Synthesis of carboxamide and sulfonyl carboxamide linked heterocycles under green conditions

Direct coupling of heteroaldehydes with heteroaryl amines / sulfonylamines is performed under green conditions using PEG-400 in the presence of oxidant CCl 3 CN/H 2 O 2 . The presence of electron withdrawing substituents on heteroaldehydes increased the yield. Further heteroaryl amines favor the reaction when compared with heteroaryl sulfonylamines


Introduction
Amide moiety represents a privileged structural motif and it plays an important role in the composition of polymers, proteins, natural products and pharmaceuticals. 1,2Various approaches were explored for efficient construction of this significant skeleton. 3,46][7] However, this method has innate drawbacks, for instance, a large amount of byproducts are generated leading to lower yields.As a result, alternative methods for amide synthesis have been developed viz., Beckmann rearrangement, 8 azide based modified Staudinger-Vilarrasa reaction, 9 amidation of aryl halides, 10 oxidative amidation of aldehydes 11 or alcohols 12 and amidation of alkynyl bromide with amines. 13Most of these reactions require relatively harsh conditions such as light, expensive oxidant, strong bases, transition-metal complexes viz., Cu, Zn, Zr, Ru, Pd, Hg, 14 high temperature etc.As such there is a quest for efficient and economically viable methods to construct amide bond.In continuation of our interest on green-reaction conditions for organic transformations 15 we herein report a simple and efficient protocol for the synthesis of carboxamide and sulfonyl carboxamide linked heterocycles using PEG-400 in the presence of an oxidant CCl3CN/H2O2 as eco-friendly and recyclable medium.

Results and Discussion
For the last couple of years we have been actively engaged on the development of functionalized heterocycles linked by amide and sulfonamide moieties.In fact, we have reported the reaction between heteroaryl acids and heteroaryl amines to develop amide linkage using 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU)/ N,N-diisopropylethylamine (DIPEA)/ N,N-dimethylformamide (DMF), 16 N,N'dicyclohexylcarbodiimide (DCC)/ 4-dimethylaminopyridine (DMAP)/ Dioxane, 17,18 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b]pyridinium-3-oxidehexafluorophosphate (HATU)/ DIPEA/DMF. 19In this communication we have adopted simple, eco-friendly methodology for the development of amide and sulfonamide linked heterocycles directly by amidation and sulfonamidation of heteroaldehydes with heteroaryl amines and sulfonylamines.Furan-2-carbaldehyde (1a), 1H-pyrrole-2-carbaldehyde (1b), thiophene-2-carbaldehyde (1c), isonicotinaldehyde (1d), 3,5-dichloroisonicotinaldehyde (1e) were purchased from Sigma-Aldrich and used as such.2,4-Dichlorooxazole-5-carbaldehyde (1f), 2,4-dichlorothiazole-5-carbaldehyde (1g) were prepared by the reaction of urea and thiourea with chloroacetic acid in the presence of conc.HCl followed by treatment with POCl3 in DMF. 20-Phenyl-1H-imidazol-2-amine (2a) was obtained by the treatment of phenacyl bromide with acetyl guanidine in DMF followed by hydrolysis in the presence of dil.H2SO4. 174-Phenylthiazol-2-amine (2b) was prepared by the reaction of phenacyl bromide with thiourea in methanol. 17N-(5-(Aminosulfonyl)-4-phenyl-1H-imidazol-2yl)benzamide (4) was prepared by the reaction of 4-phenyl-1H-imidazol-2-amine with benzoyl chloride followed by chlorosulfonylation with sulfuryl chloride under ultrasonication in DMF at 0 o C. The resultant N-(5-(chlorosulfonyl)-4-phenyl-1H-imidazol-2-yl)benzamide on further treatment with 25% NH4OH gave 4. 21 Initially, in our attempt to develop amide linkage directly from aldehydes and amines, we have chosen 1a and 2a to carry out the pilot reaction in the presence of different oxidants viz., m-CPBA in dichloromethane, H2O2 in dimethyl carbonate (DMC) and CCl3CN/H2O2 in dichloromethane.From the data given in Table 1 it was found that CCl3CN/H2O2 is the best oxidant resulting in the formation of product in 66%.In recent years, the use of green reaction solvents such as ionic liquids and polyethylene glycol (PEG-400) has gained importance. [22][23][24]  Though phase transfer catalysis is an alternative technique, it is not always possible because of sensitivity of the reactants to aqueous conditions. 25In this context, PEG-400 has become an alternative reaction media to perform organic synthesis due to its inherent advantages over toxic solvents.Moreover, PEG-400 is inexpensive, easy to handle, thermally stable, non-toxic and recyclable.In order to increase the yield, the reaction between 1a and 2a was carried out using PEG-400 in the presence of different oxidants m-CPBA, H2O2 and CCl3CN/H2O2.It was noticed that CCl3CN/H2O2 in PEG-400 is the most favourable reaction conditions for direct amidation of aldehydes with amines (Table 2).The mechanism for amidation of aldehydes with amines was proposed as shown in scheme 1.The mechanism for oxidative amidation of aldehydes with amines is proposed as shown in scheme 1.The addition of trichloromethylperoxyimidic acid (A) generated by the oxidation of trichloroacetonitrile with hydrogen peroxide to imine followed by the elimination of trichloromethyl amide resulted in 3a.The scope and generality of this reaction was subsequently examined using different heteroaldehydes and heteroaryl amines and the products were obtained in excellent yield (Table 3).The presence of electron withdrawing chloro substituent on heteroaldehydes increased the yield.
This methodology was extended to prepare sulfonyl carboxamide linked heterocycles by the reaction of heteroaldehydes with heteroaryl sulfonylamines (Table 4).Based on the obtained yield of the products it was noticed that heteroaryl amines favors the reaction with the formation of products in high yield when compared with heteroaryl sulfonylamines.This may be due to electron withdrawing effect of sulfonyl group.

Conclusions
In conclusion we have reported a green protocol for direction amidation of heteroaldehydes with heteroaryl amines / sulfonylamines in the presence of oxidant CCl3CN/H2O2 in PEG-400.The presence of electron withdrawing substituents on heteroaldehydes increased the yield.Further heteroaryl amines favor the reaction when compared with heteroaryl sulfonylamines.

Experimental Section
General.Melting points were determined in open capillaries on a Mel Temp apparatus and are uncorrected.The IR spectra were recorded on a Thermo Nicolet IR 200 FT-IR spectrometer as KBr pellets and the wave numbers were mentioned in cm -1 .The 1 H NMR and 13 C NMR spectra were recorded in DMSO-d6 on a Jeol JNM spectrometer operating at 400 and 100 MHz.All chemical shifts are reported in  (ppm) using TMS as an internal standard.High-Resolution Mass spectra were recorded on Micromass Q-TOF mass spectrometer using electrospray ionization.The microanalyses were performed on a Perkin-Elmer 240C elemental analyzer.The progress of the reaction was monitored by TLC using silica gel plates and components were visualized under UV light (254 and 365 nm).
General procedure for synthesis of amide from the reaction of aldehyde with amine.To a stirred solution of aldehyde (1 mmol), amine (1 mmol), CCl3CN (2 mmol) in PEG-400 (5mL) at 0 o C, a solution of H2O2 (30%) (3mmol) was added drop wise.Then the reaction mixture was stirred at room temperature for 8-12 h.After completion of the reaction (monitored by TLC), the reaction mixture was poured into ice water (50 mL).The solid obtained was filtered, washed with water and crude product was purified by column chromatography (silica gel, 60-120 mesh) using hexane/ethylacetate (6:4) as eluent.

Figure 1 .
Figure 1.The most common reactions for amide bond synthesis.

Table 3 .
Synthesis of heteroaryl amides from heteroaldehydes and heteroaryl amines