Generation of arynes using trimethylsilylmethyl Grignard reagent for activation of ortho-Iodoaryl or ortho-sulfinylaryl triflates

Article abstract of DOI:10.1246/cl.150060

The trimethylsilylmethyl Grignard reagent triggered efficient generation of arynes from various ortho-iodoaryl or ortho-sulfinylaryl triflates. The moderate nucleophilicity and basicity of the reagent facilitated efficient reactions between the aryne prec

Full text of DOI:10.1246/cl.150060

Received: January 21, 2015 | Accepted: February 8, 2015 | Web Released: February 17, 2015
CL-150060
Generation of Arynes Using Trimethylsilylmethyl Grignard Reagent
for Activation of ortho-Iodoaryl or 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)
The trimethylsilylmethyl Grignard reagent triggered efficient
generation of arynes from various ortho-iodoaryl or ortho-
sulfinylaryl triflates. The moderate nucleophilicity and basicity
of the reagent facilitated efficient reactions between the aryne
precursors and arynophiles containing organometallic nucleo-
phile-sensitive functionalities.
sulfonates with isopropylmagnesium chloride at ¹78 °C.4e,6 This
method enabled efficient generation and transformation of
arynes bearing electrophilic moieties, such as the ester moiety
in 1b. We recently found that the trimethylsilylmethyl Grignard
reagent serves as a better activator than those previously
reported, for generating arynes bearing a base-sensitive terminal
alkyne moiety7a or highly electrophilic 3-triflyloxybenzyne7b
from the ortho-iodoaryl triflates 1c or 1d, respectively. Herein,
we demonstrate the general scope of the trimethylsilylmethyl
Grignard reagent for generating arynes from various ortho-
iodoaryl triflates as well as the scope of applicable arynophiles.
The optimal conditions for generating 3-(propargyloxy)-
benzyne from the precursor 1c using the trimethylsilylmethyl
Grignard reagent as the activator7a were also suitable for efficient
generation of simple arynes such as 3-methoxybenzyne or
unsubstituted benzyne. Treatment of a mixture of 2-iodo-3-
methoxyphenyl triflate (1e) and furan (2) with (trimethylsilyl-
methyl)magnesium chloride at ¹78 °C afforded cycloadduct
3a in high yield (eq 1). In the case of benzyne precursor 1a,
performing the reaction at a higher temperature (0 °C) gave a
good result (eq 2). When the reaction was performed at ¹78 °C
for 1 h, 3b was obtained in only 28% yield with 66% recovery of
1a, suggesting slower generation of benzyne from 1a compared
to that when methoxy congener 1e was used.
Arynes are highly reactive intermediates that enable facile
synthesis of complex aromatic molecules, as clearly demon-
strated in a number of total syntheses of complex natural
products.1,2 Diverse heterocyclic frameworks, which are difficult
to construct by conventional methods, are straightforwardly
formed through the reactions of arynes with various type of
arynophiles.3
To effectively utilize aryne intermediates in diverse appli-
cations, numerous methods for the generation of arynes and their
precursors have been developed;4 e.g., fluoride-mediated acti-
vation of ortho-silylaryl triflates.4a Our group recently developed
new methods for generating arynes from readily available
precursors such as ortho-borylaryl triflates4l and ortho-sulfinyl-
aryl triflates.4m
ortho-Iodoaryl sulfonates are also useful as aryne precursors.
By treating them with an organometallic activator, arynes are
generated via an iodine-metal exchange reaction and subsequent
β-elimination of the sulfonyloxy group (Figure 1).4b,5-7 Suzuki
and co-workers have investigated a series of studies based on
aryne generation from ortho-iodoaryl triflates using n-butyl-
lithium as the activator.4b,5 Knochel and co-workers successfully
generated arynes from 2-magnesiated aryl sulfonates, which were
prepared in situ by treating ortho-iodoaryl 4-chlorobenzene-
OMe
OMe
Me3SiCH2MgCl
(1.5 equiv)
I
+
O
O
ð1Þ
THF
–78 °C, 4 h
OTf
1e
2
3a
94%
(5.0 equiv)
Me3SiCH2MgCl
(1.5 equiv)
I
+
O
O
ð2Þ
THF
0 °C, 1 h
OTf
1a
2
3b
95%
(5.0 equiv)
arynophile
R–Mtl
I
The trimethylsilylmethyl Grignard reagent served as an
efficient activator for the generation of an aryne bearing an
electrophilic functional group such as an ester moiety. Attempts
to generate 4-(methoxycarbonyl)benzyne from 2-iodo-4-(meth-
oxycarbonyl)phenyl triflate (1f) using various alkyl- or aryl-
metals in the presence of furan (2) at ¹78 °C showed that
(trimethylsilylmethyl)magnesium chloride was the most effec-
tive activator (Table 1, Entries 1-6). The best result was
obtained by performing the reaction at a higher temperature
(¹30 °C), affording cycloadduct 3c in excellent yield (Entry 7).
The moderate nucleophilicity of the trimethylsilylmethyl
Grignard reagent8 allowed us to utilize an aryne intermediate
bearing an organometallic nucleophile-susceptible ester group
without special care. Indeed, treatment of a mixture of 4-
(methoxycarbonyl)benzyne precursor 1f and furan (2) with an
excess of (trimethylsilylmethyl)magnesium chloride at room
temperature afforded 3c in high yield (Table 2, Entry 4). On the
OSO2R'
R
R
R
1
iodine–metal
exchange
cyclo-
addition
β
-elimination
OSO2R'
P. Knochel, et al.
MeO2C
Mtl
R
K. Suzuki, et al.
Our Previous Works
OTf
O
I
I
I
I
OTf
OSO2Ar
OTf
OTf
1a
1b
1c
1d
Me3SiCH2MgCl Me3SiCH2MgCl
THF, –78 °C Et2O, –30 °C
n-BuLi
THF, –78 °C
i-PrMgCl
THF, –78 °C to rt
Figure 1. Generation of arynes from ortho-iodoaryl sulfonates.
Tf = CF3SO2, Ar = 4-ClC6H4.
Chem. Lett. 2015, 44, 691–693 | doi:10.1246/cl.150060
© 2015 The Chemical Society of Japan | 691

Table 1. Optimization of the reaction conditions
Table 3. Reactions between various aryne precursors and aryno-
philes
O
O
R–Mtl
(1.2 equiv)
I
Me3SiCH2MgCl
(1.5 equiv)
MeO
MeO
I
+
O
O
+
Arynophile
THF
–78 °C, 1 h
OTf
THF
temp., 1 h
(5.0 equiv)
OTf
1f
2
3c
R
R
(5.0 equiv)
Product
Yield/%a
85
Entry
R-Mtl
3c/%a
Entry
1
Arynophile
Temp./°C
0
1
Product
1
2
3
4
5
6
7b
n-BuLi
i-PrMgCl
i-PrMgCl¢LiCl
EtMgBr
PhMgBr
25
64
67
55
11
77
90c
O
OMe
OMe
O
1a
O
O
5
6
N
N
N3
OH
N
Me3SiCH2MgCl
Me3SiCH2MgCl
OH
2b
1a
1a
0
0
73
87
7
8
aYields based on 1H NMR analyses, unless otherwise noted. bReaction
was performed at ¹30 °C. Isolated yield.
O
c
t-Bu
O
N
t-Bu
N
I
3
Table 2. Reaction between 1f and 2 using an excess amount of
activators
OMe
I
OMe
9
10
MeO
OMe
O
O
R–Mtl
(3.0 equiv)
I
OMe
OTBS
MeO
MeO
MeO
OTBS
+
O
O
4
1a
1f
0
86
86
THF
rt, 1 h
OTf
11
12
1f
2
3c
(5.0 equiv)
O
5c
–30
PhN
MeO
I
Entry
R–Mtl
3c/%a
NPh
OH
13
1
2
3
4
n-BuLi
8b
11
14
n-Bu
n-Bu
I
I
O
i-PrMgCl
O
6c
–78
63
i-PrMgCl·LiCl
Me3SiCH2MgCl
11
O
4
OTf
91
N
N
1g
3d
2
aYields based on 1H NMR analyses.
bAlcohol 4 was obtained in 26% yield.
b
aIsolated yields. 8.0 equiv of Me3SiCH2MgCl was used. c1.2 equiv of
Me3SiCH2MgCl was used.
other hand, 3c was obtained in poor yield when more
nucleophilic n-butyllithium, isopropylmagnesium chloride, or
the turbo-Grignard reagent was used as an activator (Entries 1-
3). From the reaction using n-butyllithium, a certain amount of
alcohol 4 was obtained, indicating that the ester moiety of 3c
further reacted with the activator (Entry 1).
heterocycle 14 bearing an ester moiety (Entry 5). A quinolyne
having an iodo group was also generated from diiodoquinolinyl
triflate 1g, which afforded cycloadduct 3d in good yield when
reacted with furan (2) (Entry 6).
An ortho-sulfinylphenyl triflate could also be activated with
the trimethylsilylmethyl Grignard reagent to generate benzyne.
This was accomplished through the treatment of a mixture of
154m and furan (2) in tetrahydrofuran with (trimethylsilyl-
methyl)magnesium chloride at room temperature, affording
cycloadduct 3b in high yield (eq 3). This result indicated that
generation of benzyne via a sulfoxide-magnesium exchange
reaction and subsequent β-elimination was efficiently prompted
by the Grignard reagent.
The optimized conditions were applicable to cycloadditions
of arynes generated from ortho-iodoaryl triflates with an array
of arynophiles. With slight modification depending on the
substrates, these conditions were applicable even to those
bearing organometallic nucleophile-susceptible functional
groups (Table 3). Cycloaddition of benzyne with furoate 5
proceeded efficiently to afford cycloadduct 6 without damaging
the ester moiety (Entry 1). Azide 7 with an unprotected hydroxy
group was also utilizable as an arynophile, providing triazole 8
(Entry 2). In this case, the yield of 8 was improved by using
a sufficient excess of the Grignard reagent to deprotonate the
hydroxy proton of 7, which facilitated complete consumption of
the aryne precursor 1a. Nitrone 9 containing an aromatic iodo
group reacted with benzyne to afford cycloadduct 10 in high
yield without losing the iodo group derived from the arynophile
(Entry 3). The [2+2] cycloaddition of benzyne and ketene silyl
acetal 11 proceeded efficiently to provide benzocyclobutene
12 (Entry 4). Cycloaddition of 4-(methoxycarbonyl)benzyne,
generated from 1f, with N-phenylpyrrole (13) afforded poly-
O
Me3SiCH2MgCl
(1.5 equiv)
S
p-tol
+
O
O
ð3Þ
THF
rt, 1 h
OTf
15
2
3b
90%
(5.0 equiv)
Interestingly, the trimethylsilylmethyl Grignard reagent
triggered benzyne generation via an iodine-magnesium ex-
change reaction prior to that via a sulfoxide-magnesium
exchange reaction (Scheme 1). Treatment of an equimolar
mixture of ortho-iodophenyl triflate (1a) and ortho-sulfinyl-
phenyl triflate 15 with (trimethylsilylmethyl)magnesium chlo-
ride in the presence of an excess amount of furan (2) afforded
692 | Chem. Lett. 2015, 44, 691–693 | doi:10.1246/cl.150060
© 2015 The Chemical Society of Japan

C. D. Gilmore, B. M. Stoltz, Angew. Chem., Int. Ed. 2011, 50, 4488.
c) A. E. Goetz, N. K. Garg, Nat. Chem. 2013, 5, 54. d) H. Yoshida,
R. Yoshida, K. Takaki, Angew. Chem., Int. Ed. 2013, 52, 8629. e) S.
Yoshida, T. Hosoya, Chem. Lett. 2013, 42, 583. f) S. S. Bhojgude,
M. Thangaraj, E. Suresh, A. T. Biju, Org. Lett. 2014, 16, 3576.
g) F.-L. Liu, J.-R. Chen, Y.-Q. Zou, Q. Wei, W.-J. Xiao, Org. Lett.
2014, 16, 3768. h) V. G. Pandya, S. B. Mhaske, Org. Lett. 2014, 16,
3836. i) Y. Sumida, R. Harada, T. Kato-Sumida, K. Johmoto, H.
Uekusa, T. Hosoya, Org. Lett. 2014, 16, 6240.
A
2 (1.0 mmol)
Me3SiCH2MgCl
(0.30 mmol)
I
+
+
+
3b
quant.
1a
0%
15
95%
recovery
(0.19 mmol)
OTf
THF
0 °C, 1 h
1a
recovery
(0.20 mmol)
(0.20 mmol)
+
O
2 (1.0 mmol)
PhMgBr
(0.30 mmol)
S
p-tol
+
3b
79%
1a
91%
recovery
15
5%
recovery
4
For representative aryne precursors and generation methods, see:
a) Y. Himeshima, T. Sonoda, H. Kobayashi, Chem. Lett. 1983, 1211.
b) T. Matsumoto, T. Hosoya, M. Katsuki, K. Suzuki, Tetrahedron
Lett. 1991, 32, 6735. c) T. Kitamura, M. Yamane, J. Chem. Soc.,
Chem. Commun. 1995, 983. d) M. Uchiyama, T. Miyoshi, Y.
Kajihara, T. Sakamoto, Y. Otani, T. Ohwada, Y. Kondo, J. Am.
Chem. Soc. 2002, 124, 8514. e) I. Sapountzis, W. Lin, M. Fischer, P.
Knochel, Angew. Chem., Int. Ed. 2004, 43, 4364. f) T. Ikawa, A.
Takagi, Y. Kurita, K. Saito, K. Azechi, M. Egi, K. Kakiguchi, Y.
Kita, S. Akai, Angew. Chem., Int. Ed. 2010, 49, 5563. g) T. Ikawa, T.
Nishiyama, T. Nosaki, A. Takagi, S. Akai, Org. Lett. 2011, 13, 1730.
h) T. Hamura, Y. Chuda, Y. Nakatsuji, K. Suzuki, Angew. Chem.,
Int. Ed. 2012, 51, 3368. i) T. R. Hoye, B. Baire, D. Niu, P. H.
Willoughby, B. P. Woods, Nature 2012, 490, 208. j) T. Ikawa, S.
Masuda, T. Nishiyama, A. Takagi, S. Akai, Aust. J. Chem. 2014, 67,
475. k) B. Michel, M. F. Greaney, Org. Lett. 2014, 16, 2684. l) Y.
Sumida, T. Kato, T. Hosoya, Org. Lett. 2013, 15, 2806. m) S.
Yoshida, K. Uchida, T. Hosoya, Chem. Lett. 2014, 43, 116.
a) T. Matsumoto, T. Hosoya, K. Suzuki, J. Am. Chem. Soc. 1992,
114, 3568. b) T. Matsumoto, T. Sohma, S. Hatazaki, K. Suzuki,
Synlett 1993, 843. c) T. Hosoya, E. Takashiro, T. Matsumoto, K.
Suzuki, J. Am. Chem. Soc. 1994, 116, 1004. d) T. Hosoya, T.
Hasegawa, Y. Kuriyama, T. Matsumoto, K. Suzuki, Synlett 1995,
177. e) T. Matsumoto, T. Sohma, H. Yamaguchi, S. Kurata, K.
Suzuki, Synlett 1995, 263. f) T. Hosoya, T. Hasegawa, Y. Kuriyama,
K. Suzuki, Tetrahedron Lett. 1995, 36, 3377. g) T. Matsumoto, T.
Sohma, H. Yamaguchi, S. Kurata, K. Suzuki, Tetrahedron 1995, 51,
7347. h) S. Futagami, Y. Ohashi, K. Imura, T. Hosoya, K. Ohmori,
T. Matsumoto, K. Suzuki, Tetrahedron Lett. 2000, 41, 1063. i) T.
Hosoya, T. Hamura, Y. Kuriyama, M. Miyamoto, T. Matsumoto, K.
Suzuki, Synlett 2000, 520. j) T. Hamura, T. Hosoya, H. Yamaguchi,
Y. Kuriyama, M. Tanabe, M. Miyamoto, Y. Yasui, T. Matsumoto, K.
Suzuki, Helv. Chim. Acta 2002, 85, 3589. k) T. Hamura, Y. Ibusuki,
K. Sato, T. Matsumoto, Y. Osamura, K. Suzuki, Org. Lett. 2003, 5,
3551. l) T. Hamura, Y. Ibusuki, H. Uekusa, T. Matsumoto, J. S.
Siegel, K. K. Baldridge, K. Suzuki, J. Am. Chem. Soc. 2006, 128,
10032. m) T. Hamura, T. Arisawa, T. Matsumoto, K. Suzuki, Angew.
Chem., Int. Ed. 2006, 45, 6842.
THF
–78 °C, 10 min
OTf
15
(0.20 mmol)
(0.16 mmol)
(0.18 mmol) (0.010 mmol)
B
Scheme 1. Selective generation of benzyne from 1a or 15 using a
different Grignard reagent (yields are based on H NMR analyses).
1
cycloadduct 3b quantitatively, with almost complete recovery of
15 (Scheme 1A). This indicated that with the trimethylsilyl-
methyl Grignard reagent, the iodine-magnesium exchange
reaction proceeded faster than the sulfoxide-magnesium ex-
change reaction.9 In contrast, treatment of the mixture with a
phenyl Grignard reagent afforded the product selectively from
15 (Scheme 1B), which was in good agreement with our
previous report.4m The orthogonality in aryne generation based
on the combination of aryne precursor and activator would
enable a sequential transformation of a bisaryne equivalent
molecule bearing both ortho-iodoaryl triflate and ortho-sulfinyl-
aryl triflate moieties.
In summary, we demonstrated that the trimethylsilylmethyl
Grignard reagent was capable of generating arynes from various
ortho-iodoaryl and ortho-sulfinylaryl triflates. This provided
easy access to numerous polycyclic aromatics equipped with
various functional groups, which is advantageous in the
construction of a chemical library that contains diversity-
enriched molecules. Further studies are underway to expand
the scope of this method.
5
The authors thank 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; JSPS KAKENHI grant numbers 24310164 (T.H.)
and 26350971 (S.Y.); a Grant-in-Aid for Scientific Research on
Innovative Areas “Chemical Biology of Natural Products” from
MEXT, Japan; the Nagase Science and Technology Foundation
(T.H.); and Suntory Institute for Bioorganic Research (S.Y.).
6
a) W. Lin, I. Sapountzis, P. Knochel, Angew. Chem., Int. Ed. 2005,
44, 4258. b) W. Lin, L. Chen, P. Knochel, Tetrahedron 2007, 63,
2787. c) D. A. Candito, D. Dobrovolsky, M. Lautens, J. Am. Chem.
Soc. 2012, 134, 15572. d) T. Ikawa, A. Takagi, M. Goto, Y.
Aoyama, Y. Ishikawa, Y. Itoh, S. Fujii, H. Tokiwa, S. Akai, J. Org.
Chem. 2013, 78, 2965. e) J.-A. García-López, M. Çetin, M. F.
Greaney, Angew. Chem., Int. Ed. 2015, 54, 2156.
Supporting Information for characterization of new compounds
is available electronically on J-STAGE.
References and Notes
1
R. W. Hoffmann, Dehydrobenzene and Cycloalkynes, Academic
Press, New York, 1967.
7
8
9
a) S. Yoshida, T. Nonaka, T. Morita, T. Hosoya, Org. Biomol. Chem.
2014, 12, 7489. b) S. Yoshida, K. Uchida, K. Igawa, K. Tomooka, T.
Hosoya, Chem. Commun. 2014, 50, 15059.
a) T. Fujioka, T. Nakamura, H. Yorimitsu, K. Oshima, Org. Lett.
2002, 4, 2257. b) T. Kobayashi, H. Ohmiya, H. Yorimitsu, K.
Oshima, J. Am. Chem. Soc. 2008, 130, 11276.
Soft electrophilic nature of iodo group would be favored by the soft
nucleophilic trimethylsilylmethyl Grignard reagent, although the
reason for the selectivity is yet to be investigated.
2
For some recent reviews on arynes, see: a) H. Yoshida, K. Takaki,
Heterocycles 2012, 85, 1333. b) C. M. Gampe, E. M. Carreira,
Angew. Chem., Int. Ed. 2012, 51, 3766. c) P. M. Tadross, B. M.
Stoltz, Chem. Rev. 2012, 112, 3550. d) A. V. Dubrovskiy, N. A.
Markina, R. C. Larock, Org. Biomol. Chem. 2013, 11, 191. e) R. W.
Hoffmann, K. Suzuki, Angew. Chem., Int. Ed. 2013, 52, 2655.
For some recent aryne chemistries, see: a) A. B. Smith, III, W.-S.
Kim, Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 6787. b) K. M. Allan,
3
Chem. Lett. 2015, 44, 691–693 | doi:10.1246/cl.150060
© 2015 The Chemical Society of Japan | 693