A method for the synthesis of a benzo[d]imidazo[1,5-b]isothiazole-5,5-dioxide derivative

Abstract

The application discloses a synthesis method of a benzo[d]imidazo[1,5-b]isothiazole-5,5-dioxide derivative. The method uses an organic solvent-water mixed solution containing benzoisothiazole-1,1-dioxide, N-aryl glycine compound and polyformaldehyde as an electrolyte, heats the electrolyte to 50-75 DEG C, places an anode and a cathode in the electrolyte, and passes direct current to perform electrochemical reaction, so as to obtain the benzo[d]imidazo[1,5-b]isothiazole-5,5-dioxide. The method does not need to use electrolyte and oxidant, and has the advantages of mild reaction condition, simple operation, green environmental protection, easy-to-obtain raw material, excellent compatibility of substrate functional groups and high reaction yield, and is beneficial to scale-up production.

Description

Technical Field

[0001] This invention relates to a method for synthesizing a benzo[d]imidazo[1,5-b]isothiazolium-5,5-dioxide derivative, and particularly to a method for synthesizing benzo[d]imidazo[1,5-b]isothiazolium-5,5-dioxide compound by catalytic oxidative decarboxylation coupling-cyclization reaction of benzo[d]imidazo[1,5-b]isothiazolium-5,5-dioxide under direct current under conditions of no added electrolyte, no added catalyst, and no chemical oxidant. This method belongs to the field of organic intermediate synthesis technology. Background Technology

[0002] Benzimido[d]imidazo[1,5-b]isothiazolium-5,5-dioxide is an important fused heterocyclic compound with diverse biological and pharmacological activities, making it a promising lead compound for drug development. Therefore, developing green and sustainable synthetic methods for this class of compounds is of great significance.

[0003] In 2022, Professor Yu Bing of Zhengzhou University disclosed a photocatalytic synthesis using lead tribromide cesium and oxygen-vacancy graphitic carbon nitride as heterogeneous photocatalysts, and Professor Chen Xiaolan disclosed a photocatalytic synthesis using eosin Y as a homogeneous photocatalyst and air as an oxidant. Both achieved visible light-mediated free radical decarboxylation coupling-cyclization reaction of benzisothiazol-1,1-dioxide and N-phenylglycine to generate tetrahydrobenzi[d]imidazo[1,5-b]isothiazol-5,5-dioxide. See (Anzai Shi, Kai Sun, Xiaolan Chen, Lingbo Qu, Yufen Zhao, Bing Yu, Perovskite as Recyclable Photocatalyst for Annulation Reaction of N-Sulfonyl Ketimines, Org. Lett., 2022, 24, 299-303), (Anzai Shi, Kai Sun, Yanxuan Wu, Panjie Xiang, Igor B. Krylov, Alexander O.Terent'ev, Xiaolan Chen, Bing Yu, Oxygen-doped carbonnitride for enhanced photocatalytic activity in visible-light-induced decarboxylative annulation reactions, J. Catal., 2022, 415 28-36) and (XiaotongWang, Anzai Shi, Xian-Qiang Huang, Xiaolan Chen, Tiesheng Li, Lingbo Qu, Bing Yu, Visible-light-induced cyclization of cyclic N-sulfonyl ketimines to (N-sulfonamide fused imidazolidines, Org. Biomol. Chem., 2022, 20, 3798-3802). Heterogeneous photocatalysts cesium lead tribromide and oxygen-vacancy graphitic carbon nitride can be recycled multiple times, but cesium lead tribromide catalysts are expensive and biotoxic; oxygen-vacancy graphitic carbon nitride catalysts have no commercial products, require additional preparation, and the preparation process is highly polluting, energy-intensive, and costly; while homogeneous photocatalysts eosin Y are not easily separated from the reaction mixture, making recycling difficult and causing environmental pollution; they also have the limitation of being prone to photobleaching.

[0004] The above method requires the use of three stoichiometric amounts of expensive N-arylglycine, of which about 1.5 stoichiometric amounts of N-arylglycine are used as the methylene source. This not only results in high reaction costs but also generates a large amount of aromatic amine byproducts, increasing the cost of product separation and purification as well as environmental costs.

[0005]

[0006] Heterogeneous photocatalyst: perovskite lead tribromide cesium; oxygen-vacancy graphitic carbon nitride

[0007] Homogeneous catalyst: Eosin Y Summary of the Invention

[0008] To address the shortcomings of existing technologies, the present invention aims to provide a method for electrochemically synthesizing benz[d]imidazo[1,5-b]isothiazolium-5,5-dioxide derivatives using inexpensive amino acid derivatives, benzisothiazolium-1,1-dioxide, and paraformaldehyde as raw materials. This method eliminates the need for external catalysts, electrolyte salts, and chemical oxidants, utilizes inexpensive raw materials, and achieves high yields of benz[d]imidazo[1,5-b]isothiazolium-5,5-dioxide derivatives under mild conditions. Furthermore, the method exhibits high atomic efficiency, functional group tolerance, environmental friendliness, and ease of operation, making it suitable for industrial production applications.

[0009] To achieve the above-mentioned technical objectives, the present invention provides a method for synthesizing benzo[d]imidazo[1,5-b]isothiazolium-5,5-dioxide derivatives. The method uses an organic solvent-water mixture containing benzo[d]imidazo[1,5-b]isothiazolium-5,5-dioxide, N-arylglycine compound, and paraformaldehyde as an electrolyte. The electrolyte is heated to 50-75°C, and an anode and cathode are placed in the electrolyte. A direct current is passed through the electrolyte to carry out an electrochemical reaction, thereby obtaining benzo[d]imidazo[1,5-b]isothiazolium-5,5-dioxide.

[0010] The benzoisothiazol-1,1-dioxide has the structure of Formula 1:

[0011]

[0012] The N-arylglycine compound has the structure of Formula 2:

[0013]

[0014]

[0015] The benzo[d]imidazo[1,5-b]isothiazol-5,5-dioxide derivative has the structure of Formula 3:

[0016]

[0017] in,

[0018] R is hydrogen, a C1-C5 alkyl group, a C1-C5 alkoxy group, or a halogen substituent;

[0019] Ar is a phenyl, naphthyl, or benzo[a]heterocyclic group, or a phenyl group containing a halogen substituent, trifluoromethoxy, C1-C5 alkylthio substituent, C1-C5 alkoxy substituent, C1-C5 alkyl substituent, or C2-C5 ester substituent.

[0020] In the benzo[d]imidazo[1,5-b]isothiazolium-5,5-dioxide derivative of this invention, the R substituent is mainly a group introduced by benzo[d]imidazo[1,5-b]isothiazolium-1,1-dioxide, which is a common small molecule substituent group. The substitution position of the R substituent on the benzene ring is not restricted and can be any position on the benzene ring that can be substituted. Common substituents include alkyl, halogen substituents, alkoxy, etc. The chain length of the alkyl group has little effect on the reaction. Common alkyl groups are C1 to C5 alkyl groups, such as methyl, ethyl, propyl, butyl, etc. Alkyl groups with more than 3 carbon atoms also include isomers, such as branched alkyl groups, such as isopropyl, isobutyl, etc. Halogen substituents include fluorine substituents, chlorine substituents, or bromine substituents, etc. Common alkoxy groups are C1 to C5 alkoxy groups, such as methoxy, ethoxy, propoxy, etc.

[0021] In the benzo[d]imidazo[1,5-b]isothiazolium-5,5-dioxide derivative of the present invention, the Ar substituent is introduced by N-arylglycine. Ar can be phenyl, naphthyl, benzo[d]heterocyclic, etc. The benzo[d]heterocyclic ring can be a benzo[d]hexa-membered heterocycle or a benzo[d]hexa-membered heterocycle. The heteroatom contained in the heterocycle is generally nitrogen, oxygen, or sulfur, and the number of heteroatoms in the heterocycle is generally 1 to 3, specifically benzo[d]pyridine, benzo[d]thiophene, benzo[d]thiazole, etc. Ar can also be a substituted phenyl derived from a phenyl group. The substituted phenyl group is a phenyl group containing a halogen substituent, trifluoromethoxy, C1-C5 alkylthio substituent, C1-C5 alkoxy substituent, C1-C5 alkyl substituent, or C2-C5 ester substituent. Halogen substituents include fluorine, chlorine, and bromine substituents; C1-C5 alkylthio substituents include methylthio and ethylthio; C1-C5 alkoxy substituents include methoxyacyl, ethoxyacyl, and propoxyacyl; C1-C5 alkyl substituents include methyl, ethyl, propyl, and isobutyl; and C2-C5 ester substituents include ethoxyacyl and butyoxyacyl.

[0022] The R substituents and Ar groups in the benzisothiazol-1,1-dioxide and N-arylglycine compounds of the present invention have a certain influence on the reaction, but in general, within the preferred selection ranges mentioned above, a relatively ideal yield of the target product can be obtained. Depending on the different substituents, the yield of the target product can reach 72-91%.

[0023] As a preferred embodiment, the organic solvent-water mixed solution uses acetonitrile and water as the mixed solvent. Acetonitrile is a polar aprotic solvent in the electrolyte, while water is a polar protic solvent. Acetonitrile, as the primary solvent, promotes the dissolution of the organic substrate, thereby improving reaction efficiency. Water, as a secondary solvent, is beneficial in small amounts, providing protons to form complex intermediates with N-arylglycine compounds through hydrogen bonding, promoting the dehydrogenation process of N-arylglycine compounds, and thus improving reaction efficiency. In a more preferred embodiment, the mixed solvent consists of acetonitrile and water in a volume ratio of (2-4):1. If the proportion of acetonitrile is too low, the solubility of the organic substrate will decrease, affecting the reaction and leading to a lower yield of the target product. Conversely, if the proportion of acetonitrile is too high, the water content will decrease, resulting in a poor promoting effect on the reaction. Therefore, the ratio of acetonitrile to water in the electrolyte should be controlled within a suitable range. Furthermore, acetonitrile is the most preferred organic solvent, and using methanol, DMSO, or DMF to replace acetonitrile does not yield a good yield of the target product.

[0024] As a preferred embodiment, the molar ratio of benzisothiazol-1,1-dioxide, N-arylglycine compound, and paraformaldehyde is 1:(1-1.5):(1-1.5). A further preferred embodiment is a molar ratio of benzisothiazol-1,1-dioxide, N-arylglycine compound, and paraformaldehyde of 1:(1.1-1.2):(1.1-1.2). In the currently reported synthesis of benz[d]imidazo[1,5-b]isothiazol-5,5-dioxide, the N-arylglycine compound serves as both a methylene and aminomethyl source, thus requiring a relatively high amount. This invention uses paraformaldehyde as the methylene source, which reduces the amount of high-cost N-arylglycine compound used.

[0025] As a preferred embodiment, the anode is a platinum electrode or a graphite electrode; the cathode is a glassy carbon electrode, a platinum electrode, a copper electrode, a graphite electrode, or a nickel electrode. As a more preferred embodiment, the anode is a graphite electrode; the cathode is a platinum electrode. Both preferred cathodes and anodes enable the reaction to proceed smoothly, and the highest yield of the target product is achieved when the cathode is a platinum electrode and the anode is a graphite electrode.

[0026] As a preferred embodiment, the electrochemical reaction conditions are: a current of 0.5–3 mA and a reaction time of 1–3 hours. When the current is too low, the electrochemical reaction efficiency will be significantly reduced, resulting in a lower yield of the target product. Conversely, when the current is too high, the electrochemical reaction efficiency will also decrease, and side reactions will increase, thereby reducing the yield of the target product.

[0027] The route for synthesizing benzo[d]imidazo[1,5-b]isothiazolium-5,5-dioxide from benzo[d]imidazo[1,5-b]isothiazolium-5,5-dioxide via an electrochemical oxidative decarboxylation coupling-cyclization reaction of benzo[d]imidazo[1,5-b]isothiazolium-5,5-dioxide in this invention is as follows:

[0028]

[0029] This invention also proposes a reasonable reaction mechanism for the above reaction, using the oxidative decarboxylation coupling-cyclization reaction of benzisothiazol-1,1-dioxide, N-phenylglycine, and paraformaldehyde as an example for specific illustration. N-phenylglycine (2) and water molecules form a complex intermediate IM1 through hydrogen bonds, which gains electrons on the platinum cathode surface and is reduced to hydrogen gas and N-phenylglycine anions (IM2). The anionic intermediate IM2 loses electrons on the graphite anode surface and is oxidized to an oxygen-centered glycine free radical (IM3), which is further decarboxylated to generate a carbon-centered methylamino free radical (IM4). Intermediate IM4 selectively attacks the C3 atom of benzisothiazol-1,1-dioxide to generate a nitrogen-centered free radical intermediate IM5, which captures a hydrogen atom of N-phenylglycine to generate intermediate IM6. Intermediate IM6 reacts with paraformaldehyde (3) via a Mannich reaction to generate imine cationic intermediate IM7, which undergoes an intramolecular cyclization reaction to generate intermediate IM8. Then, with the assistance of N-phenylglycine anion, it undergoes dehydrogenation aromatization to obtain the target product benzo[d]imidazo[1,5-b]isothiazol-5,5-dioxide (4).

[0030]

[0031] Compared with the prior art, the technical solution of the present invention brings the following beneficial technical effects:

[0032] 1) This invention uses electrons as a residue-free oxidant, which is green, safe, inexpensive and readily available.

[0033] 2) This invention requires no catalyst or electrolyte additive, reducing reaction costs and the generation of chemical waste.

[0034] 3) This invention uses inexpensive and readily available paraformaldehyde as the methylene source, which has a cost advantage; it has broad selectivity for N-arylglycine and good functional group compatibility; it has high reaction selectivity, the product is easy to separate and purify, and the yield of the target product is high.

[0035] 4) This invention activates glycine by generating hydrogen-bonded complexes, enabling the generation of active free radicals through electrolysis at low voltage. No redox co-catalysts are required, and the reaction system is simple and green.

[0036] 5) This invention provides a low-cost, green and environmentally friendly new route for the synthesis of drugs or intermediates based on benzo[d]imidazo[1,5-b]isothiazol-5,5-dioxide. Attached Figure Description

[0037] Figure 1 The 1H NMR spectrum of compound (R)-2-phenyl-1,2,3,9b-tetrahydrobenzo[d]imidazol[1,5-b]benzo[d]imidazo[1,5-b]isothiazol-5,5-dioxide.

[0038] Figure 2 The carbon NMR spectrum of compound (R)-2-phenyl-1,2,3,9b-tetrahydrobenzo[d]imidazol[1,5-b]benzo[d]imidazo[1,5-b]isothiazol-5,5-dioxide. Detailed Implementation

[0039] The following specific embodiments are intended to further illustrate the content of the present invention, rather than to limit the scope of protection of the claims of the present invention.

[0040] Unless otherwise specified, the reaction substrates used in the following examples are all conventional commercially available reagents.

[0041] The following reactions are used as standard reaction conditions:

[0042]

[0043] The specific operating steps were as follows: In a 5 mL electrochemical reaction cell, benzisothiazol-1,1-dioxide (0.2 mmol), N-phenylglycine (0.24 mmol), paraformaldehyde (0.24 mmol), acetonitrile (2.25 mL), and water (0.75 mL) were added sequentially. A graphite sheet electrode was used as the anode, and a platinum sheet electrode as the cathode. The resulting mixture was reacted at room temperature with a 1 mA DC current at 60 °C under stirring. The reaction progress was monitored using a thin-layer chromatography plate for 1.5 hours. After the reaction was completed, the yield was analyzed by gas chromatography.

[0044] Comparative Example:

[0045] The control experimental groups 1–19 in the table below all reacted according to the above reaction equations. The product yields under different reaction conditions are shown in the table below:

[0046]

[0047]

[0048] Platinum sheet electrode: 15mm × 10mm × 0.1mm;

[0049] Graphite sheet, mesh glassy carbon, copper sheet and nickel sheet electrodes: 15mm×10mm×2mm;

[0050] The table above shows that experimental groups 1-7 investigated the effects of different electrode materials on the electrochemical oxidative decarboxylation coupling cyclization reaction of benzisothiazol-1,1-dioxide and N-arylglycine. The experiments showed that using platinum or graphite sheets as anodes and platinum, graphite, nickel, copper, or mesh glassy carbon as cathodes, the reaction proceeded smoothly, and the gas phase yield of the target product could reach over 33%. However, different electrode pairs had a significant impact on the electrochemical reaction. For example, using platinum as the cathode and graphite as the anode was the optimal electrode pair for this reaction, and the gas phase yield of the target product could reach 93%.

[0051] The table above shows that experimental groups 1, 8-12 investigated the effects of different solvents on the electrochemical oxidative decarboxylation coupling cyclization reaction of benzisothiazol-1,1-dioxide and N-arylglycine. The experiments showed that the best solvent is a mixture of acetonitrile and water. If water is used alone, the reaction can hardly proceed, and if acetonitrile is used alone, the yield of the target product is low. However, the appropriate introduction of a small amount of water can form a hydrogen-bonded complex with N-phenylglycine, which is beneficial to the electrolytic reaction and improves the yield of the target product. Although replacing acetonitrile with organic solvents such as methanol and DMSO can make the reaction proceed smoothly, the yield of the target product is low.

[0052] The experimental groups 1 and 13-14 in the table above investigated the effect of current density on the electrochemical oxidative decarboxylation coupling cyclization reaction of benzisothiazol-1,1-dioxide and N-arylglycine. The experiments showed that reducing the current density significantly reduced the yield of the target product; if the current density was too high, benzisothiazol-1,1-dioxide was prone to decomposition side reactions; and 1 mA was the optimal current density for this reaction.

[0053] The experimental groups 1 and 15-17 in the table above investigated the effect of temperature on the electrochemical oxidative decarboxylation coupling cyclization reaction of benzisothiazol-1,1-dioxide and N-arylglycine. The experiments showed that lowering the temperature significantly reduced the yield of the target product, while excessively high temperatures easily led to side reactions; and 60℃ was the optimal reaction temperature for this reaction.

[0054] The experimental groups 1 and 18 in the table above investigated the effect of paraformaldehyde on the electrochemical oxidative decarboxylation coupling cyclization reaction of benzisothiazol-1,1-dioxide and N-arylglycine. The experiments showed that the electrochemical reaction could occur without the addition of paraformaldehyde, but the yield of the target product was low. However, the yield of the target product increased significantly after the addition of paraformaldehyde.

[0055] In the table above, experimental groups 1 and 19 investigated the effect of current on the electrochemical oxidative decarboxylation coupling cyclization reaction of benzisothiazol-1,1-dioxide with N-arylglycine. The experiments showed that the reaction could not occur under the condition of no current.

[0056] Examples 1-16

[0057] Examples 1-16 below all follow the reaction equations below, mainly to investigate the yield of different substrates under optimal conditions:

[0058]

[0059] The specific operating steps are as follows: In a 5 mL electrochemical reaction cell, benzisothiazol-1,1-dioxide (0.2 mmol), N-arylglycine (0.24 mmol), paraformaldehyde (0.24 mmol), acetonitrile (2.25 mL), and water (0.75 mL) were added sequentially. A graphite sheet electrode was used as the anode, and a platinum sheet electrode was used as the cathode. The resulting mixture was stirred at 60 °C under a 1 mA DC current at room temperature. The reaction progress was monitored using a thin-layer chromatography plate, and the reaction time was 1.5 hours. After the reaction was completed, the extract was concentrated using a rotary evaporator, and purified by column chromatography with petroleum ether / ethyl acetate as the eluent using silica gel.

[0060] Example 1

[0061]

[0062] (R)-2-phenyl-1,2,3,9b-tetrahydrobenzo[d]imidazo[1,5-b]isothiazole 5,5-dioxide separation yield: 89%

[0063] 1 H NMR (500MHz, CDCl3) δ7.80(d,J=7.8Hz,1H),7.68(t,J=7.5Hz,1H),7.57(t,J=7.6Hz,1H),7.48(d,J=7.7Hz,1H),7.30– 7.22(m,2H),6.86(t,J=7.3Hz,1H),6.67(d,J=8.1Hz,2H),5.40–5.22(m,2H),4.40(d,J=7.5Hz,1H),3.81–3.57(m,2H).

[0064] 13C NMR (126MHz, CDCl3) δ145.55,138.61,135.63,133.80,130.08,129.53,124.12,121.84,119.83,114.56,65.18,63.33,53.12.

[0065] Example 2

[0066]

[0067] 8-methyl-2-phenyl-1,2,3,9b-tetrahydrobenzo[d]imidazo[1,5-b]isothiazole 5,5-dioxide

[0068] Separation yield: 82%

[0069] 1 H NMR (500MHz, CDCl3) δ7.66(d,J=8.1Hz,1H),7.35(d,J=8.0Hz,1H),7.30–7.18(m,3H),6.85(t,J=7.4Hz,1H),6.72–6. 58(m,2H),5.31(d,J=7.5Hz,1H),5.25(dd,J=6.9,4.0Hz,1H),4.38(d,J=7.5Hz,1H),3.78–3.59(m,2H),2.48(s,3H).

[0070] 13 C NMR (126MHz, CDCl3) δ145.58,144.91,138.91,132.87,131.01,129.48,124.36,121.52,119.69,114.47,65.03,63.20,53.02,21.90.

[0071] Example 3

[0072]

[0073] 8-methoxy-2-phenyl-1,2,3,9b-tetrahydrobenzo[d]imidazo[1,5-b]isothiazole 5,5-dioxide

[0074] Separation yield: 85%

[0075] 1H NMR (500MHz, CDCl3) δ7.67(d,J=7.9Hz,1H),7.36(d,J=8.0Hz,1H),7.31–7.22(m,3H),6.85(t,J=7.4Hz,1H),6.67(d,J =8.1Hz,2H),5.31(d,J=7.5Hz,1H),5.25(dd,J=6.8,4.0Hz,1H),4.39(d,J=7.5Hz,1H),3.78–3.67(m,2H),2.48(s,3H).

[0076] 13 C NMR (126MHz, CDCl3) δ145.61,144.93,138.96,132.97,131.06,129.53,124.36,121.62,119.74,114.51,65.09,63.23,53.06,21.95.

[0077] Example 4

[0078]

[0079] 8-chloro-2-phenyl-1,2,3,9b-tetrahydrobenzo[d]imidazo[1,5-b]isothiazole 5,5-dioxide

[0080] Separation yield: 83%

[0081] 1 H NMR (500MHz, CDCl3) δ7.81(d,J=7.8Hz,1H),7.69(t,J=7.6Hz,1H),7.59(t,J=7.6Hz,1H),7.48(d,J=7.8Hz,1 H),7.11(d,J=8.7Hz,2H),6.63(d,J=9.1Hz,2H),5.34–5.27(m,2H),4.41(d,J=7.6Hz,1H),3.79–3.66(m,2H).

[0082] 13 C NMR (126MHz, CDCl3) δ144.26,142.17,138.20,135.46,133.93,130.26,124.15,122.64,121.98,115.01,64.98,63.35,53.25.

[0083] Example 5

[0084]

[0085] 2-(p-tolyl)-1,2,3,9b-tetrahydrobenzo[d]imidazo[1,5-b]isothiazole 5,5-dioxide

[0086] Separation yield: 85%

[0087] 1 H NMR (500MHz, CDCl3) δ7.80(t,J=7.8Hz,1H),7.66(m,J=12.3,7.5Hz,1H),7.56(m,J=7.5,3.5Hz,1H),7.47(d,J=7.8Hz,1H),7.0 6(d,J=8.1Hz,2H),6.68–6.54(m,2H),5.35–5.24(m,2H),4.33(d,J=7.4Hz,1H),3.75(dd,J=9.1,3.2Hz,1H),3.70–3.60(m,1H).

[0088] 13 C NMR (126MHz, CDCl3) δ143.45,138.87,135.80,133.76,130.02,129.39,124.06,121.79,114.88,113.78,65.86,63.39,53.63,20.54.

[0089] Example 6

[0090]

[0091] 2-(4-methoxyphenyl)-1,2,3,9b-tetrahydrobenzo[d]imidazo[1,5-b]isothiazole 5,5-dioxide separation yield: 79%

[0092] 1 H NMR (500MHz, CDCl3) δ7.79(d,J=7.8Hz,1H),7.67(td,J=7.6,1.1Hz,1H),7.56(t,J=7.5Hz,1H),7.46(d,J=7.7Hz,1H),6.85– 6.80(m,2H),6.69–6.63(m,2H),5.28(t,J=6.5Hz,2H),4.28(d,J=7.5Hz,1H),3.79–3.71(m,4H),3.62(dd,J=9.2,7.3Hz,1H).

[0093] 13 C NMR (126MHz, CDCl3) δ153.87,139.87,139.03,135.95,133.75,129.99,124.82,124.01,121.76,116.39,114.96,66.70,63.46,55.77,54.34.

[0094] Example 7

[0095]

[0096] 2-(4-(trifluoromethoxy)phenyl)-1,2,3,9b-tetrahydrobenzo[d]imidazo[1,5-b]isothiazole 5,5-dioxide

[0097] Separation yield: 82%

[0098] 1 H NMR (500MHz, CDCl3) δ7.80(d,J=7.8Hz,1H),7.69(t,J=7.6Hz,1H),7.58(t,J=7.5Hz,1H),7.48(d,J=7.8Hz, 1H),7.11(d,J=8.5Hz,2H),6.71–6.55(m,2H),5.39–5.19(m,2H),4.40(d,J=7.5Hz,1H),3.80–3.66(m,2H).

[0099] 13 C NMR (126MHz, CDCl3) δ144.26,142.17,138.19,135.44,133.93,130.25,124.1 6,121.94,121.7(q,J=188.75,7.3Hz).121.15,,115.00,64.95,63.34,53.23.

[0100] Example 8

[0101]

[0102] 2-(4-(methylthio)phenyl)-1,2,3,9b-tetrahydrobenzo[d]imidazo[1,5-b]isothiazole 5,5-dioxide separation yield: 87%

[0103] 1 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 7.7 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.25–7.10 (m, 2H), 6.54 (d, J = 8.3 Hz, 2H), 5.22 (dd, J = 6.7, 4.3 Hz, 2H), 4.44–4.22 (m, 1H), 3.74–3.56 (m, 2H), 2.34 (s, 3H).

[0104] 13 13C NMR (126 MHz, CDCl3) δ 143.97, 138.43, 135.58, 133.85, 130.44, 130.15, 127.88, 124.13, 121.90, 115.20, 65.12, 63.33, 53.21, 18.24.

[0105] Example 9

[0106]

[0107] 2-phenyl-8-((trifluoromethyl)thio)-1,2,3,9b-tetrahydrobenzo[d]imidazo[1,5-b]isothiazole 5,5-dioxide

[0108] Isolated yield: 80%

[0109] 1 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 7.8 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.49 (dd, J = 8.0, 4.5 Hz, 3H), 6.61 (d, J = 8.5 Hz, 2H), 5.37–5.22 (m, 2H), 4.50 (d, J = 7.6 Hz, 1H), 3.83 (dd, J = 9.1, 7.3 Hz, 1H), 3.65 (dd, J = 9.1, 4.7 Hz, 1H).

[0110] <C NMR (126MHz, CDCl3) δ147.15,138.27,137.54,135.02,134.01,130.39,129.7(q,J=306.25Hz)124.31,122.05,114.39,112.5(d J=2.5,Hz),63.53,63.19,52.25.

[0111] Example 10

[0112]

[0113] 2-(4-fluorophenyl)-1,2,3,9b-tetrahydrobenzo[d]imidazo[1,5-b]isothiazole 5,5-dioxide

[0114] Separation yield: 83%

[0115] 1 H NMR (500MHz, CDCl3) δ7.80(d,J=7.8Hz,1H),7.68(td,J=7.6,1.1Hz,1H),7.57(t,J=7.6Hz,1H),7.47(d,J=7. 9Hz,1H),7.02–6.90(m,2H),6.69–6.56(m,2H),5.33–5.23(m,2H),4.33(d,J=7.5Hz,1H),3.77–3.62(m,2H).

[0116] 13 C NMR (126MHz, CDCl3) δ157.2 (d, J = 59.06Hz), 142.1 (d, J = 3.13Hz), 138.62, 135.70, 133.86, 130.3(q,J=262.5Hz),130.13,124.07,121.85,116.0(q,J=13.13Hz),65.95,63.41,53.92.

[0117] Example 11

[0118]

[0119] 2-(4-chlorophenyl)-1,2,3,9b-tetrahydrobenzo[d]imidazo[1,5-b]isothiazole 5,5-dioxide

[0120] Separation yield: 84%

[0121] 1 H NMR (500MHz, CDCl3) δ7.79(d,J=7.8Hz,1H),7.68(t,J=7.6Hz,1H),7.58(t,J=7.5Hz,1H),7.47(d,J=7.8Hz,1 H),7.32(d,J=8.6Hz,2H),6.52(d,J=8.6Hz,2H),5.35–5.21(m,2H),4.37(d,J=7.5Hz,1H),3.76–3.58(m,2H).

[0122] 13 C NMR (126MHz, CDCl3) δ144.11,138.23,135.43,133.90,130.21,129.39,124.78,124.15,121.91,115.62,64.97,63.31,53.20.

[0123] Example 12

[0124]

[0125] 2-(4-bromophenyl)-1,2,3,9b-tetrahydrobenzo[d]imidazo[1,5-b]isothiazole 5,5-dioxide (4am) Separation yield: 88%

[0126] 1 H NMR(500MHz, CDCl3)δ7.80(d,J=7.8Hz,1H),7.73–7.61(m,1H),7.58(t,J=7.6Hz,1H),7.47(d,J=7.8Hz,1H),7 .33(dd,J=7.1,4.9Hz,2H),6.52(d,J=8.7Hz,2H),5.39–5.20(m,2H),4.38(d,J=7.6Hz,1H),3.79–3.62(m,2H).

[0127] 13 C NMR (126MHz, CDCl3) δ144.51,138.16,135.40,133.91,132.28,130.23,124.17,121.94,116.02,111.98,64.79,63.29,53.06.

[0128] Example 13

[0129]

[0130] 2-(4-iodophenyl)-1,2,3,9b-tetrahydrobenzo[d]imidazo[1,5-b]isothiazole5,5-dioxide

[0131] Separation yield: 91%

[0132] 1 H NMR(500MHz, CDCl3)δ7.81(d,J=7.8Hz,1H),7.69(td,J=7.6,1.1Hz,1H),7.59(t,J=7.6Hz,1H),7.54–7.49(m,2H),7.47(d,J=7.7Hz,1H),6.47– 6.38(m,2H),5.30(dd,J=7.3,4.0Hz,1H),5.26(d,J=7.6Hz,1H),4.39(d,J=7.5Hz,1H),3.72(dd,J=9.0,7.2Hz,1H),3.66(dd,J=9.1,4.1Hz,1H).

[0133] 13 C NMR (126MHz, CDCl3) δ145.07,138.16,135.40,133.92,130.26,124.17,122.00,117.42,116.50,81.46,64.59,63.27,52.88.

[0134] Example 14

[0135]

[0136] 2-(naphthalen-2-yl)-1,2,3,9b-tetrahydrobenzo[d]imidazo[1,5-b]isothiazole 5,5-dioxide

[0137] Separation yield: 84%

[0138] 11H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 7.8 Hz, 1H), 7.75–7.63 (m, 4H), 7.57 (t, J = 7.6 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.28 (t, J = 7.5 Hz, 1H), 7.01 (dd, J = 8.9, 2.5 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 5.45 (d, J = 7.6 Hz, 1H), 5.34 (dd, J = 7.0, 3.8 Hz, 1H), 4.50 (d, J = 7.6 Hz, 1H), 3.89–3.75 (m, 2H).

[0139] 13 13C NMR (126 MHz, CDCl3) δ 143.27, 138.58, 135.65, 134.53, 133.85, 130.14, 129.44, 128.33, 127.74, 126.83, 126.55, 124.16, 123.55, 121.89, 116.91, 109.33, 65.44, 63.39, 53.41.

[0140] Example 15

[0141]

[0142] 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,2,3,9b-tetrahydrobenzo[d]imidazo[1,5-b]isothiazole 5,5-dioxide

[0143] Isolated yield: 76%

[0144] 1 1H NMR (500 MHz, CDCl3) δ 7.78 (d, J = 7.8 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.59–7.50 (m, 1H), 7.45 (d, J = 7.8 Hz, 1H), 6.75 (d, J = 8.6 Hz, 1H), 6.29–6.14 (m, 2H), 5.24 (dd, J = 10.8, 6.3 Hz, 2H), 4.26 (d, J = 7.5 Hz, 1H), 4.24–4.13 (m, 4H), 3.68 (dd, J = 9.1, 3.1 Hz, 1H), 3.60 (dd, J = 9.2, 7.0 Hz, 1H).

[0145] 13C NMR (126MHz, CDCl3) δ144.10,140.51,138.89,137.59,135.82,133.74,129.97 ,124.03,121.71,117.86,108.39,104.23,66.26,64.77,64.30,63.39,54.02.

[0146] Example 16

[0147]

[0148] 2-(benzo[b]thiophen-5-yl)-1,2,3,9b-tetrahydrobenzo[d]imidazo[1,5-b]isothiazole 5,5-dioxide separation yield: 73%

[0149] 1 H NMR(500MHz, CDCl3)δ7.81(d,J=7.8Hz,1H),7.78–7.64(m,2H),7.57(t,J=7.6Hz,1 H),7.49(d,J=7.8Hz,1H),7.42(d,J=5.4Hz,1H),7.21(d,J=5.4Hz,1H),7.07(d,J= 2.3Hz,1H),6.82(dd,J=8.8,2.3Hz,1H),5.39(d,J=7.5Hz,1H),5.33(dd,J=7.4,3. 3Hz, 1H), 4.42 (d, J = 7.5Hz, 1H), 3.83 (dd, J = 9.0, 3.4Hz, 1H), 3.76 (t, J = 8.1Hz, 1H).

[0150] 13 C NMR (126MHz, CDCl3) δ143.15,140.83,138.76,135.79,133.82,131.81,130.10, 127.82,124.10,123.52,123.29,121.86,114.01,108.41,66.03,63.42,53.91.

Claims

1. A method for synthesizing a benzo[d]imidazo[1,5-b]isothiazolium-5,5-dioxide derivative, characterized in that: An organic solvent-water mixture containing benzo[d]imidazo[1,5-b]isothiazolium-5,5-dioxide was used as the electrolyte. The electrolyte was heated to 50–75°C, and an anode and cathode were placed in the electrolyte. A direct current was passed through the electrolyte to carry out an electrochemical reaction, yielding benzo[d]imidazo[1,5-b]isothiazolium-5,5-dioxide. The benzo[d]isothiazolium-1,1-dioxide has the structure of Formula 1. The N-arylglycine compound has the structure of Formula 2: The benzo[d]imidazo[1,5-b]isothiazol-5,5-dioxide derivative has the structure of Formula 3: in, R is hydrogen, a C1-C5 alkyl group, a C1-C5 alkoxy group, or a halogen substituent; Ar is a phenyl, naphthyl, or benzo[a]heterocyclic group, or a phenyl group containing a halogen substituent, trifluoromethoxy, C1-C5 alkylthio substituent, C1-C5 alkoxy substituent, C1-C5 alkyl substituent, or C2-C5 ester substituent.

2. The method for synthesizing a benzo[d]imidazo[1,5-b]isothiazolium-5,5-dioxide derivative according to claim 1, characterized in that: The organic solvent-water mixture uses acetonitrile and water as the mixed solvent.

3. The method for synthesizing a benzo[d]imidazo[1,5-b]isothiazolium-5,5-dioxide derivative according to claim 2, characterized in that: The mixed solvent is composed of acetonitrile and water in a volume ratio of (2-4):

1.

4. The method for synthesizing a benzo[d]imidazo[1,5-b]isothiazolium-5,5-dioxide derivative according to claim 1, characterized in that: The molar ratio of benzisothiazol-1,1-dioxide, N-arylglycine compound and paraformaldehyde is 1:(1-1.5):(1-1.5).

5. The method for synthesizing a benzo[d]imidazo[1,5-b]isothiazolium-5,5-dioxide derivative according to claim 1, characterized in that: The anode is a platinum electrode or a graphite electrode; The cathode is a glassy carbon electrode, a platinum electrode, a copper electrode, a graphite electrode, or a nickel electrode.

6. The method for synthesizing a benzo[d]imidazo[1,5-b]isothiazolium-5,5-dioxide derivative according to claim 5, characterized in that: The anode is a graphite electrode; the cathode is a platinum electrode.

7. A method for synthesizing a benzo[d]imidazo[1,5-b]isothiazolium-5,5-dioxide derivative according to any one of claims 1 to 6, characterized in that: The conditions for the electrochemical reaction are: current of 0.5–3 mA and reaction time of 1–3 hours.

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