Modular synthesis of unsaturated aza-heterocycles via copper catalyzed multicomponent cascade reaction

Summary The unsaturated aza-heterocycles such as tetrahydropyridines pose significant applications in both drug discovery and development. However, the methods to construct polyfunctionalized tetrahydropyridines are still limited. Herein, we report a modular synthesis of tetrahydropyridines via copper catalyzed multicomponent radical cascade reaction. The reaction features mild conditions and broad substrate scope. In addition, the reaction could scale up to gram scale with similar yield. A variety of 1,2,5,6-tetrahydropyridines with C3 and C5 substituents could be assembled from simple starting materials. More importantly, the products could serve as versatile intermediate to access various functionalized aza-heterocycles which further demonstrates its utility.

Multicomponent reactions represent one of the most efficient and practical synthetic methods in terms of atom-and step-economy for the expeditious construction of polyfunctionalized molecules with structural diversity from readily available starting materials. 36-41 Thus, a multicomponent reaction approach would offer us an alternative solution to the modular synthesis of 1,2,5,6-tetrahydropyridines with various functionalities at C3, C4 and C5 positions. In the light of recent progress of copper catalyzed radical relay process which was initiated by generating N-centered radicals in C-H functionalization 42-69 and difunctionalization of alkenes, 70-87 we envisioned that a modular synthesis of valuable 1,2,5,6-tetrahydropyridines could be accomplished by a copper catalyzed radical cascade reaction involving three simple components ( Figure 1C). Specifically, an F-masked 4-methyl-N-(2-phenylbuta-2,3-dien-1-yl)benzene-sulfonamide was designed to generate electrophilic N-centered radical via single electron transfer from copper catalyst. Followed by the N centered radical addition toward alkenes to trigger a radical 6-exo-dig cyclization. Finally, the formed allylic carbon radical reacted with a bulky Cu(II) complex to give the iScience Article 1,2,5,6-tetrahydropyridines with various substituents at C3, C4, and C5 positions, which could provide a wealth of opportunities in both drug discovery and development ( Figure 1C). Hence, we report a modular synthesis of functionalized tetrahydropyridines via copper catalyzed three components radical cascade reaction.

Discovery
To test the feasibility of the proposed strategy, substrate 1a, 1b and TMSCN were as the model substrate.
After a careful evaluation of various reaction parameters, the desired cyclization product 1c was isolated in 65% yield with Cu(CH 3 CN) 4 PF 6 as catalyst, L3 as the ligand, 1b (2 equiv) as coupling partner, TMSCN (2.5 equiv) as nucleophile and fluorobenzene as solvent (see equation in Table 1, entry 1). As expected, the ligand played a pivotal role in this reaction. While using ligands L1 and L2, no desired product was formed. The BOX ligand (L3) was proved to be optimal to give good yield and excellent regioselectivity while installing the cyanide group at less steric hindered primary carbon site. In addition, in line with the proposed mechanism, the use of a chiral ligand did not impart any enantioselectivity and the product was found to be racemic. Other solvents instead of fluorobenzene were less effective and gave diminished yield (entries 2-6). Lots of copper salts could be employed as catalyst to furnish the desired product albeit with decreased yield (entries 7-10). Elevating the reaction temperature to 50 C made the reaction sluggish (entry 11). On the other hand, there was no reaction occurred at 0 C (entry 12). In addition, no matter increasing or decreasing the loading of TMSCN would diminish the yield of the desired product (entries [13][14]. Gratifyingly, while using the alkene as limiting reagent, the reaction proceeded smoothly to give the desired product with comparable yield (entries 15-17).

Synthetic evaluation
After having established the optimal reaction conditions, we then investigated the generality of this copper catalyzed multicomponent radical cyclization reaction. To install different functional groups at C5 position of the 1,2,5,6-tetrahydropyridines, monosubstituted styrenes were first examined (Scheme 1), and the desired products (1cÀ8c) were obtained in moderate to good yields. Different substituents on the benzene ring, including the alkyl group (2c), halide (5c), alkyl halide group (6c), and alkoxyl group (3c, 7c, 8c) were all tolerated. The substrates bearing two or three substituents on the aromatic ring reacted smoothly with 1a to afford the desired products (9c-13c) in acceptable yields. An extended aromatic ring, such as 2-vinylnaphthalene, was a viable substrate and furnished the desired product 14c in a moderate yield. Alkenes bearing heterocyclic moieties worked nicely in this reaction, gave the corresponding products (15cÀ17c) in 49-75% yield. Notably, heterocycles commonly existing in therapeutics, such as benzofuran, benzothiophene and indole, were well tolerated under the current conditions, which once again showcased the robustness of our method. To our delight, the radical cyclization took place regio-selectively and obtained 18c in 61% yield when we commit our study with diene substrate. Furthermore, hetero atom substituents could be installed at the C5 position while using N-vinyl benzamide, N-vinly lactam and vinyl aryl ether as substrates, and the corresponding products 19c-21c could be obtained in medium yield.
Next, a variety of F-masked sulfonamides were investigated to install different substituents on the C3 position of the 1,2,5,6-tetrahydropyridines (Scheme 1). A variety of functional groups including both electron donating groups and electron withdrawing groups on the para position of the aryl group were all compatible with the reaction conditions and furnished the corresponding products 22c-26c in moderate yields. While changing the substituent to meta and otho position, the reaction went smoothly to give the desired products 27c-28c in 77% and 63% yield respectively. The steric more hindered substituents such as naphthalene were tolerated as well 29c-30c. Unfortunately, there was no reaction occurred while changing the aryl group into an alkyl group 31c. (B) Or each panel or group of panels can be described separately The State-of-the-Art to construct unsaturated azaheterocycles.
(C) Rational of copper catalyzed multicomponent radical cyclization (this work).

Synthetic utility
To demonstrate the potential synthetic utility of our present method, further transformations of the tetrahydropyridines products were conducted ( Figure 2). For example, the reaction of 3c and H 2 O 2 could produce the corresponding amide 40 compound in 72% yield. The Ts group on the nitrogen atom could be removed by Mg/MeOH to give 41 in 83% yield. The Compound 3c could also undergo a dehydrogenation   iScience Article unsaturated nitrogen-containing heterocycles under mild conditions. The reaction involved an N-centered radical addition toward alkenes, 6-exo-dig cyclization, and regioselective cross coupling of the formed allylic radical. The transformations of the products and gram scale set up were further showcased the utility of this reaction.

Limitations of the study
This work reports a highly efficient and regioselective method for the preparation of tetrahydropyridines via copper catalyzed multicomponent radical cascade reaction. Although a good substrate scope of alkenes and nucleophiles has been demonstrated, this method shows limitations on substrates of F-masked sulfonamides. Further optimization of catalysts and reaction conditions is needed to expand the scope of F-masked sulfonamides and improve the applicability of the method.

STAR+METHODS
Detailed methods are provided in the online version of this paper and include the following:

Preparation of substrates
General procedure for the synthesis of N-F.
2-Phenyl-2, 3-butadien-1-ol (1.46g, 10 mmol), TsNHBoc (3.53g, 13 mmol) and PPh3 (3.41g 13 mmol) were suspended in THF (15 ml). The mixture was cooled to 0 C and diethyl azodicarboxylate (DEAD 2.61g, 15 mmol) was added dropwisely. Then the reaction mixture was allowed to warm to room temperature. Water was added when the starting material was disappeared and the mixture was extracted with Et 2 O. The combined organic extracts were dried overMgSO 4 . After solvent evaporated, the residue was purified through silica gel to give the allenyl imide product. The allenyl imide was treated with TFA following the process described as above to give the product (1.94g, 65% for two steps).
In an oven dried round bottom flask with stir bar, sodium hydride (10 mmol, 2 equiv.) was taken. The sodium hydride was washed with pentane (2 times) and dried under vacuum and filled with nitrogen. Then dry DCM (40 mL) was added to it. A solution of sulfonamide (1 equiv.) in dry DCM (0.5 M) was added dropwise to the NaH suspension in DCM. The total reaction was stirred at room temperature for 30 mins. Then, a solution of NFSI (3 eq.) in dry DCM (0.5 M) was added to dropwise to the reaction mixture at room temperature. The total reaction mixture was stirred for overnight at room temperature. The reaction was quenched with ice with constant stirring. Then 50 mL of water was added to the reaction mixture. The organic part was washed with 30 mL NaHCO 3 , and 30 mL brine solution respectively. The organic part was concentrated in rotary evaporator and performed silica gel flash column chromatography to isolate the desired N-F (fluorosulfonamide, 25%-50% yield) using hexanes/ethyl acetate mixture as eluent.

Procedure A
In a dried sealed 10 mL Schlenk tube, Cu(CH 3 CN) 4 PF 6 (5 mol%), bisoxazoline ligand L3 (7.5 mol %) were dissolved in a mixed solvent of PhF (2.0 mL) under a N2 atmosphere, and the mixture was stirred for 30 min. Then substrate N-F (1a, 63.4 mg, 0.2 mmol, 1.0 eq.), styrene (1b, 42.0mg, 0.4 mmol, 2.0 eq.) and TMSCN (67 ml, 0.5 mmol, 2.5 equiv.) were added sequentially into the above solution. The tube was sealed with Teflon septum and the reaction mixture was stirred at 36 C for another 12 hours. After the reaction was completed, the mixture was quenched by a short pad of silica gel with a gradient eluent of petroleum ether and ethyl acetate, solvent was removed under vacuum, and the residue was purified by column chromatography on silica gel with a gradient eluent of petroleum ether and ethyl acetate (Petroleum ether: EtOAc = 10:1) to give the desired product 1c in 65% yield (55.8 mg).

Procedure A-1
In a dried sealed 10 mL Schlenk tube, Cu(CH3CN)4PF6 (5 mol%), bisoxazoline ligand L3 (7.5 mol %) were dissolved in a mixed solvent of PhF (2.0 mL) under a N2 atmosphere, and the mixture was stirred for 30 min. Then substrate N-F (1a, 63.4 mg, 0.2 mmol, 1.0 eq.), styrene (1b 42.0mg, 0.4 mmol, 2.0 eq.) and TMSN3 (0.5 mmol, 2.5 equiv.) were added sequentially into the above solution. The tube was sealed with Teflon septum and the reaction mixture was stirred at 36 C for another 12 hours. After the reaction was completed, the mixture was quenched by a short pad of silica gel with a gradient eluent of petroleum ether and ethyl acetate, solvent was removed under vacuum, and the residue was purified by column chromatography on silica gel with a gradient eluent of petroleum ether and ethyl acetate (Petroleum ether: EtOAc = 10:1) to give the desired product 32c in 66% yield (58.9mg).

Procedure A-2
In a dried sealed 10 mL Schlenk tube, Cu(CH 3 CN) 4 PF 6 (5 mol%), bisoxazoline ligand L3 (7.5 mol %) were dissolved in a mixed solvent of PhF (2.0 mL) under a N 2 atmosphere, and the mixture was stirred for and TMSSCN (0.5 mmol, 2.5 equiv.) were added sequentially into the above solution. The tube was sealed with Teflon septum and the reaction mixture was stirred at 36 C for another 12 hours. After the reaction was completed, the mixture was quenched by a short pad of silica gel with a gradient eluent of petroleum ether and ethyl acetate, solvent was removed under vacuum, and the residue was purified by column chromatography on silica gel with a gradient eluent of petroleum ether and ethyl acetate (Petroleum ether: EtOAc =5:1) to give the desired product 33c in 60% yield (59.0 mg).

Procedure B
In a dried sealed 10 mL Schlenk tube, Cu(OTf) 2 (10 mol %), bpy (15 mol %) were dissolved in a mixed solvent of DCE (2.0 mL) under a N 2 atmosphere, and the mixture was stirred for 30 min. Then substrate N-F (1a, 63.4 mg, 0.2 mmol, 1.0 eq.), 4-methoxystyrene (54 mg, 0.4 mmol, 2.0 eq.), AgSCF 3 (83 mg, 0.4 mmol, 2.0 eq.) and CsBr (127 mg, 0.6 mmol, 3.0 eq.) were added sequentially into the above solution. The tube was sealed with Teflon septum and the reaction mixture was stirred at 60 C for another 18 hours. After the reaction was completed, the mixture was quenched by a short pad of silica gel with a gradient eluent of petroleum ether and ethyl acetate, solvent was removed under vacuum, and the residue was purified by column chromatography on silica gel with a gradient eluent of petroleum ether and diethyl ether (Petroleum ether: diethyl ether = 15:1) to give the desired product 34c in 40% yield (42.7 mg).

Procedure C
In a dried sealed 10 mL Schlenk tube, Cu(CH 3 CN) 4 PF 6 (5 mol%), bisoxazoline ligand L3 (7.5 mol %) were dissolved in a mixed solvent of DCM and DMA (9:1, 2.0 mL, v/v = 9:1) under a N2 atmosphere, and the mixture was stirred for 30 min. Then substrate N-F (1a, 63.4 mg, 0.2 mmol, 1.0 eq.), 4-methoxystyrene (54 mg, 0.4 mmol, 2.0 eq.), and alkynyltrimethoxysilane (0.4 mmol, 2.0 eq.) were added sequentially into the above solution. The tube was sealed with Teflon septum and the reaction mixture was stirred at room temperature for another 12 hours. After the reaction was completed, the mixture was quenched by a short pad of silica gel with a gradient eluent of petroleum ether and ethyl acetate, solvent was removed under vacuum, and the residue was purified by column chromatography on silica gel with a gradient eluent of petroleum ether and ethyl acetate to give the desired product 35c-39c. To a solution of 20c (87.0 mg, 0.2 mmol) in anhydride methanol (2 mL) was added Mg turnings (6.0 eq.) and the reaction mixture was stirred under sonication for 5h at room temperature. After the completion of the reaction, the mixture was quenched with brine, and extracted with DCM. The combined organic layers were dried overNa 2 SO 4 and concentrated in vacuum. The residue was purified by column chromatography to provide the desired product 41 as a yellow solid (46.6 mg, 83% yield). Rf = 0.1 (MeOH: DCM =1:9) To a solution of 3c (45.8 mg, 0.1 mmol) in 2 mL of PhMe was added DDQ (45.4mg, 0.20 mmol), and the reaction was stirred at 100 C for 12 hourstill 3c was completely consumed (monitored by TLC). The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting crude residue was purified via column chromatography on silica gel (8:1 hexanes/EtOAc) to afford the desired product 42 with 70% (32.0 mg) yield.