Domino Knoevenagel/Michael addition/C-acylation reactions. Synthesis of 1,3-cyclohexane-1,3-diones

The three component reactions of Meldrum’s acid, 1,3-bis-(benzotriazol-1-yl)propan-2-one or 1-benzotriazol-1-ylpropan-2-one and an aldehyde, carried out in DMF at 60 ºC gave rise to 2,4-bis-(benzotriazol-1-yl)cyclohexane-1,3-diones or 4-benzotriazol-1-ylcyclohexane-1,3-diones, respectively, in fairly high yields. Unlike similar reactions reported earlier with acetone, the reactions with 1,3-bis-(benzotriazol-1-yl)propan-2-one and 1-benzotriazol-1-ylpropan-2-one proceeded via an intramolecular acylation of the other methyl group of acetone.


Results and Discussion
The three component proline-catalyzed reaction of acetone with aldehydes and Meldrum's acid has been reported to yield triketones with no change in the 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) ring. 19Analogous products have been noted in the piperidine-catalyzed reaction starting with cyclohexanone. 20Those results prompted us to investigate the reactions under conditions that could be favorable for inducing an intramolecular C-acylation of the other methyl group of benzotriazolo-acetone 1, 2. However, one could not rule out that the reaction may take another course and yield the enol form of the ketone 5 which subsequently may cyclize to give the corresponding lactone 14.
The readily available acetone derivatives, namely 1,3-bis-benzotriazol-1-ylpropan-2-one 1 21 and 1-benzotriazol-1-ylpropan-2-one 2 22 were used in the present research as the active methylene compounds.All reactions were carried out at 60 ºC in a DMF solution under inert gas with triethylamine added as the catalyst.As expected, methylidene derivatives 4 were formed in the first stage.Their subsequent Michael reaction with the ketone 1 or 2 anion yielded the addition product 5 which next underwent an intramolecular acylation with a concomitant decomposition of the Meldrum's acid fragment.An additional support to that mechanistic concept was gained in the reaction of 4 (R 3 = Ph) with 1; under identical reaction conditions (DMF, TEA, 60 ºC) only 6 was formed, its yield being twice that high as in the three component variant (60% vs. 30%).The formation of lactones 14 or keto-esters 5 was not observed in our Scheme 1. Formation of cyclohexanediones.experiments.Since Knoevenagel condensation of aldehydes with benzotriazolo-acetone (2, R 1 = Bt, R 2 = H) is known to require forced conditions (boiling DMF), 23 the initial formation of the methylidene derivatives of 4 and their subsequent addition to Meldrum's acid seems rather unlikely.
It is noteworthy that the benzotriazole substituent were markedly effective when the acetone derivatives 1 and 2 formed the corresponding carbanions. 24,25Under analogous conditions the reaction of Meldrum's acid with benzaldehyde and 1,3-diphenylacetone 3 yielded a 1.5:1 mixture of the product of 3 addition to the appropriate methylidene derivative 4 and triphenyl-1,3-cyclohexanedione 13; the reaction rate was much lower and the yield did not exceed 25%.The 1 Hand 13 C-NMR spectra confirmed the initial structural assignments and showed that in solutions the compounds 6-13 exist in the enol form.
The configurations at C-4 (substituent R 1 ) and at C-5 (substituent R 3 ) were established by analysis of the vicinal coupling constants ( 1 H, 1 H COSY NMR spectra) and of the through-space interactions ( 1 H, 1 H NOESY NMR spectra) of compounds 8-10.High values (8.2-10.5 Hz) of the coupling constants between the vicinal protons H-4 and H-5 indicated their trans-diaxial orientation.

Experimental Section
General.Melting points were determined on a digital apparatus Electrothermal model IA9300 and are uncorrected.NMR spectra were recorded on a Bruker DPX apparatus (400 MHz) spectrometer in deuteriochloroform and deuteriodimethyl sulfoxide with tetramethylsilane as internal standard.In some cases trifluoroacetic acid (TFFA) was added to the solvent.The IR spectra were taken with Specord M80 instruments in potassium bromide pellets or Nujol.Purity and molecular mass determinations were carried out by gas chromatography-mass spectrometry (GC/MS) on a Hewlett-Packard instrument model HP 6890 equipped with a mass detector HP 5973.The analytical procedure was developed for a 30 m long capillary column, 0.2 mm in diameter, with methylsiloxane modified with phenyl groups (5% Ph, Me siloxane) in the 0.25 µm thick active phase layer.Elemental analyses were performed on EuroEA 3000 series, Euro Vector CHNS-O Elemental Analyzer.