One Pot Sequential Aldol condensation - Michael Addition – Sonogashira, and Heck Arylation toward Highly Functionalized Quinolines

Abstract A facile Pd/Cu-cocatalyzed one-pot domino aldol condensation/Michael addition/Sonogashira coupling has been developed. The reaction of 2-chloro-3-formylquinolines (CFQs), 1 acetophenones (APs), 2 and terminal acetylenes, 3 by employing triethylamine as a base, solvent as well as a ligand under mild conditions gave highly functionalized 1,5-diphenyl-3-(2-(2-phenylethynyl)quinolin-3-yl)pentane-1,5-diones, 4a-j, Additionally accomplished Heck arylation using CFQs in the presence of Pd catalyst. The present methodology gave the desired synthetic building blocks in acceptable yields.


Results and discussion
Initially, when 1a (1 mmol) 2a (2.5 mmol) and phenylacetylene, 3a (1.2 mmol) were reacted in the presence of 10 mol% of Pd(OAc) 2 /THF without a ligand, co-catalyst, and base, at room temperature (RT), desired product, 4a was not observed as shown in Scheme 2. However, observed an aldol condensation/Michael, 5 and Sonogashira product, 6 around trace amount of yields (Table 1 entry 1) (see supporting information, SI, Scheme 2). Later, different parameters including the base, catalyst, co-catalyst, solvent, and ligand were investigated in the formation of product, 4a by raising the temperature to 80 C. The results are compiled as Table 1. When the reaction was explored with an inorganic base, ligand or no ligand, gave desired product, 4a respectively in traces or in a low yield of 15% (Table 1 entry 2 and 3).
The reaction when done with THF-water along with ligand PPh 3 gave a similar yield of 18% (entry 4). When added water to avoid the complex formation with Pd catalyst, the desired product was not obtained in expected yields. Further, by adding 5 mol% of CuI as co-catalyst to Scheme 1. The developed one-pot MCR of aldol condensation/Michael addition/Sonogashira, and Heck arylation reaction Scheme 2. One-pot multicomponent reaction activate the terminal acetylene under same reaction conditions (Pd(OAc) 2 /CuI/PPh 3 /NaOH/THF-H 2 O) noticed an improvement of the reaction with a yield of 33% (entry 5). Likewise, with Pd(OAc) 2 /CuI/S-Phos/TEA/THF-H 2 O trials, it is interesting to note the strong ligand S-Phos and organic base TEA increased product yield to 41% (entry 6). The solvent dioxane/water gave a 21% yield (entry7). These investigations declared the essence of the co-catalyst, base, ligand and solvents. Even by changing the base or ligand we could not get a better yield of the product. Subsequently, when tested with (PdCl 2 (PPh 3 ) 2 ), less yield of 39% product, in DMF-H 2 O is obtained (entry 8) which revealed the effect of solvent and base toward the desired product formation. Then, the effect of a base on the reaction was explored by utilizing KOH, DIPEA, and piperidine in the aldol condensation/Michael addition product, 5 and then Sonogashira coupling, 4a product formation. However, lesser yields of 26%, 20% and trace were observed, (entry 9-11). Among the tested bases, triethylamine has accustomed better yields (entry 6 & 8). With or without ligand, co-catalyst and solvent the reactions when performed no product or product with 36%, 45% and 28% of yields (entry 12-15) were obtained. The reaction provided the desired product without a solvent while the base triethylamine act as a base as well as solvent. With changing ligand to X-phos, a yield of 45% is observed. It proved that the reaction required triethylamine as a base and solvent but after changed the ligand also, we could not observe the better yields with this palladium catalyst. The entry 13 and 14 demonstrated the use of base and solvent, in which, devoid of ligand observed 36% yield and exclusive of solvent gave 45% yield. With the advice of these studies in hand, we have utilized palladium catalyst, Pd(dppf)Cl 2 , tried the reaction with strong X-phos and S-phos ligands in the presence of THF-H 2 O solvent system. The reactions gave the noticeable yields at 40% and 45% (entry 16 and 17). A reaction with Pd(dppf)Cl 2 /CuI/ TEA showed noteworthy yield of 67% (entry 18), and no co-catalyst reaction gave the very lesser yield at 20% (entry 19, Scheme 2). The same protocol was employed to Pd(OAc) 2 and PdCl 2 (PPh 3 ) 2 and observed the attained moderate yields up to 49% and 52% respectively. Compared to Pd(OAc) 2 and PdCl 2 (PPh 3 ) 2, Pd(dppf)Cl 2 offered higher yield 67% of 4a. Entry 14 proved that the base TEA acts as solvent as well as base and ligand to carry out the reaction successfully. Amongst explored screenings, base plays a significant role in getting expected product, 4a with acceptable yield. Tertiary base activates the highly activated chlorides of the quinoline and it facilitates itself as ligand to access the product. The reaction was performed without copper catalyst and inspected the product generation. Copper activates the acetylene to the copper complex of acetylene. It is easily involved in the reaction with highly activated chlorides of quinolines and controls the homocoupling of the acetylenes. Generally, with tertiary bases like triethylamine, Sonogashira coupling reaction forms the side products of the homocouplings of the acetylenes. Surprisingly, in our experimental study we observed that the avoiding of side products. In our studies, the triethylamine played its role in the reaction to provide a good yield. According to our investigations Pd(dppf)Cl 2 /CuI/triethylamine system is an adapted system to get the expected final product. When we scan the reaction with 10 mol% of Pd catalyst and 5 mol% of co-catalyst CuI in triethylamine gave the product yield of 60% (Table 2 entry 1). Likewise when varied palladium catalyst from 7 mol% to 2 mol% with 5% co-catalyst, the reaction gave better yield 79% (Table 2 entry 3) with 5 mol% of Palladium catalyst and 5 mol% of co-catalyst.
Then attempted to get better yield by changing the mol% of co-catalyst 10% and 7% and recorded the yields 55% and 58% (Table 2 entry 6 & 7). These catalyst optimizations have accustomed the suitable reaction conditions with 5 mol% of Pd/Cu catalyst system in triethylamine.The amount of Pd catalyst when altered from 10 mol% to 7 mol%, the catalytic activity might be increased. Therefore, the reactions were attained the decreased yields as well as the lesser quantities of the Pd catalyst at 3 mol% and 2 mol% might not be enough the catalytic activity to acquire the product. While we optimized the co-catalyst with increment amounts of 10 mol% and 7 mol%, offered the reduced yields of 55% and 58% with constant amount of 5 mol% Pd catalyst. These investigations accomplish to us the utility of base, co-catalyst and catalyst is abundant to carry out the Aldol condensation followed by Michael addition and Sonogashira coupling reactions without further usage of any solvent and ligand. The 5 mol% of palladium and 5 mol% of copper in the presence of base triethylamine is the best condition in one pot manner without isolating the intermediates (Scheme 3, Table 2 entry 3).
The one pot methodology is found to be a suitable and best reaction condition to synthesize the highly 2-and 3-functionalized quinolines beneath mild reaction conditions. The synthesized 2-and 3-functionalized aldol/Michael/Sonogashira reaction products are shown in Table 3. The multicomponent one-pot domino reaction of 1a, and 2a was examined by monitoring the reaction progress through NMR analysis. The disappearance of an aldehyde proton and methyl ketone protons (proton NMR see supporting information), appearances of methine and methylene protons revealed the 1,5-dione formation. The characterization data (see supporting information) confirmed the structure of 4d.
diketone, (i). Copper activates the acetylene to the copper complex of acetylene which reacted with chlorides of quinolines and avoids the homocoupling of the acetylenes. 33 A Sonogashira reaction (ii) with 3a provided quinoline, 4a in highly regioselective.manner.
To achieve the C-2 vinyl, 3-functionalized quinolines, we explored the reactivity of the reaction with various alkenes such as methyl acrylate, ethyl acrylate, acrylamide, acrylic acid, and acrylonitrile. Firstly, the reaction was initiated with 2-chloro-3-formylquinoline, 1 (1 mmol) and 4-chloroacetophenone, 2 (2.5 mmol.), along with 1.2 mmol of the methyl acrylate as a substrate in the presence of 1,4-Dioxane via one-pot MCR approach, and NaOH used as a base (0.2 equi) in aldol-Michael reaction utilizing PdCl2(dppf) (5 mol%) heated for 5-6 h and observed traces of the expected Heck coupling product, 6. The 2-chloro-3-formylquinolines are very reactive substrates for regio-selective reactions toward nucleophilic addition due to its highly reactive formyl function at 3-position. As well, the 2-position is also a reactive center with unactivated chlorides for the cross-coupling reactions to provide the alkyl/alkenyl/alkynyl quinolines. However, the aldol-Michael product seen in good to high yields as characterized by NMR (See SI). But in proton NMR, it was confirmed the formation of the condensation-addition product, see Table 4.
Consequently, the reaction was examined with various allylic compounds such as acrylic acid, acrylamide, acrylonitrile, and ethyl acrylate, which did not proceed well. Further, the same reaction was then tried with different catalysts and bases under similar reaction conditions. The reaction with PdCl2(PPh3)2 catalyst and TEA (Triethylamine) as a base in dioxane gave the desired product in a trace amount of yield. However, the reaction intermediate 1,5-dione was formed in good to high yields. Subsequently, a variety of olefins from methyl acrylate to ethyl acrylate, acrylic acid, acrylamide, and acrylonitrile offered the polymeric compounds rather than expected products, see Table 4. A similar reaction condition indicates that the desired product formation is not observed with Pd(dba3). In Heck coupling reactions, it is well known that a base plays a significant role in accomplishing the desired product formation. For instance, NaOH was employed in the aldol-condensation-Michael addition while organic bases like TEA and Cy2NMe (N,N-Dicyclohexylmethylamine) used in the Heck arylation. Subsequently, with TEA, a trace amount of the product was observed (see Table 4, entry, 1, 3, 5) while using Cy2NMe provided a moderate yield of the desired product (entry 2, 4, 6) in palladium catalysis. To our notice, amid the other palladium catalysts, the cost-effective Pd(OAc)2 gave the desired product in noticeable quantity with both TEA (entry 7, 20%) and Cy2NMe (entry 8, 35%), respectively. Thus, the reaction protocol was shifted from the one-pot multi-component to a consecutive/sequential addition reaction without isolating the reaction intermediate from the reaction pot. Accordingly, the olefins such as methyl acrylate and acrylamide were explored to provide the desired product in a sequential one-pot approach while aliphatic olefins were not fruitful.
Besides, the parameters were modified, including the base, catalyst, solvent, and ligand to improve the efficiency of the reaction (Table 5). However, the one-pot multi-component sequential reaction (Aldol-Michael -Heck coupling) tried with catalysts like Pd(OAc)2, PdCl2(PPh3)2 or PdCl2(dppf)2 along with constant ligand (PPh3), base (TEA), and solvent (dioxane), under room temperature to mild 80 oC, and we clearly noticed that the formation of desired product 6a in lesser yields 15, 26, 19 & 23% (Table  5, entries 1, 2, 3, and 4). On the other hand, the above-mentioned substrates were tried with a combination of Pd2(dba)3/PPh3/TEA gave the moderate yield of the product about 57% (Table  5, entry 5). Further, we investigated the reaction by changing the combination of ligands and bases with catalysts for better reactivity and efficiency, and the results are shown in (Table 5, entry 6-10). We observed that, while using the combination of the Pd(OAc)2/PPh3/Cy2NMe in the presence of dioxane solvent for 6 h at 100 C, afforded the remarkable yield of the desired product (entry 6, 88%). The same reaction was explored with other palladium catalysts to produce better results and we tried with PdCl2(PPh3)2, PdCl2(dppf)2, and Pd(dba3) with different combinations of bases and ligand systems, and noticed that all the reactions yielded from moderate to good yields, as listed in Table 5 (entry 7-11). From our observation, we found that when Pd(OAc)2/PPh3 was used (entry 1, 2 and 6), together with bases TEA, Cy2NMe in the presences of toluene, and dioxane, identified that the reactions provided variant yields of the products. The reaction has produced a significant yield of 88% with base Cy2NMe in the presence of dioxane (entry 6). The same reaction has also explored with a combination of the Pd(OAc)2/dppf/ Cy2NMe in the presence of dioxane (entry 8, 64%) detected the moderate yield due to its lower catalytic activity toward unactivated quinolines at C2-position. While changed the system from Pd2(dba)3/PPh3/TEA to Pd2(dba)3/dppf/Cy2NMe, the reaction afforded 62% of yield (entry 11). The comprehensive study of the Pd(OAc)2 catalytic activity shows better than Pd2(dba)3 and also palladium acetate is cost-effective than Pd2(dba)3 comparatively. The rest of the catalysts also showed their poor catalytic activity toward desired product formation and yielded less to moderate in the presence of dioxane with base TEA, and Cy2NMe, ligand PPh3, and dppf (entry 7, 9, and 10). Then, the observed suitable reaction condition Pd(OAc)2/PPh3/Cy2NMe was optimized to various catalyst amounts for the best productivity of the reaction ( Table 6). In our studies, the appropriate amount of catalyst Pd(OAc)2 is 5 mol%, and PPh3 ligand is 5 mol% in 2 equivalents of base yielded 88% of the product ( Table 6, entry 3). As a result, we could find a suitable condition for better productivity of the Heck coupling product with a combination of catalyst system (Pd(OAc)2/PPh3/Cy2NMe/dioxane) as we discussed in our current context. The same reaction condition has also been carried out for the other examples and seen the remarkable outcome of the product ( Table 7). The acquired products were then characterized well with advanced spectral techniques similar to proton and carbon NMR, 2 D NMR (H-H COSY, H-C COSY, APT-13C NMR), HRMS, and UPLC (See supporting information, SI).
Coming to the scope of the reaction, amid the synthesized derivatives, the allylic alkenes did not give the products expectedly comparing with aryl alkenes. Whereas, the methyl acrylate, acrylamide, acrylonitrile afforded products 6j, 6k, and 6 l in fewer yields about to 45%, 40%, and 55%. In the case of aromatic i.e., styrene provided admirable yields. This is because of the ease of the reaction with Pd acetate catalyst and reaction conditions. Moreover, the styrene is a good electrophile toward the reactive center, and it can be activated easily by base and catalyst due to its electron-withdrawing nature of the phenyl group. Among the synthesized products, the electron-withdrawing and donating groups containing derivatives yielded in different amounts based on their order of reactivity. For instance, methyl and methoxy containing derivatives such as 6a, 6d, 6e, 6f, and 6i gave the yields at higher quantities, but in the case of chlorides 6 b, and 6k offered lesser yields, comparatively. Therefore, we explored the methyl and methoxy containing derivatives along with unsubstituted derivatives of aldehydes, ketones, and styrenes ( Table 4). The synthesized products may have the properties of LEDs and OLEDs, and also medicinal properties as they have the quinoline basic skeleton in their structures.
All the compounds were characterized by NMR and Mass spectrometry. The synthesized compounds confirmed as E-isomers from their vinyl protons coupling constant. The coupling constants appeared in the range of 15.

Mechanism of the reaction
A possible mechanistic pathway for the one-pot multiple-component reaction is shown in Scheme 4. Initially, aldol condensation between aldehyde, 1 and ketone 2 to give the Michael acceptor (chalcone intermediate-CI). In the next step, CI reacts with an excess of acetophenone, 2 in a NaOH assisted Michael addition . The intermediate, 1,5-dione, promptly would experience Heck coupling reaction with styrene, 5 to afford the final 2,3-functionalized quinoline, 6. In any case, accompanied by our exploration, the existence of traces of 1,5-dione and 2-alkenylquinoline aldehyde was not identified, suggesting that this protocol is a highly efficient and regioselective, suitable procedure. The Heck coupling is a familiar mechanism involving the steps like the olefin insertion, followed by oxidative addition with the metal complex. It forms the p-complex with substrate complex and olefin during the insertion process and turns to Pd r À intermediate. The b carbonhydrogen occurs by activating with a strong base and offers the product by reductive elimination by the base, Figure 2.

Experimental section
General procedure for aldol/Michael/sonogashira coupling, 4a-j One pot domino reaction was performed in glass vial. Initially 2-chloro-3-formylquinoline, 1a (1 equiv., 191 mg), acetophenone, 2a (2.5 equiv., 300 mg) in the presence of triethylamine (6 mL) along with phenylacetylene (1.2 equiv., 123 mg), 3 and Pd(dppf)Cl 2 (5 mol%, 36.58 mg), CuI (5 mol%, 9.52 mg) was stirred under parallel synthesizer at 80 C for 3 h. After disappearance of starting materials as monitored by TLC, the reaction mixture was dissolved in ethyl acetate (25 mL) and filtered off to remove any palladium catalysts. The filtrate was concentrated under reduced pressure and the residue was purified on a silica gel column using Pet. ether/ethyl acetate (9:1 v/v) as an eluent to get the desired product, 4.   A typical procedure for the sequential one-pot multi-component 2,3-functionalized quinoline heck coupling. A 60 mL sealed tube placed in an oil bath having a mixture of 2-Chloro-3-formylquinoline, 1a (1.0 mmol, 205 mg) and p-methoxyacetophenone (2.5 mmol, 1.636 g) in 10 mL of 1,4-Dioxane with 0.2 equi of NaOH, stirred at room temperature vigorously for 20-30 min. The reaction progress was checked by TLC and confirmed the formation of reaction intermediate 1,5dione, and this was purged with N2 gas to maintain the inert atmosphere in reaction pot. To this added Palladium(II)acetate catalyst (5 mol%, $12 mg), 2 equiv. of Cy2NMe (390 mg) followed by styrene, 5a (1.2 mmol, $61 mg) . The temperature was raised to 100 C and then maintained consistently for 5-6 h. The reaction was monitored by TLC and substantiated the product. After completion of the reaction, quenched with water and then the product was extracted with ethylacetate (15 mL X 3). Ethylacetate was concentrated under reduced pressure, and then the crude product was purified by column chromatography by using 100-200 mesh silica gel with 5% ethylacetate in petroleum ether. The pure product was isolated about 78% of 6a. 1,5-bis(4-methoxyphenyl)-3-(2styrylquinolin-3-yl)pentane-1,5-dione: The isolated pure product was characterized by 1H and 13 C NMR, HR-MS.

Conclusion
In summary, a three-component domino Aldol condensation, Michael addition and Sonogashira coupling reactions, has been established toward 1,5-diphenyl-3-(2-phenylethynyl)quinolin-3yl)pentane-1, 5-diones, 4. The reactions involved solvent and ligand free Pd(dppf)Cl 2 -CuI catalysis in the presence of triethylamine as a solvent as well as base. In addition, Heck coupling reactions has been accomplished utilizing Pd(OAc)2/PPh3/Cy2NMe in dioxane. Three C-C bonds formation alongside the Csp2-Csp2 coupling, is reported via solitary operation, with high catalytic activity utilizing palladium catalyst, ligand, and base combination. It is an efficient protocol in terms of high regioselectivities and yields.