Full Paper
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112, 1681; b) M.-N. Roy, V. N. G, Lindsay, A. B. Charette in Stereoselective
Synthesis: Reactions of Carbon–Carbon Double Bonds, vol. 1 (Ed.: J. G.
de Vries), Thieme, Stuttgart, 2011, pp. 731–817; c) C. A. Carson, M. A.
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103, 1151; f) H. Lebel, J.-F. Marcoux, C. Molinaro, A. B. Charette, Chem.
Rev. 2003, 103, 977.
The development of zinc-catalyzed cyclopropanation reactions repre-
sents a significant goal. For isolated examples of zinc-catalyzed synthesis
of cyclopropane derivatives, see: a) S. R. Goudreau, A. B. Charette, J. Am.
Chem. Soc. 2009, 131, 15633; b) É. Lévesque, S. R. Goudreau, A. B. Char-
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coupling of 1,3-dicarbonyl compounds, alkynals and alkenes.
This coupling process, which seemingly proceeds via a 2-furyl-
zinc(II)–carbene intermediate, merges Knoevenagel condensa-
tion, cyclization and cyclopropanation into a multicomponent
procedure. The general features of this operationally simple
multicomponent protocol are (1) the availability and low cost
of the required starting materials and catalyst, (2) a wide scope
for all the components, (3) its efficiency (even at catalyst load-
ing as low as 0.02 mol-%), and (4) its suitability for multigram
scale-up. Selected cyclopropane derivatives are suitable starting
materials for further transformations. Specifically, the ability of
ZnCl2 to promote the vinylcyclopropane/cyclopentene rear-
rangement has been demonstrated for the first time. Further-
more, the synthesis of 1,2-dioxolane derivatives by a zinc-pro-
moted aerobic oxidation of cyclopropane derivatives has also
been developed. A four-component process to yield these
cyclic peroxide derivatives has also been realized.
[3]
[4]
[5]
Experimental Section
[6]
[7]
Typical Procedure for the Zn-Catalyzed Three-Component Cou-
pling. Synthesis of Cyclopropane 4a: To a mixture of 2,4-pentane-
dione (1a; 30.0 mg, 0.30 mmol), oct-2-ynal (2a; 41.0 mg, 0.33 mmol)
and styrene (3a; 93.7 mg, 0.90 mmol), ZnCl2 (0.85 mg, 2.0 mol-%)
was added at ambient temperature under an inert gas. The Schlenk
flask was sealed with a septum and placed in a preheated oil bath
at 50 °C, and the reaction mixture was stirred at this temperature
for 5 h until the starting material was consumed (checked by TLC
analysis). The excess styrene was removed under vacuum. The re-
sulting residue was purified by flash column chromatography (SiO2;
hexane/EtOAc, 10:1) to afford 4a (82 mg, 88 %; dr > 20:1) as a pale
yellow oil.
[8]
Typical Procedure for the Zn-Catalyzed Aerobic Oxidation of
Cyclopropane Derivatives. Synthesis of 1,2-Dioxolane Deriva-
tive 11a: To a solution of cyclopropane 4w (56 mg, 0.15 mmol) in
[9]
For a multicomponent process involving Knoevenagel condensation, cy-
clization and carbene Si–H insertion, see: S. Mata, L. A. López, R. Vicente,
Chem. Eur. J. 2015, 21, 8998.
1,2-dichloroethane (0.10
M; 1.5 mL), ZnCl2 (10 mg, 50 mol-%) was
added at ambient temperature under oxygen. The Schlenk flask was
sealed with a septum and placed in a preheated oil bath at 50 °C,
and the reaction mixture was stirred at this temperature for 15 h
until the starting material was consumed (checked by TLC analysis).
After the elimination of the solvent, purification by flash column
chromatography (SiO2; hexane/EtOAc, 10:1) yielded 11a (52 mg,
89 %) as a colourless oil.
[10]
The yield obtained in this reaction could be rationalized in terms of the
isomerization of the enynone or retro-Knoevenagel condensation. The
condensation of ethyl 3-oxobutanoate (1d) with alkynal 2a under stand-
ard Knoevenagel conditions led to a 1.2:1 (Z)/(E) mixture of the corre-
sponding adducts. For a similar outcome, see ref.[9]
This side-product would arise from a competitive 1,2-hydride shift at the
carbene stage. 2-Vinylfuran 4g′ was obtained in 60 % yield when 1a and
2c were mixed with ZnCl2 in the absence of the alkene.
The cycloheptafuran derivatives 6a and 6b probably arise from the cis-
configured cyclopropane derivatives, which can further evolve under the
reaction conditions. The zinc-catalyzed [4+3] cycloaddition of enynones
with electron-rich dienes to give cycloheptafuran derivatives related to
compounds 6 has been reported recently: B. Song, L.-H. Li, X.-R. Song,
Y.-F. Qiu, M.-J. Zhong, P.-X. Zhou, Y.-M. Liang, Chem. Eur. J. 2014, 20, 5910.
A similar ring-opening process has been reported for the reactions of
furan with other metal–carbene complexes. For selected examples, see:
a) K. Miki, M. Fujita, S. Uemura, K. Ohe, Org. Lett. 2006, 8, 1741; b) A.
Caballero, M. M. Díaz-Requejo, S. Trofimenko, T. R. Belderrain, P. J. Pérez,
J. Org. Chem. 2005, 70, 6101.
[11]
[12]
Acknowledgments
Financial support from the Ministerio de Economía y Competiti-
vidad (MINECO) and the Principado de Asturias (grant nos.
CTQ2013-41511-P and GRUPIN14-013) is gratefully acknowl-
edged. R. V. is a Ramón y Cajal fellow. S. M. thanks the Princi-
pado de Asturias for a predoctoral grant (Severo Ochoa Pro-
gram). We thank Prof. J. M. González for interesting discussions
and Dr. J. Borge for his assistance in the collection of the X-ray
data.
[13]
[14]
[15]
The reaction of diene 8a with iodine afforded a complex mixture of
products.
For some applications of this iodine-catalyzed isomerization reaction,
see: E. Wenkert, M. Guo, R. Lavilla, B. Porter, K. Ramachandran, J.-H. Sheu,
J. Org. Chem. 1990, 55, 6203.
Keywords: Cyclopropanes · Dioxolanes · Oxygen
heterocycles · Multicomponent reactions · Zinc
[16]
a) For a review on the thermal rearrangements of vinylcyclopropanes,
see: J. E. Baldwin, Chem. Rev. 2003, 103, 1197; b) for a review on metal-
Eur. J. Org. Chem. 2016, 2681–2687
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