Synlett 2012(4): 524-530  
DOI: 10.1055/s-0031-1289524
ACCOUNT
© Georg Thieme Verlag Stuttgart ˙ New York

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

Antonio Massa*
Dipartimento di Chimica e Biologia, Università di Salerno, Via Ponte Don Melillo, 84084 Fisciano (SA), Italy
Fax: +39(089)969603; e-Mail: amassa@unisa.it;
Further Information

Publication History

Received 1 September 2011
Publication Date:
03 January 2012 (online)

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

    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%.