Domino cyclocondensation of arylaldehydes with 2-acetylpyridine

doi:10.1016/j.tet.2012.09.048

Tetrahedron

Volume 68, Issue 47, 25 November 2012, Pages 9616-9623

https://doi.org/10.1016/j.tet.2012.09.048 Get rights and content

Abstract

A novel synthetic route for the preparation of cyclohexane skeleton 3 was developed via the one-pot domino Claisen–Schmidt condensation reaction/Michael addition/double aldol reaction of 1 equiv of functionalized arylaldehyde 1 with 3 equiv of 2-acetylpyridine (2a).

Graphical abstract

Introduction

The formation of cyclohexane motif has been well-developed via a stepwise Michael addition of an enolate with a conjugated enone/cyclodehydration of the resulting adduct sequence or Michael-aldol reaction/dehydration of ketol sequence under the influence of catalysts.¹ It has been widely used as a useful building block in the construction of a variety of pharmacophores and/or natural products.2, 3 Extensive synthetic efforts have been reported for substituted six-membered carbocycles, in which an annulation route from acyclic functionalized precursors constitutes a tandem strategy.⁴ Normally, the base-mediated Claisen–Schmidt condensation of acetophenone and benzaldehyde with a mole ratio of 1:1 affords chalcone derivative (benzylidene acetophenone).⁵ However, when the chalcone are conducted with aryl α-enolate in a molar ratio of 2/1 under alkaline alcoholic condition, the diversified six-membered carbocyclic frameworks form via a common method from the double conjugate addition of chalcone with α-carbanion of ketone and subsequent aldol reaction (Robinson annulations), as shown in Scheme 1.⁶

In continuation of our recent investigation of the tandem aldol condensation/Michael addition for the preparation of polyoxygenated rigid and cyclic benzannulated molecules (e.g., benzo[g]indazoles, azahomoisotwistanes),⁷ a facile stereochemical route for synthesizing the novel framework of cyclohexane was studied next. As shown in Scheme 2, the formation of chalcone or 1,5-diketone was involved in the reaction of 2 and 1a with a ratio of 1:1 or 2:1 under the alkaline methanolic condition. It is noteworthy that when the ratio of 3/1 (2a/1a) is adopted in an attempt to provide cyclohexanes via one-pot facile tandem Claisen–Schmidt condensation/Michael addition/double aldol reaction, no products with the skeleton of chalcone or 1,5-diketone were isolated.

Section snippets

Results and discussion

In an attempt to develop a practical synthetic method of cyclohexane skeleton, we investigated the base-mediated cyclocondensation reaction of substituted arylaldehyde 1 with freshly distilled 2-acetylpyridine (2a). We found that by using NaOH in MeOH at reflux temperature, the intermediates of chalcone and 1,5-diketone smoothly proceeded the condensation to directly give six-membered carbocycle 3a in decent yield. Herein, we report the details of our findings. Condensation reaction of 1a

Conclusion

In summary, we have successfully presented a synthetic methodology for the skeleton of cyclohexanes 3 by the treatment of functionalized arylbenzaldehydes 1 with 2-acetylpyridine 2a, which involved a base-mediated Claisen–Schmidt condensation, a Michael reaction followed by a double aldol reaction. The novel strategy showed that the reaction condition provides an excellent stereochemical control of chiral centers on the carbocyclic skeleton 3 and dendritic benzenoid skeleton 5.

General

All other reagents and solvents were obtained from commercial sources and used without further purification. Reactions were routinely carried out under an atmosphere of dry nitrogen with magnetic stirring. Products in organic solvents were dried with anhydrous MgSO₄ before concentration in vacuo. Melting points were determined with a SMP3 melting apparatus. ¹H and ¹³C NMR spectra were recorded on a Varian INOVA-400 spectrometer operating at 200/400 and at 100 MHz, respectively. Chemical shifts (

Acknowledgements

The authors would like to thank the National Science Council of the Republic of China for its financial support (NSC 99-2113-M-037-006-MY3).

References and notes (10)

W.S. Rapson et al.
J. Chem. Soc.
(1935)
T.-L. Ho
Carbocycle Construction in Terpene Synthesis
(1988)
T.-L. Ho
Symmetry: a Basis for Synthesis Design
(1995)
E.J. Corey et al.
The Logic Chemical Synthesis
(1989)
T. Tokoroyama et al.
J. Chem. Soc., Chem. Commun.
(1983)
S.D. Burke et al.
J. Am. Chem. Soc.
(1982)
S. Katsumura et al.
Chem. Lett.
(1982)
R.W. Skeean et al.
Tetrahedron Lett.
(1976)
For reviews on the synthesis of tandem reactions,...L.F. Tietze
Chem. Rev.
(1996)
P.J. Parsons et al.
Chem. Rev.
(1996)
J.C. Wasilke et al.
Chem. Rev.
(2005)
G.H. Posner
Chem. Rev.
(1986)
R.A. Bunce
Tetrahedron
(1995)
T.-L. Ho
Tandem Organic Reactions
(1992)

There are more references available in the full text version of this article.

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Domino cyclocondensation of arylaldehydes with 2-acetylpyridine

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Conclusion

General

Acknowledgements

J. Chem. Soc.

Carbocycle Construction in Terpene Synthesis

Symmetry: a Basis for Synthesis Design

The Logic Chemical Synthesis

J. Chem. Soc., Chem. Commun.

J. Am. Chem. Soc.

Chem. Lett.

Tetrahedron Lett.

Chem. Rev.

Chem. Rev.

Chem. Rev.

Chem. Rev.

Tetrahedron

Tandem Organic Reactions