New Reactions Exploring the Chemical Spaces of the Aldol Addition of Active Methylene Compounds

Abstract

During research planning and the development of ideas, organic chemists intuitively work on the chemical space, even if they are often unaware of the nature and the extent of chemical space of organic reactions, in which they are moving. The exploration and the rational analysis of new chemical spaces originating from new tandem and multicomponent aldol additions of active methylene compounds can lead to the development of new efficient and environmentally friendly methodologies and to the synthesis of new libraries of highly functionalised compounds.

1 Introduction

2 Chemical Space of the Aldol Addition of Active Methylene Compounds

3 One-Pot Tandem Aldol Addition-Cyclization Reactions

4 Analysis of Chemical Spaces

Key words

aldol addition - active methylene compounds - tandem aldol addition-cyclization - multicomponent reactions

References and Notes

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2

Organic and inorganic substances registered by CAS have just exceeded 63 million (www.cas.org).

19

Experimental procedure for SiCl ₄ -mediated aldol reaction (Scheme  [5] ). In a flame-dried 2-necked round-bottom flask tert-butyl acetoacetate (0.30 mmol) was added to a solution of DIPEA (0.40 mmol), SiCl₄ (1.9 mmol), Denmark’s catalyst (0.04 mmol) and aldehyde (0.20 mmol) in dry CH₂Cl₂ (1.0 mL) under nitrogen at -20 ˚C. At the end of the reaction the mixture was quenched with saturated aqueous NaHCO₃ (5 mL), extracted with 15 × 3 mL CH₂Cl₂ and dried over anhydrous Na₂SO₄. After removing the solvent under reduced pressure the crude products 7 were analysed by ^¹H NMR and subjected to TMS protection.^¹5a Chiral HPLC separation of 3aa was performed with a Chiralpak AD-H column in hexane-isopropanol (98:2), 0.6 mL/min.

23

Aldehydes 1c can easily be obtained by commercially available dialkylacetal derivatives.

24

Experimental procedure for the synthesis of 3-substituted isobenzofuranone 11a. To a solution of aldehyde (0.31 mmol) in DMF (1 mL) and potassium carbonate (0.62 mmol) di-tert-butyl malonate (0.34 mmol) was added dropwise. The mixture was allowed to stir for 24 h. Then it was diluted with ethyl acetate and washed three times with water. The organic layer was dried over Na₂SO₄ and evaporated to give an oil which was purified by chromatography on silica gel [hexane-ethyl acetate (9:1 to 7:3)]; yield: 93%.