Synthesis of 5,6-Dihydropyrazolo[5,1-a]isoquinolines through Tandem Reaction of C,N-Cyclic Azomethine Imines with α,β-Unsaturated Ketones

An innovative and efficient approach has been developed for the synthesis of 5,6-dihydropyrazolo[5,1-a]isoquinolines. This one-pot tandem reaction involves the reaction of C,N-cyclic azomethine imines with α,β-unsaturated ketones, using K2CO3 as the base and DDQ as the oxidant. The process results in functionalized 5,6-dihydropyrazolo[5,1-a]isoquinolines with good yields. This convenient one-step method encompasses a tandem [3 + 2]-cycloaddition, detosylation, and oxidative aromatization.


Introduction
Nitrogen-containing heterocycles are highly valued structures and play a crucial role as components in a variety of biologically significant natural products and pharmaceuticals. These molecular skeletons are found throughout nature and play a crucial role in metabolism due to their widespread occurrence as the structural nucleus in many important natural products, including hormones, antibiotics, alkaloids, and others [1,2]. In particular, pyrazoles, five-membered heterocycles with two adjacent nitrogen atoms, are recognized for their extensive range of biological properties in both natural products and their synthetic derivatives. Many FDA-approved and commercially available drugs, such as celecoxib, rimonabant, and sildenafil, have been derived from pyrazole derivatives, highlighting the wide utilization of these groups in the development of novel bioactive molecules [3,4]. Additionally, tetrahydroquinolines are a class of nitrogen-containing heterocyclic compounds that feature a benzene ring fused with a tetrahydropyridine or piperidine ring. These compounds, found naturally as well as in synthetic derivatives, exhibit a broad range of pharmacological properties, such as antibacterial, antifungal, antiviral, antimalarial, and anti-inflammatory effects. They have been largely employed for their potent antitumor properties [5,6]. Given the value of the pyrazole and tetrahydroquinoline scaffolds, the 5,6dihydropyrazolo [5,1-a]isoquinoline, which is a pyrazole-fused tetrahydroquinoline, holds great potential as a target for the creation of unique biologically active compounds [7][8][9][10].

Results and Discussion
Recently, we published a study on the DABCO-catalyzed cycloaddition of N-Tprotected C,N-cyclic azomethine imines with γ-NHTs-α,β-unsaturated ketones followed by a cleavage of the tosyl group, resulting in the efficient synthesis of tetrahydropyrazolo [5,1a]isoquinolines (19 examples) with high yields (up to 87% yield) and excellent diastereoselectivity (up to >30:1 dr) [24]. The reaction of N-T-protected C,N-cyclic azomethine imine 1a with γ-NHTs-α,β-unsaturated ketone 2a in the presence of the DABCO catalyst provided by tetrahydropyrazolo [5,1-a]isoquinoline 3aa in an 87% yield with >30:1 dr (Scheme 2(1)). As an application of compound 3aa, we attempted the oxidative aromatization of 3aa using oxidants such as SmI 2 and DDQ, which produced the corresponding dihydropyrazolo [5,1a]isoquinoline 4aa in yields of 81% and 73%, respectively (Scheme 2 (2), (3)). This led us to question whether it would be possible to synthesize 4aa from the reac tion of 1a with 2a in a one-pot procedure. To investigate this, we initiated our study by conducting a reaction of 1a with 2a in the presence of DABCO as the base catalyst and chloranil as the oxidant in CH2Cl2 (Table 1). Upon stirring for 12 h at room temperature we were delighted to discover that the desired product 4aa was obtained in a yield of 62% (Table 1, entry 1). Inspired by these positive results, we continued our exploration by con ducting the reaction using different oxidants and bases in an effort to optimize the reaction conditions. When using other oxidants, such as DDQ and IBX, the chemical reactivity and yield were not improved ( Table 1, entries 2-3). Subsequently, various organic bases (Et3N i-Pr2NEt, pyridine, DBU, DBN) and inorganic bases (Na2CO3, K2CO3, Cs2CO3) were screened to optimize the reaction conditions (Table 1, entries 4-11). A slight increase in the reaction yield (71%) was achieved using i-Pr2NEt as the base. The inorganic bases were well tolerated in this reaction and K2CO3 resulted in a higher yield of the product 4aa (75%), though a longer reaction time was required. To further optimize the reaction conditions, various organic solvents, including ClCH2CH2Cl, CHCl3, CH3CN, THF, 1,4-diox ane, toluene, and o-xylene, were screened using K2CO3 as the base and chloranil as the oxidant. Among the solvents tested, THF was found to be the optimal reaction solvent with a slight increase in reaction temperature to 50 °C after 12 h providing the best results The optimal reaction conditions were achieved using DDQ as the oxidant and K2CO3 as the base catalyst in THF, yielding product 4aa with a good yield of 81% (Table 1, entry 19) Scheme 2. Synthesis of 5,6-dihydropyrazolo [5,1-a]isoquinoline 4aa via the reaction of C,N-cyclic azomethine imine 1a with α,β-unsaturated ketone 2a.
This led us to question whether it would be possible to synthesize 4aa from the reaction of 1a with 2a in a one-pot procedure. To investigate this, we initiated our study by conducting a reaction of 1a with 2a in the presence of DABCO as the base catalyst and chloranil as the oxidant in CH 2 Cl 2 ( Table 1). Upon stirring for 12 h at room temperature, we were delighted to discover that the desired product 4aa was obtained in a yield of 62% (Table 1, entry 1). Inspired by these positive results, we continued our exploration by conducting the reaction using different oxidants and bases in an effort to optimize the reaction conditions. When using other oxidants, such as DDQ and IBX, the chemical reactivity and yield were not improved ( Table 1, entries 2-3). Subsequently, various organic bases (Et 3 N, i-Pr 2 NEt, pyridine, DBU, DBN) and inorganic bases (Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 ) were screened to optimize the reaction conditions (Table 1, entries 4-11). A slight increase in the reaction yield (71%) was achieved using i-Pr 2 NEt as the base. The inorganic bases were well tolerated in this reaction and K 2 CO 3 resulted in a higher yield of the product 4aa (75%), though a longer reaction time was required. To further optimize the reaction conditions, various organic solvents, including ClCH 2 CH 2 Cl, CHCl 3 , CH 3 CN, THF, 1,4dioxane, toluene, and o-xylene, were screened using K 2 CO 3 as the base and chloranil as the oxidant. Among the solvents tested, THF was found to be the optimal reaction solvent, with a slight increase in reaction temperature to 50 • C after 12 h providing the best results. The optimal reaction conditions were achieved using DDQ as the oxidant and K 2 CO 3 as the base catalyst in THF, yielding product 4aa with a good yield of 81% ( This led us to question whether it would be possible to synthesize 4aa from the reaction of 1a with 2a in a one-pot procedure. To investigate this, we initiated our study by conducting a reaction of 1a with 2a in the presence of DABCO as the base catalyst and chloranil as the oxidant in CH2Cl2 (Table 1). Upon stirring for 12 h at room temperature, we were delighted to discover that the desired product 4aa was obtained in a yield of 62% (Table 1, entry 1). Inspired by these positive results, we continued our exploration by conducting the reaction using different oxidants and bases in an effort to optimize the reaction conditions. When using other oxidants, such as DDQ and IBX, the chemical reactivity and yield were not improved ( Table 1, entries 2-3). Subsequently, various organic bases (Et3N, i-Pr2NEt, pyridine, DBU, DBN) and inorganic bases (Na2CO3, K2CO3, Cs2CO3) were screened to optimize the reaction conditions (Table 1, entries 4-11). A slight increase in the reaction yield (71%) was achieved using i-Pr2NEt as the base. The inorganic bases were well tolerated in this reaction and K2CO3 resulted in a higher yield of the product 4aa (75%), though a longer reaction time was required. To further optimize the reaction conditions, various organic solvents, including ClCH2CH2Cl, CHCl3, CH3CN, THF, 1,4-dioxane, toluene, and o-xylene, were screened using K2CO3 as the base and chloranil as the oxidant. Among the solvents tested, THF was found to be the optimal reaction solvent, with a slight increase in reaction temperature to 50 °C after 12 h providing the best results. The optimal reaction conditions were achieved using DDQ as the oxidant and K2CO3 as the base catalyst in THF, yielding product 4aa with a good yield of 81% (Table 1, entry 19). After optimizing the conditions, the reaction scope and versatility of γ-NHTs-α,βunsaturated ketones were evaluated (Scheme 3). The one-pot reaction of γ-NHTs-α,βunsaturated ketones 2a-m, which possessed different electronic substituents on the aromatic ring of the enone unit, was successfully carried out, affording 5,6-dihydropyrazolo [5,1a]isoquinoline products 4aa-am in moderate to high yields. The electronic properties of the substituents had a subtle effect on the reaction outcome. Enones with electron-withdrawing groups at the para-position of the aryl ring showed higher yield efficiency than those with electron-donating substituents. Ortho-substituted chlorine on the enone aromatic ring resulted in a lower yield compared to the reaction with metaand para-substituted analogs under the same reaction conditions (4ai vs. 4ag and 4aj). Additionally, γ-NHTs-α,βunsaturated ketones bearing hetero-aromatic groups such as 2-furyl and 2-thiophenyl were well tolerated and produced the corresponding 5,6-dihydropyrazolo [5,1-a]isoquinoline products 4an and 4ao in yields of 61% and 52%, respectively. This tandem reaction was also compatible with aliphatic substituents, as demonstrated by substrate 2p, which had a methyl group, yielding product 4ap with an acceptable yield.
To demonstrate the practical applications of this tandem reaction, the large-scale syn thesis of 5,6-dihydropyrazolo [5,1-a]isoquinoline product 4aa was successfully demon strated through the one-mole-scale tandem reaction between 1a and 2a (Scheme 5). The reaction was conducted under the optimized conditions and resulted in a yield of 85% This highlights the practical applications of this tandem reaction for the synthesis of bio logically active compounds. Scheme 4. Substrate scope of β-substituted-α,β-unsaturated ketones and C,N-cyclic azomethine imines a,b . a Standard reaction conditions: 1 (0.10 mmol), 2 (0.15 mmol), K 2 CO 3 (0.005 mmol), DDQ (0.12 mmol), and THF (1.0 mL), stirred at rt for 12 h and then at 50 • C for an additional 12 h. b Isolated yield after chromatographic purification.
Finally, the substrate scope of N-T-protected C,N-cyclic azomethine imines 1 was also evaluated. Regardless of the electronic nature of the substituents on the aromatic ring, the reaction of N-T-protected C,N-cyclic azomethine imines 1 with γ-NHTs-α,β-unsaturated ketones 2a and produced the corresponding 5,6-dihydropyrazolo [5,1-a]isoquinoline products 4ba-4fa in good yields (51-81%). The position of the substituents on the substrate seemed to have a slight impact on the reaction yield, with C7-methyl-substituted substrate 1c yielding the product in higher amounts compared to C5-methyl-substituted substrate 1b.
To demonstrate the practical applications of this tandem reaction, the large-scale synthesis of 5,6-dihydropyrazolo [5,1-a]isoquinoline product 4aa was successfully demonstrated through the one-mole-scale tandem reaction between 1a and 2a (Scheme 5). The reaction was conducted under the optimized conditions and resulted in a yield of 85%. This highlights the practical applications of this tandem reaction for the synthesis of biologically active compounds. Based on the experimental results and the previously reported literature [11][12][13][14], a plausible mechanism of the tandem reaction between N-T-protected C,N-cyclic azomethine imines and α,β-unsaturated ketones for the synthesis of 5,6-dihydropyrazolo [5,1a]isoquinolines is proposed (Scheme 6). The reaction starts with the 1,3-dipolar cycloaddition of C,N-cyclic azomethine imine 1a and α,β-unsaturated ketone 2a, which produces intermediate A.

Conclusions
In summary, we have developed an efficient and effective way to synthesize 5,6-di hydropyrazolo [5,1-a]isoquinolines. Combining the reaction between C,N-cyclic azome thine imines and α,β-unsaturated ketones, we have developed a one-pot procedure tha includes a [3 + 2]-cycloaddition, detosylation, and oxidative aromatization. Using K2CO as a base and DDQ as an oxidant, we have obtained functionalized 5,6-dihydropyra zolo [5,1-a]isoquinolines in good yields. This method provides a convenient and straight forward approach to synthesize these compounds. Scheme 6. Plausible reaction mechanism.

Conclusions
In summary, we have developed an efficient and effective way to synthesize 5,6dihydropyrazolo [5,1-a]isoquinolines. Combining the reaction between C,N-cyclic azomethine imines and α,β-unsaturated ketones, we have developed a one-pot procedure that includes a [3 + 2]-cycloaddition, detosylation, and oxidative aromatization. Using K 2 CO 3 as a base and DDQ as an oxidant, we have obtained functionalized 5,6-dihydropyrazolo [5,1a]isoquinolines in good yields. This method provides a convenient and straightforward approach to synthesize these compounds.

General Information
Organic solvents were distilled prior to use. Organic solutions were concentrated under reduced pressure using a rotary evaporator. The chromatographic purification of products was accomplished using forced-flow chromatography on ICN 60 32-64 mesh silica gel 63. Thin-layer chromatography (TLC) was performed on EM Reagents 0.25 mm silica gel 60-F plates. The developed chromatograms were visualized by fluorescence quenching and with anisaldehyde staining. 1 H, 13 C{ 1 H}, and 19 F NMR spectra were recorded (400 MHz for 1 H, 100 MHz for 13 C, and 176 MHz for 19 F) and were internally referenced to residual protic solvent signals. Data for 1 H NMR are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad singlet, dd = doublet of doublets, dt = doublet of triplets, qd = quartet of doublets, ddd = doublet of doublet of doublets, m = multiplet), coupling constant (Hz), and integration. Data for 13 C NMR are reported in terms of chemical shift. IR spectra were recorded on an FT IR spectrometer and are reported in wave numbers. High-resolution mass spectra (HRMS) were measured on a Q-TOF-MS with ESI using an electron impact ionization (EI-magnetic sector) mass spectrometer. γ-Sulfonamido-α,β-unsaturated ketones [26] and C,N-cyclic azomethine imines [27] were prepared according to the literature. To a solution of C,N-azomethine imine 1 (0.10 mmol) and K 2 CO 3 (0.005 mmol, 0.05 eq) in THF (1.0 mL, 0.10 M) was added α,β-unsaturated ketone 2 (0.15 mmol, 1.5 eq) at room temperature. After stirring for 10 min at room temperature, DDQ (0.12 mmol, 1.2 eq) was added. The reaction mixture was stirred for 12 h at room temperature and then heated in an oil bath at 50 • C. After stirring for 12 h, the resulting mixture was quenched with sat. NaHCO 3 solution and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The crude residue was purified by flash column chromatography with EtOAc/hexanes as eluent to afford desired product 4 (The spectra can be found in Supplementary Materials).