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Decarboxylative difluoromethylation of aldehydes with PhSO2CF2COOK: A facile and efficient access to difluoromethylated carbinols
Tetrahedron Letters 59 (2018) 3184–3187
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Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Decarboxylative difluoromethylation of aldehydes with PhSO2CF2COOK: A facile and efficient access to difluoromethylated carbinols Yu-Jun Zhu a, Zhong-Liang Lei a, Da-Kang Huang a, Bo Lian a, Zhen-Jiang Liu a,b,⇑, Xiao-Jun Hu a, Jin-Tao Liu b,⇑ a b
School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Haiquan Road, Shanghai 201418, China Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
a r t i c l e
i n f o
Article history: Received 16 May 2018 Revised 30 June 2018 Accepted 6 July 2018 Available online 6 July 2018
a b s t r a c t A novel decarboxylative difluoromethylation reaction of PhSO2CF2COOK with aldehydes under metaland ligand-free conditions has been developed. The reaction is very mild and tolerates a wide range of aldehydes (both enolizable and non-enolizable aldehydes), providing a facile and efficient method for the synthesis of structurally diverse difluoromethylated carbinols in moderate to excellent yields. Ó 2018 Elsevier Ltd. All rights reserved.
Keywords: Decarboxylative difluoromethylation Addition Potassium phenylsulfonyldifluoroacetate Difluoromethyl alcohol
Introduction Difluoromethyl-containing compounds have gained growing interest in the fields of biological, agrochemical, and pharmaceutical science during the past decades [1] because the incorporation of a difluoromethyl group with high lipophilicity and strong electron-withdrawing ability can lead to profound changes on the physical, chemical, and biological properties of the molecules [2]. Among various difluoromethyl-containing compounds, a-difluoromethyl alcohols have attracted considerable attention since these structural motifs are among the most important and prevalent substructure units in biologically active compounds and pharmaceuticals (Fig. 1) [3]. Based on their prime importance in medicinal chemistry, a number of strategies have been developed for the synthesis of this compound species [4], including the direct and indirect nucleophilic difluoromethylation reactions of carbonyl compounds [5,6]. However, most of the reported methods have suffered from several drawbacks, which greatly restrict their applications. For example, they often require the high costs of the difluoromethylating reagents, moisture sensitive initiators or strong bases, and low reaction temperature. Therefore, it is still
⇑ Corresponding authors at: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Haiquan Road, Shanghai 201418, China (Z.-J. Liu). E-mail addresses: [email protected] (Z.-J. Liu), [email protected] (J.-T. Liu). https://doi.org/10.1016/j.tetlet.2018.07.021 0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
highly desirable to develop a mild and efficient method for the synthesis of a-difluoromethyl alcohols. In recent years, the decarboxylative addition reaction to carbonyl compounds has emerged as a powerful and eco-friendly tool for the generation of carbon-carbon bonds due to its mild reaction conditions [7]. Although great efforts have been devoted to the development of the decarboxylative addition reactions of nonfluorinated carboxylic acids and their derivatives with carbonyl compounds [7,8], the decarboxylative addition reactions of their fluorinated counterparts remained much less explored [9]. The decarboxylative addition reaction of halodifluoroacetate salts with carbonyl compounds have been reported, however, only the difluoroolefination products were given, and no difluoromethylated carbinols were produced [10]. Recently, only two examples of the decarboxylative difluoromethylation of aldehydes with difluoromethylene phosphabetaine (Ph3P+CF2CO2 ) were reported by Dilman and co-workers to afford a-difluoromethyl alcohols in excellent yields by adding a stoichiometric amount of trimethylsilyl chloride [5b]. Later, Xiao et al. investigated the decarboxylative addition reaction of potassium 2-pyridinylsulfonyldifluoroacetate (2-PySO2CF2COOK, 1) with aldehydes, but only Julia-Kocienski gem-difluoro-olefination products were obtained (Scheme 1, eq. a) [11]. It is exemplified that the substituents on the sulfonyl group of the difluoromethylating reagents have a significant effect on the chemical reactivity of the corresponding compounds [12]. Inspired by Xiao and Hu’s reports [11,12], we envisioned that an analogous compound of 1, potassium phenylsulfonyldifluoroacetate
Y.-J. Zhu et al. / Tetrahedron Letters 59 (2018) 3184–3187
Fig. 1. a-Difluoromethyl alcohol motifs in bioactive molecules.
Scheme 1. The different chemical reactivities between 2-PySO2CF2COOK 1 and PhSO2CF2COOK 2.
(PhSO2CF2COOK, 2) may possess different chemical reactivities toward carbonyl compounds. As a continuation of our interests on the decarboxylative addition reactions of fluorinated carboxylic acids and their derivatives [13], herein, we wish to report a novel decarboxylative addition reaction of potassium phenylsulfonyldifluoroacetate 2 with aldehydes. In sharp contrast to Xiao’s report [11], the decarboxylative addition reaction of PhSO2CF2COOK 2 with aldehydes exclusively affords a-phenylsulfonyldifluoromethyl alcohols in moderate to excellent yields under mild reaction conditions and no difluoroolefination product was observed in the reaction (Scheme 1, eq. b). Results and discussion At the outset, phenylsulfonyldifluoroacetic acid (PhSO2CF2COOH, 3) was selected as the substrate to explore its decarboxylative addition reaction with benzaldehyde 4a referring to our previous report [13]. Unfortunately, when the decarboxylative addition reaction of 3 with 4a was subjected to the optimized reaction conditions for the decarboxylative aldol reaction of a,a-difluoro-b-keto acid with aldehydes (toluene, 100 °C, 12 h), no reaction occurred and the PhSO2CF2COOH 3 remained intact. To our delight, when the reaction solvent was changed to DMF, the decarboxylation of 3 occurred smoothly and gave the addition product 5a in 23% yield (Scheme 2). However, the decarboxylative protonation side product, difluoromethyl phenyl sulfone 6, was isolated as the major product. This result indicated that the rate of the decarboxylative protonation of PhSO2CF2COOH 3 is much faster than that of the decarboxylative addition of 3 to aldehyde. It implies
Scheme 2. The decarboxylative addition reaction of PhSO2CF2COOH 3 with benzaldehyde 4a.
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that the decarboxylative addition reaction should be performed under proton-free conditions for obtaining high yield. With these considerations in mind, PhSO2CF2COOH 3 was then transformed into its potassium salt PhSO2CF2COOK 2, and 2 was subsequently used as the model substrate to investigate its decarboxylative addition reaction with benzaldehyde 4a. The results are summarized in Table 1. Surprisingly, the decarboxylative addition reaction of PhSO2CF2COOK 2 with benzaldehyde 4a could be proceeded at room temperature, affording the corresponding addition product 5a in moderate yield (Table 1, entry 1). Slightly elevating the reaction temperature to 28 °C led to a dramatic improvement of the yield (Table 1, entry 2). Further increase in the reaction temperature resulted in a slight reduction of the yield (Table 1, entry 3). The optimization of the reaction time showed that the reaction could be completed in 15 h at 28 °C, providing the addition product in 98% yield (Table 1, entries 2, 4–6). Reducing the amount of benzaldehyde 4a from 2.0 equiv. to 1.5 equiv. also led to a decrease on the yield (Table 1, entry 7). Among the solvents tested, DMF proved to be the best solvent for this reaction, producing the corresponding addition product 5a in good to excellent yields (Table 1, entries 2–11). Thus, the optimized reaction conditions for this novel decarboxylative difluoromethylation reaction of aldehydes were as follows: PhSO2CF2COOK 2 (1.0 equiv.) and benzaldehyde 4a (2.0 equiv.) in DMF at 28 °C for 15 h. It is noteworthy that no difluoroolefination product was observed under all the tested reaction conditions, which is sharp contrast to Xiao’s report [11]. With the optimal reaction conditions established, a variety of aldehydes (both enolizable and non-enolizable aldehydes) were employed as the substrates to evaluate the scope of the decarboxylative difluoromethylation reaction. As shown in Table 2, all the decarboxylative difluoromethylation reactions took place readily and furnished the corresponding phenylsulfonyldifluoromethylated carbinols 5 in moderate to excellent yields. Aromatic aldehydes 4a–i proved to be excellent substrates for the reaction. The electronic properties of the substituents on the phenyl ring of the aromatic aldehydes 4b–h had little impact on the reaction efficiency, and aldehydes (4b–c, g–h) with electron-donating groups gave slightly higher yield than those (4d–f) with electronwithdrawing groups. It is worth mentioning that when 4-acetylbenzaldehyde 4f was employed as the electrophilic partner, the decarboxylative difluoromethylation reaction chemoselectively proceeded at the aldehyde moiety and no difluoromethylated adduct of ketone moiety was observed. Heteroaromatic aldehyde 4j was also suitable for this decarboxylative difluoromethylation reaction, furnishing the difluoromethylated product 5j in good yield. Moreover, enolizable aliphatic aldehyde 4k was also found to be tolerated, affording the corresponding product 5k in moderate yield. In the case of a,b-unsaturated aldehyde 4l, only 1,2-addition product 5l was obtained albeit with low yield. Acetophenone and benzophenone were also evaluated for this reaction, however, no desired difluoromethylation products were found. The resulting a-phenylsulfonyldifluoromethyl alcohols are versatile intermediates in organic synthesis [6g,l–m,14]. To demonstrate their synthetic utility, the reductive desulfonylation of the product was then investigated. Taking 5a as an example, the reductive desulfonylation reaction went smoothly under the conditions of Mg0/HOAc/NaOAc in DMF/H2O [6e,g], giving the difluoromethyl alcohol 7 in excellent yield (Scheme 3, eq. a). Furthermore, the model reaction could be scaled up to gram quantities, and quantitative yield could be obtained (Scheme 3, eq. b), indicating the potential value for the application in industry. Based on our research results and referring to related literatures [9,11,13], a plausible reaction mechanism for this decarboxylative difluoromethylation reaction was proposed as shown in Scheme 4. Under the standard reaction conditions, PhSO2CF2COOK 2 first decarboxylates to generate PhSO2CF2 intermediate A along with
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Y.-J. Zhu et al. / Tetrahedron Letters 59 (2018) 3184–3187
Table 1 The decarboxylative addition reaction of PhSO2CF2COOK 2 with benzaldehyde 4a under various conditions.
a b c
Entry
2:4aa
Solvent
Temp. (°C)
Time (h)
Yield (%)b
1 2 3 4 5 6 7 8 9 10 11
1:2 1:2 1:2 1:2 1:2 1:2 1:1.5 1:2 1:2 1:2 1:2
DMF DMF DMF DMF DMF DMF DMF DMSO NMP Dioxane THF
r.t. 28 40 28 28 28 28 28 28 28 28
12 12 12 9 15 18 15 15 15 15 15
57 92 82 85 98 97 84 84 62 NRc NRc
Molar ratio. Yields of product isolated after column chromatography. NR = No reaction.
Table 2 Scope of the decarboxylative difluoromethylation reaction of aldehydes 4 with PhSO2CF2COOK 2.a
Scheme 4. Plausible reaction mechanism for the decarboxylative difluoromethylation reaction.
one equivalent of gaseous carbon dioxide evolving. The PhSO2CF2 intermediate A undergoes further addition into aldehydes 4 to give the corresponding a-phenylsulfonyldifluoromethyl alcohols 5. If there is any proton sources existed in the reaction system, the decarboxylative protonation product would be formed. Conclusions
a Reaction conditions: PhSO2CF2COOK 2 (0.25 mmol) and aldehydes 4 (0.5 mmol) in DMF (1.5 mL) at 28 °C for 15 h. Yields of product isolated after column chromatography are given.
In summary, we have successfully developed the first decarboxylative addition reaction of PhSO2CF2COOK with both enolizable and non-enolizable aldehydes under the metal- and ligandfree conditions [15]. The reaction is very mild and a wide range of difluoromethyl alcohols could be obtained in moderate to high yields. There is no any difluoroolefination product observed in all the reactions, which is remarkably different from the decarboxylative addition reaction of 2-PySO2CF2COOK with aldehydes [11]. Further studies on the application of PhSO2CF2COOK reagent are currently in progress in our laboratory. Acknowledgements
Scheme 3. The reductive desulfonylation of 5a (a) and scaled-up version of the decarboxylative difluoromethylation reaction (b).
Financial support from the National Natural Science Foundation of China (No. 21102093), the Science and Technology Commission of Shanghai Municipality (Nos. 15DZ1942203, 16090503500), Chemical Engineering and Technology (Perfume and Aroma Technology) of Shanghai Plateau Discipline, Shanghai Education Development Foundation (Shuguang Program) and Shanghai Institute of Technology (No. XTCX2016-5) is gratefully acknowledged.
Y.-J. Zhu et al. / Tetrahedron Letters 59 (2018) 3184–3187
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Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Decarboxylative difluoromethylation of aldehydes with PhSO2CF2COOK: A facile and efficient access to difluoromethylated carbinols Yu-Jun Zhu a, Zhong-Liang Lei a, Da-Kang Huang a, Bo Lian a, Zhen-Jiang Liu a,b,⇑, Xiao-Jun Hu a, Jin-Tao Liu b,⇑ a b
School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Haiquan Road, Shanghai 201418, China Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
a r t i c l e
i n f o
Article history: Received 16 May 2018 Revised 30 June 2018 Accepted 6 July 2018 Available online 6 July 2018
a b s t r a c t A novel decarboxylative difluoromethylation reaction of PhSO2CF2COOK with aldehydes under metaland ligand-free conditions has been developed. The reaction is very mild and tolerates a wide range of aldehydes (both enolizable and non-enolizable aldehydes), providing a facile and efficient method for the synthesis of structurally diverse difluoromethylated carbinols in moderate to excellent yields. Ó 2018 Elsevier Ltd. All rights reserved.
Keywords: Decarboxylative difluoromethylation Addition Potassium phenylsulfonyldifluoroacetate Difluoromethyl alcohol
Introduction Difluoromethyl-containing compounds have gained growing interest in the fields of biological, agrochemical, and pharmaceutical science during the past decades [1] because the incorporation of a difluoromethyl group with high lipophilicity and strong electron-withdrawing ability can lead to profound changes on the physical, chemical, and biological properties of the molecules [2]. Among various difluoromethyl-containing compounds, a-difluoromethyl alcohols have attracted considerable attention since these structural motifs are among the most important and prevalent substructure units in biologically active compounds and pharmaceuticals (Fig. 1) [3]. Based on their prime importance in medicinal chemistry, a number of strategies have been developed for the synthesis of this compound species [4], including the direct and indirect nucleophilic difluoromethylation reactions of carbonyl compounds [5,6]. However, most of the reported methods have suffered from several drawbacks, which greatly restrict their applications. For example, they often require the high costs of the difluoromethylating reagents, moisture sensitive initiators or strong bases, and low reaction temperature. Therefore, it is still
⇑ Corresponding authors at: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Haiquan Road, Shanghai 201418, China (Z.-J. Liu). E-mail addresses: [email protected] (Z.-J. Liu), [email protected] (J.-T. Liu). https://doi.org/10.1016/j.tetlet.2018.07.021 0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
highly desirable to develop a mild and efficient method for the synthesis of a-difluoromethyl alcohols. In recent years, the decarboxylative addition reaction to carbonyl compounds has emerged as a powerful and eco-friendly tool for the generation of carbon-carbon bonds due to its mild reaction conditions [7]. Although great efforts have been devoted to the development of the decarboxylative addition reactions of nonfluorinated carboxylic acids and their derivatives with carbonyl compounds [7,8], the decarboxylative addition reactions of their fluorinated counterparts remained much less explored [9]. The decarboxylative addition reaction of halodifluoroacetate salts with carbonyl compounds have been reported, however, only the difluoroolefination products were given, and no difluoromethylated carbinols were produced [10]. Recently, only two examples of the decarboxylative difluoromethylation of aldehydes with difluoromethylene phosphabetaine (Ph3P+CF2CO2 ) were reported by Dilman and co-workers to afford a-difluoromethyl alcohols in excellent yields by adding a stoichiometric amount of trimethylsilyl chloride [5b]. Later, Xiao et al. investigated the decarboxylative addition reaction of potassium 2-pyridinylsulfonyldifluoroacetate (2-PySO2CF2COOK, 1) with aldehydes, but only Julia-Kocienski gem-difluoro-olefination products were obtained (Scheme 1, eq. a) [11]. It is exemplified that the substituents on the sulfonyl group of the difluoromethylating reagents have a significant effect on the chemical reactivity of the corresponding compounds [12]. Inspired by Xiao and Hu’s reports [11,12], we envisioned that an analogous compound of 1, potassium phenylsulfonyldifluoroacetate
Y.-J. Zhu et al. / Tetrahedron Letters 59 (2018) 3184–3187
Fig. 1. a-Difluoromethyl alcohol motifs in bioactive molecules.
Scheme 1. The different chemical reactivities between 2-PySO2CF2COOK 1 and PhSO2CF2COOK 2.
(PhSO2CF2COOK, 2) may possess different chemical reactivities toward carbonyl compounds. As a continuation of our interests on the decarboxylative addition reactions of fluorinated carboxylic acids and their derivatives [13], herein, we wish to report a novel decarboxylative addition reaction of potassium phenylsulfonyldifluoroacetate 2 with aldehydes. In sharp contrast to Xiao’s report [11], the decarboxylative addition reaction of PhSO2CF2COOK 2 with aldehydes exclusively affords a-phenylsulfonyldifluoromethyl alcohols in moderate to excellent yields under mild reaction conditions and no difluoroolefination product was observed in the reaction (Scheme 1, eq. b). Results and discussion At the outset, phenylsulfonyldifluoroacetic acid (PhSO2CF2COOH, 3) was selected as the substrate to explore its decarboxylative addition reaction with benzaldehyde 4a referring to our previous report [13]. Unfortunately, when the decarboxylative addition reaction of 3 with 4a was subjected to the optimized reaction conditions for the decarboxylative aldol reaction of a,a-difluoro-b-keto acid with aldehydes (toluene, 100 °C, 12 h), no reaction occurred and the PhSO2CF2COOH 3 remained intact. To our delight, when the reaction solvent was changed to DMF, the decarboxylation of 3 occurred smoothly and gave the addition product 5a in 23% yield (Scheme 2). However, the decarboxylative protonation side product, difluoromethyl phenyl sulfone 6, was isolated as the major product. This result indicated that the rate of the decarboxylative protonation of PhSO2CF2COOH 3 is much faster than that of the decarboxylative addition of 3 to aldehyde. It implies
Scheme 2. The decarboxylative addition reaction of PhSO2CF2COOH 3 with benzaldehyde 4a.
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that the decarboxylative addition reaction should be performed under proton-free conditions for obtaining high yield. With these considerations in mind, PhSO2CF2COOH 3 was then transformed into its potassium salt PhSO2CF2COOK 2, and 2 was subsequently used as the model substrate to investigate its decarboxylative addition reaction with benzaldehyde 4a. The results are summarized in Table 1. Surprisingly, the decarboxylative addition reaction of PhSO2CF2COOK 2 with benzaldehyde 4a could be proceeded at room temperature, affording the corresponding addition product 5a in moderate yield (Table 1, entry 1). Slightly elevating the reaction temperature to 28 °C led to a dramatic improvement of the yield (Table 1, entry 2). Further increase in the reaction temperature resulted in a slight reduction of the yield (Table 1, entry 3). The optimization of the reaction time showed that the reaction could be completed in 15 h at 28 °C, providing the addition product in 98% yield (Table 1, entries 2, 4–6). Reducing the amount of benzaldehyde 4a from 2.0 equiv. to 1.5 equiv. also led to a decrease on the yield (Table 1, entry 7). Among the solvents tested, DMF proved to be the best solvent for this reaction, producing the corresponding addition product 5a in good to excellent yields (Table 1, entries 2–11). Thus, the optimized reaction conditions for this novel decarboxylative difluoromethylation reaction of aldehydes were as follows: PhSO2CF2COOK 2 (1.0 equiv.) and benzaldehyde 4a (2.0 equiv.) in DMF at 28 °C for 15 h. It is noteworthy that no difluoroolefination product was observed under all the tested reaction conditions, which is sharp contrast to Xiao’s report [11]. With the optimal reaction conditions established, a variety of aldehydes (both enolizable and non-enolizable aldehydes) were employed as the substrates to evaluate the scope of the decarboxylative difluoromethylation reaction. As shown in Table 2, all the decarboxylative difluoromethylation reactions took place readily and furnished the corresponding phenylsulfonyldifluoromethylated carbinols 5 in moderate to excellent yields. Aromatic aldehydes 4a–i proved to be excellent substrates for the reaction. The electronic properties of the substituents on the phenyl ring of the aromatic aldehydes 4b–h had little impact on the reaction efficiency, and aldehydes (4b–c, g–h) with electron-donating groups gave slightly higher yield than those (4d–f) with electronwithdrawing groups. It is worth mentioning that when 4-acetylbenzaldehyde 4f was employed as the electrophilic partner, the decarboxylative difluoromethylation reaction chemoselectively proceeded at the aldehyde moiety and no difluoromethylated adduct of ketone moiety was observed. Heteroaromatic aldehyde 4j was also suitable for this decarboxylative difluoromethylation reaction, furnishing the difluoromethylated product 5j in good yield. Moreover, enolizable aliphatic aldehyde 4k was also found to be tolerated, affording the corresponding product 5k in moderate yield. In the case of a,b-unsaturated aldehyde 4l, only 1,2-addition product 5l was obtained albeit with low yield. Acetophenone and benzophenone were also evaluated for this reaction, however, no desired difluoromethylation products were found. The resulting a-phenylsulfonyldifluoromethyl alcohols are versatile intermediates in organic synthesis [6g,l–m,14]. To demonstrate their synthetic utility, the reductive desulfonylation of the product was then investigated. Taking 5a as an example, the reductive desulfonylation reaction went smoothly under the conditions of Mg0/HOAc/NaOAc in DMF/H2O [6e,g], giving the difluoromethyl alcohol 7 in excellent yield (Scheme 3, eq. a). Furthermore, the model reaction could be scaled up to gram quantities, and quantitative yield could be obtained (Scheme 3, eq. b), indicating the potential value for the application in industry. Based on our research results and referring to related literatures [9,11,13], a plausible reaction mechanism for this decarboxylative difluoromethylation reaction was proposed as shown in Scheme 4. Under the standard reaction conditions, PhSO2CF2COOK 2 first decarboxylates to generate PhSO2CF2 intermediate A along with
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Table 1 The decarboxylative addition reaction of PhSO2CF2COOK 2 with benzaldehyde 4a under various conditions.
a b c
Entry
2:4aa
Solvent
Temp. (°C)
Time (h)
Yield (%)b
1 2 3 4 5 6 7 8 9 10 11
1:2 1:2 1:2 1:2 1:2 1:2 1:1.5 1:2 1:2 1:2 1:2
DMF DMF DMF DMF DMF DMF DMF DMSO NMP Dioxane THF
r.t. 28 40 28 28 28 28 28 28 28 28
12 12 12 9 15 18 15 15 15 15 15
57 92 82 85 98 97 84 84 62 NRc NRc
Molar ratio. Yields of product isolated after column chromatography. NR = No reaction.
Table 2 Scope of the decarboxylative difluoromethylation reaction of aldehydes 4 with PhSO2CF2COOK 2.a
Scheme 4. Plausible reaction mechanism for the decarboxylative difluoromethylation reaction.
one equivalent of gaseous carbon dioxide evolving. The PhSO2CF2 intermediate A undergoes further addition into aldehydes 4 to give the corresponding a-phenylsulfonyldifluoromethyl alcohols 5. If there is any proton sources existed in the reaction system, the decarboxylative protonation product would be formed. Conclusions
a Reaction conditions: PhSO2CF2COOK 2 (0.25 mmol) and aldehydes 4 (0.5 mmol) in DMF (1.5 mL) at 28 °C for 15 h. Yields of product isolated after column chromatography are given.
In summary, we have successfully developed the first decarboxylative addition reaction of PhSO2CF2COOK with both enolizable and non-enolizable aldehydes under the metal- and ligandfree conditions [15]. The reaction is very mild and a wide range of difluoromethyl alcohols could be obtained in moderate to high yields. There is no any difluoroolefination product observed in all the reactions, which is remarkably different from the decarboxylative addition reaction of 2-PySO2CF2COOK with aldehydes [11]. Further studies on the application of PhSO2CF2COOK reagent are currently in progress in our laboratory. Acknowledgements
Scheme 3. The reductive desulfonylation of 5a (a) and scaled-up version of the decarboxylative difluoromethylation reaction (b).
Financial support from the National Natural Science Foundation of China (No. 21102093), the Science and Technology Commission of Shanghai Municipality (Nos. 15DZ1942203, 16090503500), Chemical Engineering and Technology (Perfume and Aroma Technology) of Shanghai Plateau Discipline, Shanghai Education Development Foundation (Shuguang Program) and Shanghai Institute of Technology (No. XTCX2016-5) is gratefully acknowledged.
Y.-J. Zhu et al. / Tetrahedron Letters 59 (2018) 3184–3187
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