Generation of arynes via ate complexes of arylboronic esters with an ortho-leaving group

Article abstract of DOI:10.1021/ol401140d

An efficient method of generating aryne has been achieved by treating ortho-(trifluoromethanesulfonyloxy)arylboronic acid pinacol ester with tert- or sec-butyllithium. Monitoring the reaction by ¹¹B NMR has indicated that a boron-ate complex formed in situ is the eventual precursor that converts into aryne near room temperature. The prior formation of the ate complex at a low temperature has enabled us to use various arynophiles, including those bearing base-sensitive groups. The ready availability of the aryne precursors and mutual orthogonality in aryne generation with widely used ortho-silylaryl triflate have enhanced the utility of the method.

Full text of DOI:10.1021/ol401140d

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Generation of Arynes via Ate Complexes
of Arylboronic Esters with an
ortho-Leaving Group
Yuto Sumida, Tomoe Kato, 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, Japan
thosoya.cb@tmd.ac.jp
Received April 24, 2013
ABSTRACT
An efficient method of generating aryne has been achieved by treating ortho-(trifluoromethanesulfonyloxy)arylboronic acid pinacol ester with tert-
or sec-butyllithium. Monitoring the reaction by 11B NMR has indicated that a boron-ate complex formed in situ is the eventual precursor that
converts into aryne near room temperature. The prior formation of the ate complex at a low temperature has enabled us to use various arynophiles,
including those bearing base-sensitive groups. The ready availability of the aryne precursors and mutual orthogonality in aryne generation with
widely used ortho-silylaryl triflate have enhanced the utility of the method.
Aryne is a highly reactive species that has been attracting
much attention because of its intriguing structure and
properties.1 Various methods of aryne generation have
been developed so far, enabling the straightforward con-
struction of diverse aromatic molecules,2,3 with successful
application to a number of total syntheses of complex
natural products.4 Aryne is most simply generated by
eliminating two adjacent substituents on an arene ring,
with one substituent usually being an aryl anion equivalent
and the other being a leaving group.5 Decarboxylative
denitrogenation of ortho-arene-diazonium carboxylate,5a,b
fluoride-mediated activation of ortho-silylaryl triflate,5f
and halogenꢀlithium exchange of ortho-haloaryl triflate5g
aretypicalexamples. Hereinwedisclosethatarynecanalso
be efficiently generated from an ate complex of an arylboro-
nic ester that has a good leaving group at the ortho-position.
Pioneering work on aryne generation from ortho-
haloarylboronic acid had been reported half a century
ago: treatment of 2-chlorophenylboronic acid in ether with
n-butyllithium (3 equiv) in the presence of furan at rt,
(1) (a) Hoffmann, R. W. Dehydrobenzene and Cycloalkynes; Aca-
demic Press: New York, 1967. (b) Gilchrist, T. L. In The Chemistry of
Functional Groups; Patai, S., Rappoport, Z., Eds.; Wiley: Chichester, 1983;
Chapter 11. (c) Kessar, S. V. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 4, Chapter 2.3.
(d) Hart, H. In The Chemistry of Triple-Bonded Functional Groups; Patai,
S., Ed.; Wiley: Chichester, 1994; Chapter 18.
(3) For some recent aryne chemistries, see: (a) Cant, A. A.; Bertrand,
G. H.; Henderson, J. L.; Roberts, L.; Greaney, M. F. Angew. Chem., Int.
Ed. 2009, 48, 5199–5202. (b) Ikawa, T.; Takagi, A.; Kurita, Y.; Saito, K.;
Azechi, K.; Egi, M.; Kakiguchi, K.; Kita, Y.; Akai, S. Angew. Chem., Int.
Ed. 2010, 49, 5563–5566. (c) Smith, A. B., III.; Kim, W.-S. Proc. Natl.
Acad. Sci. U.S.A. 2011, 108, 6787–6792. (d) Allan, K. M.; Gilmore,
C. D.; Stoltz, B. M. Angew. Chem., Int. Ed. 2011, 50, 4488–4491. (e)
Ikawa, T.; Nishiyama, T.; Shigeta, T.; Mohri, S.; Morita, S.; Takayanagi,
S.; Terauchi, Y.; Morikawa, Y.; Takagi, A.; Ishikawa, Y.; Fujii, S.; Kita, Y.;
Akai, S. Angew. Chem., Int. Ed. 2011, 50, 5674–5677. (f) Hamura, T.;
Chuda, Y.; Nakatsuji, Y.; Suzuki, K. Angew. Chem., Int. Ed. 2012, 51,
3368–3372. (g) Bronner, S. M.; Mackey, J. L.; Houk, K. N.; Garg, N. K.
J. Am. Chem. Soc. 2012, 134, 13966–13969. (h) Candito, D. A.; Dobrovolsky,
D.; Lautens, M. J. Am. Chem. Soc. 2012, 134, 15572–15580. (i) Goetz, A. E.;
Garg, N. K. Nat. Chem. 2013, 5, 54–60.
~
ꢀ
(2) For some recent reviews on arynes, see: (a) Pena, D.; Perez, D.;
ꢀ
Guitian, E. Angew. Chem., Int. Ed. 2006, 45, 3579–3581. (b) Sanz, R.
Org. Prep. Proced. Int. 2008, 40, 215–291. (c) Wentrup, C. Aust. J. Chem.
2010, 63, 979–986. (d) Kitamura, T. Aust. J. Chem. 2010, 63, 987–1001.
(e) Yoshida, H.; Takaki, K. Heterocycles 2012, 85, 1333–1349. (f)
Yoshida, H.; Takaki, K. Synlett 2012, 23, 1725–1732. (g) Bhojgude,
S. S.; Biju, A. T. Angew. Chem., Int. Ed. 2012, 51, 1520–1522. (h) Bhunia,
A.; Yetra, S. R.; Biju, A. T. Chem. Soc. Rev. 2012, 41, 3140–3152. (i) Wu,
C.; Shi, F. Asian J. Org. Chem. 2013, 2, 116–125. (j) Dubrovskiy, A. V.;
Markina, N. A.; Larock, R. C. Org. Biomol. Chem. 2013, 11, 191–218.
(k) Hoffmann, R. W.; Suzuki, K. Angew. Chem., Int. Ed. 2013, 52, 2655–
2656.
(4) (a) For recent reviews on the synthesis of natural products via
arynes, see: Gampe, C. M.; Carreira, E. M. Angew. Chem., Int. Ed. 2012,
51, 3766–3778. (b) Tadross, P. M.; Stoltz, B. M. Chem. Rev. 2012, 112,
3550–3577.
r
10.1021/ol401140d
XXXX American Chemical Society

followed by acidic workup, afforded 1-naphthol, a cycload-
duct derivative, in 55ꢀ60% yield.6,7 While the boron-ate
complex, assumed to be formed in situ, was proposed as the
benzyne precursor in this report, no direct evidence was
shown, and to the best of our knowledge, the substrate
scopes have not been explored at all since. We presumed
that the scope of this type of reaction could be greatly
expanded by optimizing the reaction conditions. After
extensive screening of the conditions using 2,5-dimethyl-
furan (2a) as an arynophile, we succeeded in finding a
suitable combination of benzyne precursor, base, and
solvent (Table 1): the desired cycloadduct 3a was obtained
in an excellent yield by adding tert-butyllithium (1.2 equiv)
to 2-(trifluoromethanesulfonyloxy)arylboronic acid pina-
col ester (1a) in ether at ꢀ78 °C in the presence of an excess
of 2a (3 equiv) and then warming the mixture to 25 °C
(entry 1). Performing the reaction in THF instead of ether
led to a slightly lower yield of 3a (entry 2). Using
sec-butyllithium as the base also gave a satisfactory result
(entry 3), working better than tert-butyllithium for some
substrates (vide infra). However, n-butyllithium gave 3a in
a poor yield, also providing a phenolic byproduct that
presumably arose from the nucleophilic cleavage of the
triflate moiety of 1a (entry 4). All of the other bases
examined, including strong bases such as phenyllithium
and tert-butylmagnesium chloride, as well as milder bases
such as potassium tert-butoxide, cesium carbonate, and
tetrabutylammonium fluoride (1.0 M in THF), were to-
tally ineffective (entries 5ꢀ9). Changing the leaving group
of 1a to methanesulfonyloxy considerably diminished
the reaction efficiency (entry 10), whereas altering it to
p-toluenesulfonyloxy, bromo, or chloro gave the desired
product in moderate yields (entries 11ꢀ13). Neopentyl
glycol ester 1f also served as a reasonable precursor in
combination with sec-butyllithium (entries 14 and 15), but
nonesterified phenylboronic acids did not, regardless of the
type of leaving groups employed (entries 16 and 17).
Table 1. Optimization of the Reaction Conditions
entry
Ba
LG
1
base
yield (%)b
1
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Bnpg
Bnpg
B(OH)2
B(OH)2
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OMs
OTs
Br
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
t-BuLi
t-BuLi
s-BuLi
n-BuLi
PhLi
97 (95)c
76
89
27
15
<1
11
2d
3
4
5
6
t-BuMgCl
t-BuOK
Cs2CO3
n-Bu4NF
t-BuLi
t-BuLi
t-BuLi
t-BuLi
t-BuLi
s-BuLi
n-BuLi
n-BuLi
7
8e
9e
10e
11
12
13
14
15
16f
17f
12
0
3
64
54
68
58
73
18
40
Cl
OTf
OTf
OTf
Cl
1f
1g
1h
a pin = pinacol; npg = neopentyl glycol. b Determined by 1H NMR
unless otherwise noted. c Isolated yield in parentheses. d THF was used as
a solvent instead of Et2O. e Base was added at 0 °C, and the reaction was
then warmed up to 25 °C. f 3.6 equiv of n-butyllithium was used.
mixture at 240 K, the signal for 1a (δ 27.8 ppm) completely
disappeared and, instead, a new peak (δ 5.8 ppm) with a
comparable chemical shift to the analogous boron-ate
complexes appeared.9 This peak gradually disappeared
with increasing the temperature to 300 K, accompanied
by the emergence of another peak (δ 32.7 ppm), which was
identical to t-BuBpin, separately prepared,10 showing the
progression of the reaction. A similar tendency was ob-
The intermediacyofa boron-ate complex in thisreaction
was strongly suggested by the NMR study. The reaction of
1a and 2a (1.4 equiv) carried out in THF-d8 was continu-
1
served in the H and 19F NMR studies.8 These results
1
ously monitored by H, 11B, and 19F NMR at various
strongly indicate that the boron-ate complex 4 formed in
situ is the eventual benzyne precursor, which is stable in
the solution below 0 °C, but breaks down into benzyne,
t-BuBpin, and LiOTf near rt.
temperatures, before and after the addition of tert-butyl-
lithium (1.2 equiv). A set of 11B NMR spectra are shown in
Figure 1.8 By the addition of tert-butyllithium to the
The optimized conditions were generally applicable to
various arynophiles showing a broad substrate scope for
the method (Table 2). Although the use of a strong base
was required for this reaction, we found that arynophiles
bearing base-sensitive groups could also be used by adding
them after the boron-ate complex was formed, at the time
(5) For representative aryne precursors and generation methods, see:
(a) Stiles, M.; Miller, R. G. J. Am. Chem. Soc. 1960, 82, 3802. (b)
Friedman, L.; Logullo, F. M. J. Am. Chem. Soc. 1963, 85, 1549. (c)
Wittig, G.; Hoffmann, R. W. Org. Synth. 1967, 47, 4. (d) Campbell,
C. D.; Rees, C. W. J. Chem. Soc., C 1969, 742–747. (e) Logullo, F. M.;
Seitz, A. H.; Friedman, L. Org. Synth. 1968, 48, 12. (f) Himeshima, Y.;
Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211–1214. (g) Matsumoto,
T.; Hosoya, T.; Katsuki, M.; Suzuki, K. Tetrahedron Lett. 1991, 32,
6735–6736. (h) Kitamura, T.; Yamane, M. J. Chem. Soc., Chem.
Commun. 1995, 983–984. (i) Sapountzis, I.; Lin, W.; Fischer, M.;
Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 4364–4366. (j) Hoye,
T. R.; Baire, B.; Niu, D.; Willoughby, P. H.; Woods, B. P. Nature 2012,
490, 208–212.
(6) Cainelli, G.; Zubiani, G.; Morrocchi, S. Chim. Ind. (Milan, Italy)
1964, 46, 1489–1490.
(7) For preparation of benzyneꢀnickel(0) and ꢀpalladium(0) com-
plexes from ortho-bromophenylboronic acid pinacol ester, see: Retbøll,
M.; Edwards, A. J.; Rae, A. D.; Willis, A. C.; Bennett, M. A.; Wenger, E.
J. Am. Chem. Soc. 2002, 124, 8348–8360.
(8) See Supporting Information for 1H and 19F NMR spectra.
(9) (a) Hatakeyama, T.; Hashimoto, T.; Kondo, Y.; Fujiwara, Y.;
Seike, H.; Takaya, H.; Tamada, Y.; Ono, T.; Nakamura, M. J. Am.
Chem. Soc. 2010, 132, 10674–10676. (b) Nave, S.; Sonawane, R. P.;
Elford, T. G.; Aggarwal, V. K. J. Am. Chem. Soc. 2010, 132, 17096–
17098. (c) Chen, J. L.-Y.; Scott, H. K.; Hesse, M. J.; Willis, C. L.;
Aggarwal, V. K. J. Am. Chem. Soc. 2013, 135, 5316–5319.
(10) t-BuBpin was prepared according to: Clary, J. W.; Rettenmaier,
T. J.; Snelling, R.; Bryks, W.; Banwell, J.; Wipke, W. T.; Singaram, B.
J. Org. Chem. 2011, 76, 9602–9610.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Scope of Arynophiles
Figure 1. 11B NMR spectra (193 MHz) measured during the
reaction of 1a and 2a (1.4 equiv) in THF-d8: (i) the signal for 1a
(δ 27.8 ppm) was observed at 300 K; (ii) no distinct signal could
be observed when the temperature was decreased to 210 K; (iii) a
broad peak for 1a reappeared at 240 K; (iv) by adding t-BuLi at
240 K, the signal for 1a disappeared and a new peak regarded as
the boron-ate complex 4 (δ 5.8 ppm) appeared; (v) by increasing
the temperature to 283 K, a new peak identical to t-BuBpin
(δ 32.7 ppm) gradually appeared; (vi) the signals converged in a
single peak at 300 K.
when no free base exists in the reaction mixture (Method
B). Using either of the methods, with slight modifications
as needed, benzyne generated from 1a smoothly reacted
with various arynophiles, including dienes 2bꢀ2d (entries
1ꢀ3), 1,3-dipolar compounds 2eꢀ2g (entries 4ꢀ6), and
ketene silyl acetal 2h (entry 7), to give corresponding
cycloadducts 3bꢀ3h efficiently. Notably, the reaction
could be uneventfully performed in gram-scale as demon-
strated in the reaction with 2d (entry 3). In addition, the
reaction with β-ketoester 2i was remarkably improved by
the combined use of cesium fluoride, by which the enoliza-
tion of 2i was facilitated, affording the formally benzyne-
inserted product 3i in high yield (entry 8).
a Isolated yields. b Molar ratio: 1a/arynophile/base = 1.2/1.0/1.4. c Molar
ratio: 1a/arynophile/base = 1.0/3.0/1.1ꢀ1.2. d Molar ratio: 1a/arynophile/
base = 1.2ꢀ1.5/1.0/1.2ꢀ1.5. e 5.0 mmol of 2d were used. f Yields of the
products obtained from the reactions performed with method A determined
by 1H NMR in parentheses. g A solution prepared from 1a and s-BuLi was
added to a separately prepared mixture of 2i and CsF (1.0 equiv).
borylation of ortho-halophenols.11 Furthermore, Ir-cata-
lyzed direct ortho-borylation of phenols, reported by
Hartwig and co-workers,12 particularly suited our purpose
as clearly demonstrated in the short-step syntheses of some
ortho-borylaryl triflates prepared from phenols 5aꢀ5c.
Based on this strategy, regioisomers of an indazole-type
steroid analog, 3l and 3l0, could be easily prepared from
β-estradiol derivative 5c (Figure 2).13
Some notable results were obtained from experiments
performed to compare the reactivities of ortho-borylaryl
triflate and ortho-silylaryl triflate, which is one of the most
widely used aryne precursors. The reaction of aryl triflate
1m,3b having both boryl and silyl groups at each ortho-
position, with 2a using sec-butyllithium afforded the ex-
pected silyl-containing product 3m exclusively in 81%
The ready synthetic accessibility to aryne precursors further
enhanced the utility of the method. The key intermediate,
ortho-hydroxyarylboronic acid, could be smoothly prepared
using conventional methods such as treating ortho-lithiated
phenols with trialkyl borate and Pd-catalyzed Miyaura
(11) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995,
60, 7508–7510.
(12) (a) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi,
N. R.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 390–391. (b)
Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N. Angew. Chem.,
Int. Ed. 2002, 41, 3056–3058. (c) Boebel, T. A.; Hartwig, J. F. J. Am.
Chem. Soc. 2008, 130, 7534–7535.
(13) See Supporting Information for details.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 1. Selective Generation of 3-Silylaryne from 2-Boryl-6-
silyl-4-tolyl triflate 1m under either Base- or Fluoride-Activat-
ing Conditions
Scheme 2. Mutual Orthogonality in Benzyne Generation between
ortho-Borylphenyl Triflate and ortho-Silylphenyl Triflatea
a Yields determined by 1H NMR.
Figure 2. Preparation of aryne precursors by Ir-catalyzed direct
ortho-borylation of phenols followed by triflation and their
applications.
principle, the back-to-back generation of arynes, in any order,
would be possible using a substrate that has both ortho-
borylaryl triflate and ortho-silylaryl triflate substructures.14
In summary, we have demonstrated that arynes could be
efficiently generated near rt from ate complexes of aryl-
boronic esters bearing an ortho-OTf group. The prior
formation of the boron-ate complex by adding tert- or
sec-butyllithium to the ester at a low temperature allowed
us to use arynophiles that have functional groups susceptible
to strong bases, greatly expanding the scope of the method.
The utility of the method was also enhanced by the ready
availability of the ortho-borylaryl triflate and mutual ortho-
gonality in aryne generation with widely used ortho-silylaryl
triflate, which will enable the facile construction of structu-
rally complex polysubstituted arenes.
yield (Scheme 1). Moreover, treatment with tetrabutylam-
monium fluoride (1.0 M in THF) at rt also provided 3m
without any of the other possible boron-containing com-
pound 3n being found, showing good agreement with the
result previously mentioned by Akai and co-workers.3b
Although this result could be attributed to the nature of
boron being more fluorophilic than silicon, we also ob-
served that the borylaryl triflates 1a and 1j could not react
under the same fluoride-activating conditions, indicating
that the ability of 1m to generate 3-silylaryne was greatly
enhanced by the trimethylsilyl group. Based on these
results, an orthogonal relationship between ortho-boryl-
phenyl triflate 1a and ortho-silylphenyl triflate7 in benzyne
generation was clearly demonstrated in competitive reac-
tions with 2a under the appropriate conditions for each
precursor (Scheme 2). The reaction performed by adding
tert-butyllithium to the mixture resulted in the complete
consumption of 1a with quantitative recovery of 7. In
contrast, fluoride could mediate the benzyne generation
only from 7, leaving 1a apparently intact, indicating
that elimination took place more rapidly from silicate than
from the boron-ate complex. These results suggest that, in
Acknowledgment. The authors thank Mr. Natsuhiko
Sugimura (Materials Characterization Central Laboratory)
and Dr. Takashi Niwa at Waseda University for 11B NMR
analyses, Dr. Hiroyuki Masuno and 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.
Supporting Information Available. Experimental pro-
cedures and characterization data, including copies of
NMR spectra, are provided. This material is available
free of charge via the Internet at http://pubs.acs.org.
(14) For sequential generation of arynes from the 1,4-benzdiyne
precursor, see: (a) Hamura, T.; Arisawa, T.; Matsumoto, T.; Suzuki,
K. Angew. Chem., Int. Ed. 2006, 45, 6842–6844. (b) Arisawa, T.;
Hamura, T.; Uekusa, H.; Matsumoto, T.; Suzuki, K. Synlett 2008,
1179–1184.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX