Visible light-driven deaminative bromosulfonylation method

Abstract

The application discloses a visible light driven deaminative bromosulfonylation method. The method comprises the following steps: under the protection of inert gas, sulfonamide shown in formula (I), alkyne shown in formula (II), 10H-phenothiazine and carbon tetrabromide are dissolved in an organic solvent, tert-butyl nitrite and trifluoroacetic acid are added, and reaction is carried out under visible light irradiation to obtain (E)-beta-bromo vinyl sulfone shown in formula (III); wherein, R 1 is selected from aryl, substituted aryl, heteroaryl, alkyl or cycloalkyl; R 2 is selected from aryl, substituted aryl, heteroaryl, alkyl or cycloalkyl; R 3 is selected from alkyl; the photocatalyst is 10H-phenothiazine; the bromine source is carbon tetrabromide; the organic solvent is 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide or acetonitrile; and the wavelength of visible light is 420-520 nm. The method has the advantages of high stereoselectivity, mild reaction condition and wide substrate application range.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a visible light-driven deamination bromosulfonation method, and more specifically, to a method for converting alkynes into (E)-β-bromovinyl sulfones with high stereoselectivity by using sulfonamide as a sulfonyl source and carbon tetrabromide as a bromine source, and by visible light irradiation in the presence of 10H-phenothiazine. Background Technology

[0002] Vinyl sulfones are widely found in pharmaceuticals, pesticides, and functional materials, and are important intermediates in organic synthesis. Halosulfonation (simultaneously introducing a sulfonyl group and a halogen atom) is one of the direct methods for synthesizing β-halovinyl sulfones. Currently, iodosulfonation and chlorosulfonation have been extensively reported, while the development of bromosulfonation is relatively lagging. Most existing bromosulfonation methods are limited to terminal alkynes, rely on prefunctionalized sulfonyl sources (such as sulfonyl bromide, sulfonyl hydrazine, and sodium sulfinate), and often require high reaction temperatures, metal catalysts, or additives to control stereoselectivity. Previous research (Adv. Synth. Catal. 2025, 367, e70053) has reported a method using sulfonyl bromide to directly initiate the reaction under UV or near-UV irradiation, but this requires the addition of bisimine auxiliaries. Another study (Org. Lett. 2026, 28, 560−566) used sodium bromide as the bromine source to achieve bromosulfonylation of terminal alkynes via diazotization deamination of sulfonamides, but only three substrate examples were reported, and the reaction required high temperatures and yielded low results. Therefore, developing a bromosulfonylation method with mild reaction conditions, high stereoselectivity, broad substrate applicability, and no need for pre-functionalized sulfonyl sources remains of significant practical value. Summary of the Invention

[0003] The present invention aims to provide a visible light-driven deamination bromosulfonylation method, which can use commercially available sulfonamides as direct sulfonyl sources to react with alkynes under visible light irradiation to obtain (E)-β-bromovinyl sulfone in high yield and with high stereoselectivity.

[0004] This invention provides a visible light-driven deaminobromosulfonylation method, comprising the following steps:

[0005] Under inert gas protection, sulfonamide of formula (I), alkyne of formula (II), 10H-phenthiazine (PTZ) and carbon tetrabromide (CBr4) are dissolved in an organic solvent, tert-butyl nitrite (TBN) and trifluoroacetic acid (TFA) are added, and the mixture is reacted at 30-50 °C for 2-12 hours under visible light irradiation at a wavelength of 420-520 nm. After the reaction is completed, post-treatment is performed to obtain (E)-β-bromovinyl sulfone of formula (III).

[0006] The reaction formula is as follows:

[0007]

[0008] Among them, R 1 Selected from aryl, substituted aryl, heteroaryl, C1-C6 alkyl, cycloalkyl, or haloalkyl; R 2 Selected from aryl, substituted aryl, heteroaryl, C1-C6 alkyl or cycloalkyl; R 3 Selected from alkyl groups.

[0009] The photocatalyst is 10H-phenthiazine (PTZ); the bromine source is carbon tetrabromide (CBr4); and the organic solvent is N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, or 1,4-dioxane.

[0010] Compared with the prior art, the method provided by the present invention has the following beneficial effects:

[0011] (1) High stereoselectivity: specifically obtains (E)-configuration products.

[0012] (2) Mild reaction conditions: visible light driven, reaction temperature 40 °C, atmospheric pressure.

[0013] (3) Wide range of substrates: applicable to terminal and endoys; sulfonamides can have a variety of functional groups, including drug molecule derivatives.

[0014] (4) Simple operation: one-pot method, no need for prefunctionalized sulfonyl source, and use of commercial reagents.

[0015] (5) Environmentally friendly: metal-free and has good atom economy. Attached Figure Description

[0016] Figure 1 The 1H NMR spectrum of product III-1 in Example III;

[0017] Figure 2 The carbon NMR spectrum of product III-1 in Example III;

[0018] Figure 3 The 1H NMR spectrum of product III-20 in Example III;

[0019] Figure 4 The carbon NMR spectrum of product III-20 in Example III;

[0020] Figure 5 The hydrogen nuclear magnetic resonance spectrum of product III-21 in Example III;

[0021] Figure 6 The image shows the carbon NMR spectrum of product III-21 from Example III. Detailed Implementation

[0022] The following examples are for illustrative purposes only and are not intended to limit the scope of protection of the invention. Experimental methods not specifically described in the examples are generally performed under conventional conditions or as recommended by the manufacturer.

[0023] I. Condition Optimization Experiment

[0024] The following optimization experiments used 4-methylbenzenesulfonamide (I-1) and phenylacetylene (II-1) as template substrates, and the product was (E)-1-((2-bromo-2-phenylvinyl)sulfonyl)-4-methylbenzene (III-1). Unless otherwise specified, the reaction scale was 0.1 mmol, the solvent volume was 0.5 mL, nitrogen protection was applied, irradiation was performed using a 25 W blue LED (450-460 nm), the reaction time was 4 h, the temperature was 40 °C, and the yield was determined by GC-MS.

[0025] Example 1: Screening of photocatalysts

[0026] The photocatalyst was modified according to Table 1 (5 mol%), with the following other conditions: I-1 (0.1 mmol), II-1 (0.1 mmol), CBr4 (0.1 mmol), TBN (0.2 mmol), TFA (0.1 mmol), and 1,4-dioxane 0.5 mL. The results are shown in Table 1, with PTZ showing the best effect (72% yield).

[0027] Table 1 Screening of photocatalysts

[0028] 1 Tetrabutylammonium decatungstate 42 2 4CzIPN 65 3 Riboflavin 69 4 10H-Phenothiazine (PTZ) 72 5 Yihong Y 59 6 Rhodamine B 51 7 Rhodamine 6G 52 8 Tetrabromofluorescein 57

[0029] Example 2: Screening of reactant equivalence ratio

[0030] With PTZ fixed as the photocatalyst, the equivalent amounts of II-1 and CBr4 were varied according to Table 2. The optimal result was I-1: II-1:CBr4 = 1:1.5:1.6 (88% yield).

[0031] Table 2 Equivalent Ratio Optimization

[0032] 1 1:1:1 72 2 1:1.3:1.3 80 3 1:1.6:1.6 85 4 1:1.5:1.6 88

[0033] Example 3: TBN Dosage Optimization

[0034] With the I-1: II-1: CBr4 ratio fixed at 1:1.5:1.6, the TBN equivalent was varied. The highest yield (91%) was achieved when the TBN equivalent was 1.5.

[0035] Table 3 TBN Dosage Optimization

[0036] 1 2.5 79 2 2.0 88 3 1.5 91 4 1.0 83

[0037] Example 4: Reaction Time Screening

[0038] With TBN = 1.5 equivalents, the yield no longer increased (91%) after a reaction time of 4 h.

[0039] Table 4 Optimization of Reaction Time

[0040] 1 1 24 2 2 47 3 3 69 4 4 91 5 5 91

[0041] Example 5: Solvent Screening

[0042] The yield was 91% when 1,4-dioxane was used as the solvent, while the yield was lower when other solvents (MeCN, DCM, THF, etc.) were used.

[0043] Example 6: Control Experiment

[0044] The yield was 33% without light, 25% without PTZ, and only 5% in air, indicating that light, PTZ, and inert atmosphere are all necessary.

[0045] II. Substrate Expansion Experiment under Optimal Conditions

[0046] Based on the above optimization, the optimal reaction conditions were determined to be: sulfonamide (0.1 mmol), alkyne (1.5 equivalents), CBr4 (1.6 equivalents), PTZ (5 mol%), TBN (1.5 equivalents), TFA (1.0 equivalents), 1,4-dioxane (0.5 mL), 40 °C, irradiation with a 25W blue LED (450-460 nm) for 4 h, under nitrogen protection.

[0047] The following examples were all performed under these optimal conditions, and the product structures were confirmed by ¹H NMR and ¹³C NMR.

[0048] Example 7: Different sulfonamide substrates

[0049] Using phenylacetylene as the alkyne, the R of sulfonamide was changed. 1 The groups were removed to obtain products III-1 to III-13. The yield and physical properties are shown in Table 5.

[0050] Table 5. Reaction results for different sulfonamide substrates

[0051] III-1 4-Methylphenyl 90 White solid 87 - 89 III-2 Phenyl 72 White solid 68 - 70 III-3 2-Methylphenyl 52 pale yellow oil — III-4 4-Methoxyphenyl 74 White solid 56 - 58 III-5 4-Chlorophenyl 92 White solid 117 - 118 III-6 2-Chlorophenyl 93 White solid 103 - 105 III-7 4-Fluorophenyl 57 White solid 86 - 88 III-8 4-Trifluoromethylphenyl 67 White solid 117 - 118 III-9 2-Naphthyl 56 Colorless oil — III-10 2-Thienyl 71 White solid 73 - 75 III-11 Cyclopropyl 52 White solid 52 - 54 III-12 Celecoxib derivatives 80 White solid 128 - 130 III-13 Vardioxobride derivatives 77 pale yellow oil —

[0052] Example 8: Different alkyne substrates

[0053] Using 4-methylbenzenesulfonamide as a sulfonamide, the R of the alkyne is changed. 2 The groups were removed to obtain products III-14 to III-21. The yield and physical properties are shown in Table 6.

[0054] Table 6. Reaction results for different alkyne substrates

[0055] III-14 4-Methylphenyl 91 White solid 116 - 118 III-15 2-Methylphenyl 72 pale yellow oil — III-16 4-Methoxyphenyl 83 White solid 96 - 98 III-17 4-Chlorophenyl 57 pale yellow oil — III-18 4-Bromophenyl 52 White solid 132 - 134 III-19 4-Methoxycarbonylphenyl 61 White solid 110 - 112 III-20 Cyclopropyl 90 White solid 80 - 82 III-21 1-Phenylenyne (endoyne) 84 White solid 88 - 90

[0056] Example 9: Gram-scale Scale-up Experiment

[0057] At a scale of 1 mmol, under optimal conditions, product III-1 was obtained in a yield of 0.296 g (88%); at a scale of 5 mmol, product III-1 was obtained in a yield of 1.394 g (83%).

[0058] III. Characterization data of typical compounds

[0059] The product numbers below correspond to those in Examples 7 and 8, and their structural formulas and ¹H NMR and ¹³C NMR data are as follows.

[0060] Product III-1

[0061]

[0062] 1 H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 8.0 Hz, 2H), 7.41 - 7.31 (m,5H), 7.20 (d, J = 8.0 Hz, 2H), 7.14 (s, 1H), 2.40 (s, 3H).

[0063] 13 C NMR (100 MHz, CDCl3) δ144.7, 138.3, 137.5, 136.1, 134.3, 130.4,129.7 (2C), 128.6 (2C), 128.0 (2C), 127.9 (2C), 21.7.

[0064] Product III-4

[0065]

[0066] 1 H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.8 Hz, 2H), 7.31 - 7.23 (m,5H), 7.07 (s, 1H), 6.77 (d, J = 8.8 Hz, 2H), 3.76 (s, 3H).

[0067] Product III-5

[0068]

[0069] 1 H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.4 Hz, 2H), 7.35 - 7.31 (m,1H), 7.26 (t, J = 10.4 Hz, 4H), 7.22 - 7.19 (m, 2H), 7.09 (s, 1H).

[0070] Product III-6

[0071]

[0072] 1 H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.0 Hz, 1H), 7.45 - 7.41 (m,2H), 7.36 (s, 1H), 7.27 - 7.25 (m, 1H), 7.22 - 7.19 (m, 4H), 7.15 - 7.11 (m,1H).

[0073] 13 13C NMR (100 MHz, CDCl3) δ 139.4, 137.9, 135.8, 134.4, 133.4, 132.5, 131.5, 130.9, 130.4, 128.3 (2C), 127.9 (2C), 126.9.

[0074] Product III-11

[0075]

[0076] 1 H NMR (400 MHz, CDCl3) δ 7.53 - 7.51 (m, 2H), 7.41 (d, J = 6.6 Hz, 3H), 7.10 (s, 1H), 2.24 - 2.18 (m, 1H), 1.16 - 1.12 (m, 2H), 0.96 - 0.91 (m, 2H).

[0077] 13 13C NMR (100 MHz, CDCl3) δ 138.4, 136.4, 132.5, 130.8, 128.8 (2C), 128.2 (2C), 32.0, 5.5 (2C).

[0078] Section III-12

[0079]

[0080] 1 H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.4 Hz, 2H), 7.36 - 7.30 (m,7H), 7.20 - 7.16 (m, 3H), 7.08 (d, J = 7.6 Hz, 2H), 6.74 (s, 1H), (s,3H)

[0081] 13 C NMR (100 MHz, CDCl3) δ 145.3, 144.3 (d, 145.3). 2 J C-F = 38 Hz), 143.2.139.9(2C), 139.6, 135.9, 133.8, 130.7,129.8(2C), 128.9(2C), 128.7(2C),128.6(2C), 128.2(2C), 125.7, 125.3(2C), 121.0 (d, 1 J C-F = 267 Hz), 106.6.21.4.

[0082] 19 F NMR (376 MHz, CDCl3) δ 62.44.

[0083] Section III-13

[0084]

[0085] 1 H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.4 Hz, 2H), 7.43 - 7.28 (m,10H), 7.21 (s, 1H), 7.18 (d, J = 8.4 Hz, 2H), 2.48 (s, 3H).

[0086] 13C NMR (100 MHz, CDCl3) δ 167.4, 161.1, 139.3, 139.2, 136.2, 136.0,134.1, 130.6, 130.1 (2C), 129.9, 128.8 (2C), 128.7 (2C), 128.5 (2C), 128.4,128.2 (2C), 128.1 (2C), 114.4, 11.8.

[0087] Product III-14

[0088]

[0089] 1 H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.0 Hz, 2H), 7.27 - 7.25 (m,2H), 7.22 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 4.0 Hz, 2H), 7.08 (s, 1H), 2.41(s, 3H), 2.39(s, 3H).

[0090] Product III-16

[0091]

[0092] 1 H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.8Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.06 (s, 1H), 6.85 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H), 2.41 (s, 3H).

[0093] 13 C NMR (100 MHz, CDCl3) δ 161.4, 144.6, 138.7, 137.6, 133.1, 130.8(2C), 129.7 (2C), 128.2, 127.8 (2C), 113.3 (2C), 55.4, 21.7.

[0094] Product III-20

[0095]

[0096] 1 H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.0Hz, 2H), 6.76 (s, 1H), 3.07 - 3.00 (m, 1H), 2.46 (s, 3H), 1.05 - 0.96 (m,4H).

[0097] 13 C NMR (100 MHz, CDCl3) δ 150.3, 144.7, 138.6, 130.8, 130.1 (2C), 127.3 (2C), 21.7, 15.4, 10.1 (2C).

[0098] Product III-21

[0099]

[0100] 1 H NMR (400 MHz, DMSO) δ 7.37 (d, J = 8.4 Hz, 2H), 7.33 - 7.27 (m,5H), 7.11 - 7.09 (m, 2H), 2.75 - 2.70 (m, 2H), 2.37 (s, 3H), 1.17 (t, J = 7.2Hz, 3H).

[0101] 13 C NMR (100 MHz, DMSO) δ 145.0, 144.8, 139.1, 137.3, 136.4, 130.2(2C), 129.6, 128.6 (2C), 128.3 (2C), 127.9 (2C), 28.2, 21.6, 12.8.

[0102] The embodiments described above are merely illustrative of the technical solutions of the present invention and are not intended to limit it. Those skilled in the art should understand that, without departing from the concept of the present invention, any combination, substitution, or modification of the technical features can be made, and all such modifications should be covered within the protection scope of the present invention. The protection scope of the present invention should be determined by the claims, and the specification can be used to interpret the claims.

Claims

1. A visible light-driven deaminobromosulfonation method, characterized in that, The method comprises: dissolving sulfonamide of formula (I), alkyne of formula (II), 10H-phenthiazide and carbon tetrabromide in an organic solvent under an inert gas atmosphere, adding tert-butyl nitrite and trifluoroacetic acid, and reacting under visible light irradiation to obtain (E)-β-bromovinyl sulfone of formula (III); the reaction formula is as follows: Among them, R 1 Selected from aryl, substituted aryl, heteroaryl, C1-C6 alkyl, cycloalkyl, or haloalkyl; R 2 Selected from aryl, substituted aryl, heteroaryl, C1-C6 alkyl or cycloalkyl; R 3 Selected from alkyl groups.

2. The visible light-driven deaminobromosulfonylation method according to claim 1, characterized in that, The wavelength of the visible light is 420-520 nm.

3. The visible light-driven deaminobromosulfonylation method according to claim 2, characterized in that, The wavelength of the visible light is 450-460 nm.

4. The visible light-driven deaminobromosulfonylation method according to claim 1, characterized in that, The organic solvent is selected from N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, or 1,4-dioxane.

5. The visible light-driven deaminobromosulfonylation method according to claim 4, characterized in that, The organic solvent is 1,4-dioxane.

6. The visible light-driven deaminobromosulfonylation method according to claim 1, characterized in that, The reaction temperature is 30-50 °C, and the reaction time is 2-12 hours.

7. The visible light-driven deaminobromosulfonylation method according to claim 6, characterized in that, The reaction temperature was 40 °C and the reaction time was 4 hours.

8. The visible light-driven deaminobromosulfonylation method according to claim 1, characterized in that, The amount of 10H-phenothiazine used is 1-10 mol% of the molar amount of sulfonamide, the amount of carbon tetrabromide used is 1.5-2.0 times the molar amount of sulfonamide, and the amount of tert-butyl nitrite used is 1.0-2.5 times the molar amount of sulfonamide.

9. The visible light-driven deaminobromosulfonylation method according to claim 8, characterized in that, The amount of 10H-phenothiazine used is 5 mol%, the amount of carbon tetrabromide used is 1.6 times, and the amount of tert-butyl nitrite used is 1.5 times.

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