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Fixation of sulfur dioxide into small molecules Cite this: DOI: 10.1039/c4ob02139h
Gang Liu,*a Congbin Fana,b and Jie Wu*b,c Sulfonyl-derived functional groups can be found in a broad range of natural products, pharmaceuticals, and materials. Among the methods for the introduction of the sulfonyl group into small molecules, the
Received 8th October 2014, Accepted 3rd December 2014
approach using sulfur dioxide is the most promising and attractive one. In the past several years, the insertion of sulfur dioxide into small molecules under transition metal catalysis or metal-free conditions via a
DOI: 10.1039/c4ob02139h
radical process has been developed. In this review, recent advances in the insertion of sulfur dioxide are
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presented.
1.
Introduction
As a unique functional group, sulfone is presented in a broad range of natural products, pharmaceuticals, agrochemical molecules, and materials. Some selected examples are shown in Fig. 1: mesotrione and cafenstrole are used as the herbicides; bicalutamide has been recognized for the treatment of prostate cancer; eletriptan is used for the treatment of migraine.1 Moreover, the compounds with a sulfone unit have been used as useful intermediates in organic synthesis due to
Fig. 1
Representative sulfones in pharmaceuticals.
a Jiangxi Key Laboratory of Organic Chemistry, Jiangxi Science & Technology Normal University, Nanchang 330013, China. E-mail: [email protected] b Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China. E-mail: [email protected]; Fax: +86 21 6564 1740; Tel: +86 21 6510 2412 c State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
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the versatile reactivity of the sulfonyl group.2 Thus, there are a variety of preparative methods available for the introduction of the sulfonyl group. For instance, it can be generated by alkylation of a sulfinate salt,3 or by oxidation of the corresponding sulfide or sulfoxide.4 However, the methods commonly suffered from the scope limitation. For example, most of sulfinate salts are not commercially available, and they are usually synthesized starting from the corresponding sulfonyl chlorides.5 It is known that multi-step procedures with harsh reaction conditions are usually required for the preparation of sulfonyl chlorides. Additionally, compounds with oxidationsensitive functional groups may not be tolerated under the oxidative conditions. Among the processes for introducing the sulfonyl building block, fixation of sulfur dioxide into small molecules is promising and attractive. Indeed, continuous efforts have been devoted for the applications of sulfur dioxide in organic synthesis, due to the enormous scale of annual production.6 Although sulfur dioxide has been used as a reagent or a coordination partner in various organic transformations,7–9 there are restrictions for the utilization of sulfur dioxide in organic synthesis, due to its notorious toxicity as well as its gaseous state.10 Additionally, the transition metal catalyzed insertion of SO2 is more difficult than that of carbon monoxide (CO)11 although the reaction pathways are similar. This might be attributed to the amphoteric characteristic of sulfur dioxide, behaving as a Lewis acid or a base, a mild oxidant or a reductant, or an oxygen donor or an acceptor. Since a breakthrough was reported by Willis12 for the generation of aryl N-aminosulfonamides using innocuous and bench-stable reliable DABCO·(SO2)2 (named: DABSO) as the SO2 source,13 the rapid development for the insertion of sulfur dioxide into small molecules has been witnessed. As a result, the wide utilization of sulfur dioxide in chemistry and biology has been described by Bisseret and Blanchard.13a So far, the transformations proceeded under transition metal catalysis or
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metal-free conditions via a radical process. In this review, recent advances in the insertion of sulfur dioxide are presented.
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2. Transition metal catalyzed sulfonylation 2.1
Synthesis of N-aminosulfonamides
As mentioned above, the pioneering work was reported by Willis and co-workers.12 They described the first example for the palladium-catalyzed three-component coupling of aryl iodides, sulfur dioxide, and hydrazines. The corresponding aryl N-aminosulfonamides were provided in good to excellent yields. In this transformation, the white crystalline solid DABSO was used as the source of sulfur dioxide. The result was interesting, since the solid SO2-equivalent was benchstable and easy to handle. Various aryl iodides were employed as the substrates (Scheme 1). The scope of this palladium-catalyzed aminosulfonylation was further extended to aryl-, alkenyl- and heteroaryl halides.14 However, the nucleophile was limited to N,N-dialkylhydrazines. During the reaction process, only a slight excess amount of DABSO (1.2–2.2 equiv.) was employed. A variety of substituents on the halide coupling partner could be tolerated under the reaction conditions. Moreover, the products can be converted into the corresponding primary sulfonamides via a telescoped and deprotection sequence. Employing hydrazine·SO2 complex as both the N-nucleophile and SO2 source was also demonstrated. The group of Wu in Fudan University reported an efficient route to aryl N-aminosulfonamides via a palladium-catalyzed three-component coupling of arylboronic acids, DABSO and hydrazines in the presence of a balloon of dioxygen (Scheme 2).15 Compared with the method using aryl iodides as the starting material described by Willis,12 this transformation employing arylboronic acids was initiated by Pd(II). Various sensitive functional groups were tolerated under the reaction conditions. For instance, the free-amino or hydroxyl-substituted products could be generated as expected. However, no product was detected when pyridinyl-substituted boronic acid was employed as the substrate in the reaction. A possible mechanism was proposed in the meantime. It is known that a transmetallation of Pd(II) with arylboronic acid would generate a Pd(II) species first, followed by insertion of sulfur dioxide
Scheme 1 Palladium-catalyzed three-component coupling of aryl iodides, sulfur dioxide, and hydrazines.
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Scheme 2 Palladium-catalyzed three-component coupling of arylboronic acids, sulfur dioxide and hydrazines.
Scheme 3 Aminosulfonylation using potassium metabisulfite as a replacement of DABSO.
and a nucleophilic attack of hydrazine would occur to produce the coupling product and Pd(0). The presence of dioxygen would oxidize the Pd(0) to Pd(II), which would re-enter the catalytic cycle. Subsequently, the Wu group found that potassium metabisulfite can be used as a replacement of DABSO (Scheme 3).16 This result is interesting and attractive, since the sulfites in Nature are produced directly by absorption of the gaseous sulfur dioxide from air. The inorganic sulfites served as the source of sulfur dioxide by introduction of a sulfonyl group into organic molecules. It was found that potassium metabisulfite was an excellent equivalent of sulfur dioxide in the reaction of palladium-catalyzed aminosulfonylation. Inferior results were obtained when other sulfites were employed in the reaction. Thus, aryl N-aminosulfonamides can be easily prepared through a palladium-catalyzed reaction of aryl halides, potassium metabisulfite, and hydrazines. Not only aryl iodides but also aryl bromides are good partners in this reaction. It is noteworthy that an appropriate pH value is crucial in the reaction system. The presence of BF4− anion was also necessary for the successful transformation. Again, some sensitive functional groups were tolerated under the reaction conditions. Additionally, the aryl chlorides were inert under the palladium-catalyzed insertion of sulfur dioxide, and the chloro group remained during the reaction process. For instance, the amino-substituted aryl N-aminosulfonamide was generated in 54% yield. The chloro-substituted aryl N-aminosulfonamide can be afforded in 40% yield.
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Scheme 4 Palladium-catalyzed aminosulfonylation of aryl iodides using Na2SO3 as the SO2 source.
Scheme 6 A copper-catalyzed three-component reaction of triethoxysilanes, DABSO, and hydrazines.
Scheme 5 Synthesis of N-amino-sulfonamides via a gold(III) and palladium(II) co-catalyzed reaction of arenes, DABSO, and hydrazines.
A two-chamber reactor for the palladium-catalyzed aminosulfonylation of aryl iodides using Na2SO3 as the source of sulfur dioxide was reported by Wu and co-workers in Germany (Scheme 4).17 In tube A, the raw material sodium sulfite reacted with concentrated sulfuric acid to produce sulfur dioxide at room temperature. The generated SO2 gas is conducted into reaction tube B through a poly( propene) pipe. The author pointed out that the reaction system was safe enough since sulfur dioxide was highly soluble in the organic solvent. However, the pressure of sulfur dioxide was roughly calculated to be approximately 150 kPa on the basis of the amount of sodium sulfite and the system volume. Further investigation found that arene can also be used as the substrates for the synthesis of N-amino-sulfonamides. This transformation was co-catalyzed by gold(III) and palladium(II) starting from arenes, DABSO, and hydrazines (Scheme 5).18 This tandem process combined the C–H functionalization and aminosulfonylation. The presence of gold(III) catalysts and NIS promoted the C–H functionalization, which generated the aryl iodides in situ. Subsequently, the palladium-catalyzed aminosulfonylation afforded the final products. Several examples are present in Scheme 5. In most cases, the corresponding N-amino-sulfonamides were obtained in moderate yields. A copper-catalyzed three-component reaction of triethoxysilanes, DABSO, and hydrazines was found by Wang (Scheme 6).19 The expected N-aminosulfonamides were obtained in moderate to good yields. Reactions using the substrates including triethoxy(aryl)silanes and triethoxy(alkyl)silanes worked well combined with insertion of sulfur dioxide. Moreover, diethoxydiarylsilanes are good partners under the reaction conditions as well. This is the first example of using a
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copper salt as the catalyst in the aminosulfonylation process through the insertion of sulfur dioxide. It is noteworthy that aryl-, alkenyl- and alkyl groups can be easily incorporated into the final products. For example, methyl N-aminosulfonamide can be furnished in 65% yield. 2.2.
Synthesis of sulfones
It was reported that metal sulfinates can be easily generated from N-aminosulfonamide derivatives in the presence of a suitable base.20 For instance, sodium sulfinates can be formed starting from N,N′,N′-trialkyl aminosulfonamides in the presence of sodium isopropoxide at ambient temperature.20h Thus, the formation of sulfones can be expected if electrophiles react with metal sulfinates. As a result, Willis and co-workers reported the synthesis of sulfones using a palladium-catalyzed aminosulfonylation process as the key step (Scheme 7).21 They found that the S–N bond can be easily cleaved in the presence of a base at high temperature. Therefore, the aminosulfonamide served as a masked sulfinate, which would react with an electrophilic coupling partner delivering the sulfonyl unit. The reaction scope was well explored. Different aryl-, heteroaryland alkenyl iodides were employed in the reactions. The elec-
Scheme 7 Synthesis of sulfones via tandem aminosulfonylation and alkylation.
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the reactivity of gold(I)–heteroatom bonds to form sulfinate anions. The corresponding sulfones and sulfonamides can be afforded through the further elaboration of the sulfinate intermediates. Based on this strategy, two targeted libraries consisting of 24 sulfones and sulfonamides based on the indazole framework were constructed. Divergent products including sulfones and sulfonamides were generated from a common versatile sulfinate intermediate.
Scheme 8 sulfinate.
Generation of sulfones via in situ formation of ammonium
Scheme 9 A gold(I)-catalyzed sulfination of aryl boronic acids with potassium metabisulfite and benzyl bromide.
trophilic coupling partner included benzylic, allylic or alkyl halides, electron-poor arenes, or cyclic epoxide. A broad range of sulfones featuring a variety of functional groups was obtained in good to excellent yields. Additionally, the method was successfully applied for the synthesis of an intermediate to Eletriptan (trade name Relpax, marketed and manufactured by Pfizer). The same group subsequently reported that a broad range of aryl and heteroaryl halides can be converted into the corresponding ammonium sulfinates in the presence of DABSO, triethylamine, and a palladium(0) catalyst (Scheme 8).22 During the reaction process, isopropyl alcohol was used both as a solvent and a formal reductant. Initially, α-bromo tert-butyl acetate was used as the trapper. The transformation was attractive, since the resulting ammonium sulfinate products can be transferred in situ into a variety of sulfonyl-containing functional groups, including sulfones, sulfonyl chlorides, and sulfonamides. For examples, a range of alkyl halides and benzyl bromides can be employed in the alkylation process. Cyclohexene oxide was also a good partner, affording the corresponding β-hydroxy sulfone. Treatment with aryl iodonium salts would provide the diarylsulfones. Additionally, the ammonium sulfinate reacted with 2-chlorobenzothiazole to produce the corresponding heterocyclic sulfone via a SNAr-type process. Toste and co-workers developed a gold(I)-catalyzed sulfination of aryl boronic acids using potassium metabisulfite as the source of sulfur dioxide (Scheme 9).23 Initially, benzylic bromide was employed as the electrophile to trap the sulfinate anion generated in situ. Based on the experimental evidence, an unprecedented mechanism was proposed, which exploited
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3. Nucleophilic addition of organometallic reagents Since sulfur dioxide can act as an electrophile, the synthesis of sulfones through nucleophilic addition of organometal reagents to sulfur dioxide can be expected in the presence of an additional electrophile. Willis reported that the addition of Grignard reagents or organolithium reagents to DABSO would afford metal sulfinates, which would react with an electrophile directly leading to sulfones (Scheme 10).24 As described above, the metal sulfinates generated in situ can be trapped with various C-electrophiles, such as alkyl, allyl, and benzyl halides, epoxides, and (hetero)aryliodoniums. As shown in Scheme 10, a broad range of sulfones were generated under the reaction conditions. In the meantime, Rocke reported that organozinc reagents can be employed in the above transformation as well.25 The reaction pathway was similar to that of using Grignard reagents or organolithium reagents. During the reaction process, organozinc reagents react with DABSO, giving rise to the resulting zinc sulfinate salts. Then alkylation can occur in the presence of alkyl halide to furnish the corresponding sulfones (Scheme 11). Compared with the reactions using Grignard reagents or organolithium reagents, the scope of this transformation was broader and more functional groups can be compatible with organozinc reagents. For example, nitrile, secondary carbamates, and nitrogen-containing heterocycles can be tolerated under the reaction conditions.25 Willis reported the generation of aryl, heteroaryl, and alkenyl sulfones via a palladium-catalyzed three-component
Scheme 10 Synthesis of sulfones via a reaction of Grignard reagents with DABSO.
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Scheme 11 Synthesis of sulfones from organozinc reagents, DABSO, and alkyl halides. Scheme 13 A metal-free three-component reaction of aryldiazonium tetrafluoroborates, DABCO·(SO2)2, with hydrazines.
Scheme 12 Generation of sulfones via a palladium-catalyzed threecomponent reaction of aryl lithium species, aryl/heteroaryl/alkenyl ( pseudo)halides, and DABSO.
reaction of aryl lithium species, aryl/heteroaryl/alkenyl ( pseudo)halides, and DABSO.26 Again, the easy-to-handle bench-stable solid surrogate was used in the transformation. During the reaction process, the utilization of an electron-poor XantPhos-type ligand was crucial for the successful transformation. Moreover, exploiting the ability of the sulfone group to direct ortho metalation was performed to introduce ortho functionality. Additionally, this methodology was applied for the synthesis of a medicinal agent that is currently under development, starting from bis-halogenated quinoline (Scheme 12).
4.
Free radical reactions
Recently, the insertion of sulfur dioxide into small molecules via a radical process was described. Jie Wu and co-workers reported a metal-free three-component reaction of aryldiazonium tetrafluoroborates, DABSO, with hydrazines, leading to the formation of aryl N-aminosulfonamides in good yields (Scheme 13).27 Compared with the procedures for the synthesis of N-aminosulfonamides under transition metal cata-
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Scheme 14 A proposed mechanism for the three-component reaction of aryldiazonium tetrafluoroborates, DABCO·(SO2)2, with hydrazines.
lysis, a broad functional-group tolerance was observed. The sensitive functional groups including amino, hydroxy, nitro, and ester survived under the reaction conditions. For example, the nitro-substituted aryl N-aminosulfonamide was furnished in 67% yield. Additionally, the reaction worked well when sterically hindered substrates were employed in the transformation. Moreover, the reaction was highly efficient, which proceeded smoothly at room temperature and completed in 10 min. The reaction mechanism was proposed based on the experimental evidence as well as the computational studies. A possible mechanism which might proceeds through a radical process is shown in Scheme 14. During the reaction process, an aryl radical was believed to be formed, which then reacted with sulfur dioxide leading to a sulfonyl radical. The latter can be trapped by the hydrazine radical to give rise to the corresponding aryl N-aminosulfonamide. This method can be extended to the formation of benzo[b]thiophene 1,1-dioxides through a copper(I)-catalyzed reaction of 2-alkynylaryldiazonium tetrafluoroborate with DABSO.28 Aryldiazonium tetrafluoroborates were employed as substrates in the above transformation. Since aryldiazonium tetrafluoroborates can be easily generated from aromatic amines, therefore aromatic amines were considered as the aryl source29
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Scheme 17
Scheme 15
Reaction of aromatic amines, DABSO, and hydrazines.
Scheme 16 Synthesis of 1-(2,3-dihydrobenzofuran-3-yl)-methanesulfonohydrazides via insertion of sulfur dioxide.
in the insertion reaction of sulfur dioxide. It was found that the reaction of aromatic amines (including heteroaromatic amines), DABSO, and hydrazines proceeded efficiently with good functional group tolerance (Scheme 15).30 For example, 4-hydroxyphenyl N-aminosulfonamide was obtained in 55% yield. The pyridinyl-substituted aryl N-aminosulfonamide can be afforded as well, although the yield was 23%. Additionally, the scaffold of indole or quinoline can be incorporated in the final product. Moreover, 2,4,6-trimethylphenyl N-aminosulfonamide can be produced in good yield (73%) under the reaction conditions, which was difficult to be formed under transition metal catalysis. This route is more interesting since aromatic amines are easily available. There is no doubt that the in situ generated diazonium ion is the key intermediate during the aminosulfonylation process. Prompted by the above result,30 a three-component reaction of 2-(allyloxy)anilines, DABSO and hydrazines was designed and reported by Wu’s group (Scheme 16).31 The reaction conditions were mild, leading to 1-(2,3-dihydrobenzofuran-3-yl)methanesulfonohydrazides in good yields. The transformation was initiated with 2-(allyloxy)anilines via a radical process,
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Aminosulfonylation using triazenes as the starting material.
which proceeded through an intramolecular 5-exo-cyclization and the insertion of sulfur dioxide. A broad reaction scope was demonstrated and various functional groups including nitro, chloro, and bromo groups were tolerated. A shown in Scheme 16, the aryl radical was identified as the key intermediate, which undergoes the intramolecular 5-exo-cyclization to produce 2,3-dihydrobenzofuran-3-yl-methyl radical. Followed by the insertion of sulfur dioxide and reaction with the hydrazine radical furnished the final products. In the meantime, the Wu’s group in Germany described the aminosulfonylation reaction using triazenes as the starting material catalyzed by boron trifluoride etherate or copper chloride.32 The desired sulfonamides were generated in good yields. It was found that the triazenes were more stable than the equivalent diazonium salts. During the reaction process, the triazenes can produce aryl amino radicals under the reaction conditions (Scheme 17).
5. Conclusion and outlook We have summarized herein the recent advancements in the insertion of sulfur dioxide into small molecules under transition metal catalysis or metal-free conditions via a radical process. The sulfonyl group can be easily introduced into small molecules using sulfur dioxide as the source, which is promising and attractive in organic synthesis. The methods have been extensively applied in the construction of some drugs. Although the successes via fixation of sulfur dioxide into small molecules have been achieved, some challenges still remain, such as the scope limitation of nucleophiles and the combination of C–H bond activation with insertion of sulfur dioxide. Higher efficient synthetic routes starting from easily available substrates via C–O bond activation can be also expected. Moreover, it is believed that more achievements of efficient insertion of sulfur dioxide into the synthesis of sulfones and derivatives related to drugs will be evolved.
Acknowledgements Financial support from the National Natural Science Foundation of China (no. 21032007, 21172038) is gratefully
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acknowledged. We thank Prof. Tianning Diao (New York University) for English review.
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Fixation of sulfur dioxide into small molecules Cite this: DOI: 10.1039/c4ob02139h
Gang Liu,*a Congbin Fana,b and Jie Wu*b,c Sulfonyl-derived functional groups can be found in a broad range of natural products, pharmaceuticals, and materials. Among the methods for the introduction of the sulfonyl group into small molecules, the
Received 8th October 2014, Accepted 3rd December 2014
approach using sulfur dioxide is the most promising and attractive one. In the past several years, the insertion of sulfur dioxide into small molecules under transition metal catalysis or metal-free conditions via a
DOI: 10.1039/c4ob02139h
radical process has been developed. In this review, recent advances in the insertion of sulfur dioxide are
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presented.
1.
Introduction
As a unique functional group, sulfone is presented in a broad range of natural products, pharmaceuticals, agrochemical molecules, and materials. Some selected examples are shown in Fig. 1: mesotrione and cafenstrole are used as the herbicides; bicalutamide has been recognized for the treatment of prostate cancer; eletriptan is used for the treatment of migraine.1 Moreover, the compounds with a sulfone unit have been used as useful intermediates in organic synthesis due to
Fig. 1
Representative sulfones in pharmaceuticals.
a Jiangxi Key Laboratory of Organic Chemistry, Jiangxi Science & Technology Normal University, Nanchang 330013, China. E-mail: [email protected] b Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China. E-mail: [email protected]; Fax: +86 21 6564 1740; Tel: +86 21 6510 2412 c State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
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the versatile reactivity of the sulfonyl group.2 Thus, there are a variety of preparative methods available for the introduction of the sulfonyl group. For instance, it can be generated by alkylation of a sulfinate salt,3 or by oxidation of the corresponding sulfide or sulfoxide.4 However, the methods commonly suffered from the scope limitation. For example, most of sulfinate salts are not commercially available, and they are usually synthesized starting from the corresponding sulfonyl chlorides.5 It is known that multi-step procedures with harsh reaction conditions are usually required for the preparation of sulfonyl chlorides. Additionally, compounds with oxidationsensitive functional groups may not be tolerated under the oxidative conditions. Among the processes for introducing the sulfonyl building block, fixation of sulfur dioxide into small molecules is promising and attractive. Indeed, continuous efforts have been devoted for the applications of sulfur dioxide in organic synthesis, due to the enormous scale of annual production.6 Although sulfur dioxide has been used as a reagent or a coordination partner in various organic transformations,7–9 there are restrictions for the utilization of sulfur dioxide in organic synthesis, due to its notorious toxicity as well as its gaseous state.10 Additionally, the transition metal catalyzed insertion of SO2 is more difficult than that of carbon monoxide (CO)11 although the reaction pathways are similar. This might be attributed to the amphoteric characteristic of sulfur dioxide, behaving as a Lewis acid or a base, a mild oxidant or a reductant, or an oxygen donor or an acceptor. Since a breakthrough was reported by Willis12 for the generation of aryl N-aminosulfonamides using innocuous and bench-stable reliable DABCO·(SO2)2 (named: DABSO) as the SO2 source,13 the rapid development for the insertion of sulfur dioxide into small molecules has been witnessed. As a result, the wide utilization of sulfur dioxide in chemistry and biology has been described by Bisseret and Blanchard.13a So far, the transformations proceeded under transition metal catalysis or
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metal-free conditions via a radical process. In this review, recent advances in the insertion of sulfur dioxide are presented.
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2. Transition metal catalyzed sulfonylation 2.1
Synthesis of N-aminosulfonamides
As mentioned above, the pioneering work was reported by Willis and co-workers.12 They described the first example for the palladium-catalyzed three-component coupling of aryl iodides, sulfur dioxide, and hydrazines. The corresponding aryl N-aminosulfonamides were provided in good to excellent yields. In this transformation, the white crystalline solid DABSO was used as the source of sulfur dioxide. The result was interesting, since the solid SO2-equivalent was benchstable and easy to handle. Various aryl iodides were employed as the substrates (Scheme 1). The scope of this palladium-catalyzed aminosulfonylation was further extended to aryl-, alkenyl- and heteroaryl halides.14 However, the nucleophile was limited to N,N-dialkylhydrazines. During the reaction process, only a slight excess amount of DABSO (1.2–2.2 equiv.) was employed. A variety of substituents on the halide coupling partner could be tolerated under the reaction conditions. Moreover, the products can be converted into the corresponding primary sulfonamides via a telescoped and deprotection sequence. Employing hydrazine·SO2 complex as both the N-nucleophile and SO2 source was also demonstrated. The group of Wu in Fudan University reported an efficient route to aryl N-aminosulfonamides via a palladium-catalyzed three-component coupling of arylboronic acids, DABSO and hydrazines in the presence of a balloon of dioxygen (Scheme 2).15 Compared with the method using aryl iodides as the starting material described by Willis,12 this transformation employing arylboronic acids was initiated by Pd(II). Various sensitive functional groups were tolerated under the reaction conditions. For instance, the free-amino or hydroxyl-substituted products could be generated as expected. However, no product was detected when pyridinyl-substituted boronic acid was employed as the substrate in the reaction. A possible mechanism was proposed in the meantime. It is known that a transmetallation of Pd(II) with arylboronic acid would generate a Pd(II) species first, followed by insertion of sulfur dioxide
Scheme 1 Palladium-catalyzed three-component coupling of aryl iodides, sulfur dioxide, and hydrazines.
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Scheme 2 Palladium-catalyzed three-component coupling of arylboronic acids, sulfur dioxide and hydrazines.
Scheme 3 Aminosulfonylation using potassium metabisulfite as a replacement of DABSO.
and a nucleophilic attack of hydrazine would occur to produce the coupling product and Pd(0). The presence of dioxygen would oxidize the Pd(0) to Pd(II), which would re-enter the catalytic cycle. Subsequently, the Wu group found that potassium metabisulfite can be used as a replacement of DABSO (Scheme 3).16 This result is interesting and attractive, since the sulfites in Nature are produced directly by absorption of the gaseous sulfur dioxide from air. The inorganic sulfites served as the source of sulfur dioxide by introduction of a sulfonyl group into organic molecules. It was found that potassium metabisulfite was an excellent equivalent of sulfur dioxide in the reaction of palladium-catalyzed aminosulfonylation. Inferior results were obtained when other sulfites were employed in the reaction. Thus, aryl N-aminosulfonamides can be easily prepared through a palladium-catalyzed reaction of aryl halides, potassium metabisulfite, and hydrazines. Not only aryl iodides but also aryl bromides are good partners in this reaction. It is noteworthy that an appropriate pH value is crucial in the reaction system. The presence of BF4− anion was also necessary for the successful transformation. Again, some sensitive functional groups were tolerated under the reaction conditions. Additionally, the aryl chlorides were inert under the palladium-catalyzed insertion of sulfur dioxide, and the chloro group remained during the reaction process. For instance, the amino-substituted aryl N-aminosulfonamide was generated in 54% yield. The chloro-substituted aryl N-aminosulfonamide can be afforded in 40% yield.
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Scheme 4 Palladium-catalyzed aminosulfonylation of aryl iodides using Na2SO3 as the SO2 source.
Scheme 6 A copper-catalyzed three-component reaction of triethoxysilanes, DABSO, and hydrazines.
Scheme 5 Synthesis of N-amino-sulfonamides via a gold(III) and palladium(II) co-catalyzed reaction of arenes, DABSO, and hydrazines.
A two-chamber reactor for the palladium-catalyzed aminosulfonylation of aryl iodides using Na2SO3 as the source of sulfur dioxide was reported by Wu and co-workers in Germany (Scheme 4).17 In tube A, the raw material sodium sulfite reacted with concentrated sulfuric acid to produce sulfur dioxide at room temperature. The generated SO2 gas is conducted into reaction tube B through a poly( propene) pipe. The author pointed out that the reaction system was safe enough since sulfur dioxide was highly soluble in the organic solvent. However, the pressure of sulfur dioxide was roughly calculated to be approximately 150 kPa on the basis of the amount of sodium sulfite and the system volume. Further investigation found that arene can also be used as the substrates for the synthesis of N-amino-sulfonamides. This transformation was co-catalyzed by gold(III) and palladium(II) starting from arenes, DABSO, and hydrazines (Scheme 5).18 This tandem process combined the C–H functionalization and aminosulfonylation. The presence of gold(III) catalysts and NIS promoted the C–H functionalization, which generated the aryl iodides in situ. Subsequently, the palladium-catalyzed aminosulfonylation afforded the final products. Several examples are present in Scheme 5. In most cases, the corresponding N-amino-sulfonamides were obtained in moderate yields. A copper-catalyzed three-component reaction of triethoxysilanes, DABSO, and hydrazines was found by Wang (Scheme 6).19 The expected N-aminosulfonamides were obtained in moderate to good yields. Reactions using the substrates including triethoxy(aryl)silanes and triethoxy(alkyl)silanes worked well combined with insertion of sulfur dioxide. Moreover, diethoxydiarylsilanes are good partners under the reaction conditions as well. This is the first example of using a
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copper salt as the catalyst in the aminosulfonylation process through the insertion of sulfur dioxide. It is noteworthy that aryl-, alkenyl- and alkyl groups can be easily incorporated into the final products. For example, methyl N-aminosulfonamide can be furnished in 65% yield. 2.2.
Synthesis of sulfones
It was reported that metal sulfinates can be easily generated from N-aminosulfonamide derivatives in the presence of a suitable base.20 For instance, sodium sulfinates can be formed starting from N,N′,N′-trialkyl aminosulfonamides in the presence of sodium isopropoxide at ambient temperature.20h Thus, the formation of sulfones can be expected if electrophiles react with metal sulfinates. As a result, Willis and co-workers reported the synthesis of sulfones using a palladium-catalyzed aminosulfonylation process as the key step (Scheme 7).21 They found that the S–N bond can be easily cleaved in the presence of a base at high temperature. Therefore, the aminosulfonamide served as a masked sulfinate, which would react with an electrophilic coupling partner delivering the sulfonyl unit. The reaction scope was well explored. Different aryl-, heteroaryland alkenyl iodides were employed in the reactions. The elec-
Scheme 7 Synthesis of sulfones via tandem aminosulfonylation and alkylation.
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the reactivity of gold(I)–heteroatom bonds to form sulfinate anions. The corresponding sulfones and sulfonamides can be afforded through the further elaboration of the sulfinate intermediates. Based on this strategy, two targeted libraries consisting of 24 sulfones and sulfonamides based on the indazole framework were constructed. Divergent products including sulfones and sulfonamides were generated from a common versatile sulfinate intermediate.
Scheme 8 sulfinate.
Generation of sulfones via in situ formation of ammonium
Scheme 9 A gold(I)-catalyzed sulfination of aryl boronic acids with potassium metabisulfite and benzyl bromide.
trophilic coupling partner included benzylic, allylic or alkyl halides, electron-poor arenes, or cyclic epoxide. A broad range of sulfones featuring a variety of functional groups was obtained in good to excellent yields. Additionally, the method was successfully applied for the synthesis of an intermediate to Eletriptan (trade name Relpax, marketed and manufactured by Pfizer). The same group subsequently reported that a broad range of aryl and heteroaryl halides can be converted into the corresponding ammonium sulfinates in the presence of DABSO, triethylamine, and a palladium(0) catalyst (Scheme 8).22 During the reaction process, isopropyl alcohol was used both as a solvent and a formal reductant. Initially, α-bromo tert-butyl acetate was used as the trapper. The transformation was attractive, since the resulting ammonium sulfinate products can be transferred in situ into a variety of sulfonyl-containing functional groups, including sulfones, sulfonyl chlorides, and sulfonamides. For examples, a range of alkyl halides and benzyl bromides can be employed in the alkylation process. Cyclohexene oxide was also a good partner, affording the corresponding β-hydroxy sulfone. Treatment with aryl iodonium salts would provide the diarylsulfones. Additionally, the ammonium sulfinate reacted with 2-chlorobenzothiazole to produce the corresponding heterocyclic sulfone via a SNAr-type process. Toste and co-workers developed a gold(I)-catalyzed sulfination of aryl boronic acids using potassium metabisulfite as the source of sulfur dioxide (Scheme 9).23 Initially, benzylic bromide was employed as the electrophile to trap the sulfinate anion generated in situ. Based on the experimental evidence, an unprecedented mechanism was proposed, which exploited
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3. Nucleophilic addition of organometallic reagents Since sulfur dioxide can act as an electrophile, the synthesis of sulfones through nucleophilic addition of organometal reagents to sulfur dioxide can be expected in the presence of an additional electrophile. Willis reported that the addition of Grignard reagents or organolithium reagents to DABSO would afford metal sulfinates, which would react with an electrophile directly leading to sulfones (Scheme 10).24 As described above, the metal sulfinates generated in situ can be trapped with various C-electrophiles, such as alkyl, allyl, and benzyl halides, epoxides, and (hetero)aryliodoniums. As shown in Scheme 10, a broad range of sulfones were generated under the reaction conditions. In the meantime, Rocke reported that organozinc reagents can be employed in the above transformation as well.25 The reaction pathway was similar to that of using Grignard reagents or organolithium reagents. During the reaction process, organozinc reagents react with DABSO, giving rise to the resulting zinc sulfinate salts. Then alkylation can occur in the presence of alkyl halide to furnish the corresponding sulfones (Scheme 11). Compared with the reactions using Grignard reagents or organolithium reagents, the scope of this transformation was broader and more functional groups can be compatible with organozinc reagents. For example, nitrile, secondary carbamates, and nitrogen-containing heterocycles can be tolerated under the reaction conditions.25 Willis reported the generation of aryl, heteroaryl, and alkenyl sulfones via a palladium-catalyzed three-component
Scheme 10 Synthesis of sulfones via a reaction of Grignard reagents with DABSO.
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Scheme 11 Synthesis of sulfones from organozinc reagents, DABSO, and alkyl halides. Scheme 13 A metal-free three-component reaction of aryldiazonium tetrafluoroborates, DABCO·(SO2)2, with hydrazines.
Scheme 12 Generation of sulfones via a palladium-catalyzed threecomponent reaction of aryl lithium species, aryl/heteroaryl/alkenyl ( pseudo)halides, and DABSO.
reaction of aryl lithium species, aryl/heteroaryl/alkenyl ( pseudo)halides, and DABSO.26 Again, the easy-to-handle bench-stable solid surrogate was used in the transformation. During the reaction process, the utilization of an electron-poor XantPhos-type ligand was crucial for the successful transformation. Moreover, exploiting the ability of the sulfone group to direct ortho metalation was performed to introduce ortho functionality. Additionally, this methodology was applied for the synthesis of a medicinal agent that is currently under development, starting from bis-halogenated quinoline (Scheme 12).
4.
Free radical reactions
Recently, the insertion of sulfur dioxide into small molecules via a radical process was described. Jie Wu and co-workers reported a metal-free three-component reaction of aryldiazonium tetrafluoroborates, DABSO, with hydrazines, leading to the formation of aryl N-aminosulfonamides in good yields (Scheme 13).27 Compared with the procedures for the synthesis of N-aminosulfonamides under transition metal cata-
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Scheme 14 A proposed mechanism for the three-component reaction of aryldiazonium tetrafluoroborates, DABCO·(SO2)2, with hydrazines.
lysis, a broad functional-group tolerance was observed. The sensitive functional groups including amino, hydroxy, nitro, and ester survived under the reaction conditions. For example, the nitro-substituted aryl N-aminosulfonamide was furnished in 67% yield. Additionally, the reaction worked well when sterically hindered substrates were employed in the transformation. Moreover, the reaction was highly efficient, which proceeded smoothly at room temperature and completed in 10 min. The reaction mechanism was proposed based on the experimental evidence as well as the computational studies. A possible mechanism which might proceeds through a radical process is shown in Scheme 14. During the reaction process, an aryl radical was believed to be formed, which then reacted with sulfur dioxide leading to a sulfonyl radical. The latter can be trapped by the hydrazine radical to give rise to the corresponding aryl N-aminosulfonamide. This method can be extended to the formation of benzo[b]thiophene 1,1-dioxides through a copper(I)-catalyzed reaction of 2-alkynylaryldiazonium tetrafluoroborate with DABSO.28 Aryldiazonium tetrafluoroborates were employed as substrates in the above transformation. Since aryldiazonium tetrafluoroborates can be easily generated from aromatic amines, therefore aromatic amines were considered as the aryl source29
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Scheme 17
Scheme 15
Reaction of aromatic amines, DABSO, and hydrazines.
Scheme 16 Synthesis of 1-(2,3-dihydrobenzofuran-3-yl)-methanesulfonohydrazides via insertion of sulfur dioxide.
in the insertion reaction of sulfur dioxide. It was found that the reaction of aromatic amines (including heteroaromatic amines), DABSO, and hydrazines proceeded efficiently with good functional group tolerance (Scheme 15).30 For example, 4-hydroxyphenyl N-aminosulfonamide was obtained in 55% yield. The pyridinyl-substituted aryl N-aminosulfonamide can be afforded as well, although the yield was 23%. Additionally, the scaffold of indole or quinoline can be incorporated in the final product. Moreover, 2,4,6-trimethylphenyl N-aminosulfonamide can be produced in good yield (73%) under the reaction conditions, which was difficult to be formed under transition metal catalysis. This route is more interesting since aromatic amines are easily available. There is no doubt that the in situ generated diazonium ion is the key intermediate during the aminosulfonylation process. Prompted by the above result,30 a three-component reaction of 2-(allyloxy)anilines, DABSO and hydrazines was designed and reported by Wu’s group (Scheme 16).31 The reaction conditions were mild, leading to 1-(2,3-dihydrobenzofuran-3-yl)methanesulfonohydrazides in good yields. The transformation was initiated with 2-(allyloxy)anilines via a radical process,
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Aminosulfonylation using triazenes as the starting material.
which proceeded through an intramolecular 5-exo-cyclization and the insertion of sulfur dioxide. A broad reaction scope was demonstrated and various functional groups including nitro, chloro, and bromo groups were tolerated. A shown in Scheme 16, the aryl radical was identified as the key intermediate, which undergoes the intramolecular 5-exo-cyclization to produce 2,3-dihydrobenzofuran-3-yl-methyl radical. Followed by the insertion of sulfur dioxide and reaction with the hydrazine radical furnished the final products. In the meantime, the Wu’s group in Germany described the aminosulfonylation reaction using triazenes as the starting material catalyzed by boron trifluoride etherate or copper chloride.32 The desired sulfonamides were generated in good yields. It was found that the triazenes were more stable than the equivalent diazonium salts. During the reaction process, the triazenes can produce aryl amino radicals under the reaction conditions (Scheme 17).
5. Conclusion and outlook We have summarized herein the recent advancements in the insertion of sulfur dioxide into small molecules under transition metal catalysis or metal-free conditions via a radical process. The sulfonyl group can be easily introduced into small molecules using sulfur dioxide as the source, which is promising and attractive in organic synthesis. The methods have been extensively applied in the construction of some drugs. Although the successes via fixation of sulfur dioxide into small molecules have been achieved, some challenges still remain, such as the scope limitation of nucleophiles and the combination of C–H bond activation with insertion of sulfur dioxide. Higher efficient synthetic routes starting from easily available substrates via C–O bond activation can be also expected. Moreover, it is believed that more achievements of efficient insertion of sulfur dioxide into the synthesis of sulfones and derivatives related to drugs will be evolved.
Acknowledgements Financial support from the National Natural Science Foundation of China (no. 21032007, 21172038) is gratefully
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acknowledged. We thank Prof. Tianning Diao (New York University) for English review.
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