Enhancing the synthetic utility of 3-haloaryne intermediates by their efficient Generation from readily synthesizable ortho-iodoaryl triflate-type precursors

Article abstract of DOI:10.1246/cl.170136

Generation of 3-haloarynes from o-iodoaryl triflate-type precursors is reported. The method enables the generation of 3-fluorobenzyne with significantly high electrophilicity at -78 °C, allowing the formation of a three-component-coupled product between 3

Full text of DOI:10.1246/cl.170136

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Enhancing the Synthetic Utility of 3-Haloaryne Intermediates by their Efficient
Generation from Readily Synthesizable ortho-Iodoaryl Triflate-type Precursors
Suguru Yoshida,* Akira Nagai, Keisuke Uchida, and Takamitsu Hosoya*
Advance Publication on the web March 10, 2017
doi:10.1246/cl.170136
©
2017 The Chemical Society of Japan
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Publication manuscripts.

Enhancing the Synthetic Utility of 3-Haloaryne Intermediates by their Efficient
Generation from Readily Synthesizable ortho-Iodoaryl Triflate-type Precursors
Suguru Yoshida,* Akira Nagai, Keisuke Uchida, and Takamitsu Hosoya*
Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering,
Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062
(
E-mail: s-yoshida.cb@tmd.ac.jp, thosoya.cb@tmd.ac.jp)
Generation of 3-haloarynes from o-iodoaryl triflate-type
precursors is reported. The method enables the generation of
-fluorobenzyne with significantly high electrophilicity at
78 °C, allowing the formation of a three-component-coupled
product between 3-fluorobenzyne, tetrahydrofuran that is used
as a solvent, and a thiol. The ready availability of the
precursors and the orthogonality in the conditions for
generating arynes from o-silylaryl triflate-type precursors also
enhance the synthetic utility of 3-haloaryne intermediates,
rendering a diverse range of aromatic compounds easily
accessible.
A Garg, Houk, and coworkers (2014)
Hal
Hal
Hal
3
−
OTf
CsF
A
B
SiMe3 MeCN
0 °C
6
3-halobenzyne
(Hal = F, Cl, Br, I)
B Our previous works
I
Me3SiCH2MgCl
A
B
OTf
FG
FG
FG
R
N
R
R
Keywords: Aryne | Aryl halide | Grignard reagent
O
O
OTf
S
S
O
MeO2C
R'
R'
N3
Halogenated aromatic compounds are frequently found
in bioactive compounds, including natural products and
1
,2
C
This work
Hal
pharmaceuticals. They also serve as important synthetic
intermediates for a diverse range of aromatic compounds with
the aid of halo groups, which are broadly transformable via
numerous reliable reactions such as transition metal-catalyzed
Hal
Hal
Hal
I
OTf Me3SiCH2MgCl
THF
A
or
OTf
I
B
R
R
R
R
3
3-haloaryne
cross-coupling reactions. Despite the importance of aryl
(
Hal = F, Cl, Br, I)
halides, their syntheses still rely largely on the conventional
Figure 1. (A) Recent report on 3-halobenzynes generated from o-
silylphenyl triflates. (B) Our previous studies based on the generation of
various arynes from o-iodoaryl triflate-type precursors. (C) Synthetic
application of 3-haloarynes generated from halogenated o-iodoaryl
triflates.
methods,
such
as
Friedel–Crafts-type
electrophilic
halogenations and Sandmeyer-type halogenations via
arenediazonium salts, limiting the number of synthesizable
3
aryl halides. In particular, the synthesis of multisubstituted
haloarenes using these methods is difficult, and therefore, a
complementary approach is required.
Table 1. Optimization of the reaction conditions
BnN3 2
Recent advances in synthetic aryne chemistry have
greatly expanded the range of available aromatic
(5.0 equiv)
F
F
R–Mtl
I
(2.0 equiv)
N
N
4
–10
compounds.
These advances include the application of
N
THF
temp., 1 h
OTf
aryne species bearing a functional group such as silyl, boryl,
and triflyloxy group, which enables the further transformation
1
3
Bn
6
–8
Entry
R–Mtl
Temp.
Yield/%
of the products. The potential of 3-haloaryne species as
synthetic intermediates has also been demonstrated in the
pioneering works by Garg and coworkers using several o-
a
1
2
3
4
5
6
Me
Me
3
3
SiCH
SiCH
2
2
MgCl −78 °C
80
a
MgCl
rt
76
b
silylaryl triflate-type precursors bearing a halo group (Figure
n-BuLi
i-PrMgCl
−78 °C
−78 °C
−78 °C
24
8
b
1
A). However, the synthetic application of 3-haloarynes is
48
b
limited probably owing to the poor availability of o-silylaryl
triflate-type precursors.
i-PrMgCl·LiCl
36
b
PhMgBr
−78 °C
55
a
b
1
In our recent studies on synthetic aryne chemistry, we
successfully generated several synthetically useful aryne
species from o-iodoaryl triflate-type precursors by treatment
Isolated yields. Yields determined by H NMR analysis.
We initially screened for the reaction conditions that
efficiently generated 3-fluorobenzye from 3-fluoro-2-
iodophenyl triflate (1), which was easily prepared from m-
7
with a silylmethyl Grignard reagent (Figure 1B). We
assumed that this approach would also be suitable for
generating 3-haloarynes because precursors are easy to
1
1
fluoroanisole in three steps (Table 1). Using benzyl azide (2)
as an arynophile, we found that a silylmethyl Grignard
reagent efficiently activated 1 to generate 3-fluorobenzyne in
tetrahydrofuran (THF) at −78 °C or at room temperature,
affording the desired cycloadduct 3 in high yields (entries 1
7
,10
prepare and the moderate nucleophilicity of the activator
exhibits a broad functional group tolerance (Figure 1C).
Herein, we demonstrate the usefulness of 3-haloaryne species
for the syntheses of various aromatic compounds based on
their generation from o-iodoaryl triflate-type precursors.
1
2
and 2). Formation of a regioisomeric product was not
observed indicating that the reaction proceeded in
a

2
regioselective manner (vide infra). The use of more
nucleophilic activators, such as n-butyllithium and isopropyl-
and phenylmagnesium halides, decreased the yield of 3,
probably owing to the undesired reactions caused by the high
electrophilicity of 3-fluorobenzyne (entries 3–6).
(entries 7 and 8). These perfect regioselectivities observed in
the reactions of 3-fluorobenzyne can be attributed to the
highly distorted structure of 3-fluorobenzyne, which was
9
8
d
computationally predicted by Garg, Houk, and co-workers.
A
HS–n-C12H25 20
(
5.0 equiv)
F
Table 2. Reactions between 3-fluorobenzyne and various arynophiles
Me3SiCH2MgCl
(8.0 equiv)
F
F
Me3SiCH2MgCl
(2.0 equiv)
I
A
B
THF
rt, 1 h
n-C12H25
+
arynophile
S
F
THF
78 °C, 1 h
(5.0 equiv)
21a
63%
OTf
I
–
1
HS–n-C12H25 20
(5.0 equiv)
Me3SiCH2MgCl
(2.0 equiv)
Entry
1
Arynophile
Me
Product
Yield/%a
71
OTf
F
1
F
Me
S
n-C12H25
THF
O
4
O
5
–
78 °C, 1 h
O
2
2a
7
4%
Me
B
Me
F
F
F
OMe
OMe
O
+
O
2
6
8
7
9
48
O
I
II
OH
Figure 2. (A) Temperature-dependent reactions of 3-fluorobenzyne with
thiol 20 in THF. (B) Addition/elimination equilibrium between 3-
fluorobenzyne (I) and THF.
F
3
4
Ph
N
82
76
NPh
F
OMe
MeO
OTBS
Table 3. Reactions between arynes generated from o-iodoaryl triflates 23
and thiol 20 in THF
10
12
OTBS 11
HS–n-C12H25 20
(5.0 equiv)
R'–Mtl
(8.0 equiv)
F
F
Ph
N
R
R
R
Ph
5
6
13
65
58
I
S
N+
n-C12H25
t-Bu
+
–O
t-Bu
O
THF
Temp., 1 h
n-C12H25
OTf
S
O
2
3
21
22
N
N
N3 i-Pr
a
N
Entry
1
R
23
R’–Mtl
SiCH MgCl
n-BuLi
Temp. 21/% 22/%
14
15
i-Pr
i-Pr
H
23a
23a
23b
23b
Me
3
2
rt
92
81
57
29
0
0
0
0
i-Pr
b
2
H
−78 °C
rt
F
3
4
OMe
OMe
Me
Me
3
3
SiCH
SiCH
2
MgCl
MgCl
2
−78 °C
HN
7b
82
86
16
18
17
a
b
O
Isolated yields. 2.0 equivalents of n-BuLi was used.
N
O
F
The high electrophilicity of 3-fluorobenzyne changed the
course of the reaction with thiol 20 in THF, from which two
types of products could be obtained depending on the reaction
temperature (Figure 2A). Although performing the reaction at
Ph
8b
HN
Me
19
Ph
N
Me
a
b
room
temperature
using
8.0
equivalents
of
Isolated yields. Reactions were performed at room temperature.
(
trimethylsilyl)methylmagnesium chloride afforded sulfide
1
3
2
2
1a, which is a simple adduct, the reaction at −78 °C with
.0 equivalents of the Grignard reagent exclusively afforded
Under the optimized conditions, we examined the
reactions of 3-fluorobenzyne with various arynophiles (Table
the butoxy-inserted adduct 22a, indicating the involvement of
THF in this reaction. In contrast to the reaction of 3-
fluorobenzyne, reactions of unsubstituted benzyne or 3-
methoxybenzyne with thiol 20 in THF afforded the
corresponding sulfide 21b or 21c as a major product
independent of the reaction temperature (Table 3). These
results suggest that the mechanism that afforded 22a includes
an addition/elimination equilibrium between 3-fluorobenzyne
2
). The Diels–Alder reaction of 3-fluorobenzyne with 2,5-
dimethylfuran (4) proceeded uneventfully to afford
cycloadduct 5 in good yield (entry 1). In the reaction with 2-
methoxyfuran (6), regioselective cycloaddition and
subsequent ring-opening reaction took place, affording
naphthol 7 (entry 2). Pyrrole 8 also participated in the [2 + 4]
cycloaddition
with
3-fluorobenzyne
(entry
3).
Benzocyclobutene 11 was obtained in high yield as the sole
product of the [2 + 2] cycloaddition reaction between 3-
fluorobenzyne and ketene silyl acetal 10 (entry 4). Nitrone 12
and sterically-hindered phenyl azide 14 also reacted
regioselectively with 3-fluorobenzyne to afford the
cycloadducts 13 and 15, respectively (entries 5 and 6). The
addition reactions of amines 16 and 18 with 3-fluorobenzyne
also proceeded regioselectively at room temperature to afford
(
I) and THF, which provides the oxonium intermediate II
owing to the significantly high electrophilic nature of I,
followed by the nucleophilic addition of thiol 20 to II (Figure
1
4
2
B).
3
-fluoroanilines 17 and 19, respectively, in high yields

3
BnN3 2
Miyaura cross-coupling reaction with 3-thienylboronic acid
(30) efficiently afforded the 3,5-disubstituted aniline
derivative 31 (Scheme 2). As o-iodoaryl triflate-type 3-
haloaryne precursors were easily prepared from the
corresponding o-halophenols by ortho-iodination and
triflylation, transformations via 3-haloarynes in combination
with cross-coupling chemistry would render a wide variety of
aromatics accessible, including those difficult to synthesize by
conventional aromatic modification methods such as Friedel–
Crafts-type reactions.
(
5.0 equiv)
Me3SiCH2MgCl
Bn
F
F
F
(2.0 equiv)
N
N
N
N
+
N
THF, rt, 1 h
N
2
5
Bn
25'
HS–n-C12H25 20
55%
(25/25' = 76/24)
(5.0 equiv)
Me3SiCH2MgCl
(8.0 equiv)
F
I
F
S
n-C12H25
+
THF, rt, 1 h
n-C12H25
OTf
S
2
4
HS–n-C12H25 20
26
21a
(
5.0 equiv)
Me3SiCH2MgCl
2.0 equiv)
68%
(26/21a = 65/35)
(
complex mixture
THF, –78 °C, 1 h
S
Scheme 1. Reactions of 4-fluorobenzyne.
3
0
HN
B(OH)2
O 16
5.0 equiv)
Me3SiCH2MgCl
(
1.4 equiv)
To compare the reactivity between 3-fluorobenzyne and
-fluorobenzyne, we examined the reactions between 4-
fluorobenzyne and arynophiles (Scheme 1). Treatment of 4-
fluoro-2-iodophenyl triflate (24) with a silylmethyl Grignard
reagent in the presence of benzyl azide (2) at room
S
(
amphos)2PdCl2
(5.0 mol %)
K CO
(
4
Br
2
3
(2.0 equiv)
(3.0 equiv)
2
7b
THF
rt, 1 h
DME
Me
N
Me
N
reflux, 19 h
O
O
2
9
31
81%
temperature provided
a
regioisomeric mixture of
5
3%
benzotriazoles 25 and 25’ in moderate yield with moderate
selectivity. Although the reaction between 4-fluorobenzyne
and thiol 20 at room temperature afforded a regioisomeric
mixture of sulfides 26 and 21a, the reaction at –78 °C gave a
complex mixture of products and the three-component-
coupled adduct between 4-fluorobenzyne, THF, and thiol 20,
was not obtained. These results indicate that electrophilicity
of 4-fluorobenzyne is lower than that of 3-fluorobenzyne.
The conditions that allowed for the efficient generation
of 3-fluorobenzyne were also effective for the generation of 3-
chloro-, 3-bromo-, and 3-iodoarynes from o-iodoaryl triflate-
type precursors 27a–27c; treatment of a mixture of the
precursor 27 and benzyl azide (2) in THF with
+
isomer 29' 6%
Scheme 2. Synthesis of 3,5-disubstituted phenylmorpholine 31.
Furthermore, the combined use of 3-haloarynes with
another type of aryne precursor, which is orthogonal in the
conditions for aryne generation, further enhanced the
synthetic utility of 3-haloarynes generated from o-iodoaryl
triflate-type precursors. For example, reaction of 3-
fluorobenzyne, generated from 3-fluoro-2-iodophenyl triflate
1) by treatment with a silylmethyl Grignard reagent in THF
at −78 °C, with 5-azido-3-methoxy-2-(trimethylsilyl)phenyl
triflate (32) afforded benzotriazole 33 exclusively, leaving
the silyl and triflyoxy groups untouched (Scheme 3). The
subsequent generation of a second aryne from 33 triggered by
cesium fluoride in the presence of 2,5-dimethylfuran (4)
provided multisubstituted naphthalene derivative 34 in good
(
6d
(
trimethylsilyl)methylmagnesium
temperature provided the corresponding benzotriazoles 28a–
8c in good yields. In these cases, a small amount of
chloride
at
room
2
regioisomers 28a’–28c’ were also obtained. The proportion of
the minor proximal adduct 28’ increased as the
electronegativity of halogen at the 3-position decreased,
showing the same tendency as that reported by Garg, Houk,
7g
yield. This result demonstrated that aryne relay chemistry
using o-iodoaryl triflate-type 3-haloaryne precursors and
arynophiles bearing an o-silylaryl triflate moiety would render
a wide variety of haloarenes accessible.
8
d
and co-workers using o-silylaryl triflate-type precursors.
N3
Me
Table 4. Reactions of 3-haloarynes, generated from o-iodoaryl triflates,
OTf
SiMe3
32
5.0 equiv)
with azide 2
O
Me
BnN3 2
MeO
F
(
5.0 equiv)
F
4
Hal
Hal
Hal
Me3SiCH2MgCl
(2.0 equiv)
Bn
(
(2.0 equiv)
N
N
OTf
I
N
N
N
N
N
N
Me3SiCH2MgCl
2.0 equiv)
N
CsF
(2.5 equiv)
N
+
N
(
THF
rt, 1 h
N
Me
Me
Me
Me
1
2
7
Bn
THF
78 °C, 1 h
OTf
MeCN
rt, 3 h
distal
proximal
O
–
2
8
28'
MeO
MeO
SiMe3
a
b
Me
34
72%
Entry
Hal
27
Yield/%
28/28’
3
3
4
3%
1
2
3
Cl
Br
I
27a
27b
27c
62
72
94/6
Scheme 3. Synthesis of fluoroarene 34 based on aryne relay chemistry.
88/12
83/17
65
b
a
In summary, we have shown that 3-fluoro-, 3-chloro-, 3-
bromo-, and 3-iodoarynes were efficiently generated from the
corresponding o-iodoaryl triflate-type precursors using a
silylmethyl Grignard reagent as an activator. Several synthetic
aspects of 3-haloarynes that rendered diverse aromatic
compounds easily available have also been demonstrated.
Further studies on synthetic applications involving the 3-
haloaryne chemistry are now in progress.
Combined isolated yields of regioisomers. The ratios of regioisomers
were determined based on the isolated yield of each regioisomer.
The products obtained from reactions via 3-halorayne
intermediates can be further transformed to diverse aromatic
compounds through various carbon–halogen bond
functionalization reactions. For example, the regioselective
addition reaction of morpholine (16) to 3-bromo-5-
methylbenzyne, generated from 27b, followed by Suzuki–

4
This paper is dedicated to Professor Teruaki Mukaiyama
in celebration of his 90th birthday (Sotsuju).
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Tf O. This work was supported by Platform for Drug
2
Discovery, Informatics, and Structural Life Science of MEXT
and AMED, Japan; JSPS KAKENHI Grant Numbers
1
5H03118 (B; T.H.), 16H01133 (Middle Molecular Strategy;
T.H.), 26350971 (C; S.Y.); Suntory Foundation for Life
Sciences (S.Y.); Naito Foundation (S.Y.).
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