Iodoalkyne-Based Catalyst-Mediated Activation of Thioamides through Halogen Bonding

Article abstract of DOI:10.1002/asia.201601130

Halogen bonding catalysis has recently gained increasing attention as a powerful tool to activate organic molecules. However, the variety of the catalyst structure has been quite limited so far. Herein, we report the first example of the use of an iodoalkyne as a halogen bond donor catalyst. By using an iodoalkyne bearing a pentafluorophenyl group as a catalyst, thioamides were efficiently activated and reacted with 2-aminophenol to generate benzoxazoles in good yield. Mechanistic studies, including ¹³C NMR spectroscopic analysis and several control experiments, provided concrete evidence that this catalytic activation is based on halogen bonding. Thus, the results obtained in this study demonstrate that iodoalkynes can serve as a new scaffold for future development of halogen bonding catalysis.

Full text of DOI:10.1002/asia.201601130

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Accepted Article
Title: Iodoalkyne-Based Catalyst Mediated Activation of Thioamides through Halo-
gen Bonding
Authors: Akinobu Matsuzawa; Shiho Takeuchi; Kazuyuki Sugita
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COMMUNICATION
Iodoalkyne-Based Catalyst Mediated Activation of Thioamides
through Halogen Bonding
[a]
[a]
[a]
Akinobu Matsuzawa,* Shiho Takeuchi and Kazuyuki Sugita*
Abstract: Halogen bonding catalysis has recently gained increasing
attention as a powerful tool to activate organic molecules. However,
the variety of the catalyst structure has been quite limited so far.
Herein we report the first example of the use of an iodoalkyne as a
halogen bond donor catalyst. By using an iodoalkyne bearing a
pentafluorophenyl group as a catalyst, thioamides were efficiently
activated and reacted with 2-aminophenol to generate benzoxazoles
reported that neutral and cationic iodoarenes were able to
activate nitrogen-, oxygen- and halogen-containing
5
,6
electrophiles.
In most of these studies, cationic
iodoarenes were used as catalysts, as these compounds
activates organic molecules much more effectively than
7
neutral iodoarenes. The use of cationic iodoarenes is,
however, not without disadvantages, as both their solubility
13
in good yield. Mechanistic studies, including C-NMR spectroscopic
analysis and several control experiments, provided concrete
evidence that this catalytic activation is based on halogen bonding.
Thus, the results obtained in this study demonstrated that
iodoalkynes can serve as a new scaffold for future development of
halogen bonding catalysis.
8
and their stability are generally low. Indeed, highly
nucleophilic substrates have not yet been used in XB
donor-catalysed reactions. It is also worth noting that all the
aforementioned reactions have been conducted at room
temperature or below, which might be related to the
instability of the catalysts at high temperatures. Therefore, it
is of great importance to find effective XB donor catalysts
with good solubility and stability.
Halogen bonding (XB) is a noncovalent interaction between
a positive region of a halogen atom (
 hole) and a Lewis
Recent studies on XB in solution revealed that
1
base. One of the characteristics of XB is its high
directionality, i.e., the bond angle (R—X···B; X = halogen
atom, B = Lewis base) is always close to 180°. Since its
9
iodoalkynes are good XB donors. However, their use in
organocatalysis still remains to be reported. As their charge
neutrality should endow iodoalkynes with increased
solubility and stability relative to cationic iodoarenes, we
envisioned that iodoalkynes could represent ideal XB donor
catalysts.
2
discovery in 1863, XB has been exploited in a variety of
1
b,1g,1h
research areas, including crystal engineering,
1
a,1c,1g,1h
supramolecular
chemistry,
and
medicinal
1
e,1i
chemistry.
Conversely, the use of XB in organic
Thioamides were selected as the XB acceptors for our
investigation, because activation of the thiocarbonyl group
through XB has not been reported in the literature. Initially,
synthesis is still in its infancy. Given that hydrogen bonding,
which is similar to XB in strength, is widely used as a tool to
3
activate organic molecules, XB should hold potential to be
1
a
was treated with 2-aminophenol (
2
; 3 equiv) in CH
3
CN at
exploited in a similar fashion in organic synthesis. Bolm and
co-workers reported the first example of the use of XB in
10
8
0 °C (Table 1). In the presence of iodoalkyne 4a (10
mol%), benzoxazole 3a was obtained in 33% yield (entry 1).
A brief screening of the reaction solvents revealed that less
polar solvents, such as toluene, afforded better results
4
organocatalysis. They found that iodoperfluoroalkanes
(Figure 1) were able to activate quinoline derivatives and
promote hydrogen transfer reactions with a Hantzsch ester.
Following this breakthrough discovery, several groups
(entries 1-5). Enhanced reaction rates were observed when
the reaction was carried out at elevated temperatures, and
3
a
was obtained quantitatively within 12 h at 100 °C (entry
6
). When the amount of was lowered to 2 equiv, the yield
2
of 3a dropped significantly (entry 7). This problem could be
overcome by conducting the reaction at a concentration of
1
.0 M (entry 8). Attempts to further reduce the amount of
were unsuccessful; for example, 3a was obtained in only
7% yield when 1.2 equiv of was employed (entry 9). A
2
5
2
control experiment in the absence of 4a afforded 3a in 21%
yield, clearly demonstrating the accelerative effect of 4a on
this reaction (entry 10). Subsequently, we investigated
other XB donors for this reaction. Even though cationic
iodoarene 4b afforded 3a quantitatively, approximately 30%
Figure 1. Structures of representative XB donors.
1
of 4b decomposed during the reaction, as determined by H
NMR spectroscopic analysis of the crude mixture (entry 11).
[
a]
Dr. A. Matsuzawa, S. Takeuchi, Prof. Dr. K. Sugita
Department of Synthetic Medicinal Chemistry, Faculty of
Pharmaceutical Sciences
In contrast, decomposition of 4a was not observed under
1
1
the same reaction conditions (entry 8), demonstrating the
advantage of iodoalkynes over cationic iodoarenes.
Moreover, it still remains unclear whether 4b promoted the
reaction, as decomposition products derived from 4b might
be the actual active catalysts. Neutral iodoarene 4c was
also investigated as a catalyst (entry 12). In this case,
Hoshi University
2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
E-mail: a-matsuzawa@hoshi.ac.jp
k-sugita@hoshi.ac.jp
Supporting information for this article is given via a link at the end of
the document.
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however, the reaction was not accelerated efficiently, most
likely due to a lack of sufficient levels of XB with the
thioamide functionality.
Table 2. Substrate scope of the transformation of thioamides catalyzed by
iodoalkyne 4a.
a
Table 1. Initial screening of the reaction conditions.
a
Entry
x (equiv)
Solvent
T (°C)
Conc. (M)
Yield
b
(
%)
33
12
54
49
56
1
2
3
4
5
6
7
8
3.0
3.0
3.0
3.0
3.0
3.0
2.0
2.0
1.2
2.0
2.0
2.0
MeCN
DMF
80
80
0.2
0.2
0.2
0.2
0.2
0.2
0.2
1.0
1.0
1.0
1.0
1.0
AcOEt
PhCl
80
80
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
80
100
100
100
100
100
100
100
quant.
57
quant.
57
9
c
10
11
12
21
d
e
quant.
35
1
[
a] Yields were determined by H-NMR analysis, using DMF as an
internal standard. Yields in the absence of 4a are shown in
parentheses. [b] Isolated yield. [c] T = 130 °C in PhCl. [d] t = 24 h. [e]
T = 90 °C. [f] T = 120 °C in PhCl.
1
[
a] Concentration of 1a. [b] Determined by H-NMR analysis, using DMF
as an internal standard. [c] Reaction conducted in the absence of 4a. [d]
4
b
was used as a catalyst. [e] 4c was used as a catalyst.
spectrum of 4a in C
iodine-carrying carbon atom was observed at 22.6 ppm
Figure 2a). Upon addition of 4 equiv of thioamide 1a, the
6 6
D , the peak corresponding to the
(
peak shifted downfield by 3.0 ppm (Figure 2b). In sharp
contrast, the signal corresponding to the other acetylenic
carbon shifted only by 0.4 ppm after addition of 1a. These
5
b,5h,5i,12
results are consistent with the literature
and clearly
indicated that the iodine atom interacted with thioamide 1a
.
With the optimized reaction conditions in hand, we then
The involvement of XB was further supported by several
control experiments depicted in Scheme 1. First, the
catalytic activity of non-iodinated alkynes 4d and 4e was
investigated the substrate scope of the reaction using
iodoalkyne 4a as the catalyst. As background reactions
were observed for all substrates, the yields both in the
presence and in the absence of 4a are shown in Table 2.
While this catalytic system was able to efficiently promote
investigated. Thus, the reaction of 1a and
2 in the presence
the reaction for

-non-branched aliphatic thioamides
-branched aliphatic and aromatic
(entries 1 and 2), both

thioamides were less reactive and required higher
temperatures (entries 3-6). The catalytic transformation of
primary thioamide 1g was rapid, and complete conversion
was achieved within 12 h at 90 °C (entry 7). Tertiary
thioamide 1h was also susceptible to catalytic conversion
using 4a, although elevated temperatures were required to
complete the reaction (entry 8). Interestingly, N-
methylthioamide 1i could not be used as a substrate with
this catalytic system, as the reaction was not accelerated
efficiently (entry 9).
13
Figure 2. Comparison of the C-NMR spectra of (a) 4a and (b) 4a and 1a
in C
D .
6 6
In order to confirm that XB is operative in this system,
1
3
we carried out several mechanistic studies. In the C-NMR
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which S-methylation of thioamides is followed by the
reaction with 2-aminophenol, the iodoalkyne catalysis
presented herein allowed for direct access to benzoxazoles
from thioamides. The involvement of XB was supported by
1
3
several
mechanistic
studies,
including
C-NMR
spectroscopic analysis. Importantly, this is the first example
of an activation of the thioamide functionality through XB.
The advantages of the use of iodoalkynes over other types
of XB donor catalysts include (1) high solubility in organic
solvents, (2) high stability towards nucleophiles and
elevated temperatures, and (3) ease of preparation. Further
studies in order to expand the scope of this iodoalkyne-
based methodology are currently ongoing in our laboratory.
Scheme 1. Control experiments using non-iodinated alkynes and TfOH.
of either 4d or 4e afforded 3a in 9% or 25% yield,
respectively. These yields were comparable to that
obtained in the absence of the catalyst (Table 1, entry 10)
and thus corroborate the importance of the presence of the
iodine atom for the catalytic activity of 4a. Next, we Acknowledgements
investigated the possibility of hidden acid catalysis, which is
5
frequently discussed in the context of XB donor catalysis.
For this reaction, this possibility could be discarded,
because addition of 1 mol% of TfOH in place of catalyst 4a
This work was financially supported by Challenge Research
Grant of Hoshi University.
1
3
afforded 3a in only 39% yield.
Based on these observations, we would like to propose
a plausible catalytic cycle (Scheme 2). First, thioamide is
activated by 4a via XB to form This complex
to generate complex with
and aniline. Finally, the
regenerates catalyst
. We initially expected that addition of 4a to gave
complex , in which hydrogen bond-assisted halogen
Keywords: halogen bonds • organocatalysis • iodoalkynes •
thioamides • heterocycles
5
6
.
[1]
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2
In conclusion, we have demonstrated that iodoalkyne 4a
could act as an XB donor catalyst for the activation of
thioamides and promote the reaction with 2-aminophenol.
Compared to the conventional two-step transformation, in
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Scheme 2. Plausible catalytic cycle for the transformation of thioamides to
benzoxazoles.
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2
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
An iodoalkyne bearing a
Akinobu Matsuzawa,* Shiho Takeuchi,
Kazuyuki Sugita*
pentafluorophenyl group was found
to be effective in catalytic activation
of thioamides through halogen
bonding. Thus activated thioamides
reacted with 2-aminophenol to
produce benzoxazoles in good yield.
Mechanistic studies provided
concrete evidence that this catalytic
activation is based on halogen
bonding.
Page No. – Page No.
Iodoalkyne-Based Catalyst Mediated
Activation of Thioamides through
Halogen Bonding
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