of DOI:10.1016/j.tetlet.2017.08.079

Accepted Manuscript
Direct C-H substitution reaction of anilides using hypervalent iodine and their
regioselective issues
Kohki Yamamoto, Shinichiro Kamino, Daisuke Sawada
PII:
S0040-4039(17)31105-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.08.079
TETL 49269
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
19 July 2017
28 August 2017
31 August 2017
Please cite this article as: Yamamoto, K., Kamino, S., Sawada, D., Direct C-H substitution reaction of anilides using
hypervalent iodine and their regioselective issues, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.
2017.08.079
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Direct C-H substitution reaction of anilides using
hypervalent iodine and their regioselective issues
Kohki Yamamoto†, Shinichiro Kamino†,‡, Daisuke Sawada†,‡,*
†Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,
Okayama University, Okayama-shi, Okayama 700-8530, Japan
‡Next-generation Imaging Team, RIKEN-CLST, Kobe-shi, Hyogo 650-0047,
Japan
* Corresponding author. Tel.: +81-86-251-7931; Fax: +81-86-251-7931.
E-mail address: dsawada@okayama-u.ac.jp (D. Sawada).

Abstract: The direct C-H substitution reactions of anilides using hypervalent
iodine proceeded to afford azide, chloro, bromo, and fluoro derivatives, and their
regioselectivity were described. In the specific reaction conditions, the unique
regioisomers were obtained.
Keywords: Hypervalent iodine, Anilide substitution, Regioselective reaction

There are great number of nitrogen-containing compounds in our society, and
among them, aniline derivatives are an important family in various fields, such as
pharmaceuticals, functional molecules, and bioactive molecules. Therefore,
further modification would provide more useful compounds. In the last decades,
the late-stage functionalization through the direct cleavage of C-H bond has
arisen in the synthetic chemistry, and recently its significance has been
recognized.1 For the efficient late-stage functionalization, C-H activation using
hypervalent iodine is a powerful method, which is nonmetal, safe and easy to
handle under mild conditions.2 A lot of transformations of phenol derivatives with
hypervalent iodine have been reported,2,3 and the same strategies have also
been applied to aniline derivatives, affording acetoxy,4 alkoxy,5 fluoro,6 hydroxy,7
and tosyloxy8 anilides. Moreover, aryl-aryl coupling reactions of anilides with
other aromatic compounds affording biaryl or annulated compounds have been
reported.9 However, there was little inclusive discussion about the regioselectivity
in these reactions. In the course of our research projects, we investigated the
same kinds of reaction to prepare the other derivatives of anilides, and found
unique regioselectivity to be presented here.
According to the reaction conditions in the above precedent papers, at first, we
tried to introduce an azide group to tert-Butoxycarbonyl (Boc) protected aniline
using TMSN3, PhI(OAc)2 (PIDA) in hexafluoroisopropanol (HFIP).3b However, the
desired reaction did not proceed, and the starting material decomposed (Table 1,
entry 1). Because the Boc group was removed in some of the decomposed
products, the Ms-protected aniline derivative was reacted under the same
conditions,9d-e,10 however, the starting material was recovered (entry 2). Whereas
Boc-protected p-toluidine derivative showed almost the same results as entry 1
(entry 3), the introduction of the azide group was successful for the Ms-protected
p-toluidine, and the corresponding 2-N3 derivative was obtained in 35% yield with
37% of recovered starting material (entry 4). Other protecting groups were
examined for the amine moiety; the Ac-protected p-toluidine did not brought the
introduction of azide group (entry 5), and the N-methyl p-toluidine gave the
decomposed products accompanied with a trace amount of an azide derivative
and 19% of the starting material (entry 6). For other toluidine derivatives, i.e.,
Ms-protected o- and m-toluidine, the desired products were not

Table 1
Modification of anilides with hypervalent iodine and TMSX
yield (% )
(position)
entry
R
P
X
Rsm (%)
1
H
Boc
Ms
Boc
Ms
Ac
N3
N3
N3
N3
N3
N3
N3
N3
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
F
0
26
93
10
37
89
19
56
62
0
2
H
0
3
4-CH3
4-CH3
4-CH3
4-CH3
2-CH3
3-CH3
H
0
4
35 (2)
0
5
6
Me
Ms
Ms
Ms
Ms
Ms
Ms
Ts
trace (-)
0
7
8
0
9
35 (4)
64 (2) / 26 (3)
78 (4)
77 (4)
59 (2)
34 (2)
66 (2)
0
10
11
12
13
14
15
16
17 a
18b
19 c
20 d
21 e
22
23
24
25
26
4-CH3
2-CH3
3-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
0
0
0
0
Ns
68
28
0
Ac
Me
Ms
Ms
Ms
Ms
Ms
Ms
Ms
Ms
Ms
Ms
61 (2)
56 (2)
48 (2)
58 (2)
27 (4) f
86 (2)
0
8
0
5
0
0
Br
I
12
93
12
9
CN
CF3
OAc
0
0
0
0
aTFE was used as a solvent.
b CH2Cl2 was used as a solvent.
c MeCN was used as a solvent.
d Toluene was used as a solvent.
e KF was used instead of TMSF.
f The structure is shown in the right.

obtained, and a part of the starting material decomposed (entries 7 and 8), and
we do not have a reasonable explanation for these results. Following the
azidation reaction, we investigated the introduction of a chloro group. The
Ms-protected aniline was reacted with TMSCl under the same reaction conditions,
to give the 4-chloro derivative in moderate yield (entry 9).11 However, the
Ms-protected p-toluidine provided some interesting results, and this reaction
afforded two derivatives. We carefully confirmed their structure, which were
turned out to be 2- and 3-chloro p-toluidine derivatives in 64% and 26% yields,
respectively (entry 10).12 In contrast, for the Ms-protected o- and m-toluidine, the
4-chloro derivatives were obtained as a single product in good yields (entries 11
and 12). Additionally, Ts- and o-nitrobenzenesulfonyl (Ns)-, and Ac-protected
compounds afforded only 2-chloro derivatives (entries 13,13 14, and 1514), and
the decomposition of the starting material was observed with methyl compounds
(entry 15).
Concerning the regioselectivity in entry 10 in Table 1, we further investigated the
reaction conditions. No solvents other than HFIP afforded the regioisomers; only
the 2-substituted derivatives were obtained in 2,2,2-trifluoroethanol (TFE),
CH2Cl2, CH3CN, and toluene (entries 17 ~ 20).15 In terms of substituents, we next
intended to prepare other anilide derivatives. In entries 21 ~ 26, several reagents
were used, and a fluorine atom was introduced at the 4-position using KF as
reported previously,6 whereas a bromine atom was introduced at the 2-position
using TMSBr. Other reagents such as TMSI, TMSCN, TMSCF3, and TMSOAc16
did not provide the desired products, and the starting material was partially
decomposed in entries 23 ~ 26.
The two regioisomers obtained in entry 10, Table 1, especially the 3-chloro
derivative are noteworthy, and we speculate the reaction mechanism. As shown
in Scheme 1, we assume that this reaction proceeds through the nitrenium ion
1,4,9d and the sulfonyl protecting groups for the amine moiety contribute to the
formation of arenium ions 2 and 3, derived from the nitrenium ion 1.9d They also
probably prevent the overoxidation of the substrates. Under specific reaction
conditions, those were the reaction of Ms-protected p-toluidine with TMSCl in
HFIP, two products were acquired, which were 2- and 3-chloro derivatives. While
the arenium ion 2 was reacted with TMSCl to form the 2-chloro derivative, no

direct arenium ion was available to prepare the 3-chloro derivative. After the
reaction of arenium ion 3 with TMSCl, however, it was assumed that the migration
of the chloride and rearomatization would proceed to afford the 3-chloro
compound.4a The methyl substituent on the benzene ring would contribute to the
stabilization of arenium ion 3, and HFIP might play some role in maintaining the
arenium ions. The reason why Ts- and Ns-protected compounds provided only
the 2-Cl derivative was not clear, however, these protecting groups might
stabilize the arenium ion 2 more than Ms-protected compound (entries 13 and
14).9d Regarding the other substituents, the regioselectivity of the products could
depend on the nucleophilicity of the reagents, and we assumed that a hard
nucleophile (TMSF) would attack the tertiary carbocation (3), whereas a soft
nucleophile (TMSBr) would attack the sterically unhindered carbocation (2).
In summary, we presented the information about the direct C-H substitution
reactions of anilide derivatives with Cl, N3, F, and Br using a hypervalent iodine
reagent. Also, we found unique regioselectivity in these reactions, which we
believe would be helpful for late-stage functionalization of biologically active
compounds.
Acknowledgments
We are grateful for financial support from The Naito Foundation.
Supplementary data

References and notes
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Legends
Table 1. Modification of anilides with hypervalent iodine and TMSX.
Scheme 1. Proposed mechanism to produce the 2- and 3-chloro derivatives in
entry 10.

Graphical Abstract

Highlights
The direct C-H substitution reactions of anilides proceeded using
hypervalent iodine.
Azide-, chloro-, bromo-, and fluoro-substituted derivatives were
obtained.
The unique regioisomers were obtained in the specific reaction
conditions.