Catalysis by Amberlyst A-21: A Greener Approach to 4,5,6,7-Tetrahydro-1H-indazol-3(2H)-ones via Construction of Cyclohexanones

Abstract The 4,5,6,7-tetrahydro-1H-indazol-3(2H)-one derivatives have been synthesized in good yields via a two-step method in a single pot. The initial step involved the construction of cyclohexanone ring from aromatic aldehydes and β-ketoester in i-PrOH using an inexpensive and reusable catalyst (i.e., Amberlyst A-21) under mild reaction conditions. The utility of this catalyst has been demonstrated in synthesizing a range of cyclohexanone derivatives. The catalyst can be recovered and recycled, which makes this procedure simple, convenient, economically viable, and environmental friendly. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.] GRAPHICAL ABSTRACT


INTRODUCTION
The development of methodologies that involve the use of inexpensive and reusable catalysts under mild and environmentally friendly reaction conditions is one of the major goals in green and sustainable chemistry. Methodologies leading to various carbocyclic/heterocyclic structures are in high demand for both academic and industrial applications.

RESULTS AND DISCUSSION
Our strategy was based on the construction of the cyclohexanone ring under clean conditions followed by the formation of fused indazole ring. We explored the use of Amberlyst A-21 as an inexpensive and readily available catalyst for the first step. The resin-bound (or heterogeneous) catalysts are gaining increased interest among modern organic chemists as the use of homogenous catalysts often involved their cumbersome separation from the products and subsequent disposal as well as toxicities. Additionally, resin-bound catalysts are easy to handle and recover and also provide enhanced safety for potentially explosive reagents. Amberlyst A-21 is a weakly basic, macroreticular ion-exchange resin with alkyl amine functionality (it is bonded to the macroreticular structure of ion exchange resin). We performed a systematic study on the reaction of 4-bromobenzaldehyde (1a) and ethyl acetoacetate (2a) in the presence of Amberlyst A-21 under various conditions (Table 1). While the use of macroreticular weak base polymeric catalyst (Amberlyst A-21) in various chemical transformations has been reported in the literature, [11][12][13][14][15] its use in the construction of cyclohexanone ring has not been explored extensively earlier. On the other hand synthesis of cyclohexanone 3 has been carried out earlier via the condensation of an aldehyde with β-keto esters or 1,3-diketone in the presence of a base such as piperidine, [16,17] pyrrolidine, [18] and morpholine [19] or a strong base (e.g., NaOMe). [20] The Amberlyst A-21-mediated reaction of 1a with 2a was carried out initially in i-PrOH at 80 °C in the presence of 5% w/w catalyst (entry 1, Table 1) when the desired product 3a was isolated only in 23% yield after 15 h. Though the increase in catalyst loading increased the product yield significantly (entries 2 and 3, Table 1) the best result was obtained when 20% w/w Amberlyst A-21 was used (entry 4, Table 1). The product 3a was isolated in 90% yield in this case and was obtained by filtering the reaction mixture followed by washing the solid resin with warm i-PrOH (55-60 °C) (to elute all the organic compounds from the resin) and then reducing the volume of combined filtrate via evaporation to give the crystalline product on cooling. Notably, further increase in catalyst loading did not improve the yield of 3a (entry 5, Table 1). Similarly, the increase in reaction temperature or time did not improve the product yield. The use of other solvents [e.g., 1,4-dioxane, tetrahydrofuran (THF), dimethylformamide (DMF), toluene, EtOAc, and MeCN] was also examined but they were found to be less effective (entries 6-11, Table 1). While the reasons for these observations are not clearly understood, it is known that the reactivity of polystyrene resin is mainly governed by the accessibility of the reactants to the catalytic sites via swelling of the resin in solvents. It seemed that the swelling of resin perhaps was more effective in i-PrOH than any other solvents tested. The recyclability of the catalyst was examined by recovering it via filtration, washing with i-PrOH and THF, and reusing it for an additional three runs in the reaction of 1a with 2a. The product 3a was isolated without significant loss of its yield in these cases (entry 4, Table 1). Moreover, these reactions were performed under open air and therefore do not require the use of an inert or anhydrous atmosphere. Nevertheless, the use of Amberlyst A-21 (20% w/w) in i-PrOH at 80 °C was identified as the optimum reaction conditions for the synthesis of 3a.
To demonstrate the generality and scope of the Amberlyst A-21-mediated synthesis of cyclohexanones we prepared several other derivatives as shown in Fig. 2 using a range of aldehydes 1. Thus 1 was reacted with ethyl acetoacetate (2a) in the presence of Amberlyst A-21 in i-PrOH at 80 °C for 15 h under open air. The desired products 3 were isolated in good yields irrespective of the nature and type of aldehydes (e.g., aryl, heteroaryl, or alkyl aldehydes) employed. Once again the potential utility of these compounds was demonstrated by converting the two representative compounds 3d and 3f to the corresponding 4,5,6,7-tetrahydro-1H-indazol-3(2H)ones separately via the reaction with hydrazine (Scheme 3). However, the reaction of 3e with hydrazine was not clean, perhaps due to the presence of reactive aldehyde moiety as an additional functional group. Scheme 3. Synthesis of ethyl 6-hydroxy-6-methyl-3-oxo-4-p-tolyl-2,3,4,5,6,7-hexahydro-1H-indazole-5carboxylate (5d) and ethyl 4-(4-chlorophenyl)-6-hydroxy-6-methyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-indazole-5-carboxylate (5f). Based on the fact that Amberlyst A-21 is a weakly basic, macroreticular resin with alkyl amine functionality, a plausible mechanism for the present two-step method in a single pot is shown in Scheme 4. The reaction seemed to proceed via a Knoevenagel condensation of 1 with 2 in the initial step. The resin facilitates the generation of carbanion E-1 from 2 possessing an active methylene group. The reaction of E-1 with the aldehyde 1 affords the Knoevenagel product (E-2), which on Michael type addition by the carbanion E-1 affords E-3. An intramolecular aldol type condensation of E-3 mediated by the resin provides the cyclohexanone derivatives 3. The reaction of hydrazine 4 with 3 in the same pot affords the 4,5,6,7-tetrahydro-1H-indazol-3(2H)-one derivatives (5).

CONCLUSIONS
In conclusion, 4,5,6,7-tetrahydro-1H-indazol-3(2H)-one derivatives have been synthesized in good yields via a two-step method in a single pot. The initial step involved the construction of cyclohexanone ring from aromatic aldehydes and β-ketoester in i-PrOH using inexpensive and reusable catalyst (i.e., Amberlyst A-21) under mild reaction conditions. The utility of this catalyst has been demonstrated in synthesizing a range of cyclohexanone derivatives. The catalyst can be recovered and recycled, which makes this procedure simple, convenient, economically viable, and environmentally friendly. The present Amberlyst A-21-catalyzed method therefore has potential for the generation of library of small molecules useful for synthetic and medicinal applications.

General Procedure for the Preparation of Compounds 5a-c
Amberlyst A-21 (20% w/w) was added to a solution of ethyl acetoacetate 2a (2.2 mmol) and aldehyde 1 (1.0 mmol) in ethanol (10 ml), and the mixture was stirred at 80 °C for 15 h to ensure the completion of the reaction (monitored by TLC). The reaction mass was cooled to room temperature, and hydrazine hydrate 4 (1.0 mmol) was added. The mixture was stirred at 80 °C for another 12 h. After completion of the reaction (confirmed by TLC) the resin was separated by filtration. The filtrate was concentrated under low vacuum to give the crude product, which was purified by recrystallization from ethanol to afford the pure product 5a-c.

Recovery of the Catalyst
The recovered Amberlyst A-21 resin, obtained by filtering off the reaction product, was washed successively with THF (5 mL) and EtOH (5 mL) three times and dried at 100 °C for 2 h. The efficiency of the catalyst was not changed significantly after using it three additional times in the model reaction, shown in Table 1.