Generation of arynes triggered by sulfoxidemetal exchange reaction of ortho-sulfinylaryl triflates

Article abstract of DOI:10.1246/cl.130899

Arynes were efficiently generated from readily available ortho-sulfinylaryl triflates by the treatment with phenylmagnesium bromide in tetrahydrofuran at 78 C. Aryne generation was initiated by a rapid sulfoxidemetal exchange reaction, followed by the immediate elimination of the ortho-OTf group. Various arynophiles efficiently reacted with arynes generated by this method within 10min, providing the corresponding adducts in high yields.

Full text of DOI:10.1246/cl.130899

CL-130899
Received: September 27, 2013 | Accepted: October 10, 2013 | Web Released: October 19, 2013
Generation of Arynes Triggered by Sulfoxide-Metal Exchange Reaction
of ortho-Sulfinylaryl Triflates
Suguru Yoshida, Keisuke Uchida, and Takamitsu Hosoya*
Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering,
Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062
(E-mail: thosoya.cb@tmd.ac.jp)
t-BuLi or
Arynes were efficiently generated from readily available
ortho-sulfinylaryl triflates by the treatment with phenylmagne-
sium bromide in tetrahydrofuran at ¹78 °C. Aryne generation
was initiated by a rapid sulfoxide-metal exchange reaction,
followed by the immediate elimination of the ortho-OTf group.
Various arynophiles efficiently reacted with arynes generated by
this method within 10 min, providing the corresponding adducts
in high yields.
F–
Bpin
OTf
O
SiMe3
OTf
s-BuLi
Ref. 5f
Ref. 6
A
C
D
This
Work
I
S
R
n-BuLi
Ref. 5g
OTf
OTf
B
Figure 1. Generation of aryne from aryl triflates with an ortho-
activatable anion equivalent group.
Arynes, generally depicted by a highly strained carbon-
carbon triple bond on the arene structure, have always captivated
the organic chemists because of their distinctive reactivity,
enabling the facile construction of complex aromatic frame-
works that are difficult to achieve by conventional methods.1-3
Indeed, the utility of aryne chemistry has been clearly
demonstrated in a number of total syntheses of complex natural
products.4
O
S
PhMgBr
Ph
O
+
73%
O
THF
60 °C
Br
sulfoxide-metal
exchange
Ph– +MgCl
O
MgCl
–BrMgCl
Br
In line with the growing importance of arynes, various
efficient methods for generating them, as well as their
precursors, have been developed,5 as exemplified by the
fluoride-mediated activation of ortho-silylaryl triflates A5f and
the halogen-lithium exchange reaction of ortho-haloaryl triflates
B5g (Figure 1). Our group recently reported a new route using
readily available ortho-borylaryl triflates C, from which arynes
could be efficiently generated near room temperature via boron-
ate complexes, formed in situ by the treatment of boronic esters
with tert- or sec-butyllithium.6 This aryne generation method
was mutually orthogonal to the popular method using ortho-
silylaryl triflates A, expanding the utility of aryne chemistry.
Herein, we disclose another efficient way of generating aryne,
being achieved by the rapid Grignard exchange reaction of
ortho-sulfinylaryl triflates D.
A pioneering study of aryne generation based on the
sulfoxide-metal exchange reaction was reported by Furukawa
and co-workers:7 the treatment of ortho-sulfinylphenyl bromide
with phenylmagnesium bromide in the presence of furan
afforded the corresponding cycloadduct in 73% yield
(Scheme 1). Only a few examples, however, were shown in
this study, and to the best of our knowledge, further synthetic
applications of this method have not been reported. This is
possibly because the long-time heating conditions (60 °C, 6 h)
required to generate aryne, due to the poor leaving-group ability
of the bromide, are undesirable for substrates bearing sensitive
functional groups, and also because ortho-sulfinylaryl halides
are not so readily available.
Scheme 1. Furukawa’s method of aryne generation.7
Table 1. Optimization of the reaction conditions
Ph
R2–Mtl
(x equiv)
O
S
Ph
R1
O
O
+
THF
Temp., 10 min
OTf
Ph
Ph
1
(1.2 equiv)
2
3a
Entry R1
1
R2-Mtl
x
Temp./°C Yield/%a
1
2
3
4
5
6
p-Tol 1a n-BuLi
p-Tol 1a n-BuMgCl
p-Tol 1a i-PrMgCl
1.8
1.8
1.8
¹78
¹78
¹78
¹78
¹78
¹78
0
57
74
76
p-Tol 1a i-PrMgCl¢LiCl 1.8
69
p-Tol 1a PhMgBr
p-Tol 1a PhMgBr
1.8
1.5
2.0
2.0
2.0
quant
83c
98
53
89
7b p-Tol 1a PhMgBr
8b Me
9b Me
1b PhMgBr
1b PhMgBr
¹78
0
aIsolated yields. bReaction was performed for 1 h. c10% of 1a was
recovered (1H NMR yield).
precursors such as A-C in Figure 1, could enhance the
efficiency of aryne generation and could also make the aryne
precursors more available. After an extensive screening of the
reaction conditions using 1,3-diphenylisobenzofuran (2) as an
arynophile, we found that the sulfoxide-metal exchange reaction
of ortho-sulfinylphenyl triflate with organolithium or Grignard
reagents rapidly generated benzyne even at low temperatures
(Table 1). For instance, the treatment of the mixture of 2-(p-
tolylsulfinyl)phenyl triflate (1a, 1.2 equiv) and 2 in THF with n-
In order to expand the synthetic utility of this type of aryne
generation method, we presumed that changing the leaving
group from halogen to the (trifluoromethanesulfonyl)oxy group,
which is frequently used as a leaving group in useful benzyne
116 | Chem. Lett. 2014, 43, 116–118 | doi:10.1246/cl.130899
© 2014 The Chemical Society of Japan

A: via the bromo–lithium exchange reaction
Table 2. Scope of arynophiles
Br
S-p-Tol
S-p-Tol
O
S
1) n-BuLi, Et2O
Tf2O
mCPBA
PhMgBr
1a
53%
(2 steps)
(1.5 equiv)
i-Pr2NEt
CH2Cl2
CH2Cl2
2) p-TolSSO2-p-Tol
p-Tol
OH
OH
OTf
Arynophile
+
14a
15a
77%
16a
THF
–78 °C, 10 min
(5.0 equiv)
OTf
Product
1a
B: via the ortho-lithiation of phenols
Entry
1
Arynophile
Product
Yield/%a
79
1) TMEDA, TBSOTf
Et2O
2) n-BuLi
MeO
MeO
MeO
DBU
Et2NH
OH
S-p-Tol
OCONH-i-Pr
S-p-Tol
i-PrNCO
O
CH2Cl2
3) p-TolSSO2-p-Tol
MeCN
4
6
8
5
7
9
OH
OH
14d
17d
76% (2 steps)
15d
63%
OMe
OMe
PhN
MeO
O
S
Tf2O
Ph
N
2
3
83
80
i-Pr2NEt
mCPBA
CH2Cl2
O
S
O
S
p-Tol
CH2Cl2
Ph
Ph
Ph
p-Tol
p-Tol
OTf
1d
92% (2 steps)
Ph
Ph
N
OTf
OTf
O
1c
1e
Ph
Ph
Ph
N
Figure 2. Two synthetic methods of ortho-sulfinylaryl triflates.
N
N3CH2Ph
4
5
71
89
10
12
11
13
N
Ph
O
Table 3. Reactions of arynes generated from ortho-sulfinylaryl triflates
1c-1e with diene 2
t-Bu
O
N
t-Bu
N
Ph
O
S
Ph
Ph
Ph
PhMgBr
(1.8 equiv)
aIsolated yields.
p-Tol
+
O
O
THF
OTf
R
R
–78 °C, 10 min
Ph
Ph
3
2
1
butyllithium (1.8 equiv) at ¹78 °C for 10 min provided the
desired cycloadduct 3a, albeit in moderate yield (Entry 1). The
yield of the product was improved by the use of Grignard
reagents instead of n-butyllithium (Entries 2-5). Among the
Grignard reagents examined, phenylmagnesium bromide afford-
ed the best result furnishing 3a quantitatively (Entry 5). This
result clearly showed the superior leaving-group ability of the
triflyloxy group compared with bromide or chloride. The use of
decreased amount of the Grignard reagent (from 1.8 to 1.5 equiv)
lowered the yield of 3a (Entry 6). The side reaction of
phenylmagnesium bromide with phenyl p-tolyl sulfoxide, which
is simultaneously produced as the result of sulfoxide-magne-
sium exchange reaction of 1a, is a plausible reason why the
excess amount of Grignard reagent is required to obtain the
product in high yield. Furthermore, the rate of benzyne
generation from 2-(methylsulfinyl)phenyl triflate (1b) was
relatively slower than that from 1a, which can be attributed to
the difference in the rates of the sulfoxide-magnesium exchange
reactions between these sulfoxides (Entries 8 and 9 vs. 5 and 7).
The optimized reaction conditions were applicable to
various arynophiles (Table 2). Not only dienes such as furan 4
and pyrrole 6 but also substrates with base- and/or nucleophile-
sensitive functional groups, such as cyclopentadienone 8, azide
10, and nitrone 12, efficiently reacted with the benzyne
generated from 1a, affording the corresponding cycloadducts
in good yields.
Various ortho-sulfinylaryl triflates could be prepared from
ortho-bromophenols or phenols in few steps, which is one of the
advantages of this method. For example, the dilithiation of 2-
bromophenol (14a) followed by C-thiolation afforded ortho-
sulfenylphenol 15a (Figure 2A). The triflylation and subsequent
mono-oxidation of sulfide 16a with mCPBA furnished ortho-
sulfinylaryl triflate 1a.8 1,2-Naphthalyne precursor 1c was also
prepared similarly. Furthermore, by applying the synthetic
method of ortho-silylaryl triflates reported by Garg and co-
workers,9 we succeeded in preparing some ortho-sulfinylaryl
triflates by the ortho-lithiation of phenol derivatives. Thus, an
aryl carbamate derivative prepared from 3-methoxyphenol (14d)
(1.2 equiv)
Entry
1
Sulfoxide
1
Product
3
Yield/%a
97
Ph
O
S
p-Tol
1c
1d
1e
O
3c
3d
3e
OTf
Ph
Ph
MeO
MeO
O
S
2b
3c
93
84
p-Tol
O
OTf
Ph
Ph
O
S
p-Tol
O
N
N
OTf
Ph
aIsolated yields. bReaction was performed for 1 h. c1.0 equiv of 1e and
3.0 equiv of 2 were used.
was ortho-lithiated and then thiolated to afford sulfide 17d,
which was decarbamoylated, triflylated, and oxidized to afford
3-methoxybenzyne precursor 1d in high yield (Figure 2B).8 3,4-
Pyridyne precursor 1e was prepared similarly. In both of these
syntheses, S-p-tolyl p-toluenethiosulfonate10,11 served as a useful
thiolation reagent, enabling efficient and odorless electrophilic
carbon-sulfur bond formation.
Using the optimized conditions, 1,2-naphthalyne, 3-meth-
oxybenzyne, and 3,4-pyridyne could be uneventfully generated
from precursors 1c-1e at low temperature, which smoothly
reacted with diene 2 to provide cycloadducts 3c-3e in high
yields (Table 3).
It is worth noting that the sulfinyl group of the aryne
precursor not only served as an anion equivalent group but also
served as a directing group for the ortho-metalation of the
sulfinyl group under appropriate conditions. This allowed us
to introduce an additional substituent at the ortho-position,
enabling the direct preparation of more functionalized aryne
precursors from a simple one. For example, although not fully
optimized yet, we succeeded in demonstrating that the ortho-
magnesiation of 2-(p-tolylsulfinyl)phenyl triflate (1a) with the
Chem. Lett. 2014, 43, 116–118 | doi:10.1246/cl.130899
© 2014 The Chemical Society of Japan | 117

N3CH2Ph
(10)
PhMgBr
p-TolS
O
S
p-TolS
aspects of the method from other popular aryne generation
methods will enable us the multiple use of aryne chemistry to
easily prepare structurally complex aromatic compounds.
•
1) TMPMgCl LiCl
THF
N
N
p-Tol
1a
+
isomer
N
2) p-TolSSO2-p-Tol
THF
–78 °C, 10 min
18'
OTf
Bn
1f
54%
(77% brsm) recovered
18
1a 30%
72% (18/18' = 83/17)
The authors thank Prof. Dr. Shoichi Shimizu and Prof. Dr.
Hayato Ichikawa at Nihon University for helpful discussions,
Ms. Ayako Hosoya at Tokyo Medical and Dental University for
HRMS analyses, and Central Glass Co., Ltd. for a generous gift
of Tf2O. This work was partially supported by Platform for
Drug Discovery, Informatics, and Structural Life Science from
MEXT, Japan.
Scheme 2. Direct conversion of an aryne precursor into more function-
alized precursor via sulfoxide-directed ortho-magnesiation.
A: in the presence of ortho-iodophenyl triflate
2 (0.30 mmol)
PhMgBr
(0.20 mmol)
O
S
I
p-Tol
+
3a
+
+
1a
19
quant.
recovery
THF
–78 °C
10 min
76%
22%
OTf
1a
(0.20 mmol)
OTf
(0.14 mmol) recovery
References and Notes
19
(0.20 mmol)
(0.05 mmol) (0.20 mmol)
1
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B: in the presence of ortho-silylphenyl triflate and ortho-borylphenyl triflate
2,5-dimethylfuran (22)
(1.0 mmol)
PhMgBr
(0.40 mmol)
O
S
Me
SiMe3
Bpin
OTf
p-Tol
O
+
+
+
20
+
21
THF
–78 °C
10 min
quant.
recovery
(0.20 mmol) (0.20 mmol)
quant.
recovery
OTf
1a
(0.20 mmol)
OTf
20
21
Me
23
2
(0.20 mmol) (0.20 mmol)
79%
(0.16 mmol)
Figure 3. Preferential generation of benzyne from ortho-sulfinylphenyl
triflate 1a in the presence of other popular benzyne precursors.
Knochel-Hauser base,11 followed by the reaction with an
electrophile such as S-p-tolyl p-toluenethiosulfonate, could
afford a new thiolated benzyne precursor 1f as the sole product
(Scheme 2). In this reaction, the sulfoxide-directed ortho-
magnesiation selectively occurred at one of the two possible
benzene rings, which can be attributed to the higher acidity of
the aromatic hydrogen for the triflyloxy-substituted benzene than
that for the tolyl group, due to the electron-withdrawing effect of
the triflyloxy group. The cycloaddition of the aryne generated
from newly synthesized 3-(p-tolylsulfanyl)benzyne precursor 1f
with benzyl azide (10) efficiently provided benzotriazole
derivatives 18 and 18¤ with moderate regioselectivity.
We also found that benzyne generation from ortho-sulfinyl-
phenyl triflate 1a by the Grignard reagent could be selectively
carried out in the presence of other popular benzyne precursors
without affecting them. For instance, treating a 1:1 mixture of 1a
and 2-iodophenyl triflate (19)5g with an equimolar amount of
PhMgBr in the presence of diene 2 at ¹78 °C afforded
cycloadduct 3a in 76% yield with the quantitative recovery of
19 and unreacted 1a (22%) (Figure 3A). Considering that the
reaction of 2-(p-tolylsulfinyl)iodobenzene with the phenyl
Grignard reagent prefers iodo-magnesium exchange to sulfox-
ide-magnesium exchange,7 the sulfoxide-metal exchange reac-
tion of 1a must be significantly enhanced by the electron-
withdrawing effect of the triflyloxy group. Furthermore, the
treatment of a mixture of three different types of aryne
precursors 1a, ortho-silylphenyl triflate 20,5f and ortho-boryl-
phenyl triflate 216 with PhMgBr in the presence of 2,5-
dimethylfuran (22) resulted in the selective consumption of
1a, leaving 20 and 21 intact (Figure 3B). These results and our
previous study6 clearly showed that the rate of aryne generation
significantly depends on the type of the anion equivalent group
adjacent to the triflyloxy group and its activating conditions.
In summary, we showed that arynes can be efficiently
generated from readily available ortho-sulfinylaryl triflates,
being triggered by the Grignard exchange reaction. The different
3
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118 | Chem. Lett. 2014, 43, 116–118 | doi:10.1246/cl.130899
© 2014 The Chemical Society of Japan