Gold(iii) promoted formation of dihydroquinazolinones: double X–H activation by gold

An efficient 2-furyl gold–carbene promoted synthetic method was developed for the formation of dihydroquinazolinones from enynones by dual insertion of anthranilamides. In this organic transformation a new C–O and two C–N bond formations occurred and dihydroquinazolinones were obtained with a quaternary centre in moderate to very good yields in one-pot synthesis.


Introduction
Nitrogen-containing heterocyclic molecules 1 such as quinazolinones have gained much attention due to their wide range of biological and pharmacological applications. 2 Dihydroquinazolinone derivatives like fenquizone, 3 and quinethazone 4 are drugs for edema and hypertension. It was reported that bouchardatine exhibits antiobesity activitity, 5 and penipanoid C exhibits tobacco mosaic virus inhibition 6 ( Fig. 1). Further, substituted dihydroquinazolinone derivatives displayed signicant cytotoxic activity. 7 Hence, the development of new synthetic methods for the formation of dihydroquinazolinones is a limitless frontier. Cooperative catalysis 8 has been established as a handy tool for the synthesis of several biologically valuable molecules and different procedures were reported for the synthesis of dihydroquinazolinone derivatives. 9 Exploration of gold-catalyzed 10 organic transformations has attracted much attention in recent years due to their broad functional group tolerance and selectivity for the formation of valuable heterocyclic molecules in one-pot reaction conditions. 11 The recent literature indicating that exploitation of enynal/enynone has recognised as good donor or donor-donor carbene precursors for C-H/X-H insertion and cyclopropanation reactions. 12 Several reports are available for synthesis of substituted furans from enynones in presence of metal catalysts via a 5-exo-dig cyclization. 13 The reaction mechanism was proposed via (2-furyl) metalcarbene 14 intermediate would react with one nucleophile 15 to produce addition products (Scheme 1, eqn (1)). López and Vicente co-workers reported a method for synthesis of functionalized furans from enynones in the presence of zinc catalyst. 16 Recently, Zhu et al. developed metal carbene promoted method for synthesis of vinyl-substituted dihydroindoles. 17 Hashmi and co-workers studied the stabilization effects of gold carbene complexes. 18 Double insertion of isocyanides to enynones produced pyrrole-fused heterocyclic molecules via (2-furyl) metal-carbene intermediate was reported by Jia and Li co-workers (Scheme 1, eqn (2)). 19 Very recently, we have reported formation of tetraarylmethane derivatives by reaction of enynones with indoles via (2-furyl) gold-carbene intermediate (Scheme 1,eqn (3)). 20 Our current research 21 efforts focused to explore the reactivity of enynones under gold catalysis. We envisioned that reaction of enynones (1) in the presence of gold-catalyst would produce gold-carbene complex-I, which would react with anthranilamide (2) may give corresponding dihydroquinazolinone derivative 3 (Scheme 1, eqn (4)).

Results and discussion
Accordingly, we have conducted an experiment by using substrates 1a and 2a in the presence of AuCl 3 (Scheme 2). Very interestingly, 21% yield of the corresponding product 2-(4benzoyl-5-phenylfuran-2-yl)-2-phenyl-2,3-dihydroquinazolin-4(1H)-one 3a was observed. The product 3a was further conrmed by single crystal X-ray analysis. 22 It is noteworthy that in this organic transformation two C-N bonds were formed by dual insertion of anthranilamide with a quaternary centre. This interesting observation encouraged us to optimize this reaction to get the better yields of the product 3a.
The above experiments concludes that Table 1, entry 17 is the best suitable reaction conditions. Then substrate scope was tested by utilizing different enynones (1a-k) with anthranilamide 2a under the optimal conditions. These results are incorporated in the Table 2.
The substrates which are bearing electron-donating groups such as 1b and 1c were tested with 2a to provide 76% and 72% yields of corresponding products 3b and 3c, respectively. Electron-withdrawing functional group containing enynone such as 1d react with 2a to give the corresponding dihydroquinazolinone derivative 3d in 68% yield. Substrates bearing electron-donating groups like 1e and 1f reacted with 2a to produce 75% and 74% yields of the corresponding dihydroquinazolinone derivatives 3e and 3f, respectively. Both electron-donating and electron-withdrawing functional groups containing enynone like 1g reacted with 2a to generate the corresponding product 3g in 71% yield. The substrates which are having electron-donating groups at ortho position of R 2 like 1h to provide the corresponding products 3h, 3i and 3j in moderate yields, respectively ( Table 2, entries 8-10). Alkyl substitution at R 2 position containing substrate like 1k produced the product 3k in 43% yield ( Table 2, entry 11).
Control experiments were conducted to clarify the reaction mechanism (Scheme 4). The substrate 1a was tested under optimized conditions to produce good yields of product 3a 0 (Scheme 4, eqn (1)). A reaction was conducted by utilizing 3a 0 with anthranilamide 2a in the presence of gold-catalyst to provide 32% yield of product 3a (Scheme 4, eqn (2)). Without using catalyst one reaction was conducted by using 3a 0 and 2a, Table 3 Scope of substituted dihydroquinazolinones (3) a a Reaction conditions: all reactions were carried out at 80 C under nitrogen atmosphere with 1 (1.0 equiv.), and 2 (1.5 equiv.) in the presence of KAuCl 4 (10 mol%), FeCl 3 (2.0 equiv.) and solvent (3 mL) in oil bath; yields are for isolated products 3.
in this case product 3a was not observed (Scheme 4, eqn (3)). Then 1a was tested with 2-(prop-2-yn-1-yloxy)benzohydrazide 4 to give 62% yield of product 5. The structure of the compound 5a further charaecterized by single crystal X-ray analysis. 22 Formation of dihydroquinazolinones can be proposed by the reaction mechanism as shown in Scheme 5. Gold catalyst would coordinate with enynone 1a may form complex-A, which would further generate 2-furyl gold carbene complex-I via intramolecular of 5-exo-dig cyclised zwitterionic complex-B. 24 Then, it would produce ketone (3a 0 ), 13,14 which would coordinate with ferric chloride as a lewis acid in a regioselective fashion then it would reacts with anthranilamide (2a) may generate IM-I. Subsequent activation of IM-I by metal catalyst may lead to cyclization to form intermediate IM-II, which would nally afford the product 3a.

Conclusion
In conclusion, we have established gold-catalyzed reaction of enynones with dual insertion of anthranilamides to produce a novel approach for synthesis of dihydroquinazolinones. It is signicant that in this organic transformation new C-O and two C-N bonds were formed with a quaternary centre with good functional group tolerance.

General information
Reactions were carried out in oven dried reaction asks under nitrogen atmosphere and also solvents and reagents were transferred by oven-dried syringes to ambient temperature. TLC was performed on Merck silica gel aluminium sheets using UV as a visualizing agent. Solvents were removed under reduced pressure. Columns were packed as slurry of silica gel in hexane and ethyl acetate solvent mixture. The elution was assisted by applying pressure with an air pump. 13 C NMR spectra were recorded on 75, 100 and 125 MHz spectrometers. 1 HNMR spectra were recorded on 300, 400 and 500 MHz spectrometers in appropriate solvents using TMS as internal standard. The following abbreviations were used to explain multiplicities: All reactions were performed under nitrogen atmosphere with freshly distilled and dried solvents. All solvents were distilled using standard procedures. Unless otherwise noted, reagents were obtained from Aldrich, Alfa Aesar, and TCI used without further purication. Synthesis of enynones (1a-l) were prepared by following reported procedures. 25 General procedure for synthesis of dihydroquinazolinone derivatives (3a) To a 10 mL round-bottomed ask equipped with magnetic stir bar the substrate 2-aminobenzamide 2a (0.45 mmol, 61 mg, 1.5 equiv.) was taken and dissolved in dry CH 3 CN (3 mL) at 80 C (oil bath) aer that 1,3-diphenyl-2-(3-phenylprop-2-yn-1-ylidene) propane-1,3-dione 1a (0.3 mmol, 100 mg, 1 equiv.) was added. To this reaction mixture KAuCl 4 (10 mol%, 11 mg) and FeCl 3 (0.6 mmol, 97 mg, 2.0 equiv.) was added and stirred at 80 C for 5 h under nitrogen atmosphere. Progress of the reaction was monitored by using TLC. Aer completion of the reaction, the reaction mixture was ltered through celite plug and washed with ethyl acetate. The ethyl acetate layer was concentrated under reduced pressure to get crude residue which was puried by column chromatography through silica gel using hexane and ethyl acetate as eluent (10 : 3.5) to give 113 mg of the product 2-(4-benzoyl-5-phenylfuran-2-yl)-2-phenyl-2,3-dihydroquinazolin-4(1H)-one 3a (81% yield). The same reaction was conducted on a gram scale by utilizing 1a (1 g) and 2a (0.61 g) produced the corresponding product 3a in 74% yield (1.03 g). A similar experimental procedure was adopted for the synthesis of all the furan containing dihydroquinazolinones (3b-y) and 5.