Design and application of new imidazolylsulfonate-based benzyne precursor: An efficient triflate alternative

Article abstract of DOI:10.1021/ol300529j

Several o-(trimethylsilyl)aryl imidazolylsulfonates were synthesized in a simple process and successfully applied in cycloadditions involving benzyne intermediates. The precursor offers an efficient alternative for generating benzynes compared to widely used ortho TMS triflates under similar reaction conditions. With the utilization of this new precursor, the formation of potentially genotoxic trifluoromethanesulfonate side product is eliminated. The applicability of the new benzyne precursor was demonstrated in different types of cycloaddition reactions to prepare heterocyclic molecules.

Full text of DOI:10.1021/ol300529j

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2022–2025
Design and Application of New
Imidazolylsulfonate-Based Benzyne
Precursor: An Efficient Triflate Alternative
†
Szabolcs Kovacs, Adam I. Csincsi, Tibor Zs. Nagy, Sandor Boros, Geza Timari,
†
†
‡
‡
ꢀ
,†
ꢀ
and Zoltan Novak*
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
€ €
Institute of Chemistry, Eotvos Lorand University, Pazmany Peter stny 1/a, H-1117
Budapest, Hungary, and Sanofi, Chinoin Zrt, To utca 1-4, H-1045 Budapest, Hungary
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
novakz@elte.hu
Received March 1, 2012
ABSTRACT
Several o-(trimethylsilyl)aryl imidazolylsulfonates were synthesized in a simple process and successfully applied in cycloadditions involving
benzyne intermediates. The precursor offers an efficient alternative for generating benzynes compared to widely used ortho TMS triflates under
similar reaction conditions. With the utilization of this new precursor, the formation of potentially genotoxic trifluoromethanesulfonate side
product is eliminated. The applicability of the new benzyne precursor was demonstrated in different types of cycloaddition reactions to prepare
heterocyclic molecules.
Arynes are reactive intermediates due to their strained
structures caused by the presence of a distorted triple bond
in the six-membered carbacycle.1 This exotic compound
class can be transformed efficiently in nucleophilic or
electrophilic reactions,2 in pericyclic reactions,3 and in
transition-metal-catalyzed reactions.4 The power of aryne
chemistry has been demonstrated in numerous natural
product syntheses.5 Generation of o-arynes requires two
eliminable functional groups, which are in ortho positions
to each other. Several aryne precursors have been used for
the generation of the reactive intermediate including dia-
zonium carboxylates,6 iodonium triflates,7 benzotriazole,8
halotriflates,9 fluorolithium, and magnesium compounds,1a
but the most frequently used aryne precursor is 2-(trimethyl-
silyl)phenyl triflate. With the aid of Kobayashi’s method,
benzynes can be generated in a straightforward manner
in a fluoride-induced reaction under mild reaction conditions.10
(2) (a) Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T. Angew.
Chem., Int. Ed. 2002, 41, 3247–3249. (b) Tambar, U. K.; Stoltz, B. M.
J. Am. Chem. Soc. 2005, 127, 5340–5341. (c) Liu, Z.; Larock, R. C. J. Am.
Chem. Soc. 2005, 127, 13112–13113. (d) Łaczkowski, K. Z.; Garcia, D.;
~
Pena, D.; Cobas, A.; Perez, D.; Guitian, E. Org. Lett. 2011, 13, 960–963.
(e) Liu, Z.; Larock, R. C. Org. Lett. 2003, 5, 4673–4675. (f) Liu, Z.;
Larock, R. C. Org. Lett. 2004, 6, 99–102. (g) Bronner, S. M.; Bahnck,
K. B.; Garg, N. K. Org. Lett. 2009, 11, 1007–1010. (h) McAusland, D.;
Seo, S.; Pintori, D. G.; Finlayson, J.; Greaney, M. F. Org. Lett. 2011, 13,
3667–3669. (i) Okuma, K.; Nojima, A.; Matsunaga, N.; Shioji, K. Org.
Lett. 2009, 11, 169–171. (j) Ramtohul, Y. K.; Chartrand, A. Org. Lett.
2007, 9, 1029–1032. (k) Biju, A. T.; Glorius, F. Angew. Chem., Int. Ed.
ꢀ
2010, 49, 9761–9764. (l) Remond, E.; Tessier, A.; Leroux, F. R.;
ꢀ
Bayardon, J.; Juge, S. Org. Lett. 2010, 12, 1568–1571. (m) Yoshioka,
E.; Kohtani, S.; Miyabe, H. Org. Lett. 2010, 12, 1956–1959. (n) Pintori,
D. G.; Greaney, M. F. Org. Lett. 2010, 12, 168–171. (o) Dubrovskiy,
A. V.; Larock, R. C. Org. Lett. 2010, 12, 3117–3119. (p) Chai, G.; Qiu,
Y.; Fu, C.; Ma, S. Org. Lett. 2011, 13, 5196–5199. (q) Biswas,
K.; Greaney, M. F. Org. Lett. 2011, 13, 4946–4949. (r) Alajarin, M.;
Lopez-Leonardo, C.; Raja, R.; Orenes, R. Org. Lett. 2011, 13, 5668–
5671. (s) Yoshida, H.; Morishita, T.; Ohshita, J. Org. Lett. 2008, 10,
3845–3847. (t) Yoshida, H.; Morishita, T.; Fukushima, H.; Ohshita, J.;
Kunai, A. Org. Lett. 2007, 9, 3367–3370. (u) Allan, K. M.; Gilmore,
C. D.; Stoltz, B. M. Angew. Chem., Int.Ed. 2011, 50, 4488–4491.
(v) Yoshioka, E.; Kohtani, S.; Miyabe, H. Angew. Chem., Int. Ed.
2011, 50, 6638–6642. (w) Gilmore, C. D.; Allan, K. M.; Stoltz, B. M.
J. Am. Chem. Soc. 2008, 130, 1558–1559. (x) Hong, D.; Chen, Z.; Lin, X.;
Wang, Y. Org. Lett. 2010, 12, 4608–4611. (y) Huang, X.-C.; Liu, Y.-L.;
Liang, Y.; Pi, S.-F.; Wang, F.; Li, J.-H. Org. Lett. 2008, 10, 1525–1528.
†
€
€
ꢀ
Eotvos Lorand University.
‡ Sanofi.
(1) For reviews, see: (a) Hoffmann, R. W. Dehydrobenzene and Cyclo-
alkynes; Academic Press: New York, 1967. (b) Hart, H. In The Chemistry of
Triple-Bonded Functional Groups, Supplement C2; Patai, S., Ed.; Wiley:
Chichester, U.K., 1994; Chapter 18. (c) Gilchrist, T. L. In The Chemistry of
Functional Groups, Supplement C2; Patai, S., Rappoport, Z., Eds.; Wiley:
Chichester, U.K., 1983; Chapter 11. (d) Wenk, H. H.; Winkler, M.; Sander, W.
Angew. Chem., Int. Ed. 2003, 42, 502–528. (e) Pellissier, H.; Santelli, M.
Tetrahedron 2003, 59, 701–730. (f) Bhunia, A.; Yetra, R. S.; Biju, T. A.
Chem. Soc. Rev. 2012, 41, 3140–3152.
r
10.1021/ol300529j
Published on Web 04/11/2012
2012 American Chemical Society

However, the trifluoromethansulfonate functional group is
an excellent leaving group for aryne generation, but the
instability of triflates, the high cost of triflating agents, and
the formation potentially genotoxic triflic acid appear
as significant drawbacks in industrial applications. To
circumvent these problems Albaneze-Walker introduced
imidazolylsulfonates as a triflate alternative for Suzuki
coupling.11 The stable arylimidazolylsulfonates are easily
prepared and straightforwardly transformed in the palladium-
catalyzed coupling. In addition, the formed imidazole-
sulfonic acid hydrolyzes during the workup to produce
imidazole and sulfuric acid instead of toxic trifluoromethane-
sulfonic acid.
HMDS to get TMS-protected bromophenols. After
lithiation with BuLi, the formed o-silyl lithium phenolate
intermediate can be reacted with sulfonyldiimidazole
to obtain the new benzyne precursor (2). Through the
three-step synthesis, the target compounds can be
prepared without purification and isolation of any
intermediates.
Scheme 1. Synthesis of New Imidazolylsulfonate-Based Ben-
zyne Precursorsa
To exploit the advantages of imidazolylsulfonates
over triflates, we aimed to design a new benzyne pre-
cursor family for organic syntheses. In the first step
of the synthesis, o-bromophenols were silylated with
(3) (a) Xie, C.; Zhang, Y. Org. Lett. 2007, 9, 781–784. (b) Buszek,
K. R.; Luo, D.; Kondrashov, M.; Brown, N.; VanderVelde, D. Org.
Lett. 2007, 9, 4135–4137. (c) Garr, A. N.; Luo, D.; Brown, N.; Cramer,
C. J.; Buszek, K. R.; VanderVelde, D. Org. Lett. 2010, 12, 96–99. (d)
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. (e) Hamura, T.; Arisawa, T.; Matsumoto, T.; Suzuki, K.
Angew. Chem., Int. Ed. 2006, 45, 6842–6844. (f) Feltenberger, J. B.;
Hayashi, R.; Tang, Y.; Babiash, E. S. C.; Hsung, R. P. Org. Lett. 2009,
11, 3666–3669. (g) Ren, H.; Luo, Y.; Ye, S.; Wu, J. Org. Lett. 2011, 13,
2552–2555. (h) Jin, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2007, 46,
3323–3325. (i) Shi, F.; Waldo, J. P.; Chen, Y.; Larock, R. C. Org. Lett.
2008, 10, 2409–2412. (j) Zhang, F.; Moses, J. E. Org. Lett. 2009, 11,
1587–1590. (k) Dubrovskiy, A. V.; Larock, R. C. Org. Lett. 2010, 12,
1180–1183. (l) Spiteri, C.; Keeling, S.; Moses, J. E. Org. Lett. 2010, 12,
3368–3371. (m) Wu, C.; Fang, Y.; Larock, R. C.; Shi, F. Org. Lett. 2010,
12, 2234–2237. (n) Candito, D. A.; Panteleev, J.; Lautens, M. J. Am.
Chem. Soc. 2011, 133, 14200–14203. (o) Cant, A. A.; Bertrand, G. H. V.;
Henderson, J. L.; Roberts, L.; Greaney, M. F. Angew. Chem., Int. Ed.
2009, 48, 5199–5202. (p) Li, P.; Zhao, J.; Wu, C.; Larock, R. C. Org. Lett.
2011, 13, 3340–3343.
a Key: (1) o-bromophenol derivative (5 mmol), HMDS (15 mmol),
THF, 70 °C; (2) nBuLi (5 mmol), THF, À84 °C; (3) SDI (7.5 mmol), rt;
(b) synthesis of 2f: 2-hydroxy-3-trimethylsilylpyridine (0.6 mmol), SDI
(0.9 mmol), Cs2CO3 (0.3 mmol) in THF at rt.
Scheme 2. Pericyclic Reactions of Sulfonylimidazolyl-Based
Benzyne Precursor with Heterocyclic DienesaÀc
~
ꢀ
ꢀ
(4) (a) Caeiro, J.; Pena, D.; Cobas, A.; Perez, D.; Guitian, E. Adv.
Synth. Catal. 2006, 348, 2466–2474. (b) Sato, Y.; Tamura, T.; Kinbara,
A.; Mori, M. Adv. Synth. Catal. 2007, 349, 647–661. (c) Liu, Y.-L.;
Liang, Y.; Pi, S.-F.; Huang, X.-C.; Li, J.-H. J. Org. Chem. 2009, 74,
3199–3202. (d) Worlikar, S. A.; Larock, R. C. Org. Lett. 2009, 11, 2413–
2416. (e) Liu, Z.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2005, 127,
15716–15717. (f) Jeganmohan, M.; Bhuvaneswari, S.; Cheng, C.-H.
Angew. Chem., Int. Ed. 2009, 48, 391–394. (g) Henderson, J. L.;
Edwards, A. S.; Greaney, M. F. Org. Lett. 2007, 9, 5589–5592.
(h) Liu, Z.; Larock, R. C. Angew. Chem., Int. Ed. 2007, 46, 2535–2538.
(i) Pi, S.-F.; Tang, B.-X.; Li, J.-H.; Liu, Y.-L.; Liang, Y. Org. Lett. 2009, 11,
2309–2312. (j) Gerfaud, T.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2009,
48, 572–577. (k) Dong, C.-G.; Hu, Q.-S. Org. Lett. 2006, 8, 5057–5060.
(l) Worlikar, S. A.; Larock, R. C. Curr. Org. Chem. 2011, 15, 3214–3232.
(5) (a) Gampe, C. M.; Carreira, E. M. Angew. Chem., Int. Ed.
201210.1002/anie.201107485. (b) Tadross, P. M.; Stoltz, B. M. Chem.
Rev. 201210.1021/cr200478h. (c) SemmeIhack, M. F.; Chong, B. P.; Jones,
L. D. J. Am. Chem. Soc. 1972, 94, 8629–8630. (d) Gillespie, J. P.; Amros,
L. G.; Stermitz, F. R. J. Org. Chem. 1974, 39, 3239–3241. (e) Ilda, H.;
Aoyagi, S.; Kibayashi, C. J. Chem. Soc. Perkin Trans. 1 1975, 2502–
2566. (f) Townsend, C. A.; Davis, S. G.; Christensen, S. B.; Link, J. C.;
Lewis, C. P. J. Am. Chem. Soc. 1981, 103, 6885–6888. (g) Watanabe, M.;
Kurosaki, A.; Furukawa, S. Chem. Pharm. Bull. 1984, 32, 1264–1267.
(h) Atanes, N.; Castedo, L.; Guitian, E.; Saa, C.; Saa, J. M.; Suau, R.
J. Org. Chem. 1991, 56, 2984–2988. (i) Perez, D.; Guitian, E.; Castedo, L.
J. Org. Chem. 1992, 57, 5911–5917. (j) Matsumoto, T.; Hosoya, T.;
Suzuki, K. J. Am. Chem. Soc. 1992, 114, 3568–3570. (k) Shair, M. D.;
Yoon, T. Y.; Mosny, K. K.; Chou, T. C.; Danishefsky, S. J. J. Am. Chem.
Soc. 1996, 118, 9509–9525. (l) Kita, Y.; Higuchi, K.; Yoshida, Y.; Iio, K.;
Kitagaki, S.; Ueda, K.; Akai, S.; Fujioka, H. J. Am. Chem. Soc. 2001,
123, 3214–3222. (m) Tambar, U. K.; Ebner, D. C.; Stoltz, B. M. J. Am.
Chem. Soc. 2006, 128, 11752–11753. (n) Soorukram, D.; Qu, T.; Barrett,
A. G. M. Org. Lett. 2008, 10, 3833–3835. (o) Allan, K. M.; Stoltz, B. M.
J. Am. Chem. Soc. 2008, 130, 17270–17271. (p) Buszek, K. R.; Brown,
N.; Luo, D. Org. Lett. 2009, 11, 201–204. (q) Tadross, P. M.; Virgil,
S. C.; Stoltz, B. M. Org. Lett. 2010, 12, 1612–1614.
a Reaction with furan: aryne precursor (0.5 mmol), furan
(0.8 mmol), CsF (1 mmol), MeCN, 40 °C. b Reaction with N-Boc-
pyrrole: aryne precursor (0.5 mmol), N-Boc-pyrrole (1 mmol),
CsF (1 mmol), MeCN, 60 °C. c Key: aryne precursor (0.8 mmol),
2-(furan-2-ylmethoxy)tetrahydro-2H-pyran (0.4 mmol), CsF (1.6 mmol),
MeCN, 40 °C.
(6) (a) Friedman, L.; Logullo, F. M. J. Am. Chem. Soc. 1963, 85,
1549–1550. (b) Logullo, F. M.; Seitz, A. H.; Friedman, L. Org. Synth.
1968, 48, 12–17. (c) For a mechanistic study, see: Buxton, P. C.; Fensome,
M.; Heaney, H.; Mason, K. G. Tetrahedron 1995, 51, 2959–2968.
(7) Kitamura, T.; Yamane, M. J. Chem. Soc., Chem. Commun. 1995,
983–984.
(8) Campbell, C. D.; Rees, J. J. Chem. Soc. 1969, 742–747.
(9) Matsumoto, T.; Hosoya, T.; Katsuki, M.; Suzuki, K. Tetrahedron
Lett. 1991, 32, 6735–6736.
(10) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
1211–1214.
Org. Lett., Vol. 14, No. 8, 2012
2023

Utilizing the procedure, we prepared six different pre-
cursors (Scheme 1) including the basic compound (2a) and
mono (2b) and difluoro (2e) derivatives. Molecules with
electron-donating methyl (2d) or 1,3 dioxolyl groups (2c)
was also prepared in good yield considering the three-step
synthesis. A heterocyclic precursor such as 3-(trimethylsilyl)-
pyridin-2-yl imidazolsulfonate (2f) was synthesized from
2-hydroxy-3-trimethylsilylpyridine and sulfonyldiimida-
zole in the presence of Cs2CO3.
Scheme 3. Synthesis of Benzotriazolesa
With diverse imidazolylsulfonate-based precursors in
hand, we aimed to demonstrate their applicability in
different types of cycloaddition reactions where benzynes
are key intermediates.12
First, to prove the applicability of the new precursor in
benzyne chemistry, we performed several cycloadditions
with dienes such as furans and N-Boc-pyrrole (Scheme 2).
To our delight, we proved the formation of the benzyne
with successful trapping of this reactive intermediate with
both heterocyclic dienes in pericyclic reaction. Reaction of
Boc-pyrrole afforded the appropriate cycloadduct (3a)
with 60% yield. Reaction with the methyl-substituted
precursor gave a similar result, and product 3b was ob-
tained with 50% yield. Reaction of furans gave results
similar to those obtained with pyrroles, and we obtained
the bridged heterocycles 3cÀe bearing substituents
delivered either by the precursor or the furan.
a Key: aryne precursor (0.34 mmol), azide (1.02 mmol), CsF (1.02
mmol), MeCN, 60 °C.
After the first successful demonstration of the applic-
ability of our new precursor in benzyne chemistry, we
sought current synthetic transformations in which o-tri-
methylsilyl triflates are used as precursors.
A cycloaddition reaction of benzynes with azides gave
benzotriazoles ina straightforward mannerasdescribed by
Larock and co-workers.3i First, the unsubstituted sulfony-
limidazolyl (2a) precursor was reacted with several azides
in MeCN at 60 °C. As expected, the appropriate benzo-
triazoleproductswereisolatedwith37À76% yield depend-
ing on the functional groups attached to nitrogen atom of
the benztriazol ring.
3-(trimethylsilyl)pyridin-2-yl imidazolylsulfonate (2f) gave
3-benzyltriazolopyridine (4j) regioselectively.
To compare the reactivity of 2-(trimethylsilyl)phenyl
triflate and imidazolylsulfonate in this cycloaddition, we
monitored their reactions with benzyl azide. The compara-
tive studies showed that both precursors had similar
reactivity under the applied conditions.14
We continued our investigations into the formation of
3-aryl-substituted indazoles as an important heterocyclic
compound family to demonstrate the synthetic applicabil-
ity of our benzyne precursor.
N-Benzyl-substituted benzotriazole(4a) was synthesized
with 69% yield, while the presence of a long alkyl chain
increased the yield of the appropriate product (4b)
(Scheme 3). The cycloaddition can be achieved successfully
also with other alkyl azides bearing chloride and ester
functional groups (4c, 4e).
Scheme 4. Synthesis of Indazolesa
Only the thioether (4d) was obtained in moderate yield.
Precursors with fluoro or methyl functionality gave regioi-
someric mixtures of 5- and 6-substituted benzotriazoles 4f
and 4g in 1:1 and 7:3 ratios, respectively.13 Electron-rich
disubstituted precursor 2c provided a better yield of the
appropriate benzotriazole (4i) than 2e bearing two fluo-
ride groups. Reaction of benzyl azide and heterocyclic
(11) Albaneze-Walker, J.; Raju, R.; Vance, A. J.; Goodman, J. A.;
Reeder, R. M.; Liao, J.; Maust, T. M.; Irish, A. P.; Espino, P.; Andrews,
R. D. Org. Lett. 2009, 11, 1463–1466.
(12) Besides cyloaddition, we reacted the benzyne precursor 2a with
phenol as a simple nucleophile, and diphenyl ether was isolated in 79%
yield after the reaction.
(13) Cheong, P. H.-Y.; Paton, R. S.; Bronner, S. M.; Im, G-Y. J.;
Garg, N. K.; Houk, K. N. J. Am. Chem. Soc. 2010, 132, 1267–1269.
a Key: tosylhydrazone (0.4 mmol), aryne precursor (0.48 mmol),
TEBAC (0.1 mmol), CsF (1.2 mmol), THF, 70 °C.
2024
Org. Lett., Vol. 14, No. 8, 2012

Applying Larock’s conditions3p for the reaction of
trimethylsilyl imidazolesulfonates with N-tosylhydra-
zones, we were able to prepare several indazoles bearing
electron-withdrawing and electron-donating substituents
on the phenyl ring in position 3 (Scheme 4, 5aÀe). The
presence of a 1,3-dioxolyl group in the benzyne precursor
did not affect the reaction, and the appropriate indazole
was obtained with a yield similar to obtained for the
unsubstituted derivative.
As described by Tambar and Stoltz, o-acyl alkylation of
the aromatic ring takes place straightforwardly when
benzyne is generated from o-silyl-aryltriflates in the pre-
sence of β-ketoesters.2b
All the representative reactions gave the appropriate acy-
lalkylated product with good to excellent yield (Scheme 5,
6aÀd).
Summarizing our results, we designed and developed a
new benzyne precursor family as a good alternative for
o-silyl phenyltriflate due to its stability and easy handling
properties. The sulfonylimidazol based precursors were
conveniently prepared from o-bromophenols in a sim-
ple multistep procedure without the isolation of any
intermediate. The formation of imidazolesulfonic acid
in the reaction eliminates the problems of potentially
genotoxic trifluoromethyl sulfonates because of its hy-
drolytic cleavage to imidazole and sulfuric acid after
aqueous workup. We demonstrated that the sulfonyli-
midazole-based benzyne precursors could be success-
fully utilized in several transformations, and their
observed reactivity offers a good alternative for ben-
zyne generation in addition to the widely used o-tri-
methylsilylaryl triflates.
Scheme 5. Acyl Alkylation of Benzynea
Acknowledgment. We thank Sanofi for the generous
research support and Graduate Scholarship for Sz.K. The
€ €
ꢀ
aidofProf K. Torkos (Eotvos LorandUniversity, Institute
€ €
ꢀ
of Chemistry) and Dr. Zs. Eke (Eotvos Lorand University,
Institute of Chemistry) in providing the necessary analy-
tical background is gratefully acknowledged. This work
was supported by OTKA-NKTH (CK 80763). The European
Union and the European Social Fund have provided
financial support to the project under Grant Agreement
ꢀ
No. TAMOP 4.2.1./B-09/KMR-2010-0003.
a Key: aryne precursor (0.5 mmol), β-ketoester derivative (0.4 mmol)
and CsF (1 mmol) were stirred in MeCN at 80 °C.
Supporting Information Available. Experimental pro-
cedures, characterization data, and NMR spectra for all
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
Adopting the conditions of Stoltz, we prepared several
compounds from our sulfonylimidazolyl-based precursor.
(14) For further details, see the Supporting Information.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
2025