Condensation of 4-Tert-butyl-2,6-dimethylbenzenesulfonamide with Glyoxal and Reaction Features: A New Process for Symmetric and Asymmetric Aromatic Sulfones

The synthesis of substituted aza- and oxaazaisowurtzitanes via direct condensation is challenging. The selection of starting ammonia derivatives is very limited. The important step in developing alternative synthetic routes to these compounds is a detailed study on their formation process. Here, we explored an acid-catalyzed condensation between 4-tert-butyl-2,6-dimethylbenzenesulfonamide and glyoxal in aqueous H2SO4, aqueous acetonitrile and acetone, and established some new processes hindering the condensation. In particular, an irreversible rearrangement of the condensation intermediate was found to proceed and be accompanied by the 1,2-hydride shift and by the formation of symmetric disulfanes and sulfanes. It has been shown for the first time that aldehydes may act as a reducing agent when disulfanes are generated from aromatic sulfonamides, as is experimentally proved. The condensation between 4-tert-butyl-2,6-dimethylbenzenesulfonamide and formaldehyde resulted in 1,3,5-tris((4-(tert-butyl)-2,6-dimethylphenyl)sulfonyl)-1,3,5-triazinane. It was examined if diimine could be synthesized from 4-tert-butyl-2,6-dimethylbenzenesulfonamide and glyoxal by the most common synthetic procedures for structurally similar imines. It has been discovered for the first time that the Friedel–Crafts reaction takes place between sulfonamide and the aromatic compound. A new synthetic strategy has been suggested herein that can reduce the stages in the synthesis of in-demand organic compounds of symmetric and asymmetric aromatic sulfones via the Brønsted acid-catalyzed Friedel–Crafts reaction, starting from aromatic sulfonamides and arenes activated towards an electrophilic attack.

The important milestone in advancing the chemistry of high-energy materials is the discovery of caged nitramines such as N-polynitro-substituted aza-and oxaazaisowurtzitanes. Transiting from the cyclic to the strained cage structure allows the energy-mass characteristics of these compounds to be enhanced considerably.
Since the discovery of N-polynitro-substituted aza-and oxaazaisowurtzitanes in the mid-80s and to present, the synthetic technologies for these compounds have been developed and upgraded worldwide; however, their production cost remains high so far, limiting their use for large-scale applications.
The most promising and cost-effective synthetic method towards N-polynitro-substituted aza-and oxaazaisowurtzitanes is the direct condensation between ammonia derivatives and glyoxal, followed by the exhaustive nitration of the resulting aza-and oxaazaisowurtzitanes.
At this point, the formation mechanism of the hexaazaisowurtzitane cage is underexplored. In the overwhelming majority of cases, the hexaazaisowurtzitane cage originates from the condensation of ammonia derivatives containing an aromatic moiety or a multiple bond linked to the amino group via the methylene bridge [7,38,39]. The reasons behind it having such a high selectivity towards the structure of ammonia derivatives are unknown. There is, therefore, no doubt that the most important step in designing alternative synthetic routes to N-polynitro-substituted aza-and oxaazaisowurtzitanes is an in-depth study into that process in order to identify new formation mechanisms towards aza-and oxaazaisowurtzitane cages, in particular, the structure-property relationship for the starting ammonia derivatives and their capability of being condensed with glyoxal to furnish hexaazaisowurtzitane derivatives.
Since the discovery of N-polynitro-substituted aza-and oxaazaisowurtzitanes in the mid-80s and to present, the synthetic technologies for these compounds have been developed and upgraded worldwide; however, their production cost remains high so far, limiting their use for large-scale applications.
The most promising and cost-effective synthetic method towards N-polynitro-substituted aza-and oxaazaisowurtzitanes is the direct condensation between ammonia derivatives and glyoxal, followed by the exhaustive nitration of the resulting aza-and oxaazaisowurtzitanes.
At this point, the formation mechanism of the hexaazaisowurtzitane cage is underexplored. In the overwhelming majority of cases, the hexaazaisowurtzitane cage originates from the condensation of ammonia derivatives containing an aromatic moiety or a multiple bond linked to the amino group via the methylene bridge [7,38,39]. The reasons behind it having such a high selectivity towards the structure of ammonia derivatives are unknown. There is, therefore, no doubt that the most important step in designing alternative synthetic routes to N-polynitro-substituted aza-and oxaazaisowurtzitanes is an in-depth study into that process in order to identify new formation mechanisms towards aza-and oxaazaisowurtzitane cages, in particular, the structure-property relationship for the starting ammonia derivatives and their capability of being condensed with glyoxal to furnish hexaazaisowurtzitane derivatives.
The detailed study on the condensation between benzamide and glyoxal in a ratio of 2:1 in different polar protic and aprotic solvents revealed that the carbamide group in the benzamide molecule undergoes hydrolysis under the glyoxal condensation conditions, and the condensation products undergo intramolecular transpositions (1,2-hydride shift; cyclization). No formation of caged compounds was documented. In view of this, we concluded that aromatic carboxamides (probably all carboxamides) are of little utility as the scaffold for the synthesis of aza-and oxaazaisowurtzitanes via direct condensation [43].
We earlier synthesized a range of new oxaazaisowurtzitane derivatives by the condensation between substituted sulfonamides and glyoxal, discovered some polyheterocyclic caged systems, and established new condensation patterns [40][41][42][43]. In particular, the increased basicity of the amido group in the sulfonamide molecule was found to facilitate the incorporation of aza groups into the oxaazaisowurtzitane cage. Unlike benzenesulfonamide, 4-dimethylaminobenzenesulfonamide was condensable with glyoxal to yield an oxaazaisowurtzitane derivative bearing three aza groups. In addition, the condensation of 4-dimethylaminobenzenesulfonamide furnished a byproduct that may be suggestive of the formation of a dioxatetraazaisowurtzitane derivative [42].
In the present study, we chose the high-basicity substituted sulfonamide 1 as a substrate for the study. In contrast to 4-dimethylaminobenzenesulfonamide, its donor substituents are not liable to protonation and cannot lead to a decreased basicity of sulfonamide in highly acidic media. The chemistry of sulfonamide 1 is almost understudied. We have not managed to find data on its condensation with aldehydes.
The condensation between sulfonamide 1 was examined in aqueous H 2 SO 4 , aqueous acetonitrile, and acetone over an H 2 SO 4 catalyst. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was analyzed by HPLC.
We also examined if diimine could be formed from sulfonamide 1 and glyoxal under the conditions mostly used for the synthesis of structurally similar imines. The compound is of interest as the scaffold for the synthesis of the respective hexaazaisowurtzitane derivative via trimerization. The presumed trimerization mechanism is described in [38].
First, we looked into the condensation between sulfonamide 1 and glyoxal in aqueous H 2 SO 4 . The reactions were carried out at room temperature for 2 h. Because sulfonamide 1 is poorly soluble in water, it was dissolved in aqueous H 2 SO 4 . The minimum content of H 2 SO 4 required for the dissolution was 73% in the mixture. The enhanced solubility of the amide appears to be due to protonation. The sulfonamide was dissolved in aqueous H 2 SO 4 first, and glyoxal was then added portion-wise to the mixture with vigorous stirring at room temperature for 1-2 min. All of the experiments used 0.3 g of sulfonamide and 0.5 mL of water. The condensation was studied at an H 2 SO 4 content of 73% to 83% in the mixture.
In the experiments with aqueous H 2 SO 4 , sulfonamide 1 was hydrolyzed to 4-(tertbutyl)-2,6-dimethylbenzenesulfonic acid (6), which was desulfated to 1-(tert-butyl)-3,5dimethylbenzene (7) (Scheme 2). Acid 6 is highly soluble in water; therefore, its content in the extract assayed by HPLC does not reflect the accurate quantity. Once extracted, some of the acid remained in the aqueous phase. Scheme 1. A presumed mechanism for the formation of compound 2 from diol 5.
In the experiments with aqueous H2SO4, sulfonamide 1 was hydrolyzed to 4-(tert-butyl)-2,6-dimethylbenzenesulfonic acid (6), which was desulfated to 1-(tert-butyl)-3,5-dimethylbenzene (7) (Scheme 2). Acid 6 is highly soluble in water therefore, its content in the extract assayed by HPLC does not reflect the accurate quan tity. Once extracted, some of the acid remained in the aqueous phase. To identify acid 6, the counter synthesis thereof was effected by the procedure re ported in [44].
The attempt to isolate acid 6 by extraction with ethyl ether acidified with HCl ap peared to furnish protonated acid 6(H + ) monohydrate as crystals (Scheme 3). The stability of this compound comes from the charge delocalization in the aromatic system. The broad singlet of two acid protons in the 1 H NMR was at 9.58. The elemental analysis data suggest that the compound was isolated in the hydrated form. Good water solubility can be distinguished among the properties of this compound. Since the thiols are air-oxidizable to disulfane with no catalysts [45,46], we hypoth esized that disulfane 3 is formed by the interaction of two molecules o 4-tert-butyl-2,6-dimethylbenzenethiol (8) in the presence of atmospheric oxygen (Scheme 4). To identify acid 6, the counter synthesis thereof was effected by the procedure reported in [44].
The attempt to isolate acid 6 by extraction with ethyl ether acidified with HCl appeared to furnish protonated acid 6(H + ) monohydrate as crystals (Scheme 3). The stability of this compound comes from the charge delocalization in the aromatic system. The broad singlet of two acid protons in the 1 H NMR was at 9.58. The elemental analysis data suggest that the compound was isolated in the hydrated form. Good water solubility can be distinguished among the properties of this compound. Scheme 1. A presumed mechanism for the formation of compound 2 from diol 5.
To identify acid 6, the counter synthesis thereof was effected by the procedure re ported in [44].
The attempt to isolate acid 6 by extraction with ethyl ether acidified with HCl ap peared to furnish protonated acid 6(H + ) monohydrate as crystals (Scheme 3). The stability of this compound comes from the charge delocalization in the aromatic system. The broad singlet of two acid protons in the 1 H NMR was at 9.58. The elemental analysis data suggest that the compound was isolated in the hydrated form. Good water solubility can be distinguished among the properties of this compound. Since the thiols are air-oxidizable to disulfane with no catalysts [45,46], we hypoth esized that disulfane 3 is formed by the interaction of two molecules o 4-tert-butyl-2,6-dimethylbenzenethiol (8) in the presence of atmospheric oxygen (Scheme 4). Since the thiols are air-oxidizable to disulfane with no catalysts [45,46], we hypothesized that disulfane 3 is formed by the interaction of two molecules of 4-tert-butyl-2,6dimethylbenzenethiol (8) in the presence of atmospheric oxygen (Scheme 4). In that case, thiol 8 was generated by the reduction of acid 6 with glyoxal, as was experimentally confirmed. Holding amide 1 in 80% H2SO4 in the absence of glyoxal did not furnish disulfane 3 and sulfane 4. Replacing glyoxal by formaldehyde (a sulfonamide-to-formaldehyde molar ratio of 1:1) resulted in a small amount of sulfane 4 (0.4% in the extract (HPLC)); reaction time was 2 h; the H2SO4 content in the mixture was 80% with trace amounts of compound 3. When formaldehyde was added portion-wise, 1,3,5-tris((4-(tert-butyl)-2,6-dimethylphenyl)sulfonyl)-1,3,5-triazinane (9) precipitated abundantly (Scheme 5). Most of the formaldehyde left the reaction mixture at the outset In that case, thiol 8 was generated by the reduction of acid 6 with glyoxal, as was experimentally confirmed. Holding amide 1 in 80% H 2 SO 4 in the absence of glyoxal did not furnish disulfane 3 and sulfane 4. Replacing glyoxal by formaldehyde (a sulfonamide-toformaldehyde molar ratio of 1:1) resulted in a small amount of sulfane 4 (0.4% in the extract (HPLC)); reaction time was 2 h; the H 2 SO 4 content in the mixture was 80% with trace amounts of compound 3. When formaldehyde was added portion-wise, 1,3,5-tris((4-(tertbutyl)-2,6-dimethylphenyl)sulfonyl)-1,3,5-triazinane (9) precipitated abundantly (Scheme 5). Most of the formaldehyde left the reaction mixture at the outset of the synthesis. 1,3,5-Triazinane 9 was obtained in a 50.5% yield (no optimization of the synthetic process was performed). We have not managed to find information on the use of aldehydes as reducing agents of substituted sulfoacids.
In that case, thiol 8 was generated by the reduction of acid 6 with glyoxal, as was experimentally confirmed. Holding amide 1 in 80% H2SO4 in the absence of glyoxal did not furnish disulfane 3 and sulfane 4. Replacing glyoxal by formaldehyde (a sulfona mide-to-formaldehyde molar ratio of 1:1) resulted in a small amount of sulfane 4 (0.4% in the extract (HPLC)); reaction time was 2 h; the H2SO4 content in the mixture was 80% with trace amounts of compound 3. When formaldehyde was added portion-wise 1,3,5-tris((4-(tert-butyl)-2,6-dimethylphenyl)sulfonyl)-1,3,5-triazinane (9) precipitated abundantly (Scheme 5). Most of the formaldehyde left the reaction mixture at the outse of the synthesis. 1,3,5-Triazinane 9 was obtained in a 50.5% yield (no optimization of the synthetic process was performed). We have not managed to find information on the use of aldehydes as reducing agents of substituted sulfoacids. Scheme 5. The formation of 1,3,5-triazinane 9.
Sulfane 4 was likely generated by the Friedel-Crafts reaction through the SEA mechanism to give an intermediate arene σ-complex 10 (Scheme 6). The (4-tert-butyl-2,6-dimethylphenyl)sulfonium (11 + ) cation attacked compound 7 activated at the 4th position. The stability of cation 11 + is explained by the charge delocalization in the aromatic system activated by donor substituents. H + acted as the Lewis acid in tha process. Sulfane 4 was likely generated by the Friedel-Crafts reaction through the S E Ar mechanism to give an intermediate arene σ-complex 10 (Scheme 6). The (4-tert-butyl-2,6dimethylphenyl)sulfonium (11 + ) cation attacked compound 7 activated at the 4th position. The stability of cation 11 + is explained by the charge delocalization in the aromatic system activated by donor substituents. H + acted as the Lewis acid in that process.

22, 27, x FOR PEER REVIEW 6 of 16
Scheme 6. A presumed mechanism for the formation of sulfane 4. Table 1 lists major reaction products in the extract after sulfonamide 1 reacted with glyoxal in a ratio of 2:1 in H2SO4 of varied concentrations. Table 1. Composition of the extract from the reaction mixture after sulfonamide 1 reacted with glyoxal in a ratio of 2:1 in H2SO4 of varied concentrations at room temperature.
As the H 2 SO 4 content in the mixture was raised from 76% (Table 1, Entry 2) to 83% ( Table 1, Entry 8), the content of sulfonamide 1 increased, and the content of compound 2 sharply decreased (in the extract) through to its complete absence when the H 2 SO 4 content in the mixture was 81% (Table 1, Entry 6), which was likely due to the activated hydrolysis of the condensation products.
Over the entire acidity range in question, amide 1 was observed to be hydrolyzed to acid 6, and the latter was desulfated to compound 7, in which case the hydrolysis rate was increasing up to the H 2 SO 4 content of 79% in the mixture for acid 6 ( Table 1, Entries 1-4) and up to the H 2 SO 4 content of 81% for compound 7 (Table 1, Entries 1-6) as the reaction mixture acidity was raised. The H 2 SO 4 content above 77% in the mixture resulted in sulfane 4 ( Table 1, Entries 3-8). The content of 4 in the reaction products was rising up to the H 2 SO 4 content of 82% in the mixture. The increase in sulfane 4 in the reaction mixture concurrently with a decline in compounds 3 and 7 is on a par with the suggested formation mechanism of sulfane 4 (Scheme 6; Table 1, Entries 3-8).
The reactions performed in pure H 2 SO 4 with no extra water afforded the highest yields of compounds 2 and 4. The highest amount of compound 2 (33% in the mixture (HPLC)) was achieved when the condensation was conducted in a small amount of H 2 SO 4 (31.5% in the mixture) at room temperature for 11 h. Compound 4 was best formed (32% in the mixture (HPLC)) when the condensation was carried out in H 2 SO 4 (64% in the mixture) for 4 h at 60 • C. In both cases, glyoxal was added portion-wise to the mixture for 1-2 min.
Further, we examined the condensation between sulfonamide 1 and glyoxal in aqueous acetonitrile. Water addition to the mixture was required to enhance the solubility of glyoxal (40%) and prevent it from precipitation as a tarry low-solubility sediment. The reactions were carried out at 30 • C for 5 h. The condensation was investigated by varying the H 2 SO 4 content from 1% to 63% in the mixture.
The condensation of sulfonamide 1 with glyoxal took place actively when the H 2 SO 4 content was 30-63%, resulting in a large number of products, among which the major one was N,N'-(1,2-bis((4-(tert-butyl)-2,6-dimethylphenyl)sulfonamido)ethane-1,2-diyl)diacetamide (12) (Scheme 7). The highest content of 18% of this compound in the extract was obtained when the H 2 SO 4 content was 63%. Compound 12 resulted most probably from the condensation between acetamide and diol 5. In this case, acetamide originated from the acid-catalyzed hydrolysis of acetonitrile. The generation of compound 12 corroborates that diol 5 originates also from the condensation between sulfonamide 1 and glyoxal.
The condensation between sulfonamide 1 and glyoxal in acetone (no extra water added) led to a large number of products, among which the major one was a tarry product from the reaction with acetone. The highest content of 16% of the compound in the extract was obtained when the H 2 SO 4 content was 24%. The 13 C NMR spectrum of the compound had signals at 208.4 (C=O), 54.9 (CH 2 ), 53.6 (CH 2 ) and 23.2 (CH 3 ), as well as signals typical of the aromatic system at 154.6 (C), 138.1 (C), 136.6 (C) and 128.3 (CH). It was impossible to resolve the structure of the compound.
The reactions were carried out at 30 °C for 5 h. The condensation was investigated by varying the H2SO4 content from 1% to 63% in the mixture.
The condensation of sulfonamide 1 with glyoxal took place actively when the H2SO4 content was 30-63%, resulting in a large number of products, among which the major one was N,N'-(1,2-bis((4-(tert-butyl)-2,6-dimethylphenyl)sulfonamido)ethane-1,2-diyl)diacetamid e (12) (Scheme 7). The highest content of 18% of this compound in the extract was obtained when the H2SO4 content was 63%. Compound 12 resulted most probably from the condensation between acetamide and diol 5. In this case, acetamide originated from the acid-catalyzed hydrolysis of acetonitrile. The generation of compound 12 corroborates that diol 5 originates also from the condensation between sulfonamide 1 and glyoxal. The condensation between sulfonamide 1 and glyoxal in acetone (no extra water added) led to a large number of products, among which the major one was a tarry product from the reaction with acetone. The highest content of 16% of the compound in the extract was obtained when the H2SO4 content was 24%. The 13 C NMR spectrum of the compound had signals at 208.4 (C=O), 54.9 (CH2), 53.6 (CH2) and 23.2 (CH3), as well as signals typical of the aromatic system at 154.6 (C), 138.1 (C), 136.6 (C) and 128.3 (CH). It was impossible to resolve the structure of the compound.
We further examined the condensation between sulfonamide 1 and glyoxal in order to obtain the respective diimine. The reaction was conducted under conditions used for the synthesis of structurally similar imines [47][48][49][50][51][52][53]. Glyoxal was dewatered by distillation of the water-toluene azeotrope. The content of the reaction products was quantified by HPLC.
The reaction almost did not proceed in methylene chloride or chloroform at reflux in the presence of Et3N and excess TiCl4, in aqueous formic acid in the presence of sodium benzenesulfinate at room temperature, and in methylene chloride or dichloroethane in the presence of pyrrolidine (10% in the mixture) and 4 Å molecular sieves (1 g/mmol).

Scheme 7. The formation of compound 12.
We further examined the condensation between sulfonamide 1 and glyoxal in order to obtain the respective diimine. The reaction was conducted under conditions used for the synthesis of structurally similar imines [47][48][49][50][51][52][53]. Glyoxal was dewatered by distillation of the water-toluene azeotrope. The content of the reaction products was quantified by HPLC.
The reaction almost did not proceed in methylene chloride or chloroform at reflux in the presence of Et 3 N and excess TiCl 4 , in aqueous formic acid in the presence of sodium benzenesulfinate at room temperature, and in methylene chloride or dichloroethane in the presence of pyrrolidine (10% in the mixture) and 4 Å molecular sieves (1 g/mmol).
Refluxing sulfonamide 1 with dewatered glyoxal in a 16% toluene solution of titanium (IV) isopropoxide for 8 h furnished disulfane 3 (6% in the mixture (HPLC)). The reaction performed in excess pure titanium (IV) isopropoxide at 160 • C for 12 h increased the content of disulfane 3 from 6% to 24% in the mixture. Glyoxal in this reaction acted as a reducing agent. Compound 3 was not formed in the absence of glyoxal.
We believe that compounds 13 and 14, as well as sulfane 4, originated from the Friedel-Crafts reaction via the S E Ar mechanism illustrated in Scheme 6. In the case of compound 13, cation 15 + electrophilically attacked toluene, while in the case of compound 14, cation 15 + electrophilically attacked compound 7. The existence of cation 15 + is corroborated by numerous studies on the synthesis of analogous compounds from sulfoacid chloroanhydrides and aromatics in the presence of Lewis acids [54][55][56]. The stability of cation 15 + , as well as of 11 + , is explained by the charge delocalization in the aromatic system activated by donor substituents. H + acted as the Lewis acid. The formation of cation 15 + in that case may be due to the detachment of the ammonia molecule from the protonated sulfonamide molecule 1(H + ) or due to the water detachment from the protonated sulfoacid 6(H + ) (Scheme 8). Because the reaction proceeded in zeolite-predewatered solvents at reflux that give an azeotropic mixture with water, the first option taking place to cleave the C-N is the most probable.

Scheme 8. A presumed mechanism for the formation of compounds 13 and 14.
We believe that compounds 13 and 14, as well as sulfane 4, originated from the Friedel-Crafts reaction via the SEAr mechanism illustrated in Scheme 6. In the case of compound 13, cation 15 + electrophilically attacked toluene, while in the case of compound 14, cation 15 + electrophilically attacked compound 7. The existence of cation 15 + is corroborated by numerous studies on the synthesis of analogous compounds from sulfoacid chloroanhydrides and aromatics in the presence of Lewis acids [54][55][56]. The stability of cation 15 + , as well as of 11 + , is explained by the charge delocalization in the aromatic system activated by donor substituents. H + acted as the Lewis acid. The formation of cation 15 + in that case may be due to the detachment of the ammonia molecule from the protonated sulfonamide molecule 1(H + ) or due to the water detachment from the protonated sulfoacid 6(H + ) (Scheme 8). Because the reaction proceeded in zeolite-predewatered solvents at reflux that give an azeotropic mixture with water, the first option taking place to cleave the C-N is the most probable.
Glyoxal was not involved in the formation of compounds 13 and 14, as is experimentally proved. Refluxing sulfonamide 1 in toluene over the TfOH catalyst (3% in the mixture) for 5 h also furnished compound 13 (80% in the mixture (HPLC)). Refluxing sulfonamide 1 in 1,2-DCE over the TfOH catalyst (3% in the mixture) for 5 h resulted also Scheme 8. A presumed mechanism for the formation of compounds 13 and 14.
Glyoxal was not involved in the formation of compounds 13 and 14, as is experimentally proved. Refluxing sulfonamide 1 in toluene over the TfOH catalyst (3% in the mixture) for 5 h also furnished compound 13 (80% in the mixture (HPLC)). Refluxing sulfonamide 1 in 1,2-DCE over the TfOH catalyst (3% in the mixture) for 5 h resulted also in compound 14 (68% in the mixture (HPLC)). The reaction in toluene was slower than in 1,2-DCE and was incomplete, which is likely due to TfOH reacting with toluene and escaping the reaction mixture. Since the synthesis of the sulfones was out of the scope of the present study, no optimization of the process for compounds 13 and 14 was performed.
Sulfones have been known for long and are widely applied in the synthesis of polymers [57][58][59][60], bioactive compounds [61,62], agrochemicals [63,64], fluorescent compounds [65] and other organics. Despite this, we have not managed to find reports on the synthesis of aromatic sulfones by the Brønsted acid-catalyzed Friedel-Crafts reaction in which aromatic sulfonamides and aromatics are utilized as the starting reactants. The synthetic process discovered herein for symmetric and asymmetric sulfones can be useful as an alternative to the common synthetic methods. This process can significantly shorten the stages in the synthesis of in-demand organic compounds [57][58][59][60][61][62][63][64][65], is easy to perform, and provides a good yield. The basic requirement for this process is probably the use of aromatic sulfonamides highly activated by donor substituents. Additionally, this process can probably be used for the synthesis of sulfones from aromatic sulfoacids highly activated by donor substituents.

Materials and Methods
The reagents were purchased from commercial sources and used as received, unless mentioned otherwise. Commercially available compounds were used without further purification, unless stated otherwise. Melting points were determined on a Stuart SMP30 melting point apparatus (Bibby Scientific Ltd., Staffordshire, UK). Infrared (IR) spectra were recorded on a Simex FT-801 Fourier transform infrared spectrometer (Simex, Novosibirsk, Russia) in KBr pellets or in a liquid film. 1  For preparative chromatography, silica gel Kieselgel 60 (0.063-0.2 mm, Macherey-Nagel GmbH & Co. KG, Dueren, Germany) was used. HPLC analysis was performed on an Agilent 1200 chromatograph (Agilent Technologies, Waldbronn, Germany) with a diode array detector. The separation was carried out on a Hypersil ODS (100 × 2.1 mm, a 5 µm mesh) column. Mixed solvents A (0.2% phosphoric acid) and B (acetonitrile) were used as the mobile phase. The mobile phase composition was varied in the gradient mode: the concentration of solvent B was linearly raised from 45 to 100% for 25 min and maintained at this level for another 25 min. The flowrate of the eluent was 0.25 mL/min, the column temperature was 25 • C, detection was run at a 210 nm wavelength, and the sample volume was 3 µL. The column conditioning time between successive injections was 15 min.

Experimental Section
4.1. Synthesis of 2-((4-(Tert-butyl)-2,6-dimethylphenyl)sulfonamido)-N-((4-(tert-butyl)-2,6dimethylphenyl)sulfonyl)acetamide (2) Sulfonamide 1 (3 g, 0.012 mol) was dissolved in H 2 SO 4 (2 mL, 94%) at room temperature. Glyoxal (0.902 g, 40%, 0.006 mol) was then added portion-wise to the mixture with stirring at 22-24 • C for 3-4 min. During the portion-wise addition, a great quantity of a tarry sediment precipitated. The whole was further periodically stirred manually once an hour for 11 h. Upon completion of the time, the reaction mixture was poured over with water (20 mL) and extracted with ethyl acetate. The extract was washed with water and brine, and dried over Na 2 SO 4 and evaporated to dryness on a rotary evaporator in vacuo (50 • C bath temperature). The residue was subjected to preparative chromatography. Mixed chloroform and glacial acetic acid in a volume ratio of 10:0.5 were used as the eluent. Fractions with Rf = 0.48 were collected. The solvents were removed to dryness from the collected fractions in vacuo by a rotary evaporator (50 • C bath temperature). The residue was recrystallized from diethyl ether and dried at room temperature until constant weight to furnish compound 2 as a white crystalline powder.

Synthesis of 1,2-Bis(4-(tert-butyl)-2,6-dimethylphenyl)disulfane (3)
Mixed toluene (30 mL) and glyoxal (0.3 g, 40%, 0.002 mol) were refluxed with distillation for 40-50 min until about 5-6 mL of the solvent remained in the flask. The mixture was then evaporated to dryness in a rotary evaporator in vacuo (70 • C bath temperature). To the residue in the flask were added titanium (IV) isopropoxide (6.5 mL) and sulfonamide 1 (1 g, 0.004 mol). The whole was then heated to 160 • C and stirred vigorously for 12 h. Upon completion, the reaction mixture was poured over with water (80 mL) and stirred vigorously for 1 h at room temperature. To the mixture was then added ethyl acetate (20 mL), followed by stirring for another 1 h. Upon completion, the mixture was filtered through a paper filter. The filter cake was washed with ethyl acetate several times. The extract was washed with water and brine, and dried over Na 2 SO 4 and evaporated to dryness in a rotary evaporator in vacuo (50 • C bath temperature). The residue was subjected to preparative chromatography. Toluene was used as the eluent. Fractions with Rf = 0.76 were collected. The solvent was removed from the collected fractions in vacuo by a rotary evaporator (60 • C bath temperature) before the onset of crystallization. To the residue was added a small amount of acetonitrile, and the precipitation was allowed to finish. The suspension was filtered. The filter cake was washed with acetonitrile and dried at room temperature until constant weight. The result was compound 3 as a white crystalline powder. Yield: 0.164 g (97.5% assay (HPLC)), 0.414 mmol (20% calculated as compound 1). Mp = 125-127 • C. IR (KBr): ν = 2965, 2953, 2902, 2865, 1592, 1554, 1478, 1461, 1444, 1405, 1392 4.3. Synthesis of Bis(4-(tert-butyl)-2,6-dimethylphenyl)sulfane (4) Sulfonamide 1 (1 g, 0.004 mol) was dissolved in H 2 SO 4 (1.33 mL, 94%). The mixture was then heated to 60 • C, and glyoxal (0.3 g, 40%, 0.002 mol) was added portion-wise with stirring for 1-2 min. The whole was then stirred for 4 h, maintaining the same temperature. Upon completion, the reaction mixture was poured over with water (20 mL) and ethyl acetate-extracted. The extract was washed with water and brine, and dried over Na 2 SO 4 and evaporated to dryness in a rotary evaporator in vacuo (50 • C bath temperature). The residue was subjected to preparative chromatography. Toluene was used as the eluent. Fractions with Rf = 0.74 were collected. The solvent was removed from the collected fractions by a rotary evaporator in vacuo before the onset of crystallization (60 • C bath temperature). To the residue was added a small amount of acetonitrile, and the precipitation was allowed to finish. The suspension was filtered. The filter cake was washed with acetonitrile and dried at room temperature until constant weight to give compound 4 as a white crystalline powder.
Yield Compound 8 (5 g, 0.021 mol) was added dropwise to H 2 SO 4 (11 mL, 94%) with vigorous stirring for 1 h at a constant temperature of 25 • C. The whole was then vigorously stirred for 5 h. Upon completion, a saturated NaCl solution (8.5 mL) was poured into the mixture. The mixture was cooled to 10 • C, stirred for 15 min and filtered. The filter cake was transferred to a beaker into which diethyl ether (35 mL) was then poured. To the mixture was further added H 2 SO 4 with vigorous stirring until the sediment was fully dissolved. The extract was removed by decantation. The residue was extracted twice again with diethyl ether (8 mL each), repeating the procedure. The combined extracts were dried over CaCl 2 and evaporated to dryness in a rotary evaporator. The result was protonated acid 6(H + ) monohydrate as a white crystalline powder.
Yield: 0.55 g (96% assay (HPLC)), 0.697 mmol (50.5% calculated as compound 1). Mp = 235- 23   H 2 SO 4 (80 mL, 94%) was added portion-wise to mixed acetonitrile (80 mL), water (3.8 mL), sulfonamide 1 (3 g, 0.012 mol) and glyoxal (0.902 g, 40%, 0.006 mol) for 2-3 min, maintaining the temperature below 15 • C. The whole was then heated to 30 • C and stirred for 5 h. Upon completion, the reaction mixture was poured over with water (400 mL) and extracted with ethyl acetate. The extract was washed with water and brine, and dried over Na 2 SO 4 and evaporated to dryness in a rotary evaporator in vacuo (40 • C bath temperature). The residue was subjected to preparative chromatography. Mixed chloroform and gracious acetic acid in a volume ratio of 10:0.5 were used as the eluent. Fractions with Rf = 0.15 were collected. The solvents were evaporated to dryness from the collected fractions by a rotary evaporator in vacuo (60 • C bath temperature). The residue was recrystallized from mixed diethyl ether and acetone in a volume ratio of 4:1 and dried at room temperature until constant weight. The result was compound 12 as a white crystalline powder.

Synthesis of 5-(Tert-butyl)-1,3-dimethyl-2-tosylbenzene (13)
A mixture of sulfonamide 1 (1 g, 0.004 mol), toluene (27 mL, dewatered with zeolites) and TfOH (0.44 mL) was stirred at reflux for 5 h. The whole was then cooled, poured over with water (50 mL) and stirred vigorously for 15 min. The mixture was further separated on a separation funnel. The water layer was additionally extracted once with toluene (8 mL). The organic phases were combined, washed with water and brine, and dried over Na 2 SO 4 and evaporated to dryness in a rotary evaporator in vacuo (70 • C bath temperature). The residue was subjected to preparative chromatography. Toluene was used as the eluent. Fractions with Rf = 0.18 were collected. The solvent was evaporated to dryness from the collected fractions by a rotary evaporator in vacuo (60 • C bath temperature). The result was compound 13 as a yellowish resin that crystallizes over time.

Synthesis of 2,2 -Sulfonylbis(5-(tert-butyl)-1,3-dimethylbenzene) (14)
Mixed sulfonamide 1 (1 g, 0.004 mol), 1,2-DCE (13.4 mL, dewatered with zeolites) and TfOH (0.33 mL) were stirred at reflux for 5 h. The mixture was then cooled, poured over with water (50 mL), and stirred vigorously for 15 min. The mixture was further separated on a separation funnel. The water layer was additionally extracted once with toluene (8 mL). The organic phases were combined, washed with water and brine, and dried over Na 2 SO 4 and evaporated to dryness in a rotary evaporator in vacuo (70 • C bath temperature). The residue was subjected to preparative chromatography. Fractions with Rf = 0.24 were collected. The solvent was evaporated to dryness from the collected fractions by a rotary evaporator in vacuo (60 • C bath temperature). The result was compound 14 as a yellowish resin that crystallizes over time.
It was discovered that diimine could not be obtained by the condensation between sulfonamide 1 and glyoxal in the media most often used for the synthesis of structurally similar imines, in aprotic solvents at reflux in the presence of strong Lewis or Brønsted acids or dewatering agents such as titanium (IV) isopropoxide.
The Friedel-Crafts reaction between an aromatic sulfonamide and a benzene derivative was carried out for the first time. A new synthetic strategy has been proposed herein that can considerably shorten the stages in the synthesis of in-demand organic compounds of symmetric and asymmetric sulfones via the Brønsted acid-catalyzed Friedel-Crafts reaction, starting from aromatic sulfonamides and arenes activated towards an electrophilic attack.
The present study allows for the conclusion that aqueous H 2 SO 4 (73-83% in the mixture), aqueous acetonitrile or acetone are not suitable media for the acid-catalyzed cascade condensation of sulfonamide 1 with glyoxal. The condensation in these media comes amid a large number of side products, some of which are formed irreversibly.