been identified as effective organocatalysts.3 R-Oxo-
ketenes4 are well-known to react with nucleophiles to
produce 1,3-dicarbonyl compounds,5a but in sharp con-
trast with simple ketenes, they almost exclusively react as
1-oxadienes with unsaturations (XdY or CtX) in inverse
electron demand [4 þ 2] oxa-DielsꢀAlder cycloaddi-
tions.5b We have recently reported a switch of periselectiv-
ity in R-oxo-ketene six-electron cycloadditions, revealing
their reactivity as excellent dienophiles in [2 þ 4] aza-
DielsꢀAlder cycloadditions with 1-aza-dienes.5c Based
on this unique reactivity, we surmised that pyrazolidin-3-
one 6 could be obtained from the carbonyl compound 1,
the substituted hydrazine 2, and the diazo compound 3 in a
single catalyst-free domino three-component reaction as
follows: the rapid formation of hydrazone 4a, which upon
heating should undergo a 1,2-hydrogen shift to give the
corresponding azomethine imine 1,3-dipole 4b,6 followed
by Wolff rearrangement7 of 3 to 5, providing the two
partners of an original 1,3-dipolar cycloaddition leading
to the pyrazolidinone 6 (Scheme 1).
mixture of benzaldehyde, phenylhydrazine, and 5,5-di-
methyl-2-diazo-cyclohexan-1,3-dione (diazodimedone) in
toluene to microwave irradiation at 140 °C for 15 min
(ramp up time = 2 min), and rewardingly, the spiro
pyrazolidin-3-one 6a was obtained in 74% yield as the
only detectable regio- and diastereomer (Figure 1). A
slightly better yield of 6a (80%) was obtained when the
diazo compound was introduced after 10 min of reaction,
and the latter protocol (consecutive reaction) was pre-
ferred for this study. The reaction was found very general
and accommodates a broad range of each of the three
substrates (Figure 1): carbonyl compounds 1 can include
aromatic (e.g., in 6aꢀd), aliphatic (in 6e and 6f), and R,β-
unsaturated (in 6h) aldehydes as well as acyclic (in 6i and
6j), cyclic (in 6kꢀn), heterocyclic (in 6o), and functiona-
lized (in 6j) ketones; aryl- (e.g., in 6a), functionalized aryl-
(in 6m), heteroaryl- (in 6g), alkyl- (e.g., in 6l), and functio-
nalized alkyl- (in 6d) hydrazines 2 could be used without
noticeable change in efficiency; and finally six- (e.g., in 6a
and 6c) and seven-membered cyclic (in 6f and 6n) and
acyclic (in 6b and 6k) diazo compounds 3 revealed good
precursors of the corresponding R-oxo-ketenes. The struc-
tures of spiro pyrazolidinones 6h and 6i have been resolved
by X-ray diffraction analyses, which confirmed the chemo-,
regio- and stereochemical outcome of the reaction.8 No-
tably, in most cases the overall transformation allowed the
construction of a chiral all-carbon quaternary center9
adjacent to a second stereocenter with excellent control of
the diastereoselectivity. In the case of ketones, the con-
struction of two adjacent quaternary centers resulted in the
formation of interesting and challenging structures includ-
ing bis-spiro scaffolds (in 6lꢀo). The example of compound
6h is particularly interesting regarding the periselectivity of
6π electrocyclic processes with R-oxo-ketenes, the 1,3-dipo-
lar cycloaddition mode being preferred to the predictable
[4 þ 2] and [2 þ 4] modes.10 Our current understanding of
the reaction, which accounts for both the observed regio-
and diastereoselectivity, invokes a thermodynamically con-
trolled stepwise (or concerted very asynchronous) process
via disrotatory 6π electrocyclization of a zwitterionic species
as depicted in Scheme 2.11
Scheme 1. Planned Synthesis of Pyrazolidin-3-ones
The feasibility of the key 1,3-dipolar cycloaddition relies
on the unprecedented behavior of R-oxo-ketenes as effi-
cient dipolarophiles. Besides this, crucial for the success of
this synthetic plan is the faster formation of the hydrazone
4a comparedto the R-oxo-ketene 5 toavoid the irreversible
nucleophilic addition of hydrazine 2 to 5. Also, hydrolysis
of the R-oxo-ketene 5 with the water produced concomi-
tantly with the formation of the hydrazone 4a should be
avoided. In early experiments, we submitted a 1:1:1
(3) Reviews: (a) Claramunt, R. M.; Elguero, J. Org. Prep. Proced. Int.
1991, 23, 273. (b) Hanessian, S.; McNaughton-Smith, G.; Lombart,
H.-G.; Lubell, W. D. Tetrahedron 1997, 53, 12789. For organocatalytic
properties, see:(c) Gould, E.; Lebl, T.; Slawin, A. M. Z.; Reid, M.; Smith,
A. D. Tetrahedron 2010, 66, 8992 and references therein.
(4) Reviews: (a) Wentrup, C.; Heilmayer, W.; Kollenz, G. Synthesis
1994, 1219. (b) Kollenz, G.; Ebner, S. In Science of Synthesis: Houben-
Weyl methods of molecular transformations; Danheiser, R., Ed.; Georg
Thieme Verlag: Stuttgart, Germany, 2006; Vol. 23, Chapter 9, p 271.
(c) Reber, K. P.; Tilley, S. D.; Sorensen, E. J. Chem. Soc. Rev. 2009,
38, 3022.
(8) CCDC 800272 (6h), 800274 (6i), and 800273 (10a) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge via the Internet from The Cambridge Crystal-
(9) Quaternary Stereocenters: Challenges and Solutions for Organic
Synthesis; Christoffers, J., Baro, A., Eds.; Wiley-VCH: Weinheim, Germany,
2005.
(10) For examples of [4 þ 2] cycloadditions between R-oxo-ketenes
and hydrazono compounds, see: (a) Pulina, N. A.; Zalesov, V. V.;
Glebova, E. A. Chem. Heterocycl. Compd. 2002, 38, 1289. For examples
of [2 þ 4] cycloadditions of R,β-unsaturated hydrazones, see:(b) Waldner,
A. Helv. Chim. Acta 1989, 72, 1435.
(11) The enthalpies of formation obtained from DFT (B3LYP/6-
311G**) calculations (Gaussian) of the three possible products, i.e. the
pyrazolidinone 6h, the oxazinone A resulting from a [4 þ 2] cycloaddi-
tion, and the δ-lactam B resulting from a [2 þ 4] cycloaddition, are,
respectively and relatively to 6h, 0.0, þ10.1, and þ6.8 kcal/mol (see
Supporting Information for details). A full study on the periselectivity of
R-oxo-ketenes cycloadditions is in progress and will be reported in due
time.
(5) For recent examples from our laboratory, see: (a) Presset, M.;
Coquerel, Y.; Rodriguez, J. J. Org. Chem. 2009, 74, 415. (b) Presset,
M.; Coquerel, Y.; Rodriguez, J. Org. Lett. 2009, 11, 5706. (c) Presset,
M.; Coquerel, Y.; Rodriguez, J. Org. Lett. 2010, 12, 4212.
(6) (a) Grigg, R.; Kemp, J.; Thompson, N. Tetrahedron Lett. 1978,
19, 2827. (b) Le Fevre, G.; Hamelin, J. Tetrahedron Lett. 1978, 19, 4503.
ꢀ
(c) Arrieta, A.; Carrillo, J. R.; Cossio, F. P.; Dıaz-Ortiz, A.; Gomez-
Escalonilla, M. J.; de la Hoz, A.; Langa, F.; Moreno, A. Tetrahedron
1998, 54, 13167.
(7) For an authoritative review, see: Kirmse, W. Eur. J. Org. Chem.
2002, 2193.
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