One-pot, sequential four-component synthesis of novel heterocyclic [3.3.3] propellane derivatives at room temperature

An efficient, one-pot, two-step, four-component reaction for the synthesis of propellane derivatives is described by the condensation reaction between acenaphthenequinone, malono derivatives, primary amines and β-ketoester or β-diketone derivatives in the presence of triethylamine in ethanol at room temperature. Using this procedure, all the products were obtained in good to excellent yields.


Introduction
In modern organic chemistry, the improvement of reaction efficiency, the reduction of waste, the avoidance of toxic reagents and the responsible utilization of our resources have become critical objectives. 1,2 Multi-component reactions, are useful tools for the synthesis of biologically and pharmacologically important compounds because of their environmentally friendly, green characteristics and atom efficient. [3][4][5][6] Therefore, the design and application of multi-component reactions has attracted great attention from research groups working in areas such as biological, medicinal and organic chemistry.

Results and discussion
In the rst step, the reaction between acenaphthoquinone (1), malononitrile (2a), ethyl acetoacetate (5a) and benzyl amine (4c), as a model reaction, was investigated in the presence of different molar ratios of Et 3 N in some solvents (5 mL) at room temperature and the results are summarized in Table 1. For this propose to a stirred mixture of acenaphthoquinone 1 (1 mmol) and malononitrile 2a (1 mmol) in EtOH (5 mL) at room temperature different amount of Et 3 N were added to form the corresponding Knoevenagel adduct and then ethyl acetoacetate 5a (1 mmol) and benzyl amine 4c (1 mmol) were added to obtain the corresponding product 6a. As it is shown in Table 1, higher yield and shorter reaction time were obtained when the reaction was carried out in the presence of 1 mmol of the Et 3 N in ethanol at room temperature (Table 1, entry 4). It should be mention that simultaneity of this four-component condensation reaction was studied in the presence of 1 mmol Et 3 N in EtOH at room temperature and we observed that benzyl amine has remained intact in this condition and the corresponding propellane was not formed.
In the next step, the scope and efficiency of the process was explored under the optimized conditions. For this purpose, acenaphthoquinone was condensed with alkyl malonates, aliphatic and aromatic amines and dicarbonyl compounds in the presence of Et 3 N (1 mmol) to afford the corresponding products 6. The structural diversity of reactants is summarized in Fig. 2 and the results are displayed in Table 2.
The synthetic pathway for the synthesis of titled compounds is consisting of two steps. At rst, compound 3 are obtained from acenaphthoquinone 1 and alkyl malonates 2. Then, the resulting products are treated with primary amines 4 and bdicarbonyl compounds 5 to afford the related propellane derivatives as the desired products. As Table 2 indicates, a variety of alkyl malonates, aliphatic and aromatic amines and b-dicarbonyl compounds were successfully applied in this process to afford the corresponding propellane derivatives as novel compounds in good to excellent yields.
To demonstrate the generality and scope of this method, malono derivatives, various acyclic b-dicarbonyl compounds such as methyl acetoacetate, ethyl acetoacetate and ethyl benzoylacetate were treated with a broad range of aliphatic and aromatic amines in the presence of Et 3 N (1 mmol) in EtOH at room temperature and the results are shown in Table 2. Use of malononitrile leads to shorter reaction times and higher yields compared to application of other alkylmalonates such as methyl cyanoacetate or ethyl cyanoacetate (compare 6b with 6p and 6l with 6q). As it is shown in Table 2, benzyl amines bearing electron-donating or -withdrawing substituents gave the desired propellanes in high yields and in short reaction times and it seems that when the methoxy group is placed on the aromatic ring, reactivity is better than when the chlorine group is on the ring. Moreover, the presence of 3,5-dimethyl group on the aromatic ring has the best efficiency. Some aromatic amines were also screened to carry out the four-component reaction by this method and the results are listed in Table 2 (entries 6h-6j). Generally, aliphatic amines are more reactive than aromatic amines. Ortho-substituted anilines, whatever the nature of the substituted groups, required a longer reaction period. For instance, reaction of acenaphthenequinone, malononitrile and 2,6-dimethylaniline with ethyl acetoacetate gave the desired product (6j) in 70% yield aer 3.1 h. Moreover, aliphatic amines such as ethyl amine and butyl amine were used for the synthesis of the corresponding product in excellent yields ( Table 2, entries 6l-6o). In the same way, Some cyclic and acyclic 1.3-dicarbonyl compounds were also screened to carry out the one pot fourcomponent reaction by this method and the results are listed in Table 2. As it is shown in Table 2, aliphatic b-keto esters are more reactive than aromatic b-keto esters (compare 6a and 6c) and no products were obtained when cyclic 1.3-dicarbonyl compounds were involved in this one-pot room temperature reaction.

Scheme 1
The synthesis of propellane derivatives via the reaction between acenaphthoquinone, malono derivatives, dicarbonyl compounds and primary amines in the presence of Et 3 N in EtOH at room temperature.  The proposed mechanism for the synthesis of propellane compounds 6 in the presence of Et 3 N is shown in Scheme 2. Based on this mechanism, Et 3 N is effective catalyst for the formation of olen (3) which readily prepares in situ by Knoevenagel condensation of acenaphthoquinone (1) with the active methylene of compound (2). Next, the formation of enamine (7) occurs through condensation of amine (4) with dicarbonyl compound (5). Then, the enamine (7) attacks to olen (3) in a Michael addition to produce intermediate (8). Aer proton transfer and tautomerization, intermediate (8) converts to intermediate (10), through intramolecular cyclization by nitrogen attack of enamine to carbonyl group. In this stage, nucleophilic addition of amino group to C]O bond afforded intermediate (10). Then, intramolecular O-cyclization and the tautomerization of imino group to amino group lead to propellanes (6).

Experimental
All chemicals were purchased from Merck or Fluka chemical companies. The 1 H NMR (400 MHz) and 13  General procedure for the synthesis of propellane derivatives 6 Triethylamine (1.0 mmol) was added to a stirred mixture of acenaphthoquinone 1 (1 mmol), malono derivatives 2 (1 mmol) in EtOH (5 mL) and the reaction mixture was stirred to complete the formation of related Knoevenagel adduct 3 (monitored by TLC). Subsequently, dicarbonyl compound 5 (1 mmol) and primary amine 4 (1 mmol) were added to this reaction mixture at once and dropwise over 10 min, respectively and reacted at room temperature for the appropriate amount of time (see Table 2). Aer completion of the reaction conrmed by TLC, the reaction mixture was ltered and washed with ethanol to afford the pure product 6a-l.