ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Sequential 1,4- and 1,2-Addition Reactions
to r,β-Unsaturated N‑Acyliminium Ions:
A New Strategy for the Synthesis of
Spiro and Bridged Heterocycles
Arife Yazici and Stephen G. Pyne*
School of Chemistry, University of Wollongong, Wollongong, New South Wales, 2522,
Australia
Received October 13, 2013
ABSTRACT
Novel bicyclic and tetracyclic spirocycles and tricyclic bridged heterocyclic systems can be readily prepared from sequential 1,4- and 1,2-addition
reactions of latent bis-nucleophiles to r,β-unsaturated N-acyliminium ions.
N-Acyliminium ions are well establishedimportant reac-
tive intermediates in CÀC and CÀheteroatom bond form-
ing reactions.1 Both intermolecular1a,b,e,f and intramo-
lecular1aÀd,g versions have been extensively developed, the
latter variants providing access to novel polycyclic, spiro-
cyclic, and bridged heterocyclic ring structures. In stark
contrast, the chemistry of R,β-unsaturated N-acyliminium
ions (e.g., 1 in Scheme 1) is largely undeveloped.2À4 In
principle, these are attractive reactive intermediates for
the one-pot synthesis of novel difunctionalized hetero-
cycles, e.g. 2 (Scheme 1), because of their potential for
sequential 1,4- and 1,2-addition reactions with two nu-
cleophiles (Nu1 and Nu2) under acidic conditions. Sig-
nificantly, when these two nucleophiles are tethered or
latent bis-nucleophiles then novel spirocyclic and bridged
heterocycles 2 should be realized. These types of molecu-
lar architectures are common in bioactive natural
products,4 and therefore such a synthetic strategy would
be expected to provide valuable scaffolds for new drug
discovery and natural product synthesis programs. We
report here the realization of this approach and the
synthesis of new bi-, tri-, and tetraheterocyclic systems.
To examine the feasibily of this approach the R,β-
unsaturated N-acyliminium ion precursor 3a was treated
with allyltrimethylsilane (1.2 equiv) in the presence of
(1) For reviews on N-acyliminium ions, see: (a) Speckamp, W. N.;
Hiemstra, H. Tetrahedron 1985, 41, 4367–4416. (b) Speckamp, W. N.;
Moolenaar, M. J. Tetrahedron 2000, 56, 3817–3856. (c) Maryanoff,
B. E.; Zhang, H.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem.
Rev. 2004, 104, 1431–1628. (d) Gaskell, S. N.; Duffy, L. J.; Allin, S. M.
Nat. Prod. Commun. 2008, 3, 1825–1835. (e) Yazici, A.; Pyne, S. G.
Synthesis 2009, 339–368. (f) Yazici, A.; Pyne, S. G. Synthesis 2009, 513–
541. (g) Martinez-Estibalez, U.; Gomez-SanJuan, A.; Garcia-Calvo, O.;
Aranzamendi, E.; Lete, E.; Sotomayor, N. Eur. J. Org. Chem. 2011,
3610–3633.
(2) For DielsÀAlder reactions of R,β-unsaturated N-acyliminium
ions with dienes, see: (a) Zou, Y.; Che, Q.; Snider, B. B. Org. Lett.
€
2006, 8, 5605–5608. (b) O’Connor, P. D.; Korber, K.; Brimble, M. A.
Synlett 2008, 1036–1038.
(3) For addition reactions of nucleophiles to cyclic R,β-unsaturated
N-acyliminium ions derived from N-acyl-1,2-dihydropyridines, see: (a)
Kozikowski, A. P.; Park, P.-u. J. Org. Chem. 1984, 49, 1676–1678. (b)
Torii, S.; Inokuchi, T.; Takagishi, S.; Akahoshi, F.; Uneyama, K. Chem.
Lett. 1987, 639–642. (c) Hanson, G. J.; Russell, M. A. Tetrahedron Lett.
1989, 30, 5751–5754. (d) Alegret, C.; Riera, A. J. Org. Chem. 2008, 73,
8661–8664. (e) For an exocyclic version, see: O’Conner, P. D.; Marino,
BF3 Et2O (2.0 equiv) in CH2Cl2 solution at 0 °C to rt for
3
1 h. This reaction rapidly furnished the (E)-enamide 4a
(Scheme 2; see Supporting Information for this stereo-
chemical assignment). However, extended reaction times
(rt, 18 h) provided the novel spiro-tricyclic compound 5a in
ꢀ
M. G.; Gueret, S. M.; Brimble, M. A. J. Org. Chem. 2009, 74, 8893–8896.
(4) See for example: (a) Kotha, S.; Deb, A. C.; Lahiri, K.; Manivannan,
E. Synthesis 2009, 165–193. (b) Takao, K.-i.; Tadano, K.-i. Heterocycles
2010, 81, 1603–1629.
(5) The same results were obtained from employing 3aÀd either as a
mixture of diastereomers or as the pure major or minor diastereomer.
r
10.1021/ol4029513
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