cations are sufficiently electrophilic that they may be attacked
by nucleophiles even as weak as simple
In a preliminary experiment (Scheme 1), we treated the
simple anilide 1a, formed in one step from isonicotinoyl
chloride and m-anisidine, with triflic anhydride at -30 °C.
Warming to 0 °C returned 20% of the spirocyclic dihydro-
pyridine 2a.
arenes.5Dearomatizing addition of arenes to the N-triflyl pyri-
dinium salts yields 4-aryl-1,4-dihydropyridines. The fact that
N-sulfonylpyridinium cations may be trapped in situ by nu-
cleophiles which are unreactive toward the sulfonylating agent
raised the possibility that cyclization reactions of pyridines
containing a tethered latent nucleophile may be successful
Scheme 1. Spirocyclization of an N-Anisylisonicotinamide
The favored conformation of secondary anilides such as
1a places the two aryl rings trans to one another, but their
tertiary analogues prefer conformations in which the two
rings lie cis8 and are therefore better orientated for cycliza-
tion. We therefore repeated the cyclization with 1a’s N-
methylated analogue 1b (Table 1, entry 2). The yield of
Figure 1. Dihydropyridines by dearomatizing (a) addition (ref 5)
and (b) spirocyclization (this work).
(Figure 1).6 In this paper, we show that the target spirocycles
are formed when dearomatizing cyclization7 of an N-arylisoni-
cotinamide is triggered by N-sulfonylation in the presence of a
hindered base. The reaction generates valuable benzo-fused
spirocyclic dihydropyridines.
Table 1. Optimizing the Spirocyclization
starting
yield
(%)
entry
material 1
R )
additive
product 2
1
2
3
4
5
6
1a
1b
1b
1b
1b
1c
H
2a
2b
2b
2b
2b
2c
20
47
54
70
99
87
Me
Me
Me
Me
Bn
(4) For leading references, see: Arnott, G.; Clayden, J.; Hamilton, S. D.
Org. Lett. 2006, 8, 5325. Lemire, A.; Beaudoin, D.; Grenon, M.; Charette,
A. B. J. Org. Chem. 2005, 70, 2368. Comins, D. L.; Sahn, J. J. Org. Lett.
2005, 7, 5227. Kuethe, J. T.; Comins, D. L.; King, L.; Smith, E.; Fevrier,
F. Org. Lett. 2005, 7, 5059. Comins, D. L. J. Org. Chem. 2004, 69, 5221.
Bennasar, M.-L.; Zulaica, E.; Alonso, Y.; Bosch, J. Tetrahedron: Asymmetry
2003, 14, 469. Wang, X.; Kauppi, A.; Olsson, R.; Almqvist, F. Eur. J.
Org. Chem. 2003, 4586. Yamada, S.; Morita, C. J. Am. Chem. Soc. 2002,
124, 8184. Pabel, J.; Ho¨sl, C.; Maurus, M.; Ege, M.; Wanner, K J. Org.
Chem. 2002, 65, 9272. Ho¨sl, C.; Maurus, M.; Pabel, J.; Polborn, K.; Wanner,
K. Tetrahedron 2002, 58, 6757. Comins, D. L.; Zheng, X.; Goehring, R. R.
Org. Lett. 2002, 4, 1622. Charette, A. B.; Grenon, M.; Lemire, A.;
Pourashraf, M.; Martel, J. J. Am. Chem. Soc. 2001, 123, 11829. Bennasar,
M. L.; Juan, C.; Bosch, J. Tetrahedron Lett. 2001, 42, 585. Rezgui, F.;
Mangeney, P.; Alexakis, A. Tetrahedron Lett. 1999, 40, 6241. Bennasar,
M.; Jimenez, J-M.; Vidal, B.; Sufi, A.; Bosch, J. J. Org. Chem. 1999, 64,
9605. Bennasar, M. L.; Juan, C.; Bosch, J. Tetrahedron Lett. 1998, 39,
9275. Lavilla, R.; Gotsens, G.; Gu¨ero, M.; Masdeu, C.; Santano, C.;
Minguillon, C.; Bosch, J. Tetrahedon 1997, 53, 13959. Bosch, J.; Bennasar,
M.-L. Synlett 1995, 587.
Et3N
DMAP
pyridine
2,6-lutidine
spirocyclic product obtained increased to 47%. Extending
the reaction time led to decomposition, and reasoning that
this was caused by the triflic acid generated during the
reaction, we repeated the cyclization in the presence of a
series of bases (Table 1, entries 3-6). Satisfyingly, with
pyridine the yield of the cyclized dihydropyridine 2b
increased to 99% (Table 1, entry 5). Likewise, cyclization
of the N-benzyl anilide 1c in the presence of 2,6-lutidine
gave 2c in 87% yield (Table 1, entry 6).9The X-ray crystal
structure of 2b is illustrated in Figure 2.10
(5) Corey, E. J.; Tian, Y. Org. Lett. 2005, 7, 5535.
(6) For early examples of intramolecular trapping of N-alkyl pyridinium
salts, see: Weller, D. D.; Luellen, G. R. Tetrahedron Lett. 1981, 22, 4381.
Weller, D. D.; Stirchak, E. P.; Weller, D. L. J. Org. Chem. 1983, 48, 4597.
(7) For a general discussion of dearomatizing cyclization reactions, see:
Ort´ız, F. L.; Iglesias, M. J.; Ferna´ndez, M. J.; Sa´nchez, C. M. A.; Go´mez,
G. R. Chem. ReV. 2007, 107, 1580. Clayden, J. In Strategies and Tactics in
Organic Synthesis; Harmata, M., Ed.; Academic Press: New York, 2004;
Vol. 4, pp 72-96. Clayden, J.; Knowles, F. E.; Baldwin, I. R. J. Am. Chem.
Soc. 2005, 127, 2412. Ahmed, A.; Bragg, R. A.; Clayden, J.; Tchabanenko,
K. Tetrahedron Lett. 2001, 42, 3407. Bragg, R. A.; Clayden, J.; Bladon,
M.; Ichihara, O. Tetrahedron Lett. 2001, 42, 3411. Clayden, J.; Menet, C. J.;
Mansfield, D. J. Chem. Commun. 2002, 38. Ahmed, A.; Clayden, J.; Rowley,
M. Synlett 1999, 1954. Dearomatizing cyclization onto unactivated het-
eroaromatic rings has been reported: see (for cyclization onto pyridines):
Clayden, J.; Hamilton, S. D.; Mohammed, R. T. Org. Lett. 2005, 7, 3673.
(cyclization onto pyrroles): Clayden, J.; Turnbull, R.; Pinto, I. Org. Lett.
2004, 6, 609. (cyclization onto thiophenes): Clayden, J.; Turnbull, R.;
Helliwell, M.; Pinto, I. Chem. Commun. 2004, 2430.
A range of variously substituted anilide starting materials
3-8 were made and treated with electrophiles under similar
conditions to establish the scope of the cyclization reaction
to 9-14 (Scheme 2 and Table 2). In general, electron-rich
anilides 3-5 performed the most satisfactorily (Table 2,
(8) Itai, A.; Toriumi, Y.; Saito, S.; Kagechika, H.; Shudo, K. J. Am.
Chem. Soc. 1992, 114, 10649. Azumaya, I.; Kagechika, H.; Fujiwara, Y.;
Itoh, M.; Yamaguchi, K.; Shudo, K. J. Am. Chem. Soc. 1991, 113, 2833.
(9) Although pyridine gave an excellent yield of 2b, we found
2,6-lutidine to be generally more applicable to less reactive substrates.
(10) X-ray crystal data for 2b have been deposited with the Cambridge
Crystallographic Data Centre, deposition nno. 676939.
(11) H-cubeTM manufactured by ThalesNano. See: Desai, B.; Kappe,
O. J. Comb. Chem. 2005, 7, 641.
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