Catalytic Alkynylation of Polyfluoroarenes by Amide Base Generated In Situ

Article abstract of DOI:10.1002/chem.201901501

We herein demonstrate that the amide base generated in situ from CsF and N(TMS)₃ catalyzes the deprotonative coupling reactions of terminal alkynes with polyfluoroarenes, wherein mono- and dialkynylations occur efficiently for penta- and hexafluorobenzenes, respectively. Tetraalkynylated products could also be synthesized from dialkynylated compounds.

Full text of DOI:10.1002/chem.201901501

A Journal of
Accepted Article
Title: Catalytic alkynylation of polyfluoroarenes by amide base
generated in situ
Authors: Masanori Shigeno, Takuya Okawa, Masaya Imamatsu,
Kanako Nozawa-Kumada, and Yoshinori Kondo
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To be cited as: Chem. Eur. J. 10.1002/chem.201901501
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Catalytic alkynylation of polyfluoroarenes by amide base
generated in situ
Masanori Shigeno,*[a] Takuya Okawa,[a] Masaya Imamatsu,[a] Kanako Nozawa-Kumada,[a] and
Yoshinori Kondo*[a]
Abstract: We herein demonstrate that the amide base generated in
situ from CsF and N(TMS)3 catalyzes the deprotonative coupling
reactions of terminal alkynes with polyfluoroarenes, wherein mono-
and
dialkynylations
occur
efficiently
for
penta-
and
hexafluorobenzenes, respectively. Tetraalkynylated products could
also be synthesized from dialkynylated compounds.
The development of efficient methodologies for synthesizing
fluorine-atom-containing aromatic compounds has garnered
much attention as such scaffolds are found in a wide range of
functional materials, such as biologically active compounds,
electronic materials, and liquid crystals.1 The regioselective
substitution of a fluorine atom in polyfluoroarenes by nucleophiles
is a simple and direct protocol, given that various polyfluoroarenes
are readily available nowadays. Transition metal catalysis drives
the transformations to form C-C, C-H, C-O, C-S, C-B, and C-Si
bonds.2 Given the stringent restriction of residual transition metals
in pharmaceuticals and electronic materials, establishing
transition metal-free synthetic protocols is an important issue.
Nucleophilic aromatic substitutions (SNAr) fulfill these
requirements, wherein pronucleophiles with a stoichiometric
amount of Brønsted base or pre-prepared nucleophilic reagents
can couple with polyfluoroarenes to form C-C, C-H, C-O, C-S, C-
N, and C-B bonds.3,4 Alkynylated fluoroarenes, also obtained via
SNAr reactions, are potentially applicable in electronic materials
and can be used for further transformations based on their alkynyl
moieties.5-8 For example, Zhao, Zhang, and coworkers reported
the alkynylation of polyfluoroarenes with terminal alkynes using a
stoichiometric amount of n-BuLi (Figure 1, i).5 Cao and coworkers
also noted that the reaction using terminal alkynes is mediated by
Na and n-BuMgCl via a SRN1 mechanism involving one-electron
transfer, in which poorly reactive mono- or difluoroarenes are also
transformed by further adding NaOMe and Ca(OH)2 (Figure 1, ii).6
Alternatively, Watson and coworkers showed that alkynylated
products of hexafluoroarene are formed by using aryl alkynyl
silanes as nucleophiles in the presence of a catalytic amount of
tetrabutyl ammonium fluoride (TBAF) (Figure 1, iii).7 They also
applied the protocol to the preparation of poly(phenylene
ethynylene)s bearing alternating aryl-polyfluoroaryl units. Sanji
and coworkers reported that monosubstituted polyfluoroarenes
undergo substitution reactions with alkynyl silanes in the
presence of CsF and 18-crown-6 (Figure 1, iv).8 In the former
Figure 1. Alkynylation of polyfluoroarenes.
Brønsted base system, the highly reactive reagents n-BuLi, Na,
and n-BuMgCl were required, where these reagents potentially
limit the functional group tolerance. The latter Lewis base system
requires the use of alkynyl silanes as nucleophiles instead of
terminal alkynes, although terminal alkynes are generally more
available than alkynyl silanes. Thus, the establishment of practical
and efficient alkynylations using terminal alkynes is highly desired.
We previously found that the amide base generated in situ
from a catalytic amount of fluoride salt with a stoichiometric
amount
of
aminosilane
promotes
the deprotonative
functionalization of C-H bonds in pronucleophiles, such as
heteroarenes, acetates, and methyl(hetero)arenes, with carbonyl
compounds.9 In this study, the system is demonstrated to be
applicable to the coupling reaction of terminal alkynes with
polyfluoroarenes. The amide base generated from CsF and
[a]
Dr. M. Shigeno, T. Okawa, M. Imamatsu, Dr. K. Nozawa-Kumada,
Prof. Dr. Y. Kondo
Department of Biophysical Chemistry
Graduate School of Pharmaceutical Science, Tohoku University
6-3 Aoba, Sendai 980-8578 (Japan)
E-mail: mshigeno@m.tohoku.ac.jp (MS), ykondo@m.tohoku.ac.jp
(YK)
N(TMS)3
efficiently
catalyzes
the
dialkynylations
of
hexafluorobenzene 1a, as well as monoalkynylations of
pentafluorobenzenes (Figure 1, c).10 The current system also
Supporting information for this article is given via a link at the end of
the document.
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enables the construction of tetraalkynylated products from the
dialkynylated compounds. The details are presented herein.
Initially, the effect of fluoride salts was examined in the
reaction of hexafluorobenzene 1a and phenylacetylene 2a (Table
1). Among the alkali-metal fluoride salts, CsF was the most
effective for maximizing the reaction yield of the dialkynylated
product 3aa (isolated yield: 88%; entries 1−5).11-13
Tetramethylammonium fluoride (TMAF) and tetrabutylammonium
difluorotriphenylsilicate (TBAT) also gave 3aa in 55% and 63%
yields, respectively (entries 6 and 7). Solvents other than N,N-
dimethylformamide (DMF) were also employed, where the
reaction proceeded in dimethyl sulfoxide (DMSO) and N,N-
dimethylacetamide (DMA) with yields of 78% and 84%,
respectively. However, THF and toluene did not promote the
reaction (entries 8−11). When the reaction was performed with a
reduced amount of CsF (5 mol%) or 2a (3.0 equiv.), the product
yield decreased (entries 12 and 13). The effects of the amount of
N(TMS)3 were then examined (entries 14 and 15). When 4 equiv.
of N(TMS)3 was employed, 3aa was formed in 59% yield, along
with a significant amount of the tetrasubstituted product 4aa (30%
yield), the synthesis of which is discussed later.
The scope of alkynes was investigated under the optimized
conditions (Figure 2). Tolylacetylenes 2b−2d provided the
dialkynylated products 3ab−3ad, irrespective of the position of the
methyl substituent, with yields of 89%, 91%, and 75%,
respectively. Similarly, the reactions of methoxyphenylacetylenes
2e−2g proceeded smoothly to furnish the corresponding products
in good to high yields. 4-Biphenylacetylene 2h was converted to
the product in 85% yield.
Table 1. Optimization of the dialkynylation reaction of 1a with 2a
Entry
1
Fluoride salt
LiF
Solvent
DMF
3aa (%)a
4aa (%)a
0
0
0
0
2
NaF
DMF
Figure 2. Scope of alkynes 2 in the dialkynylation of 1a.a aIsolated yields. bCsF
(20 mol %) was used. cReaction was conducted for 24 h.
3
KF
DMF
0
0
4
RbF
DMF
61
91 (88)b
55
63
78
84
0
0
The present system was also applied to the alkynylation of
5
CsF
DMF
0
monosubstituted
pentafluorobenzenes
5
(Figure
3).
6
TMAF
TBAT
CsF
DMF
13
1
Pentafluorobenzene 5a bearing a phenyl group coupled with 2a
to form the product 6aa in 82% yield.14 The highly electron
deficient perfluorotoluene 5b also smoothly underwent the
substitution reaction at room temperature to produce 6ba in 79%
yield.15 Phenylethynyl-substituted pentafluorobenzene 5c was
used for the alkynylation reaction with various acetylenes, which
resulted in the formation of asymmetric products. Tolylacetylenes
2b and 2c reacted with 5c to afford 6cb and 6cc in 77% and 66%
yields, respectively. The reactions of arylacetylenes 2i and 2j
bearing bromo and iodo atoms, respectively, also provided the
corresponding products. Ester and cyano moieties were tolerated
in the reaction to give the products in yields of 89% and 72%,
respectively. (2-Pyridyl)acetylene 2m also underwent alkynylation
with 5c to form 6cm in 60% yield.
7
DMF
8
DMSO
DMA
THF
0
9
CsF
0
10
11
12
13c
14d
15e
CsF
0
CsF
Toluene
DMF
0
0
CsF (5 mol %)
CsF
56
82
58
59
0
DMF
1
CsF
DMF
0
The tetrasubstituted products could also be synthesized from
the disubstituted compound 3aa (Figure 4). When 3aa was
subjected to the reaction with 2a, alkynylation occurred to produce
4aa in 71% yield.16,17 Using this protocol, tetrasubstituted arenes
having two different alkynyl moieties could also be obtained. The
reactions of alkynes 2b, 2c, and 2g furnished the corresponding
CsF
DMF
30
aYields were determined by 19F-NMR spectroscopy using 4-fluorotoluene as
an internal standard. bIsolated yield. c2a (3 equiv.) was used. dN(TMS)3 (1.5
equiv.) was used. eN(TMS)3 (4 equiv.) was used.
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Figure 5. Plausible mechanism.
5c, in which CsF is regenerated. Further substitution occurs on
5c, resulting in formation of the dialkynylated product 3aa.
In summary, the catalytic amide base system generated in situ
facilitated the alkynylation of polyfluorobenzenes. Dialkynylated
products were obtained from 1a, and monoalkynylated products
were formed from monosubstituted pentafluorobenzenes 5. The
system was also used for the synthesis of tetraalkynylated
products. Application of the system to other types of SNAr
reactions is our next research project.
Figure 3. Alkynylation of pentafluorobenzenes 5.a aIsolated yields. bReaction
was conducted with N(TMS)3 (2 equiv.) at room temperature for 2 h. cReaction
was conducted with N(TMS)3 (2 equiv.) and alkyne 2 (1.1 equiv.) for 24 h.
Acknowledgements
This work was financially supported by JSPS KAKENHI Grant
Number 16H00997 in Precisely Designed Catalysts with
Customized Scaffolding (YK), JSPS KAKENHI Grant Number
19H03346 (YK), JSPS KAKENHI Grant Number 17K15419 (MS),
Grand for Basic Science Research Projects from The Sumitomo
Foundation (MS), Yamaguchi Educational and Scholarship
Foundation (MS), and also the Platform Project for Supporting
Drug Discovery and Life Science Research funded by Japan
Agency for Medical Research and Development (AMED) (MS,
KNK, and YK).
Figure 4. Construction of tetraalkynylated arenes 4aa and 7.a aIsolated yields.
Keywords: Alkynes • Polyfluoroarenes • Aromatic substitution •
Amide-base • C-C coupling
compounds 7b, 7c, and 7g in 65%, 53%, and 53% yields,
respectively.
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Entry for the Table of Contents
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Masanori Shigeno,* Takuya Okawa,
Masaya Imamatsu, Kanako Nozawa-
Kumada, and Yoshinori Kondo*
Page No. – Page No.
Catalytic alkynylation of
polyfluoroarenes by amide base
generated in situ
Amide base generated in situ from CsF and N(TMS)3 catalyzes the deprotonative
coupling reactions of terminal alkynes with polyfluoroarenes, wherein mono- and
dialkynylations occur efficiently for penta- and hexafluorobenzenes, respectively.
Tetraalkynylated products can also be synthesized from dialkynylated compounds.
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