An Approach to the Diastereoselective Synthesis of Cyclohexane-1,3-dicarboxamide Derivatives via a Pseudo Five-Component Reaction Based on Diketene

Abstract A one-pot pseudo five-component reaction for the synthesis of 2-aryl-4-hydroxy-4-methyl-6-oxo-N 1,N 3-dialkylcyclohexane-1,3-dicarboxamide derivatives involving different primary amines, various aromatic aldehydes, and diketene in the presence of triethylamine with high yields is achieved.


Figure 1 Streptovitacin A
Multicomponent reactions (MCRs) 7 provide a powerful tool for the synthesis of divergent and complex compounds. The greatest characteristic of MCRs is the generation of sev-eral bonds in single vessel, adding further reagents, without isolation of the intermediates leading to the minimization of waste and labor required.
There are various methods for the synthesis of substituted cyclohexanones; 8 one of the commonly employed methods reported for the synthesis of cyclohexanone rings involves the condensation of aldehydes with β-keto esters or 1,3-diketones in the presence of an appropriate base as a catalyst. In spite of being generally efficient, these approaches can suffer from the use of volatile or aggressive bases such as piperidine, 1b,9 pyrrolidine, 10 tetramethylguanidine, 11 potassium hydroxide, 12 morpholine, 13 or NaOMe. 14 Diketene (4-methylene-oxetan-2-one, DK) comprises a four-membered lactone ring attached to a methylene moiety and can be considered as the anhydride of acetoacetic acid. DK is an inexpensive commercially available or readily accessible, reactive, and versatile molecule. 15 DK is an ideal molecule for use in diverse organic transformations, since it possess electrophilic and nucleophilic sites that react with numerous functional groups. Notably, most of these types of reactions form 1,3-dicarbonyl compounds which themselves can subsequently be subjected to further transformations. In 1986, the chemistry of DK was extensively and comprehensively reviewed by Clemens. 16 Very recently, we also published applications of DK as a privileged synthon in the synthesis of heterocyclic compounds. 17 During, the course of writing this chapter, we found that there is no synthetic route reported leading to the construction of cyclohexanones starting from DK. We are interested in MCRs, 18 and we have also achieved and reported two five-component reactions which are rare in the chemical literature. 19 In the present work, we wish to report the diastereoselective synthesis of polysubstituted cyclohexanone ring 3 bearing methyl, aryl, hydroxy, and dicarboxamide groups, via MCR involving diketene. Thus, trans-2-aryl-cis-4-hy-

Letter Syn lett
droxy-trans-4-methyl-6-oxo-cis-N 1 ,N 3 -dialkylcyclohexane-1,3-dicarboxamide derivatives 3 were synthesized in high yields and high purity via a simple one-pot pseudo fivecomponent reaction involving a primary amine, DK, and an aromatic aldehyde in the presence of triethylamine at room temperature.
These cyclohexanones can serve as synthons in further synthetic endeavors, as they possess β-keto amide and βhydroxy ketone moieties. 20 The chemical properties of 4hydroxy-6-oxo-cyclohexane-1,3-dicarboxamides have been previously investigated. Their reactions with p-toluidine, hydrazine hydrate, and cyanoacetic acid hydrazide resulted in the formation of the dehydration product and tetrahydroindazole. 9c In a pilot reaction, benzylamine (1a, 1 mmol), and DK (1 mmol) were dissolved in CH 2 Cl 2 and stirred at ambient temperature. Upon completion of the reaction (15 min), a sample was taken and identified as the corresponding benzamide, namely N-alkyl-3-oxobutanamide 4a. 4-Chlorobenzaldehyde (2a, 1 mmol) was then added to the same vessel without isolation of 4a and the solution was left at room temperature. Although the reaction proceeded cleanly, the progress of the reaction was found to be sluggish. Even after a few days the starting materials were still present. Addition of a catalyst was considered and therefore triethylamine was added to the reaction. The reaction now proceeded smoothly and eventually the consumption of the reactants and formation of a new product was detected albeit over several days. To decrease the time of the reaction we increased the temperature from ambient to reflux temperature, but we observed the solution was getting dark giving a complicated mixture of the products. 16 The product of this reaction was isolated and identified as N 1 ,N 3 -dibenzyl-2-(4-chlorophenyl)-4-hydroxy-4-methyl-6-oxocyclohexane-1,3-dicarboxamide (3a, Table 1, entry 1; Scheme 1). 21 To establish the generality of this new synthetic strategy, a variety of aromatic aldehydes and aliphatic amines was employed and reacted with DK under the same reaction conditions to provide the respective products 3 in high to excellent yields (Table 1).
The molecular structures of the synthesized compounds 3a-g were elucidated by 1 H NMR, 13 C NMR, and FTIR spectroscopic analysis as well as elemental analysis.
For the cyclic structure 3 eight diastereoisomers are possible. Kingsbury 22 and Pandiarajan 23 investigated the methyl ester and ethyl ester of this cyclic structure using NMR spectroscopy. Kingsbury 22 reported that the reaction of methyl acetoacetate with benzaldehyde gives a mixture including three compounds, A, B, and C. Compound A was found to be the major product. However, when ethyl acetoacetate was used instead of methyl acetoacetate with various aromatic aldehydes, only a single product A was obtained ( Figure 2). 23

Figure 2 Major and minor diastereoisomers for target cyclic structure
In compound 3a, the three-H singlet at δ = 1.22 ppm was attributed to the methyl group. The spectrum also clearly indicates two multiplets at δ = 3.87-3.92 and 4.31-4.37 ppm which were assigned to the methylene protons of the two benzyl groups. The doublet at δ = 3.11 ppm with J = 12 Hz was assigned to H-1. The other doublet at δ = 3.71 ppm with J = 12.4 Hz is assigned to H-3. Since the large coupling constants J 12 and J 23 (12 and 12.4 Hz) are nearly equal, they both should be of trans-diaxial protons. The large substituents at the adjacent carbon then must inhabit the favored equatorial positions. The triplet centered at δ = 3.94-4.0 ppm (J = 9.3 Hz) was assignable to H-2. The diastereotopic methylene protons at C-5 appeared as doublets at δ = 2.74 ppm (J = 14.0 Hz) and 2.38 ppm (J = 14.0 Hz). The singlet at δ = 4.96 ppm was due to the OH proton, which disappeared on addition of D 2 O. The shape of the signal for the OH group indicates that the intramolecular hydrogen bond-

Letter Syn lett
ing between the amide carbonyl and the OH is strong. Thus compound 3 has all major groups equatorial except the hydroxyl group.
The 13 C NMR spectrum of 3a showed two signals at δ = 167.5 and 172.8 ppm which were assigned to the amide carbonyl carbons at C-1 and C-3, respectively. It also showed a signal at δ = 204.5 ppm attributed to C-6.
Among the protons in the cyclohexanone ring, H-2a appears at the highest chemical shift, presumably because it is deshielded due to the anisotropic effect of the aromatic ring at C-2. 24 Therefore, on the basis of spectroscopic analysis the structures of our products were elucidated as trans -2-arylcis-4-hydroxy-trans-4-methyl-6-oxo-cis-N 1 ,N 3 -dialkylcyclohexane-1,3-dicarboxamide derivatives 3a-g (Figure 3). 23

Figure 3 The selected 1-H chemical shifts and H-H coupling constants for 3a
The 1 H NMR spectra of 3a-g are reported in the Supporting Information section.
By taking our entire experimental outcomes into consideration, the possible mechanism for the formation of products 3a-g is proposed in Scheme 2. It is reasonable to assume that 5 results from the initial Knoevenagel condensation of the aromatic aldehyde with N-alkyl-3-oxobutanamide 4, which is derived from the nucleophilic addition of the amine group to DK, followed by ring opening and pro-ton transfer to produce N-(2-aminophenyl)-3-oxobutanamide (4), followed by the Michael addition of the N-alkyl-3oxobutanamide 4 to 5 to give intermediate 6. In the presence of triethylamine, 6 forms enol 7, which upon intramolecular aldol reaction affords the six-membered ring of the trans- 2-aryl-cis-4-hydroxy-trans-4-methyl-6-oxo-cis-N 1 ,N 3 -dialkylcyclohexane-1,3-dicarboxamide derivatives 3 (Scheme 2).
Our proposed mechanism can be supported by the individual steps, as reported previously. The reaction of aromatic aldehydes with linear 1,3-dicarbonyl compounds such as ethyl acetoacetate in the presence of an amine and different catalysts has been investigated by a number of research groups, and the formation of the similar cyclic substituted esters was reported. 10,23,25 On the other hand, treatment of cyclic 1,3-dicarbonyl compounds with aromatic aldehydes in the presence of an amine gives products such as tetrahydroquinolines, 26 acridones, 27 Hantzsch dihydropyridines, 28 or 3,5-dispirosubstituted piperidines 29 and not the expected 6-oxocyclohexane-1,3-dicarboxamide. Thus, in the present work, compounds 3a-g have been constructed by the pseudo five-component reaction of DK, primary amines, and aromatic aldehydes in a molar ratio of 2:2:1, respectively, in the presence of triethylamine as a basic catalyst.

Scheme 3 A β-lactam intermediate for the formation of N-tert-butyl-2benzylideneacetoacetamide
In summary, we have demonstrated an effective onepot pseudo five-component approach for the diastereoselective synthesis of novel trans-2-aryl-cis-4-hydroxy-trans-4-methyl-6-oxo-cis-N 1 ,N 3 -dialkylcyclohexane-1,3-dicarboxamide derivatives via cyclocondensation reaction of DK, primary aliphatic amines, and aromatic aldehydes in CH 2 Cl 2 by using triethylamine at ambient temperature. All of the products were isolated with high purity using very simple and accessible starting materials. In addition, the isolation and purification of compounds by simple filtration and hexane washing makes the process very simple, avoiding conventional chromatographic separation, rendering it a useful and attractive strategy for the synthesis of cyclohexanones and a model for their asymmetric synthesis.

Acknowledgment
Financial support for this research from Alzahra University, Iran is gratefully acknowledged. MMH is also grateful to the Iran National Science Foundation (INSF) for financial support granted by given individual research chair.

Supporting Information
Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0036-1590980. Copies of 1 H NMR, 13