An Unexpected Synthesis of 2-Sulfonylquinolines via Deoxygenative C2-Sulfonylation of Quinoline N-Oxides with Sulfonyl Chlorides

A mild, efficient and practical protocol for the preparation of 2-sulfonylquinolines through CS2/Et2NH-induced deoxygenative C2-H sulfonylation of quinoline N-oxides with readily available RSO2Cl was developed. The reaction proceeded well under transition-metal-free conditions and exhibited a wide substrate scope and functional group tolerance. The preliminary studies suggested that the nucleophilic sulfonyl sources were generated in situ via the reaction of CS2, Et2NH and sulfonyl chlorides.


Introduction
Quinolines are an important class of heterocyclic compounds that are widely present in natural products, medicine, functional materials and other fields [1][2][3][4][5][6].Among them, 2-sulfonylquinolines exhibit diverse biological activities and serve as important building blocks for complex molecules [7][8][9].Consequently, great efforts have been devoted to the synthesis of such compounds.

Results and Discussion
In our initial study, we speculated that diethylcarbamodithioic acid (Et2NCS2H) generated in situ through the reaction of CS2 and Et2NH could serve as a sulfur-containing nucleophilic reagent, which might further attack quinoline N-oxide at the C2 position in the presence of TsCl as an electrophilic activating reagent.With this in mind, a reaction of quinoline N-oxide (1a) and TsCl (2a) was carried out with 1.2 equivalents of carbon disulfide and 1.5 equivalents of diethylamine at room temperature for approximately 0.5 h using THF as the reaction solvent.Beyond our expectation, quinolin-2-yl diethylcarbamodithioate 3aa' was not detected in the reaction mixture, but 2-tosylquinoline 3aa was isolated in 55% yield (Table 1, entry 1).To further optimize the reaction conditions of this unexpected sulfonylation reaction, the influence of different solvents on the reaction was explored, among which dichloromethane was identified as the most effective solvent, producing product 3aa in 67% yield (entry 2), while other investigated solvents resulted in lower yields (entries 3-7).Among the amines tested, dimethylamine produced 3aa in 43% yield (entry 8), while diisopropylamine (entry 9), With our continuing interest in the deoxygenative C2-H functionalization of quinoline N-oxides [25,[55][56][57][58], herein, we report on an unexpected method for 2-sulfonylquinolines via CS 2 /Et 2 NH-promoted deoxygenative C2-sulfonylation of quinoline N-oxides with commercially available sulfonyl chlorides (Scheme 1c).In this reaction, sulfonyl chlorides act as both sulfonyl sources and electrophilic reagents utilized for activating quinoline N-oxides.

Results and Discussion
In our initial study, we speculated that diethylcarbamodithioic acid (Et 2 NCS 2 H) generated in situ through the reaction of CS 2 and Et 2 NH could serve as a sulfur-containing nucleophilic reagent, which might further attack quinoline N-oxide at the C2 position in the presence of TsCl as an electrophilic activating reagent.With this in mind, a reaction of quinoline N-oxide (1a) and TsCl (2a) was carried out with 1.2 equivalents of carbon disulfide and 1.5 equivalents of diethylamine at room temperature for approximately 0.5 h using THF as the reaction solvent.Beyond our expectation, quinolin-2-yl diethylcarbamodithioate 3aa' was not detected in the reaction mixture, but 2-tosylquinoline 3aa was isolated in 55% yield (Table 1, entry 1).To further optimize the reaction conditions of this unexpected sulfonylation reaction, the influence of different solvents on the reaction was explored, among which dichloromethane was identified as the most effective solvent, producing product 3aa in 67% yield (entry 2), while other investigated solvents resulted in lower yields (entries 3-7).Among the amines tested, dimethylamine produced 3aa in 43% yield (entry 8), while diisopropylamine (entry 9), morpholine (entry 10) and piperidine (entry 11) produced 3aa in only around 10% yields.Particularly, triethylamine was found to be unsuitable for the present transformation (entry 12).Increasing the amount of 2a did not significantly impact the yield of 3aa (entries 13 and 14).However, a decrease to 1.5 equivalents resulted in a 53% yield of 3aa (entry 15).Moreover, increasing the amount of diethylamine to 2 equivalents improved the yield of 3aa to 79% (entry 16), and further optimization by increasing the amount of carbon disulfide to 1.5 equivalents increased the yield to 84% (entry 17).Control experiments confirmed that the presence of carbon disulfide and secondary amine is essential for the formation of the sulfonylation products (entries 19 and 20).Particularly, triethylamine was found to be unsuitable for the present transformation (entry 12).Increasing the amount of 2a did not significantly impact the yield of 3aa (entries 13 and 14).However, a decrease to 1.5 equivalents resulted in a 53% yield of 3aa (entry 15).Moreover, increasing the amount of diethylamine to 2 equivalents improved the yield of 3aa to 79% (entry 16), and further optimization by increasing the amount of carbon disulfide to 1.5 equivalents increased the yield to 84% (entry 17).Control experiments confirmed that the presence of carbon disulfide and secondary amine is essential for the formation of the sulfonylation products (entries 19 and 20).After obtaining the optimal reaction conditions (Table 1, entry 17), we proceeded to investigate the substrate scope and limitations with respect to various heterocyclic N-oxides, as illustrated in Scheme 2. We found that a range of quinoline N-oxides were suitable for the current transformation and produced the corresponding products in 62%-84% yields (3aa−3pa).It is worth noting that some important functional groups, such as alkyl (3ba, 3da, 3fa, 3ka and 3oa), methoxy (3ga), F (3ha), Cl (3ca, 3ea, 3ia and 3la), Br (3ja and 3ma), and aryl (3pa) groups, at different positions on the quinoline rings were compatible with the reaction.In addition, tri-substituted quinoline N-oxide 1q also reacted well with TsCl and provided the expected product 3qa in 62% yield.However, isoquinoline N-oxide (3ra), quinoxaline N-oxide (3sa), pyrazine N-oxide (3ta) and several After obtaining the optimal reaction conditions (Table 1, entry 17), we proceeded to investigate the substrate scope and limitations with respect to various heterocyclic N-oxides, as illustrated in Scheme 2. We found that a range of quinoline N-oxides were suitable for the current transformation and produced the corresponding products in 62%-84% yields (3aa-3pa).It is worth noting that some important functional groups, such as alkyl (3ba, 3da, 3fa, 3ka and 3oa), methoxy (3ga), F (3ha), Cl (3ca, 3ea, 3ia and 3la), Br (3ja and 3ma), and aryl (3pa) groups, at different positions on the quinoline rings were compatible with the reaction.In addition, tri-substituted quinoline N-oxide 1q also reacted well with TsCl and provided the expected product 3qa in 62% yield.However, isoquinoline N-oxide (3ra), quinoxaline N-oxide (3sa), pyrazine N-oxide (3ta) and several substituted pyridine N-oxides (3ua-3wa) did not yield the desired products, which was likely due to their lower activities in contrast to quinoline N-oxides, which can be speculated from the belowmentioned possible mechanism that nucleophilic addition to a pyridine N-oxide would result in complete loss of aromaticity whereas with quinoline N-oxide, there would only be a partial loss of aromaticity.Interestingly, 4-phenylpyridine N-oxide as a potential substrate also produced the expected product 3xa in 51% yield.
Molecules 2022, 27, x FOR PEER REVIEW 4 of 14 substituted pyridine N-oxides (3ua-3wa) did not yield the desired products, which was likely due to their lower activities in contrast to quinoline N-oxides, which can be speculated from the below-mentioned possible mechanism that nucleophilic addition to a pyridine N-oxide would result in complete loss of aromaticity whereas with quinoline N-oxide, there would only be a partial loss of aromaticity.Interestingly, 4-phenylpyridine N-oxide as a potential substrate also produced the expected product 3xa in 51% yield.We then turned our attention to investigate the scope of sulfonyl chlorides, as shown in Scheme 3. We found that various aryl sulfonyl chlorides bearing electron-donating, electron-withdrawing or steric hindered functional groups at the different positions of the phenyl rings all reacted well with 1a to produce the corresponding products 3ab-3an in 63-84% yields.The reaction was compatible with a range of valuable substitutions, such as alkyl (3ai and 3am), methoxy (3ac), halogen atoms (3ad-3af, 3aj and 3an), acetyl (3ag) and trifluoromethoxy (3ah).In addition, di-substituted aryl sulfonyl chlorides were found efficient for the reaction and produced the desired products 3ak and 3al in 79 and 74% yields, respectively.To our delight, thiophene-2-sulfonyl chloride was also a suitable substrate to produce the target product 3ao in 62% yield.However, aliphatic sulfonyl We then turned our attention to investigate the scope of sulfonyl chlorides, as shown in Scheme 3. We found that various aryl sulfonyl chlorides bearing electron-donating, electron-withdrawing or steric hindered functional groups at the different positions of the phenyl rings all reacted well with 1a to produce the corresponding products 3ab-3an in 63-84% yields.The reaction was compatible with a range of valuable substitutions, such as alkyl (3ai and 3am), methoxy (3ac), halogen atoms (3ad-3af, 3aj and 3an), acetyl (3ag) and trifluoromethoxy (3ah).In addition, di-substituted aryl sulfonyl chlorides were found efficient for the reaction and produced the desired products 3ak and 3al in 79 and 74% yields, respectively.To our delight, thiophene-2-sulfonyl chloride was also a suitable substrate to produce the target product 3ao in 62% yield.However, aliphatic sulfonyl chlorides including methanesulfonyl chloride and trifluoromethanesulfonyl chloride failed to produce the corresponding products (3ap and 3aq), presumably owing to their relatively poor abilities for activating quinoline N-oxides compared with aryl sulfonyl chlorides.
chlorides including methanesulfonyl chloride and trifluoromethanesulfonyl chloride failed to produce the corresponding products (3ap and 3aq), presumably owing to their relatively poor abilities for activating quinoline N-oxides compared with aryl sulfonyl chlorides.To demonstrate the synthetic application of this method, a gram-scale experiment between quinoline N-oxide 1a (5 mmol, 0.7253 g) and TsCl 2a was carried out under standard conditions.As anticipated, the expected product 3aa was isolated in 81% yield (Scheme 4).To investigate the underlying reaction mechanism, a series of control experiments were conducted, as illustrated in Scheme 5. Initially, the reaction of quinoline 1a' and 2a under standard conditions failed to produce 3aa, highlighting the necessity of nitrogenoxygen groups for the reaction (Scheme 5a).Subsequently, the model reaction was carried out under standard conditions with the addition of TEMPO or BHT as the free radical inhibitors (Scheme 5b).The results indicated that the yields of product 3aa did not exhibit significant decreases, suggesting that the reaction may not proceed through a free radical pathway.Furthermore, the intermediate IM-1 was synthesized by reacting CS2 with diethylamine, followed by the addition of quinoline N-oxide 1a and To demonstrate the synthetic application of this method, a gram-scale experiment between quinoline N-oxide 1a (5 mmol, 0.7253 g) and TsCl 2a was carried out under standard conditions.As anticipated, the expected product 3aa was isolated in 81% yield (Scheme 4).
chlorides including methanesulfonyl chloride and trifluoromethanesulfonyl chloride failed to produce the corresponding products (3ap and 3aq), presumably owing to their relatively poor abilities for activating quinoline N-oxides compared with aryl sulfonyl chlorides.To demonstrate the synthetic application of this method, a gram-scale experiment between quinoline N-oxide 1a (5 mmol, 0.7253 g) and TsCl 2a was carried out under standard conditions.As anticipated, the expected product 3aa was isolated in 81% yield (Scheme 4).To investigate the underlying reaction mechanism, a series of control experiments were conducted, as illustrated in Scheme 5. Initially, the reaction of quinoline 1a' and 2a under standard conditions failed to produce 3aa, highlighting the necessity of nitrogenoxygen groups for the reaction (Scheme 5a).Subsequently, the model reaction was carried out under standard conditions with the addition of TEMPO or BHT as the free radical inhibitors (Scheme 5b).The results indicated that the yields of product 3aa did not exhibit significant decreases, suggesting that the reaction may not proceed through a free radical pathway.Furthermore, the intermediate IM-1 was synthesized by reacting CS2 with diethylamine, followed by the addition of quinoline N-oxide 1a and To investigate the underlying reaction mechanism, a series of control experiments were conducted, as illustrated in Scheme 5. Initially, the reaction of quinoline 1a' and 2a under standard conditions failed to produce 3aa, highlighting the necessity of nitrogenoxygen groups for the reaction (Scheme 5a).Subsequently, the model reaction was carried out under standard conditions with the addition of TEMPO or BHT as the free radical inhibitors (Scheme 5b).The results indicated that the yields of product 3aa did not exhibit significant decreases, suggesting that the reaction may not proceed through a free radical pathway.Furthermore, the intermediate IM-1 was synthesized by reacting CS 2 with diethylamine, followed by the addition of quinoline N-oxide 1a and p-toluenesulfonyl chloride 2a, resulting in a yield of 84% for 3aa.Meanwhile, compound 4a was also isolated and characterized by NMR (Scheme 5c,d).To investigate whether the formation of 4a necessitates the involvement of quinoline N-oxide, a three-component reaction involving CS 2 , diethylamine, and p-toluenesulfonyl chloride 2a was conducted, giving 4a in 83% yield at room temperature in DCM.It is hypothesized that key intermediate 5a may also be generated during the reaction (Scheme 5e).Next, compound 5a was synthesized using p-toluenesulfinic acid and diethylamine, and upon its reaction with quinoline N-oxide in the presence of p-toluenesulfonyl chloride, product 3aa was obtained in 85% yield (Scheme 5f,g), indicating that the in situ generated 5a could serve as the sulfonyl source in the current reaction.Finally, the model reaction was carried out in the absence of CS 2 and Et 2 NH (Scheme 5h), and the results showed that 3aa was not observed, which further demonstrated the necessity of CS 2 -Et 2 NH in the present reaction.
p-toluenesulfonyl chloride 2a, resulting in a yield of 84% for 3aa.Meanwhile, compound 4a was also isolated and characterized by NMR (Scheme 5c,d).To investigate whether the formation of 4a necessitates the involvement of quinoline N-oxide, a three-component reaction involving CS2, diethylamine, and p-toluenesulfonyl chloride 2a was conducted, giving 4a in 83% yield at room temperature in DCM.It is hypothesized that key intermediate 5a may also be generated during the reaction (Scheme 5e).Next, compound 5a was synthesized using p-toluenesulfinic acid and diethylamine, and upon its reaction with quinoline N-oxide in the presence of p-toluenesulfonyl chloride, product 3aa was obtained in 85% yield (Scheme 5f,g), indicating that the in situ generated 5a could serve as the sulfonyl source in the current reaction.Finally, the model reaction was carried out in the absence of CS2 and Et2NH (Scheme 5h), and the results showed that 3aa was not observed, which further demonstrated the necessity of CS2-Et2NH in the present reaction.

General Information
Unless otherwise noted, all solvents and reagents in this study were commercial and used without further purification. 1H, 13 C and 19 F NMR spectra were recorded at 400, 100 and 376 MHz, respectively (see Supplementary Materials).Chemical shifts were quoted in ppm relative to CDCl3 (δH = 7.26, δC = 77.0ppm).The data are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet, etc.The reactions were monitored by thin-layer chromatography (TLC) using GF254 silica gel-coated TLC plates.Mass spectra were performed on a spectrometer operating on ESI-TOF.Melting points were measured on a melting point apparatus and were uncorrected.

General Procedure for the Preparation of 2-Sulfonylquinolines 3
To a round-bottom flask were consecutively added quinoline N-oxide 1 (0.3 mmol), CS2 (0.45 mmol), diethylamine (0.6 mmol) and sulfonyl chloride 2 (0.6 mmol) in CH2Cl2 (3 mL).The reaction mixture was stirred at room temperature for about 15-30 min, which was monitored by TLC.Upon completion, CH2Cl2 (10 mL) and water (10 mL) were added to the mixture, the organic layer was separated and the aqueous layer was further extracted with CH2Cl2 (2 × 10 mL).The organic phases were combined and dried with anhydrous Na2SO4, followed by filtration and concentration under vacuo.The residue was purified by a flash chromatography column over silica gel to produce the desired product 3.

Gram-Scale Synthesis of 3aa
To a round-bottom flask were consecutively added quinoline N-oxides 1 (5 mmol, 0.7253 g), CS2 (7.5 mmol, 0.5696 g), diethylamine (10 mmol, 0.7309 g) and TsCl (10 mmol, 1.8999 g) in CH2Cl2 (50 mL).The reaction mixture was stirred at room temperature for about 0.5 h.Upon completion, water (30 mL) was added to quench the reaction.The organic layer was separated, and the aqueous layer was further extracted with CH2Cl2 (2 × 20 mL).The organic phases were combined and dried with anhydrous Na2SO4, followed by filtration and concentration under vacuo.The residue was purified by a flash chromatography column over silica gel to produce 1.1464 g of 3aa, yield: 81%.

Experimental Section 3.1. General Information
Unless otherwise noted, all solvents and reagents in this study were commercial and used without further purification. 1H, 13 C and 19 F NMR spectra were recorded at 400, 100 and 376 MHz, respectively (see Supplementary Materials).Chemical shifts were quoted in ppm relative to CDCl 3 (δ H = 7.26, δ C = 77.0ppm).The data are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet, etc.The reactions were monitored by thin-layer chromatography (TLC) using GF254 silica gelcoated TLC plates.Mass spectra were performed on a spectrometer operating on ESI-TOF.Melting points were measured on a melting point apparatus and were uncorrected.

General Procedure for the Preparation of 2-Sulfonylquinolines 3
To a round-bottom flask were consecutively added quinoline N-oxide 1 (0.3 mmol), CS 2 (0.45 mmol), diethylamine (0.6 mmol) and sulfonyl chloride 2 (0.6 mmol) in CH 2 Cl 2 (3 mL).The reaction mixture was stirred at room temperature for about 15-30 min, which was monitored by TLC.Upon completion, CH 2 Cl 2 (10 mL) and water (10 mL) were added to the mixture, the organic layer was separated and the aqueous layer was further extracted with CH 2 Cl 2 (2 × 10 mL).The organic phases were combined and dried with anhydrous Na 2 SO 4 , followed by filtration and concentration under vacuo.The residue was purified by a flash chromatography column over silica gel to produce the desired product 3.

Gram-Scale Synthesis of 3aa
To a round-bottom flask were consecutively added quinoline N-oxides 1 (5 mmol, 0.7253 g), CS 2 (7.5 mmol, 0.5696 g), diethylamine (10 mmol, 0.7309 g) and TsCl (10 mmol, 1.8999 g) in CH 2 Cl 2 (50 mL).The reaction mixture was stirred at room temperature for about 0.5 h.Upon completion, water (30 mL) was added to quench the reaction.The organic layer was separated, and the aqueous layer was further extracted with CH 2 Cl 2 (2 × 20 mL).The organic phases were combined and dried with anhydrous Na 2 SO 4 , followed by filtration and concentration under vacuo.The residue was purified by a flash chromatography column over silica gel to produce 1.1464 g of 3aa, yield: 81%.

Scheme 5 .Scheme 5 .Scheme 6 .
Scheme 5. Control experiments.Based on the above-mentioned control experiments and relevant reports in the literature [44,59], a possible reaction pathway was speculated, as shown in Scheme 6.First, a reaction between CS2 and Et2NH occurred and gave an intermediate IM-1, which further reacted with 2a to give IM-2.In the presence of IM-1, intermediate IM-2 was transformed to 4a with the release of a sulfonyl anion (Ts − ).Meanwhile, quinoline N-oxide 1a was activated by compound 2a to produce intermediate IM-3.Then, the resulting sul-

Table 1 .
Optimization of reaction conditions a .

Table 1 .
Optimization of reaction conditions a .