Cobalt( II )-catalyzed remote C5-selective C – H sulfonylation of quinolines via insertion of sulfur dioxide †

A novel and simple method for C – H sulfonylation of quinolines based on an inexpensive cobalt catalyst via insertion of sulfur dioxide is established. Excellent selectivity in the C5-position of quinolines is observed. This transformation has no need of oxidant and additive, a ﬀ ording sulfonated products in moderate to good yields. Furthermore, aromatic amines can displace aryldiazonium tetra ﬂ uoroborates as original materials via the in situ diazotization. The results of control experiments indicate that a radical pathway is involved in this sulfonylation.


Introduction
Heterocyclic aromatic sulfones are signicant skeletons due to their extensive application in organic chemistry, 1 and pharmaceutical chemistry 2 as well as material chemistry. 3Hence, the development of procedures for sulfonylation has become increasingly signicant in synthetic methodology.Classic synthetic routes to sulfones are the oxidation of thioether and the Friedel-Cras reaction. 4Nevertheless, these typical reactions usually require harsh reaction conditions, including strong oxidants, strong acids and a high reaction temperature.
In recent decades, transition-metal-catalyzed C-H functionalization has become a novel and efficient strategy in the synthesis of various organic molecules. 5Especially, a series of synthetic methods have been exhibited for the preparation of sulfones by employing different substrates. 6In pioneering studies, Dong and co-workers disclosed a Pd(II)-catalyzed o-sulfonylation protocol which allowed the isolation of the o-sulfonylation products in good yields. 7As interesting as the former, Frost et al. developed Ru(II)-catalyzed sulfonylation of 2-phenylpyridines and obtained the m-sulfonylation product in considerable yield. 8or the past few years, owing to the special properties of quinolines, 9 a series of researches were pursued by utilizing quinolines as raw materials for the C-H functionalization. 10Especially, the C5-functionalization of quinolines has achieved much attention.Prior works from many groups were focused on copper-catalyzed C-H functionalization 11 or transition-metal-free oxidative coupling reaction with a stoichiometric amount of oxidants. 12But only a few examples were developed which employed iron, 13 cobalt 14 and nickel 15 as catalyst.
Additionally, Among C5-functionalization of quinolines, the C5-sulfonylation has been successively reported by choosing sulfonyl chloride, sulnates as well as sulfonhydrazide as the source of sulfonyl, respectively (Scheme 1, eqn (1)). 16Despite their utilities represent very inspiring progress, as mentioned above, almost all of them were catalyzed by copper catalyst.In addition, a stoichiometric amount of oxidants and additives were usually indispensable, not only increasing wastes, but also making this method inadaptable to large-scale synthesis.In recent years, the advance in the synthesis of sulfones via insertion of sulfur dioxide has been accomplished rapidly. 17,18Generally, the available DABCO$(SO 2 ) 2 and inorganic sulphites such as rongalite and potassium metabisulte were used as the source of sulfur dioxide rather than toxic gaseous sulfur dioxide in organic reactions.Very recently, Wu and coworkers reported a copper-catalyzed sulfonylative C-H bond functionalization of quinolines from DABCO$(SO 2 ) 2 and aryldiazonium tetrauoroborates.21l Currently, the eld of cobalt-catalyzed C-H functionalization has started to receive considerable attention due to its cheaper and more abundant characteristics. 19Herein, we report a cobalt(II)-catalyzed and convenient protocol for highly selective C5-sulfonylation of quinolines with DABCO$(SO 2 ) 2 and aryldiazonium salts to give the desired products in moderate to excellent yields under oxidant and additive free condition.

Results and discussion
Initially, the three-component reaction of N-(quinolin-8-yl) benzamide ( 1a), DABCO$(SO 2 ) 2 and p-tolyldiazonium tetra-uoroborate (2a) was selected as the model reaction for the development of the optimal reaction conditions.The desired C5-sulfonylated product (3a) was obtained in 49% yield by using CuI as catalyst in the presence of Na 2 CO 3 in DCE for 12 h under N 2 (Table 1, entry 1).Encouraged by this result, some metal catalysts including iron(III), iron(II), nickel(II), cobalt(II), copper(I) and copper(II) were studied (Table 1, entries 2-9), the yields of target product 3a was increased to 64% by using Co(acac) 2 as catalyst (Table 1, entry 10).No product was formed in the absence of any metal catalyst (Table 1, entry 11).Aer that, we also screened several additives (Table 1, entries 12 and 13).Curiously, the higher yield was got in the absence of any additive (Table 1, entry 14).No better results were gained in further variations in solvents, temperature and so forth (Table 1, entries 15-20).Actually, we also screened the reaction condition by using Cu(acac) 2 as a catalyst, the results were shown in ESI.† Aer getting the optimized reaction condition, we next explored the scope of sulfonylation reaction of 2 with N-(quinolin-8-yl)benzamide and DABCO$(SO 2 ) 2 (Table 2).Numbers of aryl diazonium salts with different substituent groups were investigated.Overall, all the substrates could transform into corresponding products smoothly.By contrast, the compatibility of electron-donating groups on aryldiazonium tetrauoroborates was better.Moreover, the molecular structure of product 3f was conrmed by X-ray crystallographic analysis.Product 3j was got in lower yield due to the steric-hindrance effect of 2,4,6-trimethylbenzene diazonium salt (Scheme 2).
Scheme 2 Sulfonylation of quinoline amides by using anilines as the starting materials.
Considering anilines are cheap and available materials, furthermore, the stability of aryldiazonium tetrauoroborates are poor, therefore, we then investigated the possibility by using aromatic amines as original materials via the in situ diazotization.Interestingly, this reaction took place smoothly, which afforded desired products in moderate yields.
Subsequently, we studied the application values of this reaction (Scheme 3).Gram-scale synthesis was carried out under standard conditions, and sulfonated product was isolated in 69% yield.Obviously, the productive rate was reduced when the scale of reaction was amplied.Then hydrolysis reaction was performed, and the C5-sulfonated 8-aminoquinoline was acquired in 89% yield.
Several control experiments were achieved in order to gain more deep understanding about the reaction mechanism.In the rst place, three analogues (1x-z) were employed as substrates under the standard conditions and no products were detected, this result revealed that a free NH of amides and N atom of quinoline were crucial blocks for the sulfonylation (Scheme 4, eqn (1)).Next, TEMPO (2,2,6,6-tetramethyl-1piperidinyloxy) and HQ (hydroquinone) were used as free radical inhibitor respectively, and the sulfonylation reaction was absolutely suppressed (Scheme 4, eqn (2)).Additionally, 32% yield of compound 7 was isolated when 1,1-diphenylethlene was utilized as trapping agent (Scheme 4, eqn (3)), declaring that a radical pathway was included.Finally, further test about kinetic isotope effects (KIE) gave a low ratio (k ¼ 1.0) (Scheme 4, eqn (4)), suggesting that the rate determining step was not the process of cleavage of C-H bond. 20ccording to the experiment conclusions and previous reports, [11][12][13][14][15][16][17]21 a plausible mechanism was proposed (Scheme 5). Iniially, complex A was produced via the combination of L n Co II (D) and substrate 1.In the meantime, the sulfonyl radical was formed through insertion of sulphur dioxide.17f Subsequently, sulfonyl radical attacked intermediate A to afford complex B. Aer the generation of complex C via dehydrogenation process, desired product 3 was obtained through single electron transfer (SET) between complex C and tertiary amine cation radical.

Conclusions
In conclusion, we have developed a cobalt(II)-catalyzed method for highly selective C5-sulfonylation of quinolines via insertion of sulfur dioxide under oxidant and additive free condition.This transformation proved a broad substrate scope and high efficiency.Furthermore, aromatic amines could displace aryldiazonium tetrauoroborates as original materials via the in situ diazotization.Eventually, a single electron transfer (SET) mechanism was presented aer verication of control experiments.

Table 2
Substrate scope of aryl diazonium salts with 1a a

Table 3
Substrate scope of quinoline amides with