reaction conditions. However, to date, only linear dipoles
have been systematically investigated, and reactions with
cyclic dipoles have only been briefly examined using
diazotized anthranilic acid,9 which is difficult to handle.
Sydnone,10 as a representative stable and isolable cyclic 1,3-
dipole that itself bears interesting biological activity,11 has
been widely used in dipolar cycloadditions with various
dipolarophiles to yield important heterocyclic products.12
Unlike linear 1,3-dipoles, sydnone, as well as some other
mesoionic rings, affords a bicyclic adduct that is typically
unstable after cycloaddition. That adduct typically readily
undergoes spontaneous extrusion of a molecule of CO2 in a
retro-[4 + 2] fashion to reestablish a planar structure with a
reorganization of electrons. Hence, the reaction of sydnones
with arynes (Scheme 1)9 would be an ideal method to
The most easily accessed sydnone, N-phenylsydnone
(2a),13a has first been investigated as a representative
substrate to test the feasibility of the reaction (Table 1).
Table 1. Reaction Optimizationa
1a
fluoride
temp (°C), yieldb
entry (equiv) source (equiv) solvent
time (h)
(%)
1
2
1.5
1.5
1.5
1.5
1.2
1.2
CsF (2.5)
CsF (2.5)
TBAF (2.5)
TBAF (2.5)
TBAF (1.6)
TBAF (1.6)
MeCN
THF
MeCN
THF
THF
THF
rt, 36
70, 24
rt, 12
rt, 12
rt, 12
rt, 12
69c
90
3d
4d
5d
6f
95e
94
98
97
Scheme 1. Proposed Cycloaddition of Sydnones and Arynes
a All reactions were carried out on 0.4 mmol of 2a at a concentration
of 0.1 M. b Isolated yield. c Incomplete conversion even after 2 days. d Solid
anhydrous TBAF was used. e The product is significantly yellow, although
no apparent impurity was detected by NMR spectroscopy. f A THF solution
(1 M) was used.
Table 2. Reaction with Other Aryne Precursorsa
produce the 2H-indazole skeleton and should provide further
insights into the underexplored reactivity of arynes in 1,3-
dipolar cycloaddition reactions.
The preparation of sydnones is readily achieved ac-
cording to literature procedures,13 albeit in variable yields.
(8) For others’ work in aryne 1,3-dipolar cycloadditions, see: (a) Jin,
T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2007, 46, 3323. (b) Zhang, F.;
Moses, J. E. Org. Lett. 2009, 11, 1587. (c) Chandrasekhar, S.; Seenaiah,
M.; Rao, C. L.; Reddy, C. R. Tetrahedron 2008, 64, 11325. (d) Bronner,
S. M.; Bahnck, K. B.; Garg, N. K. Org. Lett. 2009, 11, 1007. (e) Campbell-
Verduyn, L.; Elsinga, P. H.; Mirfeizi, L.; Dierckx, R. A.; Feringa, B. L.
Org. Biomol. Chem. 2008, 6, 3461. (f) Huang, X.; Zhang, T. Tetrahedron
Lett. 2009, 50, 208. (g) Huang, X.-C.; Liu, Y.-L.; Liang, Y.; Pi, S.-F.; Wang,
F.; Li, J.-H. Org. Lett. 2008, 10, 1525. (h) Wu, Q.-C.; Li, B.-S.; Lin,
W.-Q.; Shi, C.-Q.; Chen, Y.-W.; Chen, Y.-X. Hecheng Huaxue (Chin. J.
Synth. Chem.) 2007, 15, 292. (i) Spiteri, C.; Sharma, P.; Zhang, F.;
Macdonald, S. J. F.; Keeling, S.; Moses, J. E. Chem. Commun. 2010, 46,
1272.
(9) (a) Huisgen, R.; Grashey, R.; Gotthardt, H.; Schmidt, R. Angew. Chem.,
Int. Ed. 1962, 1, 48. (b) Lazarus, A. Y. Zhur. Org. Khim. 1966, 2, 1322.
(10) For reviews on sydnones, see: (a) Browne, D. L.; Harrity, J. P. A.
Tetrahedron 2010, 66, 553. (b) Stewart, F. H. C. Chem. ReV. 1964, 64,
129.
(11) (a) Wagner, H.; Hill, J. B. J. Med. Chem. 1974, 17, 1337. (b) Hill,
J. B.; Ray, R. E.; Wagner, H.; Aspinall, R. L. J. Med. Chem. 1975, 18, 50.
(c) Dunkley, C. S.; Thomas, C. J. Bioorg. Med. Chem. Lett. 2003, 13, 2899.
(d) Moustafa, M. A.; Gineinah, M. M.; Nasr, M. N.; Bayoumi, W. A. H.
Arch. Pharm. 2004, 337, 164. (e) Satyanarayana, K.; Rao, M. N. A. Eur.
J. Med. Chem. 1995, 30, 641.
a All reactions were carried out on 0.4 mmol of 2a at a concentration
of 0.1 M. b Isolated yield. c A 1:1 mixture of the 5-Me isomer and the 6-Me
isomer was obtained. d See the Supporting Information for the structure
assigment. A side product was also isolated.
(12) For selected examples, see: (a) Browne, D. L.; Helm, M. D.; Plant,
A.; Harrity, J. P. A. Angew. Chem., Int. Ed. 2007, 46, 8656. (b) Rai, N. S.;
Kalluraya, B.; Lingappa, B.; Shenoy, S.; Puranic, V. G. Eur. J. Med. Chem.
2008, 43, 1715. (c) Foster, R. S.; Huang, J.; Vivat, J. F.; Browne, D. L.;
Harrity, J. P. A. Org. Biomol. Chem. 2009, 7, 4052. (d) Harju, K.;
Vesterinen, J.; Yli-Kauhaluoma, J. Org. Lett. 2009, 11, 2219.
(13) (a) Thoman, C. J.; Voaden, D. J. Org. Synth. 1965, 45, 96. (b)
Baker, W.; Ollis, W. D.; Poole, V. D. J. Chem. Soc. 1950, 1542. (c)
Applegate, J.; Turnbull, K. Synthesis 1988, 1011. (d) Azarifar, D.;
Ghasemnejad-Borsa, H. Synthesis 2006, 1123. (e) Azarifar, D.; Ghasem-
nejad-Borsa, H.; Tajbaksh, M.; Habibzadeh, S. Heterocycles 2007, 71, 1815.
To our delight, this reaction proceeded readily, a range
of reaction conditions proved operational, and excellent
yields of the desired product, 2-phenyl-2H-indazole (3a),
could be realized. Somewhat surprisingly, however, the
arguably most widely used conditions for generating
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