Domino reaction sequences leading to the formation of 2:2 adducts between acenaphthenequinone and acetophenone

A Michael-aldol domino reaction sequence of acenaphthenequinone with acetophenone in the presence of KOH in methanol solvent leading to the formation of three different 2:2 adducts arising through three distinct reaction sequences is described. Similar sequences leading to a highly substituted furan derivative were observed in the reaction between phenanthrenequinone and acetophenone.


Introduction
Current research in organic synthesis focuses on atom economy.The efficiency of a synthetic sequence is fortified by multiple bond-forming and catalytic chemical processes.The efficiency can be measured by parameters such as selectivity, overall yield, raw material, time, human resources, energy requirements, toxicity and hazard of the chemicals.Therefore step count and product yield in individual steps are important criteria when evaluating the efficiency of a synthesis.More specifically, domino and multicomponent reactions are now the cornerstone to atom economy in synthesis.5][16] The success of this strategy is revealed in the total synthesis of naturally occurring anti-Alzheimer product huperzine A. 17 In this article, we Scheme 1. Solvent-assisted Michael-aldol reaction between acenaphthenequinone and acetophenones.
The generality of this domino reaction sequence was established using substituted acetophenones such as 4-chloroacetophenone (having an electron-withdrawing group) and 4-methylacetophenone (with an electron-releasing group). 18We re-examined the base-catalysed reaction of 1 and 2a-c to optimize yields, isolate other products, if any, and to understand the mechanism involved.We have now isolated and identified two novel 2:2 adducts formed along with the reported substituted dispiro compound that is also a 2:2 adduct.
The reaction of acenaphthenequinone (1) with acetophenone (2a) in the presence of KOH in methanol was completed in 4 hours.TLC analysis of the dark brown reaction mixture indicated the presence of three products.The products were separated by column chromatography over silica gel.Two of the products (4a and 2′-benzoyl-4′-hydroxy-4′-phenyl-2H,2″Hdispiro[acenaphthylene-1,1′-cyclopentane-3′,1″-acenaphthylene]-2,2″-dione (5a)) were relatively nonpolar and were colourless solids, while the third highly polar compound 8-(7,8-dibenzoyl-7H-cyclopenta[a]acenaphthylen-9-yl)-1-naphthoic acid (6a) was obtained as a red solid.Compound 4a was identified as the dispiro compound reported earlier. 18Mass spectroscopic analysis of 5a indicated that it is a 2:2 adduct between acenaphthenequinone and acetophenone.In the 1 H NMR spectrum of 5a, a one-proton singlet was observed at δ 5.60 and two one proton doublets were seen at δ 4.55 (J = 14 Hz) and 2.67 (J = 14 Hz), along with signals for 22 aromatic protons.The structure of 5a was unequivocally established on the basis of single crystal X-ray analysis (Figure 1).Compound 6a was highly polar in nature and hence separation and purification of this material was challenging.It was separated by elution with a 1:1 mixture of methanol and ethyl acetate.Tarry material that co-eluted with 6a was separated by repeated washing with cold methanol.An analytically pure sample of 6a was generated by repeated recrystallization from a mixture of ethyl acetate and dichloromethane.Mass spectroscopic analysis of 6a indicated that it was also a 2:2 adduct.Poor solubility of this compound in almost all solvents foiled our attempts to record its 13 C NMR spectrum.However, a 1 H NMR spectrum of acceptable quality could be recorded and it showed signals for aromatic protons only.The IR spectrum of the compound indicated the presence of both a carboxylic acid and another carbonyl group.Based on the available data, we assigned the structure of the new product as the naphthoic acid derivative 6a (Chart 1).Chart 1. 2:2 Adducts formed between acenaphthenequinone and acetophenone.
We repeated the base catalyzed reaction of acenaphthenequinone with 4-methylacetophenone (2b) and 4-chloroacetophenone (2c) to examine the generality of the reaction.Three products, each analogues to 4a, 5a and 6a, were formed in these reactions indicating similarity in the reaction between acenaphthenequinone and acetophenone derivatives.Fortunately, diffraction quality crystals of 8-[7,8-bis(4-chlorobenzoyl)-7H-cyclopenta[a]acenaphthylen-9-yl]-1-naphthoic acid (6c) formed in the reaction between acenaphthenequinone and 4-chloroacetophenone could be isolated.Single crystal X-ray diffraction analysis of 6c confirmed its identity as a 2:2 adduct (Figure 2).2) is provided in Scheme 2. A solvent-assisted domino reaction sequence leading to 4a-c was reported earlier. 18We invoke 3 as an intermediate for the generation of 5a-c and 6a-c as well.It may be noted that nucleophilic addition to enediones such as 3 can take place at two different centers (marked by solid arrows in Scheme 2).Attack of methanol (path a) leads to the formation of intermediate 9 that adds to another molecule of 3 to give the 2:2 adduct 10 that then undergoes intramolecular Claisen-Schmidt condensation to give dispiro-compounds 4a-c.Addition of a second molecule of acetophenone to 3 (paths a & b) would give rise to Michael adducts 7 and 8 respectively.Condensation of 8 with a second molecule of acenaphthenequinone yields the second 2:2 adduct 14.Intramolecular carbonyl-olefin coupling followed by H-abstraction leads to the formation of 5a-c.The mechanism of carbonyl-olefin cyclization is understood in terms of ketyl intermediates generated by single electron transfer to the carbonyl group.Single electron transfer mediated carbonyl-olefin cyclizations 19,20 and single electron transfer from nucleophiles 21 are well documented in the literature.We assume that the presence of a highly electron deficient molecule such as acenaphthenequinone under strongly basic conditions enables electron transfer reactions leading to eventual carbonyl-olefin cyclization indicated in Scheme 2. 22,23 Formation of 6a-c was even more puzzling.Base-catalyzed ring opening of acenaphthenequinone to give the corresponding naphthoic acid derivative in a benzil-benzilic acid type reaction sequence is reported in the literature. 24In a similar way, crossed benzilbenzilic acid type reaction between 7 and 11 would enable a unique carbon-carbon bond forming reaction to give yet another 2:2 adduct 12 that undergoes intramolecular Claisen-Schmidt condensation and loss of water to give 6a-c.In order to establish the intermediacy of 3 in the generation of 2:2 adducts 4-6, we independently synthesised 3a by adopting the Wittig route.Independently synthesized 3a was totally consumed on further reaction with acenaphthenequinone and acetophenone in the presence of potassium hydroxide in methanol.Work up of the reaction mixture yielded dispirocompounds 4a, 5a and 6a (Scheme 3) in a 9:3:1 ratio that is close to the ratio at which these products are formed in the reaction between 1 and 2a.Furthermore, in two different control experiments, we established that 4a and 5a do not interconvert under the conditions employed by us.Prolonged treatment of 4a with acenphthenequinone in methanol in the presence of base did not result in any noticeable change.Similarly, 5a was also recovered unchanged after attempted reaction with acenaphthenequinone in methanol in the presence of base.These experiments support the mechanistic pathways depicted in Scheme 2 for independent generation of the three 2:2 adducts.

Scheme 3. Control experiment employing independently synthesized 3a.
In a related experiment, we repeated the reaction of phenanthrenequinone ( 17) with 4chloroacetophenone (2c). 25We could separate dihydrofuranol 18 as the major product along with a novel furan derivative Michael addition of aldol 19 to enedione 20 is the key step in the generation of furan 21.Subsequent dehydration, intramolecular Michael type addition and aromatization with the elimination of elements of 4-chlorobenzaldehyde completes the unusual reaction sequence for the formation of 21.We could not record the 13 C NMR spectrum of 21 due to the poor solubility of this compound in common solvents.The structure of 21, however, could be established on the basis of single crystal X-ray diffraction analysis (Figure 3).

Conclusions
We have demonstrated the independent generation of three 2:2 adducts in the base catalysed reaction between acenaphthenequinone and acetophenone in methanol.Domino reaction sequences for the formation of various products are proposed.The structures of the adducts were established on the basis of 1 H NMR, 13 C NMR and SCXRD analyses.A domino reaction sequence is possible with other cyclic 1,2-diones such as phenanthrenequinone as well.

Experimental Section
General.All reactions were conducted in oven-dried glassware.Reagents used were purchased from Aldrich Chemical Co. or Spectrochem and were used without further purification.Solvents used for experiments were distilled and dried according to procedures given in standard manuals.All reactions were monitored by thin layer chromatography (TLC).Analytical thin layer chromatography was performed on aluminium sheets coated with silica gel (Spectrochem); visualization was achieved by exposure to iodine vapours or UV radiation.Solvent removal was done on a Heidolph rotary evaporator.Gravity column chromatography was performed using 60-120 mesh silica gel (Spectrochem) and mixtures of hexane-ethyl acetate were used for elution.Melting points were recorded on a Neolab melting point apparatus.Infrared spectra were recorded using JASCO FTIR 4100 spectrometer.NMR spectra were recorded on 400 MHz Bruker FT-NMR spectrometer.Chemical shifts are reported in δ (ppm) relative to TMS as the internal standard.Single Crystal XRD was done by Bruker XRD Instrument.Elemental analysis was performed using Elementar Systeme (Vario EL III).Molecular mass was determined by fast atom bombardment (FAB) using JMS 600 JEOL mass spectrometer.Unless otherwise mentioned, all commercially available solvents and reagents were used as received and reactions were performed under normal conditions.

Conversion of 3 into 4, 5 and 6
An equimolar mixture of acenaphthenequinone (1), acetophenone (2a) and independently synthesized 3a in MeOH in the presence of KOH was stirred at 60 °C for 4 h and later kept in a refrigerator for 48 h.The reaction mixture was concentrated and the residue was chromatographed over silica gel.Products 4a (45%) and 5a (14%) were obtained on elution with a mixture (9:1) of hexane and EtOAc.Elution with a mixture (1:1) of MeOH and EtOAc yielded 6a (5%).

Attempted conversion of 4a into 5a
In a control experiment, an equimolar mixture of 1 and 4a in the presence of KOH in MeOH was stirred at 60 °C for 4 h and later kept in refrigerator for 48 h.The reaction mixture was concentrated and the residue was chromatographed over silica gel.Unreacted 1 and 4a were recovered in quantitative yield.

Attempted conversion of 5a to 4a
In another control experiment, an equimolar mixture of 1 and 5a in the presence of KOH in MeOH was stirred at 60 °C for 4 h and later kept in a refrigerator for 48 h.The reaction mixture was concentrated and the residue was chromatographed over silica gel.Unreacted 1 and 5a were recovered in quantitative yield.

Scheme 4 .
Scheme 4. Mechanism for the domino reaction between 17 and 2c.