Copper-catalyzed direct coupling of benzoxazin-2-ones with indoles for the synthesis of diverse 3-indolylbenzoxazin-2-ones: access to natural cephalandole A

A novel and facile copper-catalyzed direct coupling for the synthesis of diverse and functionalized 3-indolyl benzoxazin-2-ones from benzoxazin-2-ones and indoles has been developed. This newmethodology offers an easy and rapid approach to a variety of 3-indolylbenzo[b][1,4]oxazin-2-ones in high yield. As an application of this protocol, a gram-scale synthesis of naturally occurring cephalandole A has also been accomplished.


Introduction
Benzoxazines and benzoxazin-2-ones are important heterocyclic compounds found in natural products and biologically active molecules (Fig. 1). 1,2 These compounds possess a wide range of pharmaceutical properties such as antihypertensive, 3 antifungal, 4 antimycobacterial, 5 anti-inammatory, 6 bacterial histidine protein kinase inhibitory, 7 and D2 receptor antagonist activities. 8 In addition, compound 1 exhibits a potent effect of pyruvate kinase activators for the treatment of hereditary nonspherocytic hemolytic anemia and sickle cell anemia 9 and compound 2 is useful for the treatment of lung cancer. 10 Naturally occurring alkaloid, cephalandole A was originally isolated from Taiwanese orchid Cephalanceopsis gracilis 11 and its structure was later revised into 3 by organic structure determination using atomic resolution scanning probe microscopy. 12 Moreover, molecules bearing these skeletons have been also used as valuable building blocks for the synthesis of pharmaceuticals and photoactive materials. 13,14 Owing to the importance of benzoxazin-2-ones, several methods for their synthesis have been reported. 15,16 The general methods for benzoxazin-2-ones include the domino reaction of o-aminophenol with b-nitroacrylates, 17 cleavage of resin-bound pseudooxazolones with 2-aminophenols, 18 and TFA-catalyzed tandem reaction of benzoxazoles with 2-oxo-2-arylacetic acids. 19 In addition, enantioselective hydrogenation of benzoxazinones and enantioselective addition of indoles to ketimines to give chiral dihydrobenzoxazinones have been accomplished. 20, 21 Although several methodologies for the synthesis of benzoxazin-2-ones and dihydrobenzoxazinones have been developed, there are no reports on the direct coupling of benzoxazin-2-ones with indoles for the construction of 3-indolylbenzoxazin-2-ones so far. Recently, an iron-catalyzed oxidative sp 3 carbon-hydrogen bond functionalization of dihydrobenzoxazin-2-ones with indoles for the synthesis of 3-indolyldihydrobenzoxazin-2-ones has been described (Scheme 1a). 22 As a part of continuing efforts to develop new synthetic protocols for nitrogen heterocycles, 23 we herein report the copper-catalyzed direct coupling of benzoxazin-2-ones with indoles for the formation of diverse 3-indolyl benzoxazin-2-ones in air (Scheme 1b).

Results and discussion
Our initial study commenced with the model reaction between benzoxazin-2-one 4a and N-methylindole 5a for the optimization of reaction condition (Table 1). Various metals were examined as catalysts under several solvents in air. When using 10 mol% of CoCl 2 , ZnCl 2 and NiCl 2 at 80 C for 24 h in dichloroethane, product 6a was isolated in 32, 40, and 41% yields, respectively (entries 1-3, Table 1). Encouraged by these results, we screened other catalysts for the reaction. With 10 mol% of FeCl 3 and CuCl 2 , the yield of 6a increased to 80 and 89% respectively (entries 4-5). However, additional attempt using other copper catalysts such as CuF 2 , Cu(OAc) 2 , and Cu(OTf) 2 , failed to further increase the yield (entries 6-8).
Results of solvent screening showed that tetrahydrofuran (THF) was the best solvent (94%) among the solvents such as dioxane (87%), ethanol (66%), and water (60%) (entries 9-12). Changes in the loading of CuCl 2 to 5 mol%, 2 mol%, and 13 mol% did not improve the yield of 6a (entries 13-15). In addition, the effect of temperature was next studied. It was found out that decreasing or increasing temperature decreased the yield of 6a (entries 16 and 17). The structure of 6a was determined by spectroscopic analysis. The 1 H NMR spectrum of 6a showed a characteristic singlet singlet for indolyl C2 proton at d 8.60 ppm and N-methyl peak on indolyl moiety at d 3.85 ppm.
reactions of 4f and 4g bearing electron-withdrawing groups of 6-F and 6-Cl with 5a afforded the products 7h and 7i in 82% and 93% yield, respectively. The utility of this new methodology for the gram-scale synthesis of naturally occurring cephalandole A (3) was next demonstrated (Scheme 2). Upon treatment of 4a with indole 5m at 60 C for 12 h in THF, 3 was obtained in 75% yield. This onepot protocol has several advantages such as higher yield, fewer steps, and lower cost. The synthesized compound was conrmed to be natural product 3 by comparison of its spectroscopic data with those previously reported. 22 To elucidate the mechanism of this coupling reaction, we performed a control experiment (Scheme 3). The reaction between 4a with 5a in the absence of CuCl 2 in THF at room temperature for 30 h provided compound 8 in 93% yield. Further reaction of 8 in the presence of 10 mol% of CuCl 2 in THF at 60 C for 1 h furnished 6a in 96% yield. These results suggest that compound 8 might be the intermediate in the coupling reaction.

Conclusions
In summary, a novel and efficient copper-catalyzed direct coupling of benzoxazin-2-ones with indoles for the synthesis of diverse and functionalized 3-indolylbenzoxazin-2-ones has been developed. This methodology provides a rapid synthetic route to natural cephalandole A and its derivatives. The proposed protocol has a wide substrate scope for both benzoxazin-2-ones and indoles.

Experimental
Imino cyclic esters were synthesized in the laboratory according to known procedure. 25 All indoles were prepared by either N-alkylation or N-arylation according to known method. 26 Solvents were used without further purication. Merck precoated silica gel plates (Art. 5554) with uorescent indicator were used for analytical TLC. Flash column chromatography was performed using silica gel 9385 (Merck). Melting points are uncorrected and were determined on Fisher-Johns Melting Point Apparatus. 1 H NMR and 13 C NMR spectra were recorded on a Varian VNS (600 and 150 MHz, respectively) spectrometer in CDCl 3 using d ¼ 7.24 and 77.00 ppm as solvent chemical shi. Chemical shis (d) are expressed in units of ppm and coupling constants (J) values are given in Hz. Multiplicities are abbreviated as follows; s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet, dd ¼ doublet of doublet and td ¼ triplet of doublet. FT-IR (neat) spectra were recorded on ATR (Perki-nElmer Spectrum 2) and HRMS was obtained on JEOL JMS-700 spectrometer at Korean Basic Science Institute.

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