A new protocol for the synthesis of primary, secondary and tertiary anthranilamides utilizing N -(2-aminoarylacyl)benzotriazoles

A convenient route for efficient conversion of unprotected anthranilic acids into the corresponding N -(2-aminoarylacyl)benzotrazoles is described. N -(2-Aminoarylacyl)- benzotrazoles have been successfully used to synthesize primary, secondary and tertiary anthranilamides in high yields (71-96%).


Introduction
Amides are of great importance in synthetic organic chemistry because of the numerous natural products (e.g.peptides and proteins) and potential drug compounds that contain amide bond, like acetaminophen, an analgesic; lidocaine (Xylocaine), a local anaesthetic and loperamide (Imodium AD), an anti-diarrheal.Amides are also used in different areas of industry 1 (e.g.plastic and rubber industry, and paper industry).As a consequence, much effort has been put onto synthesize new derivatives of amides using mild ways.Anthranilamides are an example of useful compounds containing amide bond since they are used as a starting compound or an intermediate in the synthesis of biologically important compounds such as quinazolones, 2 quinazolinones 3a-c and benzoxazinones.3c,4 In addition, some amide derivatives of anthranilic acid show biological activities 5 or they are the starting materials for o-aminonitriles which are versatile synthons to get some useful heterocycles. 6Literature methods for synthesizing anthranilamides are: (i) the reaction of anthranilic acid with amine in the presence of various reagents (SOCl2, 7a EDC / HOBt, 7b CDI, 7c BAC, 7d HOSu / DCC, 7e DCC / HOBt 7f ) (ii) the reaction of anthranilesters with amines, 8 (iii) the catalytically reduction of 2-nitrobenznitriles, 9 (iv) the reaction of 2-nitrobenzoic acid activated by SOCl2 with an amine, and then catalytically reduction of nitro group, 7f,10 and (v) the reaction of isatoic anhydride with various amines 7c,f,11,12 (Scheme 1).These methods developed to get anthranilamides have some disadvantages like being lack of wide generality in use, having harsh reaction conditions or complex reaction steps.Conventional activation of a carboxyl group using thionyl chloride cannot be safely employed in the presence of a free amino group.7a The reactions having coupling reagents require anhydrous reaction conditions and activated anthranilic acid intermediates cannot usually be stored, handled in moist air or isolated.7b, e,f In addition, the method including CDI coupling with amine needs using of phosgene in the preparation of CDI.7c The reaction of anthranilesters with amines, on the other hand, requires harsh reaction conditions. 8Moreover, the synthesis of anthranilamides from 2nitrobenzonitriles involves the reduction of nitro group and the hydrolysis of nitrile group.The difficulty in purification of the products cause low yields. 9The synthesis of anthranilamides from 2-nitro benzoic acids also has some disadvantages like the difficulty in activation of carboxylic acid group with thionyl chloride and purification of products obtained by the reduction of nitro group. 10The reaction of isatoic anhydride with amine is a well-known general method for the preparation of anthranilamides.However, this method requires handling of phosgene in the preparation of isatoic anhydride. 11Therefore, newer and versatile methods having simple reaction procedure and reagents to prepare these compounds would be advantageous.
Being one of the versatile benzotriazole intermediates, N-acylbenzotriazoles have found wide application in the acylation of various nucleophiles because of the good leaving ability of benzotriazole group.They are widely employed in heterocyclic synthesis, 13a,b N-acylation, 14a-c Cacylation, 14b,15a,b S-acylation 14b,16a,b and O-acylation. 17Unlike the conventional acylating agents which are unstable to moisture and difficult to prepare and store at room temperature, Nacylbenzotriazoles are stable crystalline compounds and they are easy to use and store at room temperature.14a, 18 They can be prepared directly from carboxylic acids even in cases where an acid sensitive functionality is present.In literature, N-acylbenzotriazoles are synthesized from the reaction of carboxylic acids (i) with 1-(methylsulfonyl)benzotriazole in the presence of triethylamine 14a or (ii) with the excess amount of benzotriazole in the presence of thionylchloride 19 and from the reaction of various aldehydes with N-chlorobenzotriazole. 20So far today, various N-acylbenzotriazole derivatives have been synthesized from alkyl-, aryl-, heterocyclic-and unsaturated carboxylic acids or carboxylic acids with different functionality.However, there have been no reported studies on the direct synthesis of N-acylbenzotriazoles using anthranilic acids.Anthranilic acid component has two different functional groups (COOH and NH2).The presence of a free amino group makes the activation of carboxylic group difficult and decreases the yield.Therefore, the protection and subsequent deprotection of amino group are necessary to regenerate the amine functionality.However, the use of protecting groups has some drawbacks, like being not economical and causing time loss.
We now report a mild one pot procedure for efficient conversion of anthranilic acids into the corresponding N-acylbenzotriazoles having free amino group and subsequent reaction of Nacylbenzotriazoles with ammonia, primary and secondary amines to afford substantial anthranilamides.

Results and Discussion
As mentioned before, N-acylbenzotriazoles are highly efficient acylating agents to prepare various kinds of compounds comparing to the conventional acylating agents which are mostly sensitive to air and so, difficult to prepare and store at room temperature.Moreover, as an auxiliary group benzotriazole can be recovered almost quantitatively after the reaction.Therefore, this method has also the potential of recycling the starting material.
In the present work, anthranilic acid derivatives were successfully converted into the corresponding N-acylbenzotriazoles in the presence of free amino group (Scheme 2).Activation of anthranilic acid with benzotriazole was succeeded by using mild DCC coupling condition.The presence of ortho-substituted free amine functionality in the molecules did not cause any troubles except for 2e and 2f.The resulting compounds 2a-o were successfully isolated and purified by column chromatography as stable, yellow colored solids in 14 -93% yields (Table 1).All of the N-acylbenzotriazole derivatives prepared are novel compounds and structures of products 2a-o were fully characterized by IR, 1 H NMR and 13 C NMR spectroscopy.Elemental analysis and mass spectroscopy also supported the proposed structures.The most characteristic 1 H-NMR data indicating that benzotriazole attached to the molecules are the signals which were observed for the protons on the benzotriazole ring as doublets at 8.37 -8.17 ppm and as triplets at 7.69 -7.55 ppm.In addition to the 1 H-NMR spectral data, 12 signals were observed for the carbons in aromatic rings of the products in the 13 C-NMR spectra.During the preparation of N-(2-aminoarylacyl)benzotriazoles 2a-o, it was noticed that a byproduct 2′ (Figure 1) was formed with the desired products because of the nature and position of the substituents in the corresponding anthranilic acids.The yields of by-products were almost negligible except for 2e and 2f.The by-products 2e′ and 2f′ were isolated by column chromatography in 27 % and 42 yields respectively.Their structures were supported by 1 H and 13 C NMR spectra.The expected signals which belong to benzotriazole ring weren't observed in 1 H and 13 C NMR spectra.Moreover, for the two carbonyl carbons in the structures, two signals were observed in 13 C NMR spectra.MS spectra also support the structures of these side products.Steric hindrance of the methyl group, which is in ortho position to the carboxylic acid, caused the low yield of the desired product 2e.In case of 2f, the methoxy group present in para position to amino group increased nucleofilicity of amino group and caused the formation of by-product.The reaction of N-(2-aminoarylacyl)benzotriazoles with ammonia, various primary and secondary amines gives primary, secondary and tertiary anthranilamides.In spite of having free amino groups, no complications were observed and the reactions were rather straight forward.Therefore, anthranilamides were synthesized in high yields (71-96%).Spectroscopic studies have provided strong evidence that amides formed.Especially, the disappearance of the benzotriazole signals in the aromatic region of 1 H-NMR spectra indicates the loss of the benzotriazolyl group during the reaction and shows the formation of amides.Characteristic amide peaks were observed for all compounds on IR spectra.Moreover, mass spectra show that the expected molecular ion and the fragmentation are in accordance with the proposed structures.
Primary anthranilamides were efficiently synthesized by treatment of N-acylbenzotriazoles with excess ammonium hydroxide (27% aqueous solution) in THF at 0 o C for 2 hours (Scheme 3).The products were isolated by column chromatography in 82-96% yields (Table 2) and characterized spectrally and by elemental analyses.The 1 H-NMR spectrum showed two broad signals for each proton of amino groups attached to the carbonyl group at 8.06-7.58ppm and 7.47-6.44ppm, which are in agreement with the reported values for these types of compounds.21a,b Similarly, the signals in the 13 C-NMR spectra for carbonyl carbons were observed at 172.8-170.5 ppm, apart from six carbon signals for aromatic ring in the aromatic region.In addition to spectral and elemental analysis, the melting points of the products were measured (Table 2).Scheme 3. Synthesis of primary amides (3a-g) from N-(2-aminoarylacyl)benzotriazoles.Various primary amines were treated with anthranilbenzotriazoles in dichloromethane to give a series of secondary anthranilamides 4a-i (Scheme 4).The reactions were completed in 2-6 hours at room temperature with high yields (71-95%).The synthesized compounds gave satisfactory proton and carbon NMR data.The most characteristic signal for the secondary amides is the broad singlet which was observed at 6.35-5.82ppm for the protons of the amide nitrogen atom in 1 H-NMR.Elemental analysis, IR and mass spectroscopy also supported the structures of 4a-i.The isolated yields, literature yields and observed melting points were summarized in Table 3.   4).Structures of the products were confirmed by the results of NMR measurements.The most important evidence proving the formation of tertiary amides is the signals which were observed for the substituents attached to the amide nitrogen atom.Moreover, no broad singlet was observed except for the one accounting for the amino group on the anthranilic acid ring.

Conclusions
In conclusion, a series of N-(2-aminoarylacyl)benzotriazoles were synthesized from unprotected orthoaminoarylcarboxylic acids.By the treatment of synthesized N-(2aminoarylacyl)benzotriazoles with ammonia, primary and secondary amines, we have developed a new and practical protocol for the synthesis of anthranilamides.Advantages of this method compared to the existing methodologies are: providing neutral reaction conditions for the compounds possessing acidbase sensitive substituents, using N-acylbenzotriazoles which are more useful and stable than the corresponding acyl halides or other activated derivatives of carboxylic acids, general application and good yields that are comparable to the literature.

Experimental Section
General.Column chromatography was conducted on silica gel 70 -230 meshes.Melting points were determined on a Mettler Toledo apparatus and uncorrected.All NMR spectra were recorded on a Bruker Advance 500 DPX spectrometer in CDCl3 or DMSO-d6 with TMS as the internal reference for 1 H (500 MHz) and 13 C (125 MHz).Reagents obtained commercially were used without further purification.MS analyses were obtained with a GC-MS/MS (Thermo Finnigan PolarisQ).Elemental analysis was performed for all compounds with a Thermo Finnigan Flash EA 1112 instrument.FTIR spectra were determined on a PerkinElmer 100 FTIR spectrometer.

General experimental procedure for the preparation of N-(2-aminoarylacyl)benzotriazoles (2a-p).
A mixture of appropriate anthranilic acid (6 mmol), benzotriazole (5 mmol, 0.595 gr) and DCC (7 mmol, 1.44 gr) was stirred in CH2Cl2 (10 mL) overnight at room temperature.After completion of the reaction, the solvent was removed under reduced pressure.Purification of the residue by column chromatography over silica gel with EtOAc/ n-Hexane (1:3) or CH2Cl2 gave the desired product.

General experimental procedure for the preparation of secondary (4a-i) and tertiary athranilamides (5a-h). N-(2-Aminoarylacyl
)benzotriazoles (1 mmol) and various primary and secondary amines (1.2 mmol) were left to stir in CH2Cl2 (10 mL) for 2-6 hours at room temperature.After the reaction ended, the solvent was removed under reduced pressure.The residue was purified by column chromatography over slica gel with EtOAc/ n-hexane prepared in different proportions to afford secondary and tertiary amides.

Figure 1 .
Figure 1.The by-product produced during the activation of anthranilic acids with benzotriazole.

Table 2 .
Preparation of primary amides 3a-g

Table 3 .
Preparation of secondary amides 4a-i