Novel total syntheses of oxoaporphine alkaloids enabled by mild Cu-catalyzed tandem oxidation/aromatization of 1-Bn-DHIQs

Novel total syntheses of oxoaporphine alkaloids such as liriodenine, dicentrinone, cassameridine, lysicamine, oxoglaucine and O-methylmoschatoline were developed. The key step of these total syntheses is Cu-catalyzed conversion of 1-benzyl-3,4-dihydro-isoquinolines (1-Bn-DHIQs) to 1-benzoyl-isoquinolines (1-Bz-IQs) via tandem oxidation/aromatization. This novel Cu-catalyzed conversion has been studied in detail, and was successfully used for constructing the 1-Bz-IQ core.

A general retrosynthetic analysis of the above several oxoaporphine alkaloids 1a-f is depicted in Scheme 1. As can be seen from the Scheme 1, C-ring could be constructed via Pschorr cyclization of anilines A, which could be obtained from the reduction of nitro groups of compounds B. The 1-Bz-IQ core of compounds B could be constructed via Cu-catalyzed tandem oxidation/aromatization of 1-Bn-DHIQs C. B-ring of compounds C could be constructed via Bischler-Napieralski cyclization of amides D, which could be derived from amines E and acyl chlorides F. Amines E could be prepared from aryl aldehydes G.

Results and discussion
According to the above general retrosynthetic analysis, novel total syntheses of the six targeted oxoaporphine alkaloids 1a-f are depicted in Scheme 2. As can be seen from the Scheme 2, EDA (ethylenediamine)-catalyzed condensation of aryl aldehydes with nitromethane 13 rst produced nitroalkenes 2a-c in high yields. Next, when compounds 2a-c were treated with 6.0 equiv. of LiAlH 4 in tetrahydrofuran at reux, simultaneous reduction of both nitro group and double bond occurred in one-pot to furnish 2-aryl ethanamines 3a-c, which then immediately exposed to 1.1 equiv. of 2-arylacetyl chlorides and 3.0 equiv. of K 2 CO 3 at 0 C in a mixed solvent of dichloromethane and water (3 : 1) to afford amides 4a-f. Subsequently, treatment of compounds 4a-f with 3.0 equiv. of POCl 3 in anhydrous acetonitrile at reux gave 1-Bn-DHIQs 5a-f via Bischler-Napieralski cyclization. 14 It was observed that compounds 5a-f and compounds 5 0 a-f were interchangeable Fig. 1 The targeted oxoaporphine alkaloids 1a-f. In the above-described total syntheses of oxoaporphine alkaloids 1a-f, the key step is Cu-catalyzed conversion of 1-Bn-THIQs 5a-f to 1-Bz-IQs 6a-f. This key conversion can be achieved by some known methods. 17-21 However, these known methods oen suffered from drawbacks such as use of poisonous and hazardous strong oxidants including SeO 2 , 17 Pb(OAc) 4 , 18 and CAN, 19 inconvenient use of the photoactivated singlet O 2 , 20 or need of high reaction temperature 21 (120 C). Therefore, development of an efficient and benign method for this particular conversion might be very helpful for total syntheses of oxoaporphine alkaloids.
Copper is a cheap transition metal with low toxicity; and air (O 2 ) is an eco-friendly clean oxidant. Hence, an increasing amount of copper-catalyzed aerobic oxidations of various compounds have been recently developed. 22 For the above conversion of 1-Bn-THIQs 5a-f to 1-Bz-IQs 6a-f, CuBr 2 was used as the catalyst, and air (O 2 ) was used as the clean oxidant. So this Cu-catalyzed method might be much more benign, ecofriendly and practical than the previous known methods. [17][18][19][20][21] Advantages such as mildness (at 35 C), high efficiency and ecofriendliness prompted us to investigate the details of this potential green chemical method.
A possible mechanism for the CuBr 2 -catalyzed conversion of 1-Bn-DHIQs 5 to 1-Bz-IQs 6 was proposed in Scheme 3. 1-Bn-DHIQs 5 would rst react with CuBr 2 and a base (B ¼ DBU, etc.) to form enamine-CuBr complexes 5 0 -CuBr, which would then undergo Jenkins-like aerobic oxidation 24 to produce peroxide-CuBr complexes I-A. The intermediate Cu-complexes I-A would be unstable enough to decompose immediately to furnish 1-Bz-DHIQs 8. Compounds 8 would nally undergo DBU-promoted oxidation by O 2 to produce 1-Bz-IQs 6 according to Kumar's reports. 25 The intermediate compounds 8 could be detected by TLC during the reaction, and could also be isolated if the reaction was stopped at a middle point. For example, when CuBr 2 -catalyzed conversion of compound 5a to compound 6a was stopped at 3 h, the intermediate compound 8a was isolated in 38% yield.
In addition, a novel practical Cu-catalyzed conversion of 1-Bn-DHIQs 5 to 1-Bz-IQs 6, which was used as the key step in the above total syntheses, has also been investigated in detail; this Cu-catalyzed method has some advantages such as mildness, eco-friendliness, wide scope, ease of experimental procedure and high yields. It would provide a new general basic approach towards the total syntheses of oxoaporphine alkaloids and their derivatives.

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.

Preparation of amides 4a-f
2-Aryl acetic acid ($11 mmol) was dissolved in CH 2 Cl 2 (20 mL), and SOCl 2 (1.790 g, 15.05 mmol) was added. The resulting solution was then heated and stirred at reux for 4 h. The reaction solution was concentrated under vacuum to dryness, oily residue was then dissolved in dry CH 2 Cl 2 (10 mL), the solution was immediately used bellow. 2-Aryl ethanamine 3 (10 mmol) was dissolved in 40 mL CH 2 Cl 2 , and an aqueous solution of K 2 CO 3 (4.150 g, 30.03 mmol) in water (30 mL) was added. The biphasic mixture was cooled by an ice-bath, and was stirred at 0 to 5 C. The above freshly prepared solution of 2-aryl acetyl chloride was added dropwise into the reaction mixture over 2 min. Aer the addition was nished, stirring was continued at 0 to 5 C for 2 h. When the reaction was complete (checked by TLC, eluent: EtOAc/hexane ¼ 1 : 3), the reaction mixture was transferred into a separatory funnel. Two phases were separated, and the aqueous phase was extracted again with CH 2 Cl 2 (20 mL). The organic extracts were combined, dried over anhydrous MgSO 4 , and then concentrated under vacuum to give crude product as pale yellow solid, which was puried by ash chromatography (eluent: EtOAc/ hexane ¼ 1 : 4). Amides 4a-f 1600Amides 4a-f , 1475Amides 4a-f , 1282Amides 4a-f , 1251Amides 4a-f , 1168Amides 4a-f , 1125Amides 4a-f , 1018 + : 405.1662, found: 405.1665.

Preparation of 1-benzyl-3,4-dihydroisoquinolines 5
A corresponding amide 4 ($5 mmol) was dissolved in anhydrous acetonitrile (40 mL), and phosphorus oxychloride (2.350 g, 15.33 mmol) was slowly added into the mixture. The resulting solution was then heated and stirred at reux for 2 h. Aer the reaction was complete (checked by TLC, eluent: CH 2 Cl 2 /hexane ¼ 2 : 1), the solution was concentrated under vacuum to dryness, the residue was dissolved in CH 2 Cl 2 (50 mL). An aqueous solution of K 2 CO 3 (20 mL, 15% w/w) was added. Aer the mixture was vigorously stirred for 5 min, two phases were separated, and the aqueous phase was extracted again with CH 2 Cl 2 (20 mL). The organic extracts were combined, dried over anhydrous MgSO 4 , and then concentrated under vacuum to give crude solid product as a tautomeric mixture of 1-benzyl-3,4-dihydroisoquinoline 5 and enamine 5 0 , which was used as such for the next step.