a comprehensive classification of heterocyclic mesomeric be-
taines was proposed in 1985 by Ollis et al.1 According to this
classification, all heterocyclic mesomeric betaines can be divided
into four classes on the basis of distinct types of conjugation
present in these heteroaromatics. These are the classes of (i)
conjugated mesomeric betaines (CMB), (ii) cross-conjugated
mesomeric betaines (CCMB), (iii) pseudo-cross-conjugated
heterocyclic mesomeric betaines (PCCMB), and (iv) 1,2-ylidic
systems (N-ylides, N-oxides etc).1 This classification undoubt-
edly lead to a profound understanding of the chemical, biologi-
cal, and physical properties of individual members of this class
of compounds,3 although very little information on PCCMB has
been available to date. Conjugated mesomeric betaines (CMB)
are by far the best investigated. Their characteristic capability
to undergo 1,3-cycloadditions was applied in total syntheses of
numerous alkaloids, for example, of ipalbidine,4 δ-coniceine,5
septicine,6 vallesamidine,7 lycopodine,8 onychine9 (via iso-
mu¨nchnones), alloyohimbane,10 and lysergic acid7 (via isothio-
mu¨nchnones). Cross-conjugated heterocyclic mesomeric betaines
(CCMB) predominantly undergo 1,4-cycloadditions,11 and this
property was applied recently for the synthesis of the isos-
chizozygane alkaloid core.12 The rich chemistry of CMB and
CCMB contrasts with a remarkable lack of knowledge with
respect to pseudo-cross-conjugated systems (PCCMB). In 1985,
only three examples of PCCMB were known,1 and except for
two contributions by Potts13 no systematic investigations have
been performed. Meanwhile it was recognized that PCCMB are
relatively widespread in nature (homarine,15 nigellicine,16 and
others14). Moreover it was found that pseudo-cross-conjugation
is the condition for the formation of N-heterocyclic carbenes
(NHC) by extrusion reactions17,18 and that in a reverse process
Translation of Pseudo-Cross-Conjugation into
Chemistry: Cycloadditions of Mesomeric
Betaines to the New Ring System
Spiro[indazole-3,3′-pyrrole]
Andreas Schmidt,*,† Tobias Habeck,† Anika Sabine Lindner,†
Bohdan Snovydovych,† Jan Christoph Namyslo,†
Arnold Adam,‡ and Mimoza Gjikaj‡
Institute of Organic Chemistry, Leibnizstrasse 6, and Institute of
Inorganic Chemistry, Paul-Ernst-Strasse 4, Clausthal UniVersity
of Technology, D-38678 Clausthal-Zellerfeld, Germany
ReceiVed NoVember 21, 2006
(3) Schmidt, A. Curr. Org. Chem. 2004, 8, 653.
(4) Sheehan, S. M.; Padwa, A. J. Org. Chem. 1997, 62, 438.
(5) Straub, C. S.; Padwa, A. Org. Lett. 1999, 1, 83.
(6) Padwa, A.; Sheehan, S. M.; Straub, C. S. J. Org. Chem. 1999, 64,
8648.
(7) Marino, J. P.; Osterhout, M. H.; Padwa, A. J. Org. Chem. 1995, 60,
2704.
(8) Padwa, A.; Brodney, M. A.; Marino, J. P., Jr.; Sheehan, S. M. J.
Org. Chem. 1997, 62, 78.
(9) Padwa, A.; Heidelbaugh, T. M.; Kuethe, J. T. J. Org. Chem. 2000,
65, 2368.
Indazolium-3-amidates (X-ray analysis), readily available on
trapping the N-heterocyclic carbene indazol-3-ylidene with
isocyanates, underwent [3 + 2]-cycloadditions with activated
triple bonds to spiro[indazole-3,3′-pyrroles]. A combination
of NMR techniques such as heteronuclear single quantum
coherence (HSQC), heteronuclear multiple bond correlation
(HMBC), nuclear Overhauser enhancement spectroscopy
(NOESY), and 1H/15N correlations were applied to elucidate
the structures of the cycloadducts.
(10) Heidelbaugh, T. M.; Liu, B.; Padwa, A. Tetrahedron Lett. 1998,
39, 4757.
(11) (a) Potts, K. T.; Rochanapruk, T.; Padwa, A.; Coats, S. J.;
Hadjiarapoglou, L. J. Org. Chem. 1995, 60, 3795. (b) Padwa, A.; Coats, S.
J.; Semones, M. A. Tetrahedron 1995, 51, 6651. (c) Padwa, A.; Coats, S.
J.; Semones, M. A. Tetrahedron Lett. 1993, 34, 5405. (d) Kappe, T.
Heterocycles 1984, 21, 358.
(12) Padwa, A.; Flick, A. C.; Lee, H. I. Org. Lett. 2005, 7, 2925.
(13) (a) Potts, K. T.; Murphy, P. M.; Kuehnling, W. R. J. Org. Chem.
1988, 53, 2889. (b) Potts, K. T.; Murphy, P. M.; DeLuca, M. R.; Kuehnling,
W. R. J. Org. Chem. 1988, 53, 2898.
(14) Schmidt, A. AdV. Heterocycl. Chem. 2003, 85, 67.
(15) (a) Polychronopoulos, P.; Magiatis, P.; Skaltsounis, A.-L.; Tillequin,
F.; Vardala-Theodorou, E.; Tsarbopoulos, A. Nat. Prod. Lett. 2001, 15,
411. (b) Nishitani, H.; Kikushi, S.; Okumura, K.; Taguchi, H. Arch. Biochim.
Biophys. 1995, 322, 327. (c) Davis, A. R.; Targett, N. M.; McConnell, O.
J.; Young, C. M. Bioorg. Marine Chem. 1989, 3, 85. (d) Berking, S.
DeVelopment 1987, 99, 211.
(16) Atta-ur-Rahman, Malik, S.; Cun-heng, H.; Clardy, J. Tetrahedron
Lett. 1985, 26, 2759.
(17) Schmidt, A.; Beutler, A.; Habeck, T.; Mordhorst, T.; Snovydovych,
B. Synthesis 2006, 1882.
(18) (a) Schmidt, A.; Habeck, T.; Merkel, L.; Ma¨kinen, M.; Vainiotalo,
P. Rapid Commun. Mass Spectrom. 2005, 19, 2211. (b) Schmidt, A.; Merkel,
L.; Eisfeld, W. Eur. J. Org. Chem. 2005, 2124.
Heterocyclic mesomeric betaines (HMB) are defined as
neutral conjugated molecules that can exclusively be represented
by dipolar canonical formulas in which both the negative and
the positive charges are delocalized within a common π-electron
system.1 For decades, nomenclature (mesoion, ylide, sydnone,
mu¨nchnone, inner salt) as well as adequate representation of
these molecules was controversal. After first systematizations,2
* Corresponding author: fax +49-(0)5323-722858; tel +49-(0)5323-723861.
† Institute of Organic Chemistry.
‡ Institute of Inorganic Chemistry.
(1) Ollis, W. D.; Stanforth, S. P.; Ramsden, C. A. Tetrahedron 1985,
41, 2239.
(2) (a) Katritzky, A. R. Chem. Ind. 1955, 521. (b) Ochiai, E. In Aromatic
Amine Oxides; Elsevier: Amsterdam, 1967. (c) Katritzky, A. R.; Lagowski,
J. M. In The Chemistry of Heterocyclic N-Oxides; Academic Press, New
York, 1971. (d) Zugravesku, I.; Petrovanu, M. In N-Ylide Chemistry;
McGraw-Hill: New York, 1976. (e) Ramsden, C. A. J. Chem. Soc., Chem.
Commun. 1977, 109.
10.1021/jo062391r CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/24/2007
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J. Org. Chem. 2007, 72, 2236-2239