Green One-Pot Syntheses of 2-Sulfoximidoyl-3,6-dibromo Indoles Using N-Br Sulfoximines as Both Brominating and Sulfoximinating Reagents

A green one-pot 2,3,6-trifunctionalization of N-alkyl/aryl indoles was achieved by adding three equivalents of N-Br sulfoximine to the indole solution. A variety of 2-sulfoximidoyl-3,6-dibromo indoles were prepared with 38–94% yields using N-Br sulfoximines as both brominating and sulfoximinating reagents. Based on the results of controlled experiments, we propose that a radical substitution involving 3,6-dibromination and 2-sulfoximination occurs in the reaction process. This is first time that 2,3,6-trifunctionalization of indole in one pot has been achieved.


Introduction
The indole moiety is always attractive because of its existence in a wide range of natural products and bioactive compounds as core structures [1][2][3][4][5][6]. Hence, the development of simple and green methods for the synthesis of multisubstituted indole derivatives is an important research area. Sulfoximine derivatives, a class of sulfur-containing compounds, have attracted considerable interest for their diverse applications in organic synthesis as building blocks [7,8], in asymmetric catalysis as ligands and chiral auxiliary [9][10][11] and in pharmacology as bioactive components [12][13][14]. A simple combination of indoles and sulfoximine maybe enable the facile synthesis of a series of potentially bioactive sulfoximidoyl indoles. The successful development of the new protocol will facilitate relative research based on sulfoximines and indoles. Normally, the direct functionalization, especially multifunctionalization, of indoles via C-H activation is an atom-and step-economical approach to expand the library of indoles [15][16][17][18][19][20][21][22][23][24][25][26]. Compared to the wildly known C2-and C3-functionalization of indoles [15][16][17][18][19][20][21], the practicality of transformation on other positions is decreased and more difficult. Due to the significant advances in the development of synthetic methodologies, various dual-functionalization strategies of indoles have been developed to introduce two functional groups at the common C2 and C3 positions of the indole core simultaneously [27][28][29][30][31][32]. Among them, effective one-step dehydrogenative aminohalogenation of indoles is always a research hotspot because of the further application of aminohalogenated indoles in the fields of organic synthesis and biology. Despite several excellent works having been reported in the last decade (Scheme 1) [33][34][35][36][37][38], the field of dehydrogenative aminohalogenation of indoles remains largely unexplored. The above studies, pioneering aminohalogenation of indoles, have included the aminohalogenation of N-R indoles using sulfonamides and its derivatives as aminating reagents [33,35,36], the copper-catalyzed aminobromination of indoles using CuBr as brominating reagent aminohalogenation of N-R indoles using sulfonamides and its derivatives as aminating reagents [33,35,36], the copper-catalyzed aminobromination of indoles using CuBr as brominating reagent and active N-Br diphenylmethanimine as aminating reagent [34], the electrochemical aminoiodination of indoles using unactivated secondary amines [38]. Inspired by such dehydrogenative aminohalogenation of indoles, sulfoximines as a special aminating reagent entered our field of vision. As is known, due to our long-term research focus [39][40][41][42], the radical addition of olefins using N-X sulfoximines [43], and the curiosity about sulfoximine indoles, we wondered whether the active N-Br sulfoximines could be used as the aminating reagent or both brominating and aminating reagents to achieve the aminobromination of indoles. Fortunately, this was achieved, and 2,3,6-trifunctionalized indole derivatives were afforded accidentally in one step for the first time in the absence of any transition metal or additional additives (Scheme 1). Due to its step and atom economy, novelty, simplicity and practicality, this novel trifunctionalization of indoles represents important progress towards functionalized indoles.

Optimization
At the beginning of our investigation, the 5 mol% CuBr-catalyzed sulfoximidoylbromination of 1-methylindole (1a) using N-Br methyl phenyl sulfoximine (2a) as both brominating and aminating reagents was attempted in the presence of KOAc at room temperature (entry 1, Table S1). To our delight, the desired dual-functionalized product 4a was obtained with 29% yield as expected. However, the yield could not be improved more than 29% by varying copper salts, the amount of catalyst, temperature, or reaction time during further optimization (entries 2-10, Table S1). In the reaction process, the N-Br methyl phenyl sulfoximine (2a) was found to be consumed quickly. As such, the amount of N-Br methyl phenyl sulfoximine (2a) was evaluated, the trifunctionalized product 3aa was obtained suddenly with higher 76% isolated yield when the amount of 2a was increased threefold (entries 11-17, Table S1). According to the above results, the catalyst and base Scheme 1. (1) The reported aminohologenation of indoles by using different aminating reagent [33][34][35][36]38]; (2) The green one-pot 2,3,6-trifunctinalization of indoles by using N-Br sulfoximines as both of brominating and aminating reagents.

Optimization
At the beginning of our investigation, the 5 mol% CuBr-catalyzed sulfoximidoylbromination of 1-methylindole (1a) using N-Br methyl phenyl sulfoximine (2a) as both brominating and aminating reagents was attempted in the presence of KOAc at room temperature (entry 1, Table S1). To our delight, the desired dual-functionalized product 4a was obtained with 29% yield as expected. However, the yield could not be improved more than 29% by varying copper salts, the amount of catalyst, temperature, or reaction time during further optimization (entries 2-10, Table S1). In the reaction process, the N-Br methyl phenyl sulfoximine (2a) was found to be consumed quickly. As such, the amount of N-Br methyl phenyl sulfoximine (2a) was evaluated, the trifunctionalized product 3aa was obtained suddenly with higher 76% isolated yield when the amount of 2a was increased threefold (entries 11-17, Table S1). According to the above results, the catalyst and base seem to have little effect on the reaction compared to the amount of 2a. Therefore, the reactions were tried in the absence of copper salts or cooperation of copper salts and KOAc, and 3aa was produced with excellent 90% or 88% yield, respectively (entries 18-19, Table S1). The model reaction with 1 equiv. 1-methylindole (1a) and 3 equiv. N-Br methyl phenyl sulfoximine (2a) in the absence of transition metal and base was reset ( Table 1). The desired trifunctionalized product 3aa gave an excellent 94% isolated yield (entry 3, Table 1). Then, versatile solvents were evaluated in this simple protocol, and the desired product 3aa was afforded by all test solvents, except toluene, in 28-80% yields (Entries 4-8, Table 1). The lowest 28% yield was given by the protic solvent EtOH, and the cyclic ether solvents THF and 1,4-dioxane gave good 80% and 72% yields, respectively. The compound 3aa was also generated in moderate 64% yield using DCE as solvent. Finally, the optimum conditions of 2,3,6-trifunctionalization of indoles was chosen as 3 equiv. N-Br sulfoximines added to a solution of 1 equiv. indole derivatives (0.4 mmol) in 2 mL MeCN (entry 3, Table 1) with further stirring for 5 min at room temperature. seem to have little effect on the reaction compared to the amount of 2a. Therefore, the reactions were tried in the absence of copper salts or cooperation of copper salts and KOAc, and 3aa was produced with excellent 90% or 88% yield, respectively (entries 18-19, Table  S1). The model reaction with 1 equiv. 1-methylindole (1a) and 3 equiv. N-Br methyl phenyl sulfoximine (2a) in the absence of transition metal and base was reset ( Table 1). The desired trifunctionalized product 3aa gave an excellent 94% isolated yield (entry 3, Table 1). Then, versatile solvents were evaluated in this simple protocol, and the desired product 3aa was afforded by all test solvents, except toluene, in 28-80% yields (Entries 4-8, Table  1). The lowest 28% yield was given by the protic solvent EtOH, and the cyclic ether solvents THF and 1,4-dioxane gave good 80% and 72% yields, respectively. The compound 3aa was also generated in moderate 64% yield using DCE as solvent. Finally, the optimum conditions of 2,3,6-trifunctionalization of indoles was chosen as 3 equiv. N-Br sulfoximines added to a solution of 1 equiv. indole derivatives (0.4 mmol) in 2 mL MeCN (entry 3, Table 1) with further stirring for 5 min at room temperature.

Extending the Scope of Indole Substrates
The substrate scope of indole derivatives was investigated in this new oxidative dibromo sulfoximination of N-R (R = alkyl or aryl) indoles using N-Br methyl phenyl sulfoximine as both of brominating and sulfoximinating reagents, and a series of corresponding 3,6-dibrom-2-sulfoximidoyl indoles were afforded in 38-94% yields under the optimal reaction conditions. The details of reaction were shown in Scheme 2. According to the results, the N-alkyl indoles including chain alkyl and benzyl groups have been investigated here, and all of them afforded the corresponding 2-sulfoximidoyl-3,6-dibromo indole derivatives 3aa-g in 62-94% yields. The lower yield was given by the indoles which has longer protecting alkyl chain of N atom. So the corresponding product 3aa was given in the best 94% yield by the N-CH3 indole, and N-octyl indole gave the product 3ad in worst 62% yield. The steric N-isopropyl indole was also performed smoothly in this new protocol to lead to compound 3af in good 89% yield, and the high yield showed the steric hindrance of N-protecting groups was affected this trifunctionalization of indole rarely. Furthermore, the N-benzyl indole which has an active methylene group was evaluated in this simple protocol and led to the product 3ag in good 81% yield. Besides different Nalkyl indoles, several N-aryl indoles have also been attempted as indole substrates here, and the desired products 3ah-j have been obtained as expectant in 38-77% yields. Among

Extending the Scope of Indole Substrates
The substrate scope of indole derivatives was investigated in this new oxidative dibromo sulfoximination of N-R (R = alkyl or aryl) indoles using N-Br methyl phenyl sulfoximine as both of brominating and sulfoximinating reagents, and a series of corresponding 3,6-dibrom-2-sulfoximidoyl indoles were afforded in 38-94% yields under the optimal reaction conditions. The details of reaction were shown in Scheme 2. According to the results, the N-alkyl indoles including chain alkyl and benzyl groups have been investigated here, and all of them afforded the corresponding 2-sulfoximidoyl-3,6-dibromo indole derivatives 3aa-g in 62-94% yields. The lower yield was given by the indoles which has longer protecting alkyl chain of N atom. So the corresponding product 3aa was given in the best 94% yield by the N-CH 3 indole, and N-octyl indole gave the product 3ad in worst 62% yield. The steric N-isopropyl indole was also performed smoothly in this new protocol to lead to compound 3af in good 89% yield, and the high yield showed the steric hindrance of N-protecting groups was affected this trifunctionalization of indole rarely. Furthermore, the N-benzyl indole which has an active methylene group was evaluated in this simple protocol and led to the product 3ag in good 81% yield. Besides different Nalkyl indoles, several N-aryl indoles have also been attempted as indole substrates here, and the desired products 3ah-j have been obtained as expectant in 38-77% yields. Among them, the best yield was given by the N-(2-isopropylphenyl) indole (3ai, 77%) which contained a big 2-isopropylphenyl as protecting group of N atom. Compared to the N-(2-isopropylphenyl) indole, the N-phenyl indole and N-naphthyl indole gave corresponding products 3ah and 3aj in decreased yields 38% and 57% yields respectively. Moreover, several substituted N-methyl indoles have been evaluated in this new transformation, too. When the 4-or 7-position of N-methyl indole was occupied by electron-donating methyl group, the corresponding products 3ak and 3al were given in good 81% and excellent 94% yields, respectively. Compared to the N-methyl indole, the 7-methyl group of N-methyl indole showed no obvious effect on the yield, and the 4-methyl group would make the yield slight decreased to 81%. When the 4-position of N-methyl indole was substituted by halogen Cl or Br, the reaction yields of the corresponding products 3am and 3an were decreased to 63% and 46%, respectively.
Molecules 2023, 28, x FOR PEER REVIEW 4 of 14 them, the best yield was given by the N-(2-isopropylphenyl) indole (3ai, 77%) which contained a big 2-isopropylphenyl as protecting group of N atom. Compared to the N-(2isopropylphenyl) indole, the N-phenyl indole and N-naphthyl indole gave corresponding products 3ah and 3aj in decreased yields 38% and 57% yields respectively. Moreover, several substituted N-methyl indoles have been evaluated in this new transformation, too. When the 4-or 7-position of N-methyl indole was occupied by electron-donating methyl group, the corresponding products 3ak and 3al were given in good 81% and excellent 94% yields, respectively. Compared to the N-methyl indole, the 7-methyl group of N-methyl indole showed no obvious effect on the yield, and the 4-methyl group would make the yield slight decreased to 81%. When the 4-position of N-methyl indole was substituted by halogen Cl or Br, the reaction yields of the corresponding products 3am and 3an were decreased to 63% and 46%, respectively.

Extending the Scope of N-Br Sulfoximines Substrates
Subsequently, various N-Br sulfoximines have been implemented into this new trifunctionalization of N-methyl indoles as both of brominating and sulfoximinating reagents to evaluate the effect of different R 1 or R 2 group of N-Br sulfoximines (Scheme 3). First, versatile N-Br substituted phenyl methyl sulfoximines have been investigate into the dibromosulfoximination of N-methyl indole and all of them led to desired products 3ba-3bi smoothly in good-excellent yields (66-94%). For different N-Br para-substituted phenyl methyl sulfoximines, the electron-deficient substituents on the benzene ring led to decreased yields. Among them, the worst yield (3be, 66%) was given by the N-Br para-NO 2 phenyl methyl sulfoximines, and the highest yield (3ba, 94%) was given by the para-CH 3 phenyl methyl sulfoximines. When the N-Br para-halogenated phenyl methyl sulfoximines were investigated as substrate in this new protocol, all of them performed very well in the reaction, and the corresponding products 3bb-d were given in good-excellent 85-91% yields because of the electron withdrawal of halogen on the benzene ring. Compared to the N-Br para-bromo/chlorophenyl methyl sulfoximines, similar N-Br meta-bromo/cholorophenyl methyl sulfoximines were also achieved smoothly in this protocol and afforded corresponding products 3bf and 3bg smoothly in slightly lower 77% and 86% yields, respectively. Meanwhile, the 2-sulfoximidoyl-3,6-dibromo indoles 3bh and 3bi were obtained in good 85% and 89% yields using N-Br ortho-Bromo/cholorphenyl methyl sulfoximines as aminohalogenated substrates. The results of all tested N-Br halogenated phenyl methyl sulfoximines showed the electronic and steric effect has little influence in the yields. Subsequently, we varied the substituents of N-Br phenyl sulfoximines from steric isopropyl chain n-butyl to phenyl to evaluate the effect of substituent: the N-Br diphenyl sulfoximines led to the corresponding product 3bl in a similar 91% yield to N-Br phenyl methyl sulfoximines, and the steric N-Br isopropyl phenyl sulfoximine produced the compound 3bj in the lowest 74% yield. The N-Br n-butyl phenyl sulfoximine performed very well here and afforded the product 3bk in lower 81% yield compared to N-Br methyl phenyl sulfoximine. Besides N-Br phenyl sulfoximines, N-Br di-n-butyl sulfoximine also worked in this protocol and led to product 3bm in 77% yield.

Control Reactions
Due to the important synthetic significance and potential application of this useful new methodology, the mechanism was studied. The control reactions were assessed, and the results are shown in Scheme 4. Based on similar reported procedures [35,36,38], a radical process was proposed to have occurred, so 1.0 equiv. radical scavengers Tempo or BHT were added to the reaction mixture and led to the corresponding product 3aa in trace

Control Reactions
Due to the important synthetic significance and potential application of this useful new methodology, the mechanism was studied. The control reactions were assessed, and the results are shown in Scheme 4. Based on similar reported procedures [35,36,38], a radical process was proposed to have occurred, so 1.0 equiv. radical scavengers Tempo or BHT were added to the reaction mixture and led to the corresponding product 3aa in trace yield or low 29% yield from 94% yield as expected. Most of the starting materials were left in the reaction mixture. Combining the results in the optimization, we found only 2,3-disubstituted indole was given when the amount of N-Br sulfoximines was less than 1.5 equivalent, and the 2,3,6-trisubstituted product would be increased gradually with the increased N-Br sulfoximines, so the final step must be the radical substitution at the six-position of indoles. The radical 3,6-dibromo-2-sulfoximination of N-R (R = alkyl and Ar) indoles was proved in this new protocol.

Chemistry
All solvents were obtained from commercial sources and used without further purification unless otherwise noted. The N-bromosulfoximines were prepared according to literature protocols [44,45]. All N-protected indoles were prepared according to literature protocols [46,47]. Other chemicals were obtained from Energy Chemical and Titan. 1 H and 13 C NMR spectra were recorded on a Bruker DRX-400 spectrometer using CDCl3 or DMSO-d6 as solvent and TMS as an internal standard. Mass spectra (API) were tested on an Agilent 6100 using liquid chromatography-mass spectrometry. Single-crystal X-ray diffraction was conducted in the X-Ray and Spectral Center at Huazhong University of Science and Technology, Wuhan, China.

General Procedure (GP) for the Preparation of Products 3
N-bromosulfoximine 2 (1.2 mmol, 3 equiv.) was added to the solution of N-protected indole 1 (0.4 mmol) in MeCN (2 mL) in a 15 mL dry pressure tube equipped with a stirring bar. The reaction mixture was stirred at room temperature for another 5 min at room temperature. Then, the organic layer of the reaction mixture was removed under reduced pressure and the residue purified by column chromatography on a neutral alumina column using a mixture of petroleum ether and ethyl acetate as eluent to afford product 3.

Chemistry
All solvents were obtained from commercial sources and used without further purification unless otherwise noted. The N-bromosulfoximines were prepared according to literature protocols [44,45]. All N-protected indoles were prepared according to literature protocols [46,47]. Other chemicals were obtained from Energy Chemical and Titan. 1 H and 13 C NMR spectra were recorded on a Bruker DRX-400 spectrometer using CDCl 3 or DMSO-d 6 as solvent and TMS as an internal standard. Mass spectra (API) were tested on an Agilent 6100 using liquid chromatography-mass spectrometry. Single-crystal X-ray diffraction was conducted in the X-ray and Spectral Center at Huazhong University of Science and Technology, Wuhan, China.
General Procedure (GP) for the Preparation of Products 3 N-bromosulfoximine 2 (1.2 mmol, 3 equiv.) was added to the solution of N-protected indole 1 (0.4 mmol) in MeCN (2 mL) in a 15 mL dry pressure tube equipped with a stirring bar. The reaction mixture was stirred at room temperature for another 5 min at room temperature. Then, the organic layer of the reaction mixture was removed under reduced pressure and the residue purified by column chromatography on a neutral alumina column using a mixture of petroleum ether and ethyl acetate as eluent to afford product 3.

Conclusions
In conclusion, a green 3,6-dibromo-2-sulfoximination of N-R (R = alkyl, benzyl and aryl) indoles using N-Br sulfoximines as both brominating and sulfoximinating reagents was developed, and a total of 27 products were prepared in 38-94% yields. This protocol introduces two bromo and one sulfoximidoyl group on indole moiety with absolute atom and step economy by stirring the reaction mixture for 5 min in CH 3 CN at room temperature. This method is compatible with a wide range of substrates and affords most of the products in >60% yields. It also adheres to the principles of green chemistry. A range of potential bioactive sulfoximidoyl indoles with two good-leaving-group Br was prepared via this novel trifunctionalization of indoles in good to excellent yields. According to the control reactions, this is a radical bromosulfoximidoyl process involving Br radical and sulfoximidoyl radical generated by N-Br sulfoximine in the presence of N-R (R = alkyl, benzyl or aryl) indoles. This new green synthesis of N-methyl-3,6-dibromo-2-sulfoximidoyl indoles will facilitate the understanding of transition-metal-free trifunctionalization of indoles and the development of research based on sulfoximidoyl indoles. Additionally, the successful application of N-X sulfoximines as both sulfoximinating and halogenating reagents would further promote the development of sulfoximination and halogenation. Organic syntheses or biochemistry based on indoles or sulfoximines will be greatly developed. In the near future, we will test the bioactivity of this new sulfoximidoyl indoles as pesticide, silkworm medicine, and medicine. We will also continue to expand the library of sulfoximidoyl indoles through the functionalization of the 3-or 6-position C-Br bond.

Patents
One Chinese invention patent (CN113121403B) resulting from this work is reported in this manuscript [48].
Supplementary Materials: The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/molecules28083380/s1, including general procedure (GP) for the preparation of N-bromosulfoximines, general procedure (GP) for the preparation of N-aryl indole, general procedure (GP) for the preparation of N-alkyl indole, general procedure (GP) for the preparation of various N-methyl indole and additional optimization (Table S1. Characterization data of substrates, X-ray crystallography of product 3be, and 1 H and 13 C NMR spectra of substrates and products 3); Table S1: The additional optimization of bromosulfoximidation of N-Me indole; Table S2: Crystal data and structure refinement; References [49][50][51] are cited in the supplementary materials.