Et 2 NH/H 2 O catalyzed tandem aldol condensation - Diels-Alder cycloaddition sequence for the one-pot synthesis of (2 R ,3 S )- rel -3- aryl-1,2,3,4,5,6,7,8-octahydro-6,6-dimethyl-8-oxo-2-naphthalenecarboxylates

A tandem aldol condensation – Diels-Alder cycloaddition process is developed to combine isophorone (3,5,5-trimethyl-2-cyclohexen-1-one), aromatic aldehydes, and methyl acrylate in an efficient stereoselective one-pot synthesis of methyl (2 R ,3 S )- rel -3-aryl-1,2,3,4,5,6,7,8-octahydro-6,6-dimethyl-8-oxo-2-naphthalenecarboxylates using trace quantities of ammonium ions under aqueous conditions. Alternatively, the respective conjugated dienes which are formed in situ from the condensation of isophorone with the aldehydes can also react with methyl acrylate in a stepwise fashion leading to the same products.


Introduction
The 4+2 Diels-Alder (DA) reaction 1 is one of the most widely used organic transformations in synthetic organic chemistry [2][3][4] since it has the potential to construct a six-membered ring via simultaneous formation of two carbon-carbon bonds.In addition, the reaction can lead to the creation of up to four stereogenic centers with predictable stereoselectivity in a one step operation. 5Numerous studies are reported in recent years enhancing the reactivity and the selectivity features of DA cycloadditions by using chiral catalysts, 6,7 enantioselective reagents, 8,9 temporarily tethered reactants, 10,11 and self-assembled systems. 12,13These approaches and use of intramolecular and transannular variants of the reaction have led to the preparation of natural product molecules 14,15 and complex polycyclic systems. 16ithin the framework of our studies on the aldol condensation reaction 17,18 and its application in tandem processes, 19 we reported the synthesis of a series of 3-styryl-2-cyclohex-1ones 3, 20 obtained from the condensation of 1 with 2 (Scheme 1).These dienes were then examined for their DA activity, 21 and were further studied in a one-pot aldol condensation -DA process to construct the octahydronaphthalene structures directly.However, the results were limited to the reactions with doubly activated dienophiles, and singly activated dienophiles such as methyl acrylate (4) could react only under stepwise conditions. 22In continuation, we would like to report here the application of this strategy to the reactions of 4, which cycloadds to in situ formed dienes 3, solely producing cis-octahydronaphthalene type cycloadducts 5 (Scheme 1), a structural unit which is found in several natural products and perfumes. 23Reactions take place in aqueous medium using catalytic quantities of a simple amine.

Results and Discussion
We optimized the conditions by examining the reaction of 1 with 2,6-dichlorobenzaldehyde (2a) and methyl acrylate (4), as shown in Table 1.The progress of the reaction was monitored by GC experiments.In the presence of water and catalytic quantities of diethylamine, the intermediate diene was formed in situ.Addition of methyl acrylate (4) and dilute HCl to the mixture led to 75% formation of cis 5a after 11 h (entry 1).Use of different quantities of the amine showed that 25 mol% would be the optimum amounts (entries 2-4).When the reaction was conducted in the absence of water (entry 5), hydrochloric acid (entry 6), or the amine (entry 7), either no product was obtained or the reaction progress was not considerable.Without water or HCl, only the formation of the intermediate was noticed, while in the absence of the amine, no reaction occurred.Use of other amines also led to the formation of 5a, but in lower quantities (entries 8-10).These results showed that the optimum conditions (entry 1) could be employed to explore the one-pot combination of the three reactants to access octahydronaphthalene derivatives of type 5 directly.a yields determined by GC.
To show the generality of the procedure, the optimum conditions (Table 1, entry 1) were used to conduct the reactions with other aldehydes (Table 2).Therefore, the same process with aldehydes bearing electron withdrawing (entries 1-6) and electron releasing (entries 7-10) groups proceeded within comparable time periods.Similarly, unsubstituted homocyclic (entry 11) and heterocyclic aromatic aldehydes (entry 12) gave results equally well.
In all cases formation of a single DA product was observed.The structure of these products was assigned based on their 1 H NMR spectra.The H-2 and H-3 signals appeared at about 3 and 3.5 ppm, respectively.These two vicinal protons exhibited a "medium" 3 J H-H of about 5-6 Hz.This coupling constant is proportional with the endo stereoisomer as opposed to the exo structure, which is expected to show a larger 3 J H-H .In order to confirm the suggested cis structure for the adducts, a single crystal of 5l was prepared and analyzed by X-ray crystallography.As it is clear from Figure 1, migration of the double bond to the more stable doubly endocyclic position and the relative configuration of the two adjacent stereogenic centers correspond to the suggested structures in Table 2.  a Isolated yields.
Based on these results, a mechanism (Scheme 2) can be suggested for the process.The starting enone 1 is first deprotonated by the amine organocatalyst to give the respective enolate.The enolate is then added to the aldehyde 2 to produce the aldol intermediate, which after dehydration gives the diene 3. TLC and GC experiments prove the formation of this diene prior to addition of methyl acrylate (4).Finally addition of the dienophile 4 to the reaction mixture led to the formation of the DA adduct, which spontaneously isomerizes to the final product 5 by rearranging the double bond to the more stable doubly endocyclic position.To support the suggested mechanism, intermediate

Conclusions
In summary, we have developed an efficient and general one-pot protocol for the synthesis of various methyl (2R,3S)-rel-3-aryl-1,2,3,4,5,6,7,8-octahydro-6,6-dimethyl-8-oxo-2naphthalenecarboxylates 5.Under aqueous conditions and in the presence of catalytic quantities of Et 2 NH, a three-component process takes place and the in situ formed diene 3 reacts with methyl acrylate (4) to form the final products 5.The development of the process by using more diverse dienes and dienophiles is under further study.

Experimental Section
General.Reactions were monitored by TLC using silica-gel coated plates and ethyl acetate/hexanes mixtures as the mobile phase.Melting points are uncorrected.FT-IR spectra were recorded using KBr disks on a Bruker Vector-22 infrared spectrometer and absorptions are reported as wave numbers (cm -1 ). 1 H NMR and 13 C NMR spectra were obtained in CDCl 3 solutions and the chemical shifts are expressed as δ units with Me 4 Si as the internal standard.Mass spectra were obtained on a Finnigan MAT 8430 apparatus at ionization potential of 70 eV.Elemental analyses were performed using a Thermo Finnigan Flash EA 1112 instrument.All reagents were purchased from commercial sources and were freshly used after being purified by standard procedures.New products 5a-h,j-l were characterized based on their spectral and physical data.

Scheme 1 .
Scheme 1. One-pot and stepwise pathways for the synthesis of 5.

Table 1 .
Optimization of the one-pot reaction for the synthesis of 5a Ar = 2,4-dichlorophenyl
Product Ar in 2 and 5Reaction time (h) Yield of 5 (%) a