Temperature-controlled synthesis of N-acyl anthranilamides and quinazoline-4-ones via Pd-catalysed cascade consisting of isocyanide insertion

A one step synthesis of functionlized N-acyl anthranilamide via Pd-catalyzed carboxamidation of o -halo substituted N -phenylamide consisting of isocyanide insertion followed by oxidation of the imine intermediate has been achived successfully. Furthermore, at elevated temprature (160 o C) the Pd-catalyzed tandem reaction afforded functionlized quinazolin-4-one in a single step without the isolation of N-acyl anthranilamide and proceed through carboxamidation/de-t -butylation/cyclodehydration cascade. This work extends the application of isocyanide insertion chemistry for synthesizing diverse N-heterocycles by transition metal catalysed sequential reactions in a single step.

0] In general, we use anthranilic acids for synthesizing corresponding anthranilamide, although, this process is inherently restricted by the limited range of commercially available anthranilic acids. 213][24][25] However, mostly of them have certain drawbacks such as multistep, longer reaction time, the limited selection of commercially available starting materials and lower yields. 19-20, 22- 24This prompted us to develop a single step synthesis of N-acyl anthranilamide and the quinazoline-4-one skeleton using isocyanide-insertion chemistry.
There are many reports about Pd-metal catalyzed aminocarbonylation for the synthesis of amides from aryl halides, [26][27][28][29][30] however; the use and handling of toxic carbon monoxide limited the scope of this kind of reaction.4] In continuation of these studies, herein, we reported a synthetic protocol, enabled to furnish functionalized N-acyl anthranilamide and quinazoline-4-one skeleton starting with o-halo substituted Nphenylamide via a temperature dependent Pd-catalyzed cascade consisting of carboxamidation or carboxamidation/de-tertbutylation/cyclodehydration cascade.
Scheme 1.Recent approaches for the synthesis of N-acyl anthranilamide and quinazolin-4-one.

Results and Discussion
We initiated the study by using amide 1a and tert-butyl isocyanide 2a as a model substrates for the optimization of palladium-catalyzed carboxamidation reaction.The investigation was carried out using different catalysts, base and solvents (Table 1).The reaction did not proceed in the absence of the Pd catalyst (Table 1, entry 1).Among the three Pd-catalysts used (PdCl2, Pd(PPh)3 and Pd(OAc)2), Pd(OAc)2 was found to be the best and provided the product 3a in 72% yield in DMF/H2O as a solvent at 120 o C (Table 1, entry 4).Furthermore, PdCl2 and Pd(PPh)3 furnished inferior yields of product 3a (Table 1, entry 2 and 3).We next tested the coupling reaction using various bases such as Cs 2CO3, K2CO3, Na2CO3, K3PO4 and KOtBu in DMF/H2O at 120 o C, with Pd(OAc)2 as a catalyst, among these bases Cs2CO3 was found to be the most effective base (Table 1, entry 4).Using Pd(OAc)2 as catalyst and Cs2CO3 as base in DMSO/H2O provided slightly poor yield of 3a (Table 1, entry 9), while using toluene and CH3CN under the same conditions furnished 3a in only poor yields (Table1, entry 10 and 11).The procedure was unfavourable when base was omitted from the reaction (Table 1, entry 12).Further optimization revealed that PPh3 was essential in this reaction as well.Without PPh3, the yield decreased to 49%.When tested the carboxamidation reaction in dry DMF as solvent, the efficacy of carboxamidation reaction was affected and gave product only in trace amount (Table 1, entry 13).a Reaction conditions: All reactions were performed either in microwave tube or 10 mL round bottom flask using N-(2-bromophenyl)benzamide 1a (1.0 equiv.),t-butyl isocyanide 2a (1.1 equiv.),Pd-catalyst (5 mol %), PPh3(5 mol %) and base (1.2 equiv.),solvent (0.5 mL of H2O in 1.5 mL of solvent) at 120 o C for 15-20 min in MW or 4-5 hrs at conventional heating.b isolated yield.
It is interesting to note that at room temprature there was no conversion but the reaction was completed within 15-20 min under MW conditions at 120 o C,while in the absence of MW irradiations it took 4-5 h to reach the completion.After having optimized reaction conditions for the carboxamidation of N-(2-bromophenyl)benzamide 1a with tert-butyl isocyanide 2a, we further explore the reaction scope for other substituted N-phenylamide with a range of isocyanides (Table 2).In addition to t-butyl isocyanide, the carboxamidation of 1a with tert-octyl and cyclohexyl isocyanide substrates provided N-acyl anthranilamide products 3b and 3c in good yields (63 and 74%, respectively) when employing 5 mol % of Pd(OAc)2 in DMF/H2Ounder microwave irraditation for 20 min.Next, we investigated the scope of substituted N-phenyl amide (Table 2).To our delight, many substituents at different positions on the phenyl group are compatible with the reaction conditions, producing the corresponding products in good yields (Table 2, entries 3d-3i).For electron-donating group such as 3,4,5-trimethoxy, 4-methoxy or 2, 4-methyl substituted phenyl amide with tert-butyl or cyclohexyl isocyanides reactions work nicely and gave 58%, 55%, 59% and 61% yield respectively (Table 2, entry 3d-3g).Also, m-Cl and p-F on phenyl group were tolerated well and gave 61% and 59% yield respectively.
Table 2. Substrate scope of Pd-catalyzed cascade for the synthesis of diverse N-acyl anthranilamide derivative a .
(Table 2, entry 3h &3i).Moreover, we investigated N-phenylamide bearing an alkyl group such as t-butyl and n-propyl instead of phenyl group and the reaction gave corrosponding products in decent yield (Table 2, entry 3j-3n), however slightly lower yield obtained compared to phenyl group.There are few methods available for synthesizing quinazolin-4-one by the cyclodehydration reaction of N-acyl anthranilamides.Although, we envisaged that by conducting the Pd-catalyzed reaction at elevated temperature, both the carboxamidation and cyclodehydration sequence could be accomplished in a single step.To synthesize quinazolin-4-one selectively, we did temperature variations under previously optimized conditions (Table 3).Increasing the temperature of the reaction between 1a and 2a under the optimized catalyst conditions to 140 o C and monitoring the reaction by 1 H NMR, N-acyl anthranilamide product 3a was formed in 42% yield along with the quinazoline-4-one (4a) in 21% yield (Table 3, entry 3).When we elevated the temprature upto 160 o C, quinazoline-4-one was formed selectively (Table 3, entry 5).Also, we found that in the absence of Pd-catalyst, heating the isolated N-acyl anthranilamide 3a gave quinazoline-4-one 4a only in trace amount.This result suggested to us that cyclodehydration of 3a to 4a is assisted by the Pd-catalyst rather than being solely thermally induced.a Reaction conditions: reactions were performed in a microwave vial using N-(2-bromophenyl)benzamide 1a (1.0 equiv.),t-butylisocyanide 2a (1.1 equiv.),Pd-catalyst(5 mol %), PPh3 (5 mol %) and CS2CO3 (1.2 equiv.),solvent (0.5 mL of H2O in 1.5 mL DMF) at different temperatures for 15-20 min in MW, yields refer to isolated products.
After optimizing the reaction conditions for the selective synthesis of quinazoline-4-one by the reaction of 1a with 2a, we investigated the scope of one step cascade reaction for a broad range of N-phenylamides.A number of substituents at different positions on the phenyl group such alkyl, methoxy and phenyl compatible with the optimized reaction conditions, gave the corresponding products 4a-4i in good yields (Table 4, entries 4a-4i).Furthermore, when we tested cyclohexyl isocyanide in place of t-butyl isocyanide, no quinazoline-4-one formed, N-acyl anthranilamide was the product.Also, this experiment indirectly supports de-tert-butylation (step viii, scheme 2) during the synthesis of quinazoline-4-one.Table 4. Substrate scope of Pd-catalyzed cascade for synthesis of diverse quinazolinone derivatives a .a Reaction conditions: Pd(OAc)2 (5 mol %), Cs2CO3 (1.2 equiv.),DMF/H2O (1.7 mL), MW, 160 ο C, reaction time 20 min.Yields refer to isolated products.
A plausible mechanism for anthranilamide and quinazolinone synthesis is proposed in Scheme 2. Thus, oxidative insertion of Pd(0) into the o-halo substituted N-phenylamide (i) leads to the intermediate (ii) which on insertion of t-butyl isocyanide (2a) leads to Pd(II) species (iii), Intermediate (iii) via fast ligand exchange with water gives intermediate (iv), which can react through two differnet pathways which depend on reaction temperature.At lower temperature (120 o C) pathway A is followed, reductive elimination and subsequent tautomerization, to give N-acyl anthranilamide as product and Pd(0) for another catalytic cycle.At higher temperature (160 o C) reaction follows path B, which goes through de-tertbutylation and subsequent cyclodehydration in the persence of Pd-catalyst to furnish quinazoline product.

Conclusions
In summary, we have reported the first synthesis of N-acyl anthranilamide and quinazolin-4-one derivatives via Pd-catalyzed cascade reaction consisting of isocyanide insertion into diverse o-halo substituted N-phenylamides.This cascade reaction allows the synthesis of N-acyl anthranilamide at 120 o C by use of easily available and less expensive starting materials, while at elevated temperature (160 o C) provides quinazolin-4-one as the only detectable product.Additionally, a broad range of substrates are tolerated in this protocol which provides a diverse library of N-acyl anthranilamide and quinazolin-4-one derivatives for combinatorial and medicinal chemistry use.Moreover, reported work here contributes to expand the growing number of transition metal catalysed sequential reactions in one-pot for the synthesis of functionalized nitrogen-containing heterocycles.

Experimental Section
General.All reagents and solvents were purchased from commercial sources and used without purification.NMR spectra were recorded on a Bruker spectrometer at 300 (400) and 75 (100) MHz, respectively in deuterated solvents with TMS as internal reference (chemical shifts δ in ppm, coupling constant J in Hz.).Multiplicities are reported as follows: singlet (s), doublet (d), triplet (t), multiplet (m), and broad singlet (brs).Mass spectra and HRMS were taken in the ESI positive ion mode.The reaction progress was monitored by thin layer chromatography (TLC) on pre-coated silica gel plates.Column chromatography was performed over Merck silica gel (230-400 flash).All compounds were characterized by TLC, 1 H NMR and 13 C NMR and HRMS.
General procedure for the synthesis of substituted N-acyl anthranilamides(3a-3k).Substituted Nphenylamide 1 (1 equiv.),isocyanide 2 (1.1 equiv.),Pd(OAc)2 (5 mol %), Cs2CO3 (1.2 equiv.),PPh3(5 mol %) and DMF:H2O (3:1) as a solvent were added in a 10 mL microwave vial containing a stirring bar, the vial was sealed tightly with a Teflon cap and placed in microwave cavity for 15-20 min at a pre-selected temperature of 120 °C.After completion of the reaction as indicated by TLC, the resulting mixture was filtered through a pad of celite, and the celite was rinsed with EtOAc.The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (eluent: hexane/ EtOAc) affording the corresponding coupling product 3a-3kin 74-32% yields.
General procedure for the synthesis of substituted quinazoline-4-one (4a-4i).Substituted N-phenylamide 1 (1 equiv.),isocyanide 2 (1.1 equiv.),Pd(OAc)2 (5 mol %), Cs2CO3 (1.2 equiv.),PPh3(5 mol %) and DMF:H2O (3:1) as a solvent were added in a 10 mL microwave vial containing a stirring bar, the vial was sealed tightly with a Teflon cap and placed in a microwave cavity for 15-20 min at a pre-selected temperature of 160 °C.After completion of the reaction as indicated by TLC, the resulting mixture was filtered through a pad of celite, and the celite was rinsed with EtOAc.The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (eluent: hexane/ EtOAc) affording the corresponding coupling products 4a-4i in 63-43% yields.

Table 1 .
Optimization of conditions for N-acyl anthranilamide synthesis.

Table 3 .
Optimization of condition for quinazolinone synthesis a .