One-Pot Synthesis of Difluoromethyl Thioethers from Thiourea and

and Wenbin Yi. School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210094, P. R. China. Org. Lett. , 2018, 20 (1...
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Cite This: Org. Lett. 2018, 20, 170−173

One-Pot Synthesis of Difluoromethyl Thioethers from Thiourea and Diethyl Bromodifluoromethylphosphonate Tianqi Ding,† Lvqi Jiang,† and Wenbin Yi* School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210094, P. R. China S Supporting Information *

ABSTRACT: A straightforward one-pot synthesis of difluoromethyl thioethers from thiourea and diethyl bromodifluoromethylphosphonate has been developed. Thiourea is a cheap and friendly sulfur reagent, while diethyl bromodifluoromethylphosphonate is a low-cost and stable difluorocarbene precursor. The strategy enabled the introduction of SCF2H moieties into indoles, pyrroles, and activated arenes and formed a number of difluoromethyl thioethers.

O

rganofluorine chemistry is a topic of current interest because the incorporation of fluorine or fluorinecontaining groups can alter the physical, chemical, and biological properties of the parent molecules.1 In the organofluorine family, the SCF3 group has received special attention because of its high electron-withdrawing capability, good lipophilicity, and bioavailability.2 In recent years, more than a dozen attractive synthetic methods for the introduction of the SCF3 group into target compounds have been successively reported.3 In this context, the difluoromethylthio group (SCF2H) has emerged as the next potential subject in this field. The SCF2H group has the potential to serve as a lipophilic OH or NH surrogate,4 and SCF2H-containing molecules have been shown to be uniquely effective in bioactive compounds, such as the β-lactamase-resistant oxcephalosporin antibiotic flomoxef sodium,5a,b the pesticide pyriprole,5c the herbicide SSH-108,5d a nifedipin analogue,5e and potential fungicides (Figure 1).5f The traditional synthesis of SCF2H moieties involves nucleophilic attack of in situ-generated difluoromethyl carbene intermediates by thiolates using reagents such as ClCF2H, TMSCF2Br, ClCF2CO2Na, PhS(O)(NTs)CF2H, HCF2OTf, and Ph3P+CF2CO2−.6 Most of these approaches suffer from limited availability of the thiol substrates, incompatibility of the strongly basic reaction conditions with sensitive functionalities, and the low selectivity of the CF2 insertion step. Compared with the indirect methods, the direct introduction of the SCF2H group is more attractive and ideal. In recent years, several electrophilic and nucleophilic difluoromethylthiolating reagents have been developed (1a−g, Figure 2).7−13 These reagents were able to difluoromethylthiolate a variety of substrates under mild reaction conditions. However, the widespread use of these reagents has been hampered by either the lack of atom economy or step efficiency in delivering the difluoromethylthio group. In 2015, Goossen’s group reported a copper−CF2H complex generated in situ from copper thiocyanate and TMS-CF2H that © 2017 American Chemical Society

Figure 1. SCF2H- and SO2CF2H-containing drugs and agrochemicals.

Figure 2. Difluoromethylthiolating reagents.

converted organothiocyanates into various difluoromethyl thioethers from alkyl halides or aryl amines via their diazonium salts.14 This strategy was then successfully applied to the difluoromethylthiolation of electron-rich arenes by C−H bond Received: November 15, 2017 Published: December 7, 2017 170

DOI: 10.1021/acs.orglett.7b03538 Org. Lett. 2018, 20, 170−173

Letter

Organic Letters Table 1. Optimization of the Reaction Conditionsa

functionalization according to a one-pot, two-step C−H thiocyanation/difluoroalkylation process using N-thiocyanatosuccinimide (NTS) as the source of sulfur and TMS-CF2H as the source of CF2H.15 Thiourea is usually in the solid state without a pungent smell and easy to use, store, and transport. In recent years, efficient generation of C−S bonds via one-pot thioetherification of organic halides using thiourea as the sulfur source has been developed.16 In connection with the challenges associated with simple and practical difluoromethylthiolation, we envisioned that combining thiourea and difluorocarbene precursors might provide the possibility to access difluoromethyl thioethers. It was reported that the reaction of indole, thiourea, and iodine in a 1:2:1 ratio can form S-(3-indolyl)isothiuronium iodide 3, which then affords indolethiol 4 (Scheme 1).17 Scheme 1. Proposed Mechanism for the Difluoromethylthiolation of Indoles

entry

solvent (1:1)

1 2 3 4 5 6 7 8 9 10 11 12c 13 14 15 16 17 18

MeOH/H2O EtOH/H2O MeCN/H2O THF/H2O dioxane/H2O DMF/H2O dioxane/H2O dioxane/H2O dioxane/H2O dioxane/H2O dioxane/H2O dioxane/H2O dioxane/H2O dioxane/H2O dioxane/H2O dioxane/H2O dioxane/H2O dioxane/H2O

NaOH 2 2 2 2 2 2 3 4 5 6 7 5 5 5 5 5 5 5

M M M M M M M M M M M M M M M M M M

[:CF2]

yield (%)b

BrCF2P(O)(OEt)2 BrCF2P(O)(OEt)2 BrCF2P(O)(OEt)2 BrCF2P(O)(OEt)2 BrCF2P(O)(OEt)2 BrCF2P(O)(OEt)2 BrCF2P(O)(OEt)2 BrCF2P(O)(OEt)2 BrCF2P(O)(OEt)2 BrCF2P(O)(OEt)2 BrCF2P(O)(OEt)2 BrCF2P(O)(OEt)2 BrCF2COOC2H5 ClCF2CO2Na BrCF2TMS FSO2CF2COOH FSO2CF2COOTMS ClCF2COPh

19 32 43 5 64 29 76 85 92 92 90 75 − − 52 trace trace 88

a

Conditions: (i) 2a (0.25 mmol), I2 (0.25 mmol), KI (0.25 mmol), thiourea (0.5 mmol), solvent (1 mL); (ii) NaOH/H2O (0.5 mL); (iii) difluorocarbene precursor (0.25 mmol). bYields were determined by GC. cYield was obtained at gram scale (2 g).

Scheme 2. One-Pot Difluoromethylthiolation of Indolesa,b Moreover, a convenient method for the difluoromethylation of phenols and thiophenols using diethyl bromodifluoromethylphosphonate (BrCF2P(O)(OEt)2) as a difluorocarbene precursor has been described.18 Encouraged by the reported literature, we decided to develop a one-pot reaction process to achieve the direct difluoromethylthiolation of indoles (Scheme 1). We commenced our study by examining the difluoromethylthiolation of indole with thiourea and diethyl bromodifluoromethylphosphonate under conditions similar to those reported by Lodeiro (Table 1, entry 1),17b which gave the difluoromethylthiolation product 5a in only 19% yield. After screening of different solvents (Table 1, entries 2−6), dioxane/ H2O was found to be optimal (Table 1, entry 5) and hence was selected for further studies. Increasing the concentration of sodium hydroxide to 5 M improved the yield of 5a to 92% (Table 1, entry 9). The reaction could be conducted on a 2 g scale (Table 1, entry 12). No improvement was observed by using other difluorocarbene precursors since poorer yields were obtained (Table 1, entries 13−17). 2-Chloro-2,2-difluoroacetophenone gave the product 5a in 88% yield (Table 1, entry 18), but it is more expensive than BrCF2P(O)(OEt)2. With the optimized reaction conditions (Table 1, entry 5) in hand, difluoromethylthiolation of different indole derivatives was conducted to explore the reaction scope. As shown in Scheme 2, many substrates with various electron-donating or electron-withdrawing substituents at the 5-, 6- and 7-positions of indole were produced in moderate to good yields ranging from 70 to 94% (5b−h). The substrate with a substituent at the 4-position yielded product 5i in 42% yield, probably because of the steric effect. Products of 2-substituted or N-substituted

a

Conditions: (i) indole 2 (0.5 mmol), I2 (0.5 mmol), KI (0.5 mmol), thiourea (1 mmol), dioxane/H2O (2 mL); (ii) 5 M NaOH (1 mL); (iii) BrCF2P(O)(OEt)2 (0.5 mmol). bYields of isolated pure products are shown. c(i) 50 °C, overnight.

indoles (5j−n) were produced in 63−80% yield. Moreover, 3methylindole (2o) could be transformed into 2-difluoromethylthiolated product 5o in 65% yield. Further extension of the 171

DOI: 10.1021/acs.orglett.7b03538 Org. Lett. 2018, 20, 170−173

Letter

Organic Letters reaction scope for biologically interesting N-heterocyclic rings, for example, lilolidine (2p), resulted in difluoromethylthiolated product 5p in 80% yield. Pyrroles are a class of nitrogen heterocycles commonly found in natural products, biologically active molecules, and dyes for solar cells.19 To further broaden the substrate scope of this reaction, a series of pyrrole derivatives was examined under the optimal reaction conditions (Scheme 3). We found that both

Scheme 4. Transformations of Difluoromethylthiolated Indoles

Scheme 3. One-Pot Difluoromethylthiolation of Pyrroles and Activated Arenesa,b

construct the difluoromethylthio (−SCF2H) group. In addition, both thiourea and diethyl bromodifluoromethylphosphonate are commercial, promoting the development of a lower-cost direct difluoromethylthiolation reaction. The transition-metalfree protocol, readily available reagents, and mild reaction conditions provide an alternative and practical strategy for the synthesis of difluoromethylthiolated electron-rich heterocycles and arenes.



ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03538. Experimental procedures, characterization data, and 1H, 13 C, and 19F NMR spectra for products (PDF)



AUTHOR INFORMATION

Corresponding Author

a

Conditions: (i) pyrrole or activated arene (0.5 mmol), I2 (0.5 mmol), KI (0.5 mmol), thiourea (1 mmol), dioxane/H2O (2 mL); (ii) 5 M NaOH (1 mL); (iii) BrCF2P(O)(OEt)2 (0.5 mmol). bYields of isolated pure products are shown. c(i) 50 °C, overnight.

* E-mail: [email protected] ORCID

Wenbin Yi: 0000-0003-4606-7668 Author Contributions

N−H (6a−e) and N-substituted (6f−h) difluoromethylthiolated products were produced in moderate to good yields. Arenes bearing electron-donating groups possess activated C(sp2)−H bonds as well, resulting in difluoromethylthiolated products 7a−d in 32−71% yield. However, when other electron-rich heteroarenes such as 7-azaindole, benzothiophene, and benzofuran were subjected to these conditions, formation of the desired difluoromethylthiolated products was observed in