One-pot Ugi-azide and Heck reactions for the synthesis of heterocyclic systems containing tetrazole and 1,2,3,4-tetrahydroisoquinoline

A new method for the synthesis of heterocyclic systems containing tetrazole and tetrahydroisoquinoline is developed via the performance of one-pot Ugi-azide and Heck cyclization reactions. The integration of the multicomponent and post-condensation reactions in one-pot maximizes the pot-, atom-, and step-economy (PASE).

Products 6c-k were obtained in higher yields than products 6a,b.We believe that the secondary amine in the Ugi reaction products 5 could affect the yield of the Heck reaction.To address the issue, compounds 5 were N-alkylated to afford intermediates 7 which were used in the subsequent Heck reac- tion step.Thus, an alternative one-pot Ugi-azide/N-alkylation/ Heck reaction procedure was developed (Scheme 5).A mixture of 2-bromobenzaldehyde (1a, 1 mmol), allylamine hydrochloride (2, 1 trimethylsilyl azide (3, 1 mmol) and benzyl isocyanide (1 mmol) in MeOH was reacted at 40 °C for 24 h.After evaporating the solvent, 3 mL CH 3 CN were added to the crude 1,5-DS-1H-T 5a followed by the addition of 1 equiv of benzyl bromide and 2 equiv of K 2 CO 3 for the alkylation reaction at 80 °C for 3 h to give N-benzylated compound 7a.Finally, 10 mol % of Pd(OAc) 2 , 20 mol % of PPh 3 , 2 equiv of K 2 CO 3 were added to the reaction mixture for the Heck reaction at 105 °C for 3 h under N 2 atmosphere to afford tetrazolyl-1,2,3,4-tetrahydroisoquinoline 8a in 74% isolated yield which is higher than the one-pot Ugi/Hecke reaction to give product 6b (58%).Under the alternative one-pot reaction conditions involving an N-alkylation step, the substrate scope was explored by the preparation of 10 derivatives 8a-j (Scheme 5) using seven benzaldehydes 1, two isonitriles 4, and allylamine hydrochloride (2) with trimethylsilyl azide (3) for the Ugi-azide reaction.The N-alkylations were conducted using benzyl bromide and iodomethane, respectively.The final products 8b-j were obtained in 66-74% yields.
To evaluate the scalability of the two-step one-pot reaction protocol, we performed the synthesis of tetracyclic tetrazolopyrazino[2,1-a]isoquinolin-6(5H)-one 6c in gram quantity from 10 mmol of 1a which led to the formation of product 6c in a satisfactory yield 77% (Scheme 6).The products 6 and 8 were characterized by 1 H and 13 C NMR, and HRMS analysis.In addition, single crystals of compound 6d and 8c were obtained for X-ray analysis to confirm the structures (Figure 2).

Conclusion
In conclusion, we have developed a one-pot synthesis with two or three steps for making tetrazolo-pyrazino[2,1-a]isoquinolin-6(5H)-ones.The initial Ugi-azide four-component reaction constructs the tetrazole motif while the subsequent intramolecular Heck reaction assembles the tetrahydroisoquinoline.The one-pot reaction avoids the intermediate purification which has favorable PASE in the synthesis of heterocyclic compounds.
General procedure for the one-pot synthesis of tetrazole-containing 1,2,3,4-tetrahydroisoquinolines 6 A mixture of 2-bromobenzaldehyde 1 (1 mmol), allylamine hydrochloride (2, 1 mmol), trimethylsilyl azide (3, 1 mmol) and isocyanide 4 (1 mmol) in MeOH was stirred at 40 °C for 24 h.After the reaction was complete, the solvent was evaporated under vacuum to give the crude Ugi adduct 5, which was used in the Heck reaction without further purification.To a solution of the crude intermediate 5 in MeCN (3 mL) was added 10 mol % of Pd(OAc) 2 , mol % of PPh 3 , 2 equiv of K 2 CO 3 and the mixture stirred for 3 h at 105 °C under N 2 atmosphere.After aqueous work-up, the product was purified by flash chromatography with 1:3 ethyl acetate/petroleum ether to afford products 6.
General procedure for the one-pot synthesis of tetrazolyl-1,2,3,4-tetrahydroisoquinolines 8 A mixture of 2-bromobenzaldehyde 1 (1 mmol), allylamine hydrochloride (2, 1 mmol), trimethylsilyl azide (3, 1 mmol) and isocyanide 4 (1 mmol) in MeOH was reacted at 40 °C for 24 h.After evaporating the solvent, 3 mL CH 3 CN were added to the crude 1,5-DS-1H-T 5 followed by the addition of 1 equiv of benzyl bromide or iodomethane and 2 equiv of K 2 CO 3 for the alkylation reaction at 80 °C for 3 h to give N-alkylated compounds 7. Finally, 10 mol % of Pd(OAc) 2 , 20 mol % of PPh 3 , 2 equiv of K 2 CO 3 were added to the reaction mixture for the Heck reaction at 105 °C for 3 h under N 2 atmosphere.After aqueous work-up, the crude products were purified by flash chromatography with 1:4 ethyl acetate/petroleum ether to afford products 8.

Table 1 )
[12][13][14]eaction of 5a was first examined by using 10 mol % Pd(OAc) 2 , 20 mol % PPh 3 , 2 equiv of Et 3 N in CH 3 CN or DMF at 105 °C for 24 h under N 2 atmosphere.However, the reactions failed under these conditions (Table1, entries 1 and 2).When K 2 CO 3 was used as a base to replace Et 3 N, the reactions in either CH 3 CN or DMF for 3 h both gave cyclized product 6a in 70% yield (Table1, entries3 and 4).An increase of the reaction time to 12 h did not improve the yield (Table1, entry 5).The reaction was further evaluated in the absence of ligand which afforded the product in 35% yield (Table1, entry 6).Screening of ligands, e.g., PCy 3 and P(o-tol) 3 reduced the yield of the desired product 6a (Table1, entries 7 and 8).Lowering the amount of Pd(OAc) 2 or changing the reaction temperatures resulted low yields of 6a (Table1, entries 9-11).Similar results were observed from the reactions using other bases, such as K 3 PO 4 , NaOAc, and Cs 2 CO 3 (Table1, entries[12][13][14].Investigating other Pd catalysts, suche as PdCl 2 and Pd(dba) 2 also gave low yields (Table1, entries 15 and 16).Since CH 3 CN is a more favorable solvent than DMF in green chemistry consideration