Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Visible-Light-Driven Silver-Catalyzed One-Pot Approach: A Selective Synthesis of Diaryl Sulfoxides and Diaryl Sulfones Dong Hyuk Kim,† Juyoung Lee,† and Anna Lee*,†,‡ †
Department of Chemistry and ‡Department of Energy Science and Technology, Myongji University, Yongin 17058, Republic of Korea S Supporting Information *
ABSTRACT: An efficient one-pot approach for the synthesis of diaryl sulfoxides and diaryl sulfones using aryl thiols and aryl diazonium salts was developed. The use of a visible-lightdriven silver catalysis and the subsequent singlet-oxygeninduced oxidation enabled selective synthesis of sulfoxides and sulfones in the absence of a photocatalyst. The reactions were carried out under mild reaction conditions; the desired products were obtained under air atmosphere at room temperature.
A
ryl sulfoxides and aryl sulfones are useful building blocks1 of numerous organic compounds and drug candidates2 and have exhibited many significant biological activities.2,3 They can act as prostaglandin D2 antagonists, proton pump inhibitors, antidepressants, as well as anti-inflammatory and antibacterial agents (Figure 1).3c,d,4 What is more, diaryl sulfoxides and diaryl sulfones have shown promising antitumor and antifungal properties as well as HIV-1 reverse transcriptase inhibitor activity.3a,b,4a,5
Scheme 1. Synthetic Approaches to Sulfoxides and Sulfones
Figure 1. Bioactive molecules containing an aryl/diaryl sulfoxide/ sulfone moiety.
use of organometallic reagents, in combination with iodonium salts,4a or palladium catalysts (Scheme 1, I, b).12 Thiol−ene type reactions have also been reported for the direct synthesis of βhydroxy, β-oxy, β-peroxy, β-keto sulfides, sulfoxides, and sulfones using olefins and thiols (Scheme 1, I, b).13 In spite of the availability of various approaches to the synthesis of these important bioactive moieties, there are many limitations that could pose a problem. The use of stoichiometric amounts of oxidants and toxic/sensitive catalysts or reagents in the reactions, as well as the limited functional group tolerance and operational control difficulties of these methods imply the ongoing demand
Given the significance of these moieties, their synthesis has drawn a great deal of attention from the synthetic community. The most conventional method for the synthesis of sulfoxides and sulfones is through the oxidation of sulfides.1,4a,6 This could be accomplished by either using stoichiometric amounts of peracid or inorganic oxidants (Scheme 1, I, a)7 or, as very recent studies show, through a photocatalytic oxidation process.8,9 Many other synthetic approaches to the formation of these moieties have been developed. These include the sulfonylation of arenes using strong acids,1,4a,6 nucleophilic substitution of electrophilic sulfoxide derivatives,10 and transition-metal-catalyzed arylation of sulfenate anions.11 Moreover, one-pot methods for the synthesis of aryl sulfones have been established, with the © XXXX American Chemical Society
Received: December 14, 2017
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DOI: 10.1021/acs.orglett.7b03901 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
sulfone 4a decreased over time. When pyridine was added, however, a mixture of sulfoxide 3a and sulfone 4a (3a: 19%, 4a: 51%) was obtained (entry 8). Control reactions were performed in the absence of light, the silver catalyst, or the oxidant (K2S2O8), which did not give any of the desired products (entries 9, 13, and 14). Changing the light source, in contrast, diminished the reaction yields, giving sulfoxide 3a in moderate yields (entries 10−12). The atmosphere under which the reaction takes place seemed to play an important role. While the synthesis under Ar atmosphere gave only trace amounts of the desired product (entry 15), under O2 atmosphere, sulfoxide 3a was obtained in 77% yield (entry 16). Following these results, we concluded that any further studies on this reaction should be conducted with the silver catalyst, oxidant (K2S2O8), under visible light, and air (O2). With the optimized reaction conditions in hand, the scope of the synthesis of the diaryl sulfoxides and diaryl sulfones was explored. The synthesis of the diaryl sulfoxides proved to be tolerant to various aryl thiol starting materials (Scheme 2). The
for a novel and efficient approach. Herein, we report a new onepot method for the selective synthesis of diaryl sulfoxides and diaryl sulfones via visible-light-induced silver catalysis under air (Scheme 1, II). The initial studies of the one-pot reaction conditions began with a reaction of thiols and diazonium salts, catalyzed by both silver and photoredox catalysts. The silver catalyst was expected to generate a thiyl radical from the thiol14 and the photoredox catalyst was anticipated to form aryl radicals from the aryl diazonium salts.9 The desired sulfoxides could then be formed through oxidation. To test this hypothesis, thiophenol (1a) and 4-methoxybenzenediazonium tetrafluoroborate (2a) were reacted in the presence of eosin Y (5 mol %) and AgNO3 (20 mol %) at room temperature under green LED light irradiation (530 nm) in air, which yielded sulfoxide 3a in 48% yield. However, control experiments without eosin Y generated the desired product with the same yield (48%) (Table 1, entry 1). One Table 1. Optimization of the Reaction Conditionsa
Scheme 2. Substrate Scope: Diaryl Sulfoxidesa
entry
AgNO3 (mol %)
solvent
3a yieldb (%)
4a yieldb (%)
1 2c 3c 4c 5 6 7 8c 9c,d 10c,e 11c,f 12c,g 13c 14c,h 15c,i 16c,j
20 20 10 30 20 20 20 20 20 20 20 20 0 20 20 20
DMSO DMSO DMSO DMSO CH3CN DCM DMF DMF DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO
48 82 60 72 0 0 0 19 0 55 47 37 0 0 trace 77
0 0 0 0 0 0 78 51 0 0 0 0 0 0 0 0
a
Conditions: 1a (0.5 mmol, 1.0 equiv), 2a (1.2 equiv), catalyst, K2S2O8 (3.0 equiv), solvent (0.25 M) under air at 23 °C for 15 h. b Isolated yield after column chromatography. cPyridine (3.0 equiv) was added. dIn the dark. eUnder blue LED light irradiation. fUnder white LED light irradiation. gUnder sunlight irradiation. hIn the absence of K2S2O8. iUnder Ar atmosphere. jUnder O2 atmosphere.
a
Reactions conducted on a 0.5 mmol scale. Yields are of the isolated product after column chromatography. For details, see the Supporting Information.
possible explanation of these results could be the generation of an aryl radical from the diazonium ions15 under UV or visible-light irradiation in the absence of photocatalyst.16 Following these results, we investigated various reaction conditions, of which selected examples are summarized in Table 1. As can be observed from the optimization studies, a significant improvement in the yield was observed when pyridine was added to the reaction, giving the desired product 3a in 82% yield (Table 1, entry 2). Varying the amount of AgNO3, in contrast, did not improve the reaction yields (entries 3 and 4). Solvent screening showed that the reaction does not take place in either acetonitrile or dichloromethane (entries 5 and 6), while DMF allows the formation of sulfone 4a in 78% after 15 h (entry 7). Careful TLC monitoring over the time of this reaction (entry 7) was performed, which showed that the ratio of sulfoxide 3a to
desired sulfoxides were obtained in moderate to high yields (52− 84%) in the presence of both electron-withdrawing (3g−j, 3n) and electron-donating (3d−f, 3k and 3m) substituents. The products derived from the ortho-substituted aryl thiols (3d and 3i) were obtained with lower reaction yields, compared to those obtained with meta- and para-substituted ones. However, a noticeable electronic effect of these substituents was not observed. Heteroaromatic thiols also proved to be suitable substrates under these reaction conditions, giving sulfoxide 3o in good yield (71%). Additionally, the scope of aryl diazonium salts 2 in the reaction was investigated. Substituents at all positions (ortho-, meta- and para-) were tolerated, affording the desired products (3a−c) in moderate to high yields (52−82%). Moreover, the use of naphthyl diazonium salts gave the desired products in good yields (3m: 76%, 3n: 74%). B
DOI: 10.1021/acs.orglett.7b03901 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Considering the optimization studies performed earlier (Table 1, entry 16), it is possible that a singlet oxygen (1O2) is involved in the oxidation process. To test this hypothesis, NaN3, a wellknown strong 1O2 quencher, was added to the reaction. As expected, the desired product was not obtained (Scheme 4, II), which suggests that the reaction mechanism includes a radical pathway and a 1O2-mediated oxidation process. Furthermore, diaryl sulfide C, a possible intermediate for further oxidation reactions, was detected by GC−MS during the reaction. To investigate this matter further, the synthesized (4methoxyphenyl)(phenyl)sulfane (C), was subjected to the standard reaction conditions. As a result, the desired sulfoxide 3a and sulfone 4a were obtained in DMSO and DMF, respectively. In contrast, when NaN3 was added to the mixture, no reaction was observed (Scheme 4, III). In addition, potassium persulfate (K2S2O8) does not promote the oxidation process. (Scheme 4, IV). These results indicate that after the formation of diaryl sulfide C as an intermediate, a singlet-oxygen-induced oxidation process takes place to give the desired products. The selective formation of sulfoxides in DMSO and sulfones in DMF could be due to the dependence of the rate of singlet oxygen deactivation on the chemical environment such as solvents or additional radical sources.17 Amines such as pyridine are wellknown single electron donors or acceptors in many radicalmediated reactions.9 The sulfoxide group of DMSO could also be involved in the 1O2 quenching process.18 These effects could affect the oxidative environment and cause the selective oxidation process. A proposed reaction pathway based on the present results and previous reports13b,c,19 is shown in Scheme 5. Initially, thiol 1 and
Next, the substrate scope of the synthesis of diaryl sulfones was explored (Scheme 3). Both the aryl thiols and diazonium salts Scheme 3. Substrate Scope: Diaryl Sulfonesb
b
Reactions conducted on a 0.5 mmol scale. Yields are of the isolated product after column chromatography. For details, see the Supporting Information.
Scheme 5. Proposed Reaction Pathway
were varied, giving the desired sulfones in moderate to high yields (61−85%). Similar to the results of the diarylsulfoxides (3b, 3d, and 3i in Scheme 2), the products derived from the ortho-substituted aryl thiols or diazonium salts (4b and 4g) were obtained in decreased yields, which could be due to the steric effect at the ortho-position. To gain a mechanistic insight into this one-pot synthesis, several control experiments were carried out (Scheme 4). First, TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) was employed as a radical inhibitor, which did not afford the desired product (Scheme 4, I). Next, the oxidation source was investigated.
diazonium salt 2 are excited through visible light irradiation. Then, thiyl radical A, generated by the silver catalyst from thiol 1 reacts with aryl radical B, generated from diazonium salt 2, to afford sulfide C as an intermediate. Subsequent oxidation by 1 O219a−c would provide the desired sulfoxide 3 or sulfone 4. To demonstrate the utility of this one-pot synthetic method, bioactive compounds containing a diaryl sulfoxide/sulfone moiety were synthesized (Figure 2).20 The desired sulfones 5 and 7 and sulfoxide 6 were obtained in good to high yields under the reaction conditions (see the Supporting Information for details).
Scheme 4. Control Experiments
Figure 2. Synthesis of bioactive compounds via the one-pot approach. C
DOI: 10.1021/acs.orglett.7b03901 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
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In conclusion, a highly efficient one-pot selective synthesis of diaryl sulfoxides and diaryl sulfones was developed. The transformation features a visible-light-promoted silver catalyzed reaction and focuses on controlling the oxidation process. In addition, this procedure did not require the preactivation of the aryl thiols. Therefore, the method facilitates the rapid access to various aryl sulfoxides and aryl sulfones, providing more opportunities for the synthesis of important bioactive compounds and other key synthetic intermediates.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03901. Experimental details, characterization data for the products, and NMR spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Anna Lee: 0000-0002-3450-7024 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2016R1D1A1B03931335) and the Korea Institute of Energy Technology Evaluation and Planning (KETEP) and the Ministry of Trade, Industry & Energy (MOTIE) of the Republic of Korea (No. 20174010201160).
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REFERENCES
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DOI: 10.1021/acs.orglett.7b03901 Org. Lett. XXXX, XXX, XXX−XXX
