Bis(trifluoroacetoxy)iodo benzene (PIFA)-promoted transamidation of carboxamides and carboxylic acids with amines

A simple and efficient method has been developed for the synthesis of amides promoted by PIFA [(bis(trifluoroacetoxy)iodo)benzene]. In this method, PIFA [(bis(trifluoroacetoxy)iodo)benzene] has been used as a useful promoter for the transamidation of dimethylformamide (DMF) with the amines. Besides, this hypervalent iodine smoothly promoted the N-formylation of various aromatic amines with formic acid. Notably, the small quantity of PIFA is found to be efficient for both strategies and large-scale synthesis can also be achieved. The present protocol involves a metal and solvent-free, mild, eco-friendly condition with a high yield of the amide products and moreover, the reactions are not air or moisture sensitive.


Introduction
4] In particular, N-formyl amides are commonly applied as a useful synthetic intermediate to synthesize many important compounds such as amines, 5 N-methyl amines, 6 isonitriles, 7 thioamides, 8 isoselenocyanates. 9Furthermore, in organic chemistry, the amides have a vast application in form of dyes, polymers, and agrochemicals substances.1] Eventually, the fatty acid amides can show anti-inflammatory, antimicrobial, antitubercular, and antiproliferative activities.Fundamentally, the amides have immensely surrounded many chemical strategies that have enriched the synthetic organic chemistry zone.Due to such valuable contribution of amide compound, many strategic methods have been developed for years.In this regard, some common effective solvents like dimethylformamide (DMF) have exhibited reactivity in the case of N-formylation reaction with various amines.In the reported literature, the transamidation of amines has been completed using DMF as carbonyl sources using various metal catalysts such as iron, palladium, nickel, cerium, manganese, 12 NH4I, 13 sulfated polyborate, 14 hydroxylamine hydrochloride (NH2OH.Cl), 15 H2SO4-SiO2, 16 K2S2O8, 17 graphene oxide (GO), 18 boric acid, 19 ionic liquids. 202][23][24][25] Different types of formylating reagents have been brought in for the amidation process by employing various catalytic systems such as Brønsted acids, Lewis acids, nano-oxides and many others. 26However, the previous methods still have some strategic deficiencies in terms of the condition and reagents used.
In recent advanced chemistry, iodine-containing compounds have attracted considerable attention in synthetic organic chemistry.8] Remarkably, these novel substances show promising activity in oxidation or catalytic reactions. 29][32][33] Particularly, hypervalent iodine (III) has been involved in the direct C-N bond formation and metal-free functionalization. 346][37][38][39][40][41] In this account, we have utilized the catalytic activity of PIFA 42 for the facile and collective transamidation of dimethylformamide, and formic acid.

Results and Discussion
At the initial point, at 100 o C we have conducted the transamidation reaction of aniline, 1a with 2 ml of formamide, 2a in the presence of a useful hypervalent iodine reagent phenyliodine(III) diacetate (PIDA) (20 mol%) and as a result of 75% of the N-phenylformamide, 3a was produced (Table 1, entry 1).Interestingly, in the next observation, the reaction was carried out with (bis(trifluoroacetoxy)iodo)benzene (PIFA) which provided a better yield of the desired product (82%) (Table 1, entry 2).After that, the reactions were thoroughly investigated with varying amounts of the catalyst.The use of 50 mol% of the catalyst did not improve much to form the targeted product, 3a (Table 1, entry 3).On the other hand, when the quantity of the PIFA was decreased to 10 mol% and 5 mol% there was a certain decline in the product formation (Table 1, entry 4-5).Certainly, bis(tert-butylcarbonyloxy)iodobenzene (BTBI) was not found to be a suitable hypervalent iodine catalyst for this purpose (Table 1, entry 6).Next, the reaction was checked taking 1 equiv. of PIFA and surprisingly, we got 86% of N-phenylformamide (Table 1, enty 7).Thereafter, the heating process at 140 o C did not show a considerable change in the yield while a less amount of product was generated at the lower temperature, 50 o C (Table 1, entry 8 & 9).Next, we also investigated the addition of solvent to the reaction.In this regard, the presence of DMSO was not effective for this reaction (Table 1, entry 10).Interestingly, the solvent mixture with an equal ratio of DMF and other solvents (1:1) gave an unsatisfactory yield.In addition, the other solvent medium pairing DMF with DMSO, toluene and acetonitrile were found inappropriate to get a better result (Table 1, entry 11-13).Eventually, the product was formed with 66% of yield by the use of ½ ml of DMF (Table 1, entry 14).Moreover, we examined the reaction for a prolonged time of 12 hours and the formation of the desired product was not changed (Table 1, entry 15).So, the optimized condition of the present reaction was 1 equiv. of PIFA and 2 ml of DMF upon treatment with anile at 100 o C temperature to produce the N-phenylformamide with the best yield.The reaction was also investigated in the absence of catalyst and under nitrogen atmosphere, but both conditions were not suitable ( a Reaction conditions: aniline (1a, 1 mmol), DMF (2a, 2 ml), HVIs (5 mol%-1 equiv.); 100 °C; 6 h.b Isolated yield.c DMF (0.5 mL) was used.d Reaction carried out for 12 h.e The reaction was performed under a nitrogen atmosphere.
After getting the optimized reaction condition we then engaged to increase the substrate scope (Table 2).To check the tolerance of the electron-withdrawing groups in the nucleophile, we have used 2-F and 4-F aniline and notably, both the anilines smoothly converted to the corresponding formamide products 3b and 3c in excellent yields.Even, 2-nitroaniline and 4-nitroaniline easily underwent the reaction to give the desired formamides 3d and 3e in 69% and 72% yields respectively.Importantly, sterically hindered 2,6-difluoroaniline easily underwent the reaction to produce the desired product 3f in good yield.Other difluoro substituted anilines such as 2,4-F, 3,4-F also afforded the respective compounds 3g and 3h in high yields.Interestingly, other halogen-containing anilines like 2-fluoro-4-bromoaniline, 2-bromo-4-fluoroaniline, 3-chloro-4-fluoroaniline, 3bromoaniline, 2-bromo-4-methylaniline, 2-iodo-3-bromoaniline were also equally effective for the Nformylation reaction and the corresponding formamide compounds (3i-3n) were obtained in good yields.In addition, DMA was also found to be an effective agent for the N-acylation of aniline and the N-(mtolyl)acetamide, 3o was obtained in 65% yield.
To our delight, we have applied our present method for the transamidation of various carboxylic acids namely, HCO2H, and CH3CO2H (Table 3).Notably, these carboxylic acids were easily converted to the corresponding amides under solvent-free conditions and 80 °C heating.At first, we successfully prepared the Nformylated product by the reaction of aniline with formic acid.The N-phenylformamide 3a was resulted in an excellent yield of 87%.Later on, we investigated the reaction with a few electron-withdrawing halogen and nitro-substituted anilines to get the desired products 3b-3h in high yields.It is noteworthy that formic acid also reacted with halogen-containing anilines to afford the expected compounds 3i-3n in very high yields.In addition, upon reaction with substituted anilines with acetic acid, the respective acetamide product was formed in 79% yield.Being motivated by the excellent yield formation of the corresponding products, we then performed the reaction with a large number of reactants.Under the standard reaction condition, the mixture of 5 mmol of aniline, and 20 mmol of formic acid in the presence of PIFA (100 mol%) was successfully converted to the expected N-formamide, 3a in 81% yield.

Scheme 2. Gram-scale synthesis of N-phenylformamide.
Based on the above results, we have established a probable mechanism for transamidation in the presence of PIFA which is known as an efficient promoter for several reactions. 31Initially, formamide coordinate with (bis(trifluoroacetoxy)iodo)benzene and the nucleophilic attack of amines is facilitated to form the intermediate A. Then, in the next step of the easy proton transfer process, the second intermediate B was generated and finally, the deamination led to the desired amide product 3.

Conclusions
In summary, a very simple and useful environment benign method has been developed using PIFA as a catalyst for the transamidation of DMF and formic acid.Different types of aromatic amines, mostly bearing fluoro substituents gave the corresponding amide derivatives in high yields.Notably, DMF solvent and formic acid have been successfully utilized as N-formylating agents.The readily available reagents, hypervalent iodine promoter, short reaction time, simple, aerobic and mild reaction conditions are the advantageous features of the present protocol.

Experimental Section
General.All starting materials and commercial reagent were purchased from Alfa Aesar, Sigma Aldrich, Avra, Spectrochem, TCI.Chemicals like anilines (95-99%), DMF (anhydrous, 99.5%), DMA (98%), formic acid (85%), acetic acid (glacial, 99.5%) have been used for the reactions.Thin Layer Chromatography plates were visualized by exposure to ultraviolet light (UV) with 254 nm of wavelength and then further analyzed by using iodine chamber.Thin-layer chromatography was performed using pre-coated plates.Column chromatography was performed in 120 to 200 mesh size silica gel.The reactions were carried out in round bottom flask and sealed tube.All NMR spectra were recorded by Bruker Avance 400 spectrometer ( 1 H at 400 MHz and 13 C at 100 MHz).Chemical shifts for 1 H NMR spectra have been reported in parts per million (ppm) from tetramethylsilane with the solvent resonance as the internal standard (CDCl3: δ 7.26 ppm).Similarly, 13 C NMR spectra have been reported in parts per million (ppm) from tetramethylsilane with the solvent as the internal standard (CDCl3: δ 77.16 ppm).The 1 H NMR and 13 C NMR of the known products were compared with literature reports.

Figure 1 .
Figure 1.The representative drug molecules containing amide unit.

Table 1 .
Optimization of reaction conditions for N-formylation of aniline a