Cu-catalyzed mild and efficient oxidation of THβCs using air: application in practical total syntheses of perlolyrine and flazin

A mild, efficient and environmentally benign method for synthesis of aromatic β-carbolines via Cu(ii)-catalyzed oxidation of 1,2,3,4-tetrahydro-β-carbolines (THβCs) was developed, in which air (O2) was used as the clean oxidant. This method has advantages such as environmentally friendliness, mildness, very good tolerance of functional groups, high yielding and easy experiment operation. In addition, this new methodology was successfully applied in the efficient and practical total syntheses of β-carboline alkaloids perlolyrine and flazin.


Introduction
The aromatic b-carboline skeleton is ubiquitous in many alkaloids, 1 bioactive congeners, 2 agrochemicals 3 and functional materials. 4 In view of the signicance of b-carbolines in drug discovery, agricultural chemistry and material science, development of practical, efficient and environmentally benign methods for syntheses of b-carbolines is of considerable interest and has attracted much attention from chemists. 5 Since 1,2,3,4-tetrahydro-b-carbolines (THbCs) can be readily and efficiently prepared via the Pictet-Spengler reaction, 6 so the aromatization of THbCs via dehydrogenation or oxidation is an easy and good method to obtain b-carbolines. Dehydrogenation of THbCs usually employed precious metallic catalysts including Pd, 7 Pt 8 and complexes of Ru 9 and Ir. 10 Oxidation of THbCs normally needed stoichiometric strong oxidants such as KMnO 4 , 11 MnO 2 , 12 SeO 2 , 13 DDQ, 14 TCCA 15 and IBX. 16 However, uses of expensive metallic catalysts and hazardous strong oxidants are sometimes lack of cheapness, practicality and environmental friendliness, therefore novel practical, efficient and environmentally benign methods for the conversion of THbCs to b-carbolines are highly desirable.
Oxygen is an important component of air, which is one of the most abundant resources on the earth, so the air has been used as a clean and eco-friendly oxidant for various oxidation reactions in recent decades. 17 On the other hand, copper is one of the most abundant metals on the earth's crust, thus copper salts are normally very cheap, and moreover copper is a low toxic transition metal, so an increasing amount of coppercatalyzed reactions have been developed recently. 18 Herein, we describe a new practical and very mild Cu(II)-catalyzed oxidative conversion of THbCs to b-carbolines using air as the clean oxidant.

Results and discussion
At rst, we attempted to nd out the optimized reaction conditions for the Cu-catalyzed oxidative conversion of THbCs 1 to b-carbolines 2. With the conversion 1-phenyl-THbC 1a to 1phenyl-b-carboline 2a as the model reaction, we tried the reaction under various conditions, and results are summarized in Table 1. As can be seen from Table 1, various copper reagents have been tested as catalysts (Table 1, Entries 2-11), and it was found that cupric bromide is the best catalyst for the reaction. When 0.2 equivalents of CuBr 2 was used as the catalyst, the aerobic oxidation of compound 1a took place smoothly at room temperature in DMSO in the presence of 2 equivalents of 1, 8diazabicyclo[5,4,0]undec-7-ene (DBU) to afford the desired compound 2a in high yield (Entry 2). Several amines such as DBU, 1,5-diazabicyclo[4,3,0]non-5-ene (DBN), 4-dimethylaminopyridine (DMAP), pyridine and trimethylamine have been tested as bases (Entries 2 and 12-15), DBU was found to be the most appropriate base for the reaction. Amount of DBU has signicant effect on the reaction (Entries 2 and [16][17][18][19], almost no desired product 2a could be obtained in the absence of DBU (Entry 16); and the reaction was hard to be complete even for a longer time, if less than 2.0 equivalents of DBU were used . Several other solvents such as N,N-dimethylformamide (DMF), acetonitrile, ethanol, tetrahydrofuran (THF), dichloromethane, ethyl acetate and acetone have also been examined (Entries 20-26); DMSO is obviously better than them. Additionally, when the reaction temperature was elevated, the reaction velocity increased, but the yield of desired product 2a obviously decreased (Entries 27-29).
Subsequently, we attempted the CuBr 2 -catalyzed oxidative conversion of variously substituted THbCs 1 to b-carboline 2 in DMSO with DBU as the base, and the results are summarized in Table 2. The scope of the reaction is very wide; almost all of the tested THbCs could be smoothly converted to b-carbolines in good to excellent yields. All the conversions were performed under the standard reaction conditions (see footnote of the Table 2), and a total of twenty-four variously substituted b-carbolines 2a-2x were obtained in 78-96% yields.
A possible mechanism for the CuBr 2 -catalyzed oxidative conversion of THbCs 1 to b-carbolines 2 is proposed in Scheme 1. As can be seen from Scheme 1, THbCs 1 would rst undergo CuBr 2 -catalyzed aerobic oxidation of C-N single bond to C]N double bond to produce 3,4-dihydro-b-carbolines I-A according to Adimurthy's reports. 19 3,4-Dihydro-b-carbolines I-A would then undergo DBU-promoted reversible tautomerization 20 to form unstable enamine intermediates I-B, which would also  undergo the CuBr 2 -catalyzed aerobic oxidation of C-N single bond to afford b-carbolines 2. Actually, dihydro-b-carbolines I-A could be isolated if the reaction was stopped in the midway. For example, when the CuBr 2 -catalyzed oxidative conversion of 1phenyl-THbC 1a to 1-phenyl-b-carboline 2a was stopped at 8 h, 1-phenyl-3,4-dihydro-b-carboline was obtained in 36% yield.
To showcase the synthetic utility of the above-described method for the CuBr 2 -catalyzed oxidative conversion of THbCs 1 to b-carbolines 2, we have successively applied the methodology to the efficient and practical total syntheses of two bcarboline alkaloids perlolyrine 3 and azin 4.
Perlolyrine 3 and azin 4 are both strongly uorescent 1furanyl-b-carboline alkaloids. These two particular alkaloids are widespread in nature, and have been isolated from plants, bacteria, Japanese sake and soy sauce. 1h,3b,21 Several total syntheses of perlolyrine 3 and azin 4 have been reported hitherto, 22 we herein report novel practical total syntheses of them, which are depicted in Scheme 2. Pictet-Spengler reaction of tryptamine and tryptophan methyl ester with 2-furaldehyde rst gave THbCs 5 and 6 in 82% and 83% yields, respectively. CuBr 2 -catalyzed oxidation of compounds 5 and 6 with air then furnished b-carbolines 7 and 8 in 89% and 90% yields, respectively. Next, hydroxymethylation of compounds 7 and 8 with HCHO in AcOH produced perlolyrine 3 and compound 9 in 86% and 85% yields, respectively. Hydrolysis of the ester 9 afforded azin 4 in 92% yield. Thus, perlolyrine 3 was synthesized from tryptamine in 3 steps in 63% overall yield; and azin 4 was synthesized from tryptophan methyl ester in 4 steps in 58% overall yield.

Conclusions
In conclusion, we have developed a novel method for the CuBr 2catalyzed oxidative conversion of THbCs to b-carbolines. This method has some advantages as follows: (a) the process was carried out at room temperature with air as the clean oxidant, so it is very mild and environmentally benign; (b) CuBr 2 as the catalyst is inexpensive and low-toxic; (c) all products were obtained in good to excellent yields; (d) the reaction has very good tolerance of functional groups, it seemed to be applicable to all the tested substrates; (e) experiment operation is quite easy. In addition, novel practical total syntheses of b-carboline alkaloids perlolyrine and azin were performed with the above-described CuBr 2 -catalyzed mild oxidation of THbCs as the key step.

Experimental
General 1 H NMR and 13 C NMR spectra were acquired on a Bruker AM 400 instrument, chemical shis are given on the d scale as parts per million (ppm) with tetramethylsilane (TMS) as the internal standard. IR spectra were recorded on a Nicolet Magna IR-550 instrument. Mass spectra were performed with a HP1100 LC-MS spectrometer. Melting points were measured on a Mei-TEMP II melting point apparatus. Column chromatography was performed on silica gel (Qingdao Chemical Factory). All reagents and solvents were analytically pure, and were used as such as received from the chemical suppliers.
anhydrous CuBr 2 (89.5 mg, 0.401 mmol) were added. The resulting solution was then stirred under air at room temperature (around 25 C) for 12-24 h (see Table 2). Aer the reaction was complete (checked by TLC, EtOAc/CH 2 Cl 2 ¼ 1 : 1 to 1 : 4), the reaction solution was poured into the mixed solution of EtOAc (30 mL) and aqueous ammonia (5% w/w, 25 mL). Aer the mixture was stirred for 5 minutes, two phases were separated. The aqueous layer was extracted again with EtOAc (20 mL). The organic extracts were combined and washed with brine (10 mL). The organic solution was dried over anhydrous MgSO 4 , and then was concentrated under vacuum to give the crude product, which was puried by ash chromatography (eluent: EtOAc/CH 2 Cl 2 ¼ 1 : 2 to 1 : 15) to afford pure b-carbolines 2 in 78-96% yield as indicated in the Table 2. Characterization data of the b-carbolines 2a-2x are given in the ESI † of this paper.

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