Synthesis Studies of N-acetyl Glyoxylamide Using Unreactive Amines

FIA FATHIANA WULAN, Dra. Tutik Dwi Wahyuningsih, M.Si., Ph.D; Prof. Drs. Jumina, Ph.D

2020 | Skripsi | S1 KIMIA

Sintesis senyawa glioksiamida telah dilakukan dengan menggunakan N-asetilisatin dan turunan metil antranilat sebagai bahan dasar. Beberapa strategi dilakukan untuk memudahkan sintesis glioksiamida menggunakan amina yang tidak aktif, seperti meningkatkan reaktivitas cincin isatin dan meningkatkan kekuatan nukleofilitas amina. Kemudian, dilakukan hidrolisis terhadap senyawa glioksiamida yang terbentuk. Sintesis glioksiamida dilakukan dengan mereaksikan N-asetilisatin atau N-asetil-5-niroisatin dengan amina tidak aktif sebagai nukleofil, seperti metil-2-aminobenzoat, metil-2-amino-5-metoksibenzoat, dan metil-2-amino-4-metoksibenzoat. Reaksi dilakukan pada kondisi refluks dan atmosfir nitrogen inert selama 48 jam dengan adanya katalis DIPEA dalam pelarut asetonitril untuk mendapatkan metil 2-(2-(2-asetamidofenil)-2-oxoasetamido)benzoat (glioksiamida 3), metil 2-(2-(2-asetamido-5-nitrofenil)-2-oxoasetamido)benzoat (glioksiamida 4), metil 2-(2-(2-asetamidofenil)-2-oxoasetamido)-5-metoksibenzoat (glioksiamida 5), dan metill2-(2-(2-asetamidofenil)-2-oxoasetamido)-4-metoksibenzoate (glioksiamida 6), secara berurutan. Hidrolisis gugus ester benzoat pada glioksiamida 5 dan 6 menjadi asam benzoat telah dilakukan dengan mereaksiakan glioksiamida tersebut dengan litium hidroksida dalam campuran pelarut tetrahidrofuran, metanol, dan air pada suhu ruangan untuk menghasilkan asam metil 2-(2-(2-asetamidofenil)-2-oxoasetamido)-5-metoksibenzoat (glioksiamida 7), dan asam metil 2-(2-(2-asetamidofenil)-2-oxoasetamido)-4-metoksibenzoat (glioksiamida 8), secara berurutan. Produk hasil sintesis dikarakterisasi menggunakan 1H-NMR, 13C-NMR, FT-NSI MS, dan spektrometer FTIR. Dari percobaan reaksi yang telah dilakukan, diketahui bahwa sintesis glioksiamida 3 dan 4 tidak berhasil dilakukan. Sementara glioksiamida 5 dan 6 berhasil disintesis dengan rendemen sebesar 11.77%, dan 10.62%, secara berurutan. Hasil hidrolisis dari kedua senyawa tersebut menghasilkan glioksiamida 7 dan 8 dengan rendemen sebesar 52.00 and 41.60% secara berurutan. Berdasarkan nilai rendemen, dapat dibuktikan bahwa adanya gugus pendonor elektron pada amina tidak aktif sebagai nukleofil meningkatkan kemudahan sintesis glioksiamida.

Synthesis of glyoxylamide has been carried out, starting from N-acetylisatin and methyl anthranilate derivatives as the starting material. Several strategies were performed to increase the ease of glyoxylamide syntheses, such as increasing the reactivity of the isatin ring and increasing the nucleophilicity of the amine. Then, the hydrolysis of formed glyoxylamide has also been performed. The synthesis of glyoxylamide was carried out by mixing N-acetylisatin or N-acetyl-5-nitroisatin with the nucleophiles of unreactive amines, i.e., methyl-2-aminobenzoate, methyl-2-amino-5-methoxybenzoate, and methyl-2-amino-4-methoxybenzoate. The reaction was performed under reflux and inert nitrogen gaseous atmosphere for 48 h in the presence of DIPEA as a base in acetonitrile (ACN) solvent to obtain methyl 2-(2-(2-acetamidophenyl)-2-oxoacetamido)benzoate (glyoxylamide 3), methyl 2-(2-(2-acetamido-5-nitrophenyl)-2-oxoacetamido)benzoate (glyoxylamide 4), methyl 2-(2-(2-acetamidophenyl)-2-oxoacetamido)-5-methoxybenzoate (glyoxylamide 5), and methyl 2-(2-(2-acetamidophenyl)-2-oxoacetamido)-4-methoxybenzoate (glyoxylamide 6), respectively. The hydrolysis of benzoate of glyoxylamide 5 and 6 into benzoic acid was done by mixing the corresponding glyoxylamide with lithium hydroxide in the mixture of tetrahydrofuran, methanol and water solvent media at room temperature to yield methyl 2-(2-(2-acetamidophenyl)-2-oxoacetamido)-5-methoxybenzoic acid (glyoxylamide 7), and methyl 2-(2-(2-acetamidophenyl)-2-oxoacetamido)-4-methoxybenzoic acid (glyoxylamide 8), respectively. All the synthesized products were characterized by using 1H-NMR, 13C-NMR, FT-NSI MS, and FTIR spectrometer. From the synthesis attempt, it was found that glyoxylamide 3 and 4 were not successful. The glyoxylamide 5 and 6 have been successfully synthesized with a yield of 11.77 and 10.62%, respectively. While their hydrolysis has successfully produced glyoxylamide 7 and 8 with a yield of 52.00 and 41.60%, respectively. Based on the yield of the reactions, it was proved that the presence of the electron-donating group in unreactive amine as a nucleophile could increase the ease of glyoxylamide synthesis.

Kata Kunci : glyoxylamide, methyl anthranilate, N-acetylisatin, nucleophile