cycloaddition sequence to prepare indazolo[3,2-a]isoquinolines
has been realized. At this minute, certain limitations still exist
and need to be addressed in future studies, including the poor
results obtained from electron-rich pyridinium imides, as well as
the poor regioselectivity for the 3-substituted substrates. None-
theless, these methods provide a reasonable approach to the
pyrido[1,2-b]indazole and indazolo[3,2-a]isoquinoline scaffolds,
and potential applications in library synthesis can be expected.
Scheme 5 One-pot iodocyclization–cycloaddition sequence to 5-
iodoindazolo[3,2-a]isoquinolines.
Acknowledgements
This project was financially supported by the National Natural
Science Foundation of China (No. 21002021 to F.S.), the
Key Project of the Chinese Ministry of Education (No. 210127
to F.S.), and Henan University (to C.W. and F.S.). We thank Dr
Jiang Zhou (Peking University) and Prof. Zheng Duan (Zhengz-
hou University) for their help with the spectroscopic analysis.
Notes and references
1 Y. Himeshima, T. Sonoda and H. Kobayashi, Chem. Lett., 1983, 1211.
2 (a) T. Jin and Y. Yamamoto, Angew. Chem., Int. Ed., 2007, 46, 3323;
(b) Z. Liu, F. Shi, P. D. G. Martinez, C. Raminelli and R. C. Larock, J.
Org. Chem., 2008, 73, 219; (c) F. Shi, J. P. Waldo, Y. Chen and R.
C. Larock, Org. Lett., 2008, 10, 2409; (d) C. Wu, Y. Fang, R. C. Larock
and F. Shi, Org. Lett., 2010, 12, 2234.
Scheme 6 A cycloaddition–cyclization sequence from 17 to 14.
3 (a) A. V. Dubrovskiy and R. C. Larock, Org. Lett., 2010, 12, 1180;
(b) C. Spiteri, P. Sharma, F. Zhang, S. J. F. Macdonald, S. Keeling and
J. E. Moses, Chem. Commun., 2010, 46, 1272; (c) C. Spiteri, S. Keeling
and J. E. Moses, Org. Lett., 2010, 12, 3368.
4 (a) H. Ren, Y. Luo, S. Ye and J. Wu, Org. Lett., 2011, 13, 2552;
(b) D. McAusland, S. Seo, D. G. Pintori, J. Finlayson and M. F. Greaney,
Org. Lett., 2011, 13, 3667.
5 For closely related studies, see: (a) C. Raminelli, Z. Liu and
R. C. Larock, J. Org. Chem., 2006, 71, 4689; (b) X. Huang and
T. Zhang, Tetrahedron Lett., 2009, 50, 208.
6 These names are inconsistently used in literature. We prefer to use the
name of “pyridinium imide” after Huisgen. See: (a) R. Huisgen,
R. Grashey and R. Krischke, Tetrahedron Lett., 1962, 3, 387;
(b) R. Krischke, R. Grashey and R. Huisgen, Liebigs Ann., 1977, 498.
7 For a [3 + 2] cycloaddition of arynes with azomethine imines, see: F. Shi,
R. Mancuso and R. C. Larock, Tetrahedron Lett., 2009, 50, 4067.
8 For reviews, see: (a) H.-J. Timpe, Adv. Heterocycl. Chem., 1974, 17, 213;
(b) Y. Tamura and M. Ikeda, Adv. Heterocycl. Chem., 1981, 29, 71.
9 (a) R. Huisgen, Angew. Chem., 1963, 75, 621; (b) V. Boekelheide and
N. A. Fedoruk, J. Org. Chem., 1968, 33, 2062; (c) T. Sasaki,
K. Kanematsu and Y. Yukimoto, J. Chem. Soc. C, 1970, 481.
10 (a) T. Okamoto, M. Hirobe and Y. Tamai, Chem. Pharm. Bull., 1963, 11,
1089; (b) T. Okamoto, M. Hirobe, C. Mizushima and A. Ohsawa, Chem.
Pharm. Bull., 1963, 11, 781.
11 It has been suggested that N-acyl variants do not work under the 1,3-
dipolar cycloadditions. See: H. G. O. Becker, N. Sauder and H.-
J. Timple, J. Prakt. Chem., 1969, 311, 897.
12 (a) T. Sasaki, K. Kanematsu and A. Kakehi, J. Org. Chem., 1971, 36,
2978; (b) Y. Tamura, Y. Miki, K. Nakamura and M. Ikeda, J. Heterocycl.
Chem., 1976, 13, 23; (c) C. W. Rees, R. W. Stephenson and R. C. Storr,
J. Chem. Soc., Chem. Commun., 1974, 941.
Another route from 17 to 14: a cycloaddition–cyclization
sequence
The potential application of the [3 + 2] cycloaddition of arynes
with in situ generated N-tosylisoquinolinium imides intrigued us
to move yet another step forward. The N-tosylhydrazone moiety
of the structure 17 has been demonstrated to react with arynes in
a [3 + 2] annulation fashion, partly through an in situ generated
diazo intermediate.34 If the same event could occur to compound
17 in the presence of the internal alkyne, compound 18 could be
obtained. A subsequent yet unprecedented electrophilic cycliza-
tion35 could lead to the same product 14 as obtained from
the aforementioned cyclization–cycloaddition sequence (see
Scheme 6). This new protocol might provide another option for
the synthesis of the indazolo[3,2-a]isoquinoline scaffold.
Thus, substrate 17a was first examined under the reaction con-
ditions optimized for the annulation between arynes and N-tosyl-
hydrazones.34 Delightfully, the process afforded a 77% yield of
product 18, where the internal alkyne moiety was unreactive.
Compound 18, upon treatment with catalytic quantity of AgOTf,
smoothly and cleanly cyclized to 14b in a quantitative yield
(Scheme 6). Thus, this second route to indazolo[3,2-a]isoquino-
line proved also successful.
13 H. Beyer, K. Leverenz and H. Schilling, Angew. Chem., 1961, 73, 272.
14 J. Arriau, J. Deschamps, J. R. C. Duke, J. Epsztajn, A. R. Katritzky,
E. Lunt, J. W. Mitchell, S. Q. A. Rizvi and G. Roch, Tetrahedron Lett.,
1974, 15, 3865.
15 (a) M. W. Barker and W. E. McHenry, J. Org. Chem., 1979, 44, 1175;
(b) R. A. Abramovitch and I. Shinkai, J. Am. Chem. Soc., 1974, 96,
5265.
16 R. J. Sundberg and J. E. Ellis, J. Heterocycl. Chem., 1982, 19, 573.
17 pKa Value of benzenesulfinic acid: 7.1 in DMSO or 2.1 in water. See:
evans.harvard.edu/pdf/evans_pKa_table.pdf.
Conclusions
In conclusion, we have demonstrated that aryne [3 + 2] cyclo-
addition with N-tosylpyridinium imides can be a facile, effective,
and operationally simple route to pyrido[1,2-b]indazoles and
analogues. The sulfonyl group on the imide nitrogen was the key
to this reaction. The reaction can be well extended to N-tosyliso-
quinolinium imides generated in situ from N′-(2-alkynylbenzyli-
dene)tosylhydrazides, and a one-pot cyclization–aryne [3 + 2]
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