Chinese Chemical Letters  2015, Vol.26 Issue (03):369-372   PDF    
Cu(II)-catalyzed domino reaction of 2-halobenzamide and arylmethanamine to construct 2-aryl quinazolinone
Ben-Quan Hua,b, Li-Xia Wanga , Jun-Feng Xianga, Luo Yangb, Ya-Lin Tanga     
* Corresponding authors at:a State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Institute of Chemistry, Chinese Academy of Sciences (ICCAS), Beijing 100190, China;
b Key Laboratory for Environmentally Friendly Chemistry and Application, Department of Chemistry, Xiangtan University, Hunan 411105, China
Abstract: A novel method for achieving a copper(II)-catalyzed domino reaction for the construction of 2-aryl quinazolinones, without the addition of any ligand and additive, has been developed. The domino reaction achieved N-(α-substituted)benzylation, benzylic C-H amidation, and C-C (or C-H) bond cleavage.
Key words: Copper (II)-catalysis     Domino reaction     2-Aryl quinazolinones     C-C Bond cleavage     C-H bond cleavage    
1. Introduction

Quinazolinone derivatives are of considerable interest because of the diverse range of their pharmacological activities [1],e.g., protein tyrosine kinase inhibitory,cholecystokinin inhibitory,antimicrobial, anti-convulsant,sedative,hypotensive,anti-depressant, anti-inflammatory and anti-allergy properties. Some of these compounds have also interesting biological properties [2],such as anti-malarial activity,biofungicide,and diuretic properties. Quinazolinone is an important pharmacophore and has been assigned as one kind of privileged structure in drug development [3]. In view of the importance of quinazolinones and their derivatives,many classical methods for their synthesis have been reported in the literature [4]. The main synthetic routes to quinazolinone compounds utilize 2-aminobenzoic acid or its derivatives,2-aminobenzamide,2-aminobenzonitrile, isatoic anhydride,2-carbomethoxyphenyl isocyanate,N-arylnitrilium salts, and 4H-3,1-benzoxazinones as suitable precursors. Recently,Fu et al. used substituted 2-halobenzamides and (aryl)methanamines as the starting materials,catalyzed by CuBr under air through cascade reactions Ullmann-type coupling and aerobic oxidative C-H amidation,gave 2-substituted quinazolinones in good yields [5]. In our research,using α-substituted arylmethanamines as starting materials also gave rise to 2-aryl quinazolinones as the major products surprisingly related to C-C bond cleavage [6]. We presumed that the reactions between 2-halobenzamides and (aryl)methanamines could be catalyzed by Cu(II) salts under argon atmosphere. Here,we reported Cu(II)-catalyzed domino reaction to construct 2-aryl quinazolinones,without the aid of air.

Domino reactions mediated by transition metal catalysts have become a valuable tool in organic synthesis and material science for the generation of new heterocycle compounds. Among them, Cu as one kind of cheap metals has made great progress in the formation and cleavage of carbon-carbon (heteroatom) bonds [7]. C-C bond cleavage plays an important role in organic chemistry, but is more challenging due to its inertness [8]. Herein,we described a Cu(II)-catalyzed approach for the synthesis of 2-aryl quinazolinones via domino reaction involving C-C bond cleavage.

2. Experimental

All of the reagents were used directly as obtained commercially. Column chromatography was performed with silica gel (100-200 mesh) and analytical TLC on silica 60-F24. 1H NMR and 13C NMR spectra were determined in DMSO on a Bruker Fourier 300 MHz spectrometer (or Bruker Avance III 400 MHz) and chemical shifts (δ) reported relative to internal TMS.

General procedure: Under argon protection (1 atm,with extrusion of air),a mixture of 2-iodobenzamide (1a,0.2 mmol, 49.4 mg),arylmethanamine or a-substituted benzylamine (2, 0.4 mmol),K2CO3 (0.6 mmol,83 mg) and CuBr2 (0.02 mmol, 4.5 mg) in DMSO (2 mL) was allowed to stir at 130℃ for several hours. After completion of the reaction,the resulting solution was cooled to room temperature and filtered,and the solvent of filtrate was removed with the aid of a rotary evaporator. The residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate as eluent to provide the desired product (3).

2-Aryl quinazolinone 3a-d,3f-h are known compounds,the characteristic datas of them are consistent with the reported [6] (see supporting information).

2-(2-Pyridyl) quinazolinone (3e): Eluent: petroleum ether/ ethyl acetate (1:5). Yield 33 mg (74%). White solid,mp 269-270℃. IR (KBr,cm-1): 3081,1672,1611,1012; 1H NMR (CDCl3,300 MHz): δ 10.97 (s,br,1 H),8.68 (d,1H,J = 4.2 Hz),8.61 (d,1H,J = 8.1 Hz), 8.36 (dd,1H,J = 8.1,0.9 Hz),7.93 (dd,1H,J = 7.8,1.8 Hz),7.86-7.77 (m,2H),7.56-7.47 (m,2H). 13C NMR (CDCl3,75 MHz): δ 161.4, 149.2,148.9,148.7,148.5,137.5,134.6,128.0,127.3,126.8,126.2, 122.5,122.0. HRESI-MS [M+H]+ m/z calcd. for C13H10N3O 224.08171,found: 224.08184.

3. Results and discussion

Initially,the reaction between 2-iodobenzamide and benzylamine was used as the model to optimize reaction conditions including catalysts,bases,solvents,and reaction temperatures under argon atmosphere (1 atm,with extrusion of air) for 18 h. As shown in Table 1,CuBr2 (0.1 equiv.) was used instead of CuBr,with 3 equiv. of K2CO3 (relative to the amount of 2-iodobenzamide 1a) as the base and DMSO as the solvent at 110 8C,and increased the yield obviously from 11% [5] (entry 1) to 76% under argon atmosphere (entry 2) or 74% under air (entry 3) or 63% under oxygen (entry 4). Further increasing the 2-iodobenzamide and benzylamine to 0.5 and 1.0 mmol,respectively,in the presence of CuBr 0.02 mmol equal to the amount mentioned above,led to a moderate yield of 41%. Other bases,Cs2CO3 (entry 5) and Na2CO3 (entry 6),and organic base DMAP (entry 7) were screened,and K2CO3 showed the best result (compare entries 2,5-7). The effects of reaction temperatures (entries 8-10) and solvents (entries 8, 13-15) were also investigated,130 8C and DMSO were the best choice,and gave the product 3a in 82% yield (entry 8). Other copper(II)-catalysts such as CuCl2 (entry 11) and Cu(OAc)2 (entry 12) both gave good yields,but CuBr2 was the best. For the starting materials 2-halobenzamides,the aryl iodide showed the highest reactivity (entries 8,16,17).

Table 1
Optimization of conditions for copper-catalyzed cascade coupling of 2-halobenzamides with benzylamine to form 2-phenyl quinazolinone 3a under argon atmosphere.a

Under the established conditions [using 10% mol of CuBr2 as the catalyst,3 equiv. of K2CO3 as the base (relative to the amount of 2- iodobenzamide 1a),and DMSO as the solvent,under argon atmosphere (with extrusion of air)],the domino reaction between 2-iodobenzamide 1a and arylmethanamine 2b-l was performed. As shown in Table 2,most of the substrates examined provided good yields,in general,no significant difference of reactivity was observed for the examined arylmethanamines with varied electronic properties and sites (entries 1-8). In addition to the substrates of R = H,some other a-substituted benzylamines were also investigated,and gave the 2-aryl quinazolinones related to C-C bond cleavage. The substrates of R = H (entry 1),or methyl (entry 9),or benzyl (entry 11),or phenyl (entry 12),meanwhile the aryl group was the phenyl,could prepared the same product 3a in different times (H < benzyl < methyl < phenyl). Similarly, the substrates of R = H(entry 2),ormethyl (entry 10),whileAr = p- Me-phenyl,gave 3b as the major product.

Table 2
Substrate scope for CuBr2-catalyzed domino synthesis of 2-aryl quinazolinones.a

In order to confirm the reaction promoted by CuBr2 only,we chose α-methylbenzylamine 2i as the model substrate and launched the following control experiments in DMF as shown in Scheme 1. When 2-iodobenzamide 1a was treated with α-methylbenzylamine 2i in DMF,similar to the optimized reaction conditions mentioned above in 4 hours,the Ullmann-coupling product 4i was obtained in 67% yield (Scheme 1A). The Ullmanntype product 4i was further converted into 2-phenyl quinazolinone 3a in good yield in a longer time (Scheme 1B). 2-Methyl-2-phenyl- 1,2,3,4-(H)-quinazolinone 5 [9],which was prepared from the reaction between 2-aminobenzamide and phenylacetylene catalyzed by Ph3PAuNTf2,could be transformed into the final product 3a in a good yield by the catalyst CuBr2,under the same conditions (Scheme 1C).

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Scheme 1.CuBr2-catalyzed reactions under argon atmosphere at 130℃,in DMF. (A) Ullmann-type coupling of 1a with 2i; (B) domino reaction of 4i; (C) transformation from 5 to 3a.

A possible mechanism for synthesis of 2-aryl quinazolinone catalyzed by CuBr2 is proposed in Scheme 2,which was consistent with the deduction reported previously [6]. The Ullmann-type coupling product I is prepared firstly,which is transferred into the imine II,and then intramolecular nucleophilic addition of the amide to the C55N bond provides benzylic C-H amidation product III. In the end,the target product 2-aryl quinazolinone 3 is formed undergoing C-C (or C-H) bond cleavage. A thorough mechanistic study for C-C bond cleavage is underway.

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Scheme 2.Possible mechanism for CuBr2-cataylzed domino synthesis of 2-aryl quinazolinones.
4. Conclusion

In summary,we have developed a methodology for achieving a copper(II)-catalyzed domino reaction for the construction of 2-aryl quinazolinones (3). The domino reactions achieved N-(α-substituted) benzylation,benzylic C-H amidation,and C-C (or C-H) bond cleavage by the catalyst CuBr2,without the addition of any ligand and additive. This methodology is of high tolerance toward various functional groups in the substrates,and it will attract much attention in academic and industrial research. Acknowledgments

The authors wish to thank the National Natural Science Foundation of China (Nos. 21302188,81072576,91027033) and Chinese Academy of Sciences (Nos. KJCX2-EW-N06-01 and XDA09030307) for financial support.

Appendix A. Supplementary data

Supplementary data associated with this article can be found,in the online version,at http://dx.doi.org/10.1016/j.cclet.2014.12.006.

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