A New One-Pot Synthesis of Quinoline-2-carboxylates under Heterogeneous Conditions

Quinoline-2-carboxylates are an important subclass of quinoline derivatives largely present in a variety of biologically active molecules, as well as useful ligands in metal-catalyzed reactions. Herein, we present a new one-pot protocol for synthesizing this class of derivatives starting from β-nitroacrylates and 2-aminobenzaldehydes. In order to optimize the protocol, we investigated several reaction conditions, obtaining the best results using the 2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP) as solid base, in acetonitrile. Finally, we demonstrated the generality of our approach over several substrates which led to synthesize a plethora of functionalized quinolines-2-carboxylate derivatives in good overall yields.


Results and Discussion
In order to study the reaction, we first synthesized the starting materials (Scheme 3). 2-Aminobenzaldheydes were prepared from the corresponding alcohols or nitro precursors [28,29], while β-nitroacrylates were synthesized by the Henry reaction-elimination process, starting from nitroalkanes and alkyl glyoxalates [30,31]. Once the starting materials were prepared, we switched our attention to optimize the process. Thus, first we studied the "aza-Michael-Henry domino process" between 2-aminobenzaldheyde 1a and ethyl-3-nitropent-2-enoate 2a (Table 1). Based on our previous experiences, we started testing the reaction under promoter-free and solvent-free conditions and, after a series of trials, the best result Scheme 1. Main synthetic approaches for synthesizing quinoline-2-carboxylate derivatives.

Results and Discussion
In order to study the reaction, we first synthesized the starting materials (Scheme 3). 2-Aminobenzaldheydes were prepared from the corresponding alcohols or nitro precursors [28,29], while β-nitroacrylates were synthesized by the Henry reaction-elimination process, starting from nitroalkanes and alkyl glyoxalates [30,31]. Once the starting materials were prepared, we switched our attention to optimize the process. Thus, first we studied the "aza-Michael-Henry domino process" between 2-aminobenzaldheyde 1a and ethyl-3-nitropent-2-enoate 2a (Table 1). Based on our previous experiences, we started testing the reaction under promoter-free and solvent-free conditions and, after a series of trials, the best result Scheme 2. Synthetic approach for synthesizing quinoline-2-carboxylate derivatives 4.

Results and Discussion
In order to study the reaction, we first synthesized the starting materials (Scheme 3). 2-Aminobenzaldheydes were prepared from the corresponding alcohols or nitro precursors [28,29], while β-nitroacrylates were synthesized by the Henry reaction-elimination process, starting from nitroalkanes and alkyl glyoxalates [30,31].

Results and Discussion
In order to study the reaction, we first synthesized the starting materials (Scheme 3). 2-Aminobenzaldheydes were prepared from the corresponding alcohols or nitro precursors [28,29], while β-nitroacrylates were synthesized by the Henry reaction-elimination process, starting from nitroalkanes and alkyl glyoxalates [30,31]. Once the starting materials were prepared, we switched our attention to optimize the process. Thus, first we studied the "aza-Michael-Henry domino process" between 2-aminobenzaldheyde 1a and ethyl-3-nitropent-2-enoate 2a (Table 1). Based on our previous experiences, we started testing the reaction under promoter-free and solvent-free conditions and, after a series of trials, the best result Once the starting materials were prepared, we switched our attention to optimize the process. Thus, first we studied the "aza-Michael-Henry domino process" between 2-aminobenzaldheyde 1a and ethyl-3-nitropent-2-enoate 2a (Table 1). Based on our previous experiences, we started testing the reaction under promoter-free and solvent-free conditions and, after a series of trials, the best result was obtained using a slight excess of 2a (1.1 equivalent) at 70˝C (3aa, 66%, entry 7, the presence of solvents or bases makes the reaction unproductive entry 9-12). Yield of pure isolated product; 2 The reaction was performed in the presence of 1 eq. of TMG; 3 The reaction was performed in the presence of 1 eq. of Et3N.
Successively, we studied the conversion of 3aa into 4aa (Table 2) and, after deep screening in terms of bases, solvents and temperature, we found the best yield of 4aa (86%, entry 8) at 50 °C, in acetonitrile using 1.25 equivalents of BEMP on polymer [32]. At that point, in order to achieve a one-pot process, we combined the two steps obtaining the quinoline 4aa in 58% of overall yield (Scheme 4). Successively, we studied the conversion of 3aa into 4aa (Table 2) and, after deep screening in terms of bases, solvents and temperature, we found the best yield of 4aa (86%, entry 8) at 50˝C, in acetonitrile using 1.25 equivalents of BEMP on polymer [32]. Successively, we studied the conversion of 3aa into 4aa (Table 2) and, after deep screening in terms of bases, solvents and temperature, we found the best yield of 4aa (86%, entry 8) at 50 °C, in acetonitrile using 1.25 equivalents of BEMP on polymer [32]. At that point, in order to achieve a one-pot process, we combined the two steps obtaining the quinoline 4aa in 58% of overall yield (Scheme 4). At that point, in order to achieve a one-pot process, we combined the two steps obtaining the quinoline 4aa in 58% of overall yield (Scheme 4). Finally, with the aim to demonstrate the generality of our method, we tested our reaction conditions on a wide range of 2-aminobenzaldheydes 1 and β-nitroacrylates 2. In all cases, the products were obtained in moderate to good overall yields (37%-64%), even in the presence of a variety of functionalities (Scheme 5). Scheme 5. One-pot reaction products.

Conclusions
In conclusion, we developed a new general and valuable one-pot procedure for synthesizing an important class of quinolines such as quinoline-2-carboxylates. In our approach, it was possible to prepare title compounds in good overall yields, introducing different substituent in 3-position as well as in the benzene ring. Furthermore, the mildness of our reaction conditions allowed preserving several functionalities such as ester, cyano, chlorine, fluorine and carbon-carbon double bond. In addition, the use of supported BEMP enabled us to minimize the use of materials, avoiding any complex aqueous work-up, with evident advantages from a sustainable point of view. Finally, we still demonstrated the usefulness of β-nitroacrylates as a valuable precursor of heterocyclic systems. Finally, with the aim to demonstrate the generality of our method, we tested our reaction conditions on a wide range of 2-aminobenzaldheydes 1 and β-nitroacrylates 2. In all cases, the products were obtained in moderate to good overall yields (37%-64%), even in the presence of a variety of functionalities (Scheme 5). Finally, with the aim to demonstrate the generality of our method, we tested our reaction conditions on a wide range of 2-aminobenzaldheydes 1 and β-nitroacrylates 2. In all cases, the products were obtained in moderate to good overall yields (37%-64%), even in the presence of a variety of functionalities (Scheme 5). Scheme 5. One-pot reaction products.

Conclusions
In conclusion, we developed a new general and valuable one-pot procedure for synthesizing an important class of quinolines such as quinoline-2-carboxylates. In our approach, it was possible to prepare title compounds in good overall yields, introducing different substituent in 3-position as well as in the benzene ring. Furthermore, the mildness of our reaction conditions allowed preserving several functionalities such as ester, cyano, chlorine, fluorine and carbon-carbon double bond. In addition, the use of supported BEMP enabled us to minimize the use of materials, avoiding any complex aqueous work-up, with evident advantages from a sustainable point of view. Finally, we still demonstrated the usefulness of β-nitroacrylates as a valuable precursor of heterocyclic systems. Scheme 5. One-pot reaction products.

Conclusions
In conclusion, we developed a new general and valuable one-pot procedure for synthesizing an important class of quinolines such as quinoline-2-carboxylates. In our approach, it was possible to prepare title compounds in good overall yields, introducing different substituent in 3-position as well as in the benzene ring. Furthermore, the mildness of our reaction conditions allowed preserving several functionalities such as ester, cyano, chlorine, fluorine and carbon-carbon double bond. In addition, the use of supported BEMP enabled us to minimize the use of materials, avoiding any complex aqueous work-up, with evident advantages from a sustainable point of view. Finally, we still demonstrated the usefulness of β-nitroacrylates as a valuable precursor of heterocyclic systems.

General Section
1 H-NMR were recorded at 400 MHz on a VarianMercury Plus 400. 13 C-NMR were recorded at 100 MHz. IR spectra were recorded with a PerkineElmer Paragon 500 FT-IR. Mass spectra were performed on a GC/MS system by means of the EI technique (70 eV). Microanalyses were performed with a CHNS-O analyzer Model EA 1108 from Fisons Instruments.

Chemistry Section
General Procedure for the Preparation of Compounds 4 A mixture of 2-aminobenzaldheydes 1 (1 mmol) and β-nitroacrylates 2 (1.1 mmol) was stirred, under solvent-free conditions, at 70˝C for 18 h. Then, after that the temperature was diminished at 50˝C, acetonitrile (10 mL) and PS-BEMP (1.25 mmol, 0.570 mg) were added, and the resulting solution was stirred at 50˝C for further 24 h. Finally, the resin was filtered off washing with fresh EtOAc (10 mL) and the crude products 4, obtained after removal of the solvent at reduced pressure, were purified by flash chromatography column (hexane-ethyl acetate 9:1).