2020-02-15 18:12:01
Daggupati V. Ramana, Karu Sudheer Kumar, Ealeswarapu Srujana, and Malapaka Chandrasekharam
Introduction
Ester, amide and amino groups are widely present in bioactive molecules and their incorporation into an organic molecule warrants multistep synthesis sequence. However, functionaliza- tion of inexpensive glycine ester or amide would be an effective strategy and represent important building blocks for drug de- velopment and natural product synthesis. Alkylation of arenes and heteroarenes is a challenging task in organic chemistry and Friedel-Crafts reaction is known to be the most suitable choice.[1] Traditionally alkyl halides and alcohols have been used as alkylating agents and particularly benzyl halides, benzyl alcohols and styrenes are suitable electrophiles for the genera- tion of 1,1-diarylalkanes. New developments in the Friedel- Crafts alkylation and their efficacy in aqueous media have been recently reviewed.[2] Double Friedel-Crafts alkylation of indoles with non-symmetrical divinyl ketones was achieved for the syn- thesis of complex tricyclic indoles.[3] Though double Friedel- Crafts alkylation provides easy entry to gem-diaryl alkyl com- pounds,[4] reports on glycine esters as alkylating agents in Frie- del-Crafts reactions are not very common. Several reports ap- peared on the α-C-H functionalization of glycine esters/amides using various nucleophiles in presence of metal or metal-free catalysts in organic solvents.[5] Congde Huo reported copper- catalyzed oxidative arylation of glycine derivatives with indoles in THF/H2O.[6] The same group also reported a very interesting triarylaminium salt-promoted synthesis of bisindolyl acetic esters from glycine ester derivatives where the scope of the nucleophile is limited to indole and industrially unacceptable DCM solvent was used.[7]
We have previously demonstrated the copper-catalyzed α- arylation,[8] amidation/imidation[9] of N-arylglycine esters under mild conditions. Tetrahydroquinolines (THQs) belong to a class of heterocycles of high pharmacological value and in general organic reactions in water as solvent attracted tremendous in- terest over other organic solvents due to its green and environ- mentally benign nature.[10] Therefore an efficient method for the synthesis of α-diaryl alkyl compounds from aryl/heteroaryl nucleophiles promoted by green solvents is highly warranted. In continuation of our interest in C-H functionalizations involv- ing the most abundant, less expensive, non-toxic iron and cop- per catalysts and water-mediated reactions,[11] we herein report a double Friedel-Crafts alkylation reaction of glycine ester on heteroaryl (tetrahydroquinolines, 2-meTHQ and indoles) and aryl (N-methyl aniline) nucleophiles to generate gem-diaryl/het- eroarylacetic esters with less expensive, non-toxic copper cata- lyst and environmentally benign aqueous conditions.
Results and Discussion
Methyl 2-(p-tolylamino)acetate 1a and tetrahydroquinoline 2a were chosen as model substrates and the reaction was con- ducted in the presence of 10 mol-% CuCl in DCE solvent at room temperature for 24 h under open flask conditions, antici- pating the formation of tetrahydroquinolinyl glycine ester deriv- ative resulting from α-C-H functionalization. However the formation of methyl 2,2-bis(1,2,3,4-tetrahydroquinolin-6-yl)- acetate 3aa (10 %) was observed along with the expected prod- uct (R)-methyl 2-(1,2,3,4-tetrahydroquinolin-6-yl)-2-(p-tolyl- amino)acetate 3aa (25 %). This result instigated us to optimize the conditions for the unexpected double Friedel-Crafts alkyl- ation product 3aa (Table 1). Various solvents were tested for this reaction and water was found to be the most suitable sol- vent for the predominant formation of the double Friedel-Crafts alkylation product 3aa (entries 2–11, Table 1). The solvents DCE, ACN, DCM, THF and toluene at room temperature favored the formation of 3aa, whereas the reaction conducted at 100 °C in toluene solvent resulted in the exclusive formation of 3aa in 23 %. While in MeOH, the selectivity and the overall yields were not encouraging, the reaction is not efficient in p-xylene solvent even at elevated (120° C) reaction temperature. The reaction is not successful with the solvents, DMF and DMSO, and the start- ing materials remained unreacted even at 120 °C. Among the catalysts CuI, CuII and FeCl3 employed for the reaction, CuI pro- duced an improved yield of 3aa (entries 12–17, Table 1). The conditions were then optimized for the reaction temperature, time and the catalyst loading under water solvent and CuI cata- lyst conditions (entries 18–23, Table 1). In the absence of a cata- lyst, the reaction does not proceed (entry 24, Table 1). Under the optimized reaction conditions, stirring the reaction mixture with 10 mol-% of CuI catalyst in water solvent at 100 °C for 24 h, the desired product 3aa was obtained in 85 % yield.
With the optimised conditions in hand, we examined the substrate scope for the double Friedel-Crafts alkylation reaction of glycine esters/amide with different nucleophiles i.e., 2- meTHQ, substituted indoles and N-methyl aniline to generate diverse gem-di-aryl/-heteroarylacetic esters/amide. Different N- arylglycine ester derivatives (R = Me, Et, nBu, iPr, tBu and Bn) were treated with THQ under the optimised reaction conditions to produce the corresponding desired products in excellent yields (3aa–3fa, Table 2). The scope of the nucleophile was suc- cessfully extended to 2-meTHQ, N-methyl aniline and 1-, 5- and 6,7-disubstituted indole derivatives. The copper-catalyzed reac- tion proceeds smoothly with 2-meTHQ and N-arylglycine ester 1a resulting in the formation of the desired product 3ab in 65 % yield (Table 2). N-methyl aniline was treated with different N-arylglycine esters (R = Me, Bn) and the reactions proceeded well to afford the corresponding desired products in good yields (3ac, 3fc, Table 2). Various substituted indoles employed as nucleophiles, for the double Friedel-Crafts alkylation reaction protocol with N-arylglycine ester 1a, delivered the correspond- ing products in good to excellent yields (3ad–3ag, Table 2). Under the optimized reaction conditions, we also observed the formation of α-C-H functionalization products in some of the cases, in very low yields.
The double Friedel-Crafts alkylation reaction protocol also works for the glycine amide derivative, 1-(pyrrolidin-1-yl)-2-(p- tolylamino) ethanone using 2-meTHQ or indole as nucleophiles, and delivered the corresponding alkylated products in very good yields (Scheme 1).
To understand the mechanism for the double Friedel-Crafts alkylation reaction, we carried out the following experiments as depicted in the Scheme 2. When the reaction was carried out in the presence of radical scavenger BHT (20 mol-%) under the standard conditions, the absence of the formation of the dou- ble Friedel-Crafts product and α-C-H functionalization product indicates that the reaction follows a radical-mediated path. The reaction did not proceed in the absence of oxygen implying that molecular oxygen is essential for the reaction to proceed. The intermediacy of the α-C-H functionalization is confirmed by the formation of the double Friedel-Crafts alkylated product in 58 % yield from the reaction of 3aa (0.5 mmol) with THQ (1.0 mmol).
Based on previous literature reports and our recent investiga- tions on CuI-catalyzed α-C-H functionalizations adjacent to the nitrogen atom, we proposed a plausible mechanism for this double Friedel-Crafts alkylation reaction as shown in the Scheme 3. Initially, CuI in presence of atmospheric oxygen gen- erates CuIIOO radical, which might abstract hydrogen radical from glycine derivative 1 delivering radical intermediate A, fur- ther interconverts to the iminium intermediate B. Nucleophile attack on intermediate B resulted in the α-C-H functionalization product 3. Then a second oxidation occurred on 3 compound to form another iminium intermediate C, followed by nucleo- phile addition resulted in the intermediate D. Finally, the double Friedel-Crafts alkylated product produced from the intermedi- ate D, by the loss of aniline.
Conclusions
In conclusion, we have successfully demonstrated a double Frie- del-Crafts reaction protocol of N-arylglycine esters/amide with heteroaryl (tetrahydroquinolines, 2-meTHQ and indoles) and aryl (N-methyl aniline) nucleophiles. Under the reaction condi- tions both the α-C-H functionalization and gem-diaryl/hetero- arylacetic esters/amide could be generated, however in the present investigation, the reaction conditions are optimized for double Friedel-Crafts products in excellent yields. The reaction is carried out with a less expensive, non-toxic copper catalyst in aqueous and open flask conditions. A single electron transfer (SET) mechanism was proposed for the reaction.
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