Copper-catalyzed domino sequences: a new route to pyrido-fused quinazolinones from 2′-haloacetophenones and 2-aminopyridines

A new pathway to access pyrido-fused quinazolinones via a Cu(OAc)2-catalyzed domino sequential transformation between 2′-haloacetophenones and 2-aminopyridines was demonstrated. The solvent and base exhibited a remarkable effect on the transformation, in which the combination of DMSO and NaOAc emerged as the best system. Cu(OAc)2·H2O was more active towards the reaction than numerous other catalysts. This methodology is new and would be complementary to previous protocols for the synthesis of pyrido-fused quinazolinones.

The construction of C-N bonds has attracted signicant attention as it is one of the key steps in the synthesis of valuable organic compounds. [1][2][3] Quinazolinone derivatives have emerged as a family of privileged structural motifs with a broad spectrum of pharmacological and biological activities. [4][5][6][7] Fused quinazolinones, members of this nitrogen-containing heterocycle family, have particularly gained remarkable interest from the pharmaceutical and medicinal industries. 8,9 Several efforts have been dedicated to the synthesis of pyrido-fused quinazolinones due to their pharmaceutical value. Chen et al. previously synthesized pyrido-fused quinazolinones using a Pd(OAc) 2catalyzed carbonylation/intramolecular nucleophilic aromatic substitution transformation. 10 Sun et al. described a CuIcatalyzed tandem reaction via aerobic benzylic oxidation, intramolecular cyclization, and decarbonylation of N-pyridylarylacetamides to form pyrido-fused quinazolinones. 11 Rao et al. employed Pd(OAc) 2 and a AgOTf catalyst system for direct aerobic carbonylation with DMF as carbon source to produce pyrido-fused quinazolinones. 12 Yang et al. demonstrated a carbodiimide-mediated condensation of pyridines with anthranilic acids to generate pyrido-fused quinazolinones. 13 Although interesting results have been achieved, the eld still remains to be explored. In this communication, we would like to report a new pathway to pyrido-fused quinazolinones via Cu(OAc) 2catalyzed domino sequential transformation between 2 0 -haloacetophenones and 2-aminopyridines.
The reaction between 2 0 -bromoacetophenone and 2-aminopyridine was explored (Scheme 1). By screening a series of transition metal salts, it was noticed that 11H-pyrido [2,1-b] quinazolin-11-one was generated as principal product in the presence of a copper salt. Reaction conditions were then screened, utilizing Cu(OAC) 2 $H 2 O as catalyst ( Table 1). The reaction was performed in DMSO at 20 mol% catalyst for 4 h, under an oxygen atmosphere, using 2 equivalents of 2-aminopyridine and 2 equivalents of NaOAc as a base. Initially, the inuence of temperature on the yield of 11H-pyrido[2,1-b] quinazolin-11-one was studied (Entries 1-5, Table 1). No product was recorded for the experiment conducted at room temperature. Boosting the temperature led to a remarkable improvement in the yield of the desired product. The most appropriate temperature for the transformation was noted to be 120 C, with 84% yield being detected (Entry 4, Table 1). The reactant molar ratio displayed a noticeable impact on the reaction, having conducted the reaction with different amounts of 2-aminopyridine (Entries 6-12, Table 1). The reaction utilizing reactant molar ratio of 1 : 1 afforded 64% yield. The yield was upgraded to 90% with 2.5 equivalents of 2-aminopyridine (Entry 9, Table 1). Using excess amounts of 2 0 -bromoacetophenone resulted in signicantly lower yield.
One more issue to be investigated for the reaction between 2 0 -bromoacetophenone and 2-aminopyridine was the catalyst amount (Entries 11-13, Table 1). The reaction was conducted in DMSO at 120 C for 4 h, under an oxygen atmosphere, using 2.5 equivalents of 2-aminopyridine and 2 equivalents of NaOAc as a base. No trace amount of 11H-pyrido[2,1-b]quinazolin-11-one Scheme 1 The domino sequential transformation between 2 0 -bromoacetophenone and 2-aminopyridine.
was recorded in the absence of Cu(OAc) 2 , verifying the requirement of copper species for the transformation. The best result was achieved for the reaction utilizing 20 mol% catalyst with 90% yield being obtained (Entry 13, Table 1). The reaction was signicantly regulated by the solvent, and DMSO emerged as the best solvent for the formation of 11H-pyrido[2,1-b] quinazolin-11-one (Entry 17, Table 1). A base was required for the reaction, and NaOAc was the base of choice for the system (Entry 18, Table 1). Bulky bases like DBU and tBuOK were ineffective for the transformation. The amount of NaOAc also exhibited a remarkable inuence on the reaction, and the best yield was observed in the presence of 2 equivalents of NaOAc (Entry 40, Table 1). Nevertheless, expanding the base amount to 3 equivalents resulted in lower yields. Noted that the reaction proceeded to 23% yield in the absence of the base. Moreover, by testing a series of catalyst, Cu(OAc) 2 $H 2 O exhibited better catalytic efficiency over other catalysts in the generation of the quinazolinone (Entry 1, Table 2).
Initially, (1) was transformed to (7) via the formation of peroxy-Cu(II) radical B, peroxy-Cu(I) complex C, and dioxetane intermediate D. Subsequently, an Ullmann-Goldberg coupling between (7) and (2) occurred to produce 2-oxo-2-(2-(pyridin-2ylamino)phenyl)acetaldehyde E. Additionally, E could be generated from (10) via similar copper-catalyzed oxidation sequences. 19,20 Next, E was converted to F in the presence of copper catalyst, and under oxygen (Path I). Indeed, the formation of F from (10) was previously reported by Ilangovan and Satish. 14,15 Upon base-mediated hydrolysis, G was generated, and the consequent intramolecular addition cyclization occurred to form H. In the next step, decarboxylation and oxidation occurred to form the desired product (3) in the presence of copper catalyst and oxygen. Certainly, the conversion of F to the quinazolinone was demonstrated by Liu et al. 16 For Path II, the hydration of (7) and subsequent 1,2-hydride shi led to the formation of anionic intermediate J. Consequently, decarboxylation occurred to produce (5), and (5) was oxidized to (6) in the presence of copper catalyst and oxygen. 17,21 Intermediate K was formed via an Ullmann-Goldberg coupling, and the consequent amidation cyclization occurred to furnish the desired quinazolinone (3). It should be noted that this amidation cyclization was previously mentioned by Pellón et al. 18 Noted that 45% yield of (3) was obtained for the reaction between (6) and (2). Therefore, the desired quinazolinone (3) would also be produced Path II, though Path I would be more favored.
In conclusion, a new pathway to achieve pyrido-fused quinazolinones via Cu(OAC) 2 -catalyzed domino sequential transformation between 2 0 -haloacetophenones and 2aminopyridines were demonstrated. The transformation proceeded under an oxygen atmosphere, in the presence of a base. The reaction was remarkably regulated by the solvent and the base, in which the combination of DMSO and NaOAc emerged as the best system for the generation of pyrido-fused quinazolinones. Cu(OAC) 2 $H 2 O was more active towards the reaction than a series of catalysts. Two plausible reaction pathways were suggested. The noticeable advantages of this method are the (1) available starting materials; (2) excellent yields of desired product with low cost catalyst Cu(OAc) 2 $H 2 O; and (3) broad substrate scope. This methodology would be complementary to previous synthetic protocols, and would be interested to the pharmaceutical and chemical industries. Further investigations on the reaction mechanism and on substrate scope are currently underway in our laboratory.

Conflicts of interest
There are no conicts to declare.