Letter Cite This: Org. Lett. 2018, 20, 6407−6410
pubs.acs.org/OrgLett
One-Pot Synthesis of 3‑Difluoromethyl Benzoxazole-2-thiones Zhengyu Li,† Jingnan Dong,† Zihang Yuan,† Ding-Yah Yang,*,‡ and Zhiqiang Weng*,† †
State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fujian 350108, China ‡ Department of Chemistry, Tunghai University, Taichung City 40704, Taiwan
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S Supporting Information *
ABSTRACT: A one-pot strategy for the diversified synthesis of 3-difluoromethyl benzoxazole-2-thiones is reported. The reaction of 2-aminophenol, sodium chlorodifluoroacetate, and elemental sulfur in the presence of NaOt-Bu gives exclusively 3-difluoromethyl benzoxazole-2-thiones in good yield (up to 98%). The mechanism of this reaction presumably involves first cyclization of 2-aminophenols with thiocarbonyl fluoride, followed by N-difluoromethylation with difluorocarbene. The developed synthetic procedures are versatile, robust, and easily scalable for the synthesis of 3-difluoromethyl benzoxazole-2-thione derivatives, some of which have shown insecticidal activities.
O
rganofluorine compounds continue to be of major interest due to their wide applications in chemical enterprises, including pharmaceuticals, agrochemicals, liquid crystals, dyes, and functional polymers.1 As a result, the development of synthetic methods for the synthesis of organofluorine compounds under mild conditions is highly desired.2 Among many fluoroalkyl groups, the difluoromethyl group (CF2H) is an intriguing structural motif that has received much attention from the organic synthetic community, as compounds with a CF2H moiety can act as an isostere of molecules having a hydroxymethyl (−CH2OH) unit but with improved lipophilicity.3 Different approaches for the syntheses of compounds containing the difluoromethyl group have been disclosed, including the deoxofluorination of aldehydes with SF4, DAST (N,N-diethylaminosulfur trifluoride), and its derivatives,4 as well as nucleophilic, electrophilic, and radical difluoromethylations.5 Alternatively, the difluoromethylation of heteroatom nucleophiles with a difluorocarbene reagent has also been developed for the direct preparation of compounds containing the difluoromethyl group.6 The benzoxazole-2-thione core unit is present in various biologically active molecules and pharmaceuticals (Figure 1). For example, compound A was used as a macrophage migration inhibitory factor antagonist.7 1-Acylated benzoxazole-2-thione B derivatives served as new leads for the inhibition of streptococcal hyaluronan lyases.8 The (thioxobenzoxazolyl)benzopyran derivatives C acted as cardioprotective agents (antiischemics),9 and the 3-aminomethylbenzoxazoline-2-thiones D were found to exhibit potent antibacterial activity.10 Conventionally, benzoxazole-2-thiones were synthesized from the reaction of 2-aminophenols with carbon disulfide,11 potassium ethylxanthate,12 phenyl chlorothionocarbonate,13 or tetramethylthiuram disulfide.14 Due to the significance of this substructure in various fields, the development of alternative © 2018 American Chemical Society
Figure 1. Structures of some benzoxazole-2-thione cores containing biologically active molecules.
methods that allow for easy access to 3-difluoromethyl benzoxazole-2-thiones remains important. Nevertheless, reports on the preparation of 3-difluoromethyl benzoxazole-2-thiones are sparse, limited only to the difluoromethylation of benzo[d]oxazole-2-thiol with difluorocarbene.6c,d The recent seminal works on the use of carbonothioic difluoride (SCF2) as a fluorinating agent have led to a number of developments in organofluorine chemistry including the trifluoromethylthiolation of alcohols,15 enols and phenols,16 and α-bromoketones,17 one-pot synthesis of trifluoromethylated amines18 and difluoromethylthio-substituted heterocycles,18b acyl fluorides,19 allenyl trifluoromethylthioethers,20 and 2,2difluoro-1,3-benzoxathioles.21 We envisioned that the cyclization of 2-aminophenols with a thiocarbonyl fluoride generated from the difluorocarbene/S8 system18b would afford benzo[d]oxazole-2-thiols, which may further undergo N-difluoromethyReceived: August 24, 2018 Published: October 10, 2018 6407
DOI: 10.1021/acs.orglett.8b02713 Org. Lett. 2018, 20, 6407−6410
Letter
Organic Letters lation with difluorocarbene to generate 3-difluoromethyl benzoxazole-2-thiones (Scheme 1). Scheme 1. Proposed One-Pot Synthesis of 3-Difluoromethyl Benzoxazole-2-thione
Figure 2. ORTEP diagrams of 3d (left) and 3s (right).
this reaction (entries 3−7). To further improve the yield, the one-pot N-difluoromethylation was examined in the presence of some additives. To our delight, the yield of product 3s was substantially improved to 90% with the addition of activated 4 Å molecular sieves as an additive to remove the residual moisture (entry 8). For the solvent effect, in contrast to DMF, solvents such as DMSO, NMP, DMAc, MeCN, and THF all gave inferior results (entries 9−13). Next, we studied the temperature effect on this reaction. It was found that the best reaction temperature is 70 °C. Either increasing or decreasing the reaction temperature was detrimental to the product yield (entries 14 and 15). Further, shortening the reaction time to 1 h also resulted in a drop in yield of product 3s (80%; entry 16). Having optimized the reaction conditions, we went on to investigate the scope of the reaction with regard to the oaminophenols with different substituents on the aromatic ring (Scheme 2). The unsubstituted 2-aminophenol 2a reacted smoothly and resulted in the corresponding 3-difluoromethyl benzoxazole-2-thione 3a in 80% yield. 2-Aminophenols bearing a methyl, acetyl, or bromo group at the ortho position to the hydroxyl were all found to be compatible substrates, providing the corresponding products 3b−3d in 44−84% yields. The molecular structure of 3d was also verified by single-crystal X-ray analysis (Figure 2). Various electron-donating (methyl, tertbutyl, phenyl, and methoxy) and electron-withdrawing (ester, carboxyl, nitro, fluoro, chloro, bromo, and cyano) substituents at the positions meta and para to the hydroxyl were all well tolerated, and the corresponding products 3e−3t were obtained in good yields. As an exception, 4-amino-3-hydroxybenzoic acid afforded the esterified product 3g. Note that the steric hindrance from the ortho substituent to the amino group of 2-aminophenol had a significantly negative influence on the cyclization. For instance, when 2-aminophenol 1u bore a methyl group on the C3-position and was subjected to the reaction conditions, no Ndifluoromethylated product 3u could be detected. Similarly, 1(difluoromethyl)-2-thioxo-1,2-dihydronaphtho[1,2-d]oxazole5-sulfonic acid 3y was obtained in poor yield (7% NMR yield only) along with recovery of the starting material. Conversely, the disubstituted 2-aminophenols also participated in the reaction to give the desired products (3v, 3w, and 3x) in moderate yields. In addition to 2-aminophenols, 3-amino-2pyridinols were also reactive under these reaction conditions and furnished the expected difluoromethylated products 3z and 3aa in moderate yields. Finally, 2,2-bis(3-amino-4hydroxyphenyl)hexafluoropropane 1ab was found to be capable of reacting with 2 and elemental sulfur to give the corresponding bis-N-difluoromethylated product 3ab in excellent yield (98%). To probe the scalability of the N-difluoromethylation, a scaled-up reaction was performed, as illustrated in Scheme 3. Treatment of 0.86 g of 1r and 4.5 g of 2 with 0.96 g of elemental sulfur in the presence of NaOt-Bu gave 0.91 g of the Ndifluoromethylated product 3r in 65% yield. This result highlights the robustness of this one-pot strategy for the
To test this hypothesis, the reaction of the 2-amino-4bromophenol (1s) with sodium chlorodifluoroacetate (2) and elemental sulfur was performed in the presence of a base at 70 °C for 3 h (Table 1). When NaOH was employed as a base, the Table 1. Optimization of Reactiona
entry
base
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
NaOH NaOt-Bu K2CO3 Na2CO3 KOAc KPF6 NEt3 NaOt-Bu NaOt-Bu NaOt-Bu NaOt-Bu NaOt-Bu NaOt-Bu NaOt-Bu NaOt-Bu NaOt-Bu
additive
solvent
temp (°C)
time (h)
yield (%)b
4 Å MS 4 Å MS 4 Å MS 4 Å MS 4 Å MS 4 Å MS 4 Å MS 4 Å MS 4 Å MS
DMF DMF DMF DMF DMF DMF DMF DMF DMSO NMP DMAc MeCN THF DMF DMF DMF
70 70 70 70 70 70 70 70 70 70 70 70 70 60 80 70
3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 1
26 57 5 16 7 0 3 90 10 47 3 0 0 76 84 80
a
Reaction conditions: 1s (0.10 mmol), 2 (0.50 mmol), S8 (0.50 mmol), base (0.38 mmol), solvent (1.5 mL), under N2 atmosphere. b Yield was determined by 19F NMR spectroscopy with PhOCF3 as internal standard.
proposed reaction occurred with complete chemoselectivity at the nitrogen atom to afford the desired N-difluoromethylated product 3s, albeit in low yield (entry 1). The 19F NMR spectrum of 3s showed doublet absorption peaks centered at −103.8 ppm, with the coupling constant (JH−F) of 58.2 Hz, indicating the presence of the CF2H group in R2NCF2H compounds.22 In addition, the molecular structure of 3s was unambiguously confirmed by the X-ray crystallographic analysis (Figure 2). Interestingly, this result is in clear contrast to the previous report for the reaction of 2-aminophenol with thiocarbonyl fluoride generated from Ph3P+CF2CO2− (PDFA) and sulfur, in which the HCF2S-substituted benzoxazole was obtained.18b Notably, a higher yield (57%) of 3s was produced by using NaOt-Bu as a base in DMF (entry 2). Other bases, such as K2CO3, Na2CO3, KOAc, KPF6, and NEt3, were not suitable for 6408
DOI: 10.1021/acs.orglett.8b02713 Org. Lett. 2018, 20, 6407−6410
Letter
Organic Letters Scheme 2. Scope of the Reactiona
Scheme 4. Mechanistic Study
which led to the clean formation of 3a in 90% yield (Scheme 4c). Although other conceivable scenarios cannot be ruled out at this moment, we propose a mechanistic rationale of this reaction to be the cyclization of 2-aminophenols with thiocarbonyl fluoride, followed by N-difluoromethylation with difluorocarbene (Scheme 1). To evaluate biological activities of the title compounds, a general screening on their insecticidal activities was performed (see Supporting Information). The results show that some of the 3-difluoromethyl benzoxazole-2-thiones displayed insecticidal activities against Plutella xylostella. In conclusion, we have reported a one-pot synthesis of 3difluoromethyl benzoxazole-2-thiones by the reaction of 2aminophenol, sodium chlorodifluoroacetate, and elemental sulfur in the presence of NaOt-Bu as a base. A wide range of substituted 2-aminophenols were found to be tolerable under the reaction conditions to provide the corresponding 3difluoromethyl benzoxazole-2-thione products. The whole process presumably proceeds through the cyclization of 2aminophenols with thiocarbonyl fluoride and subsequent Ndifluoromethylation with difluorocarbene. Because of simplicity, one-pot operation, and the use of readily available materials, the present method is valuable for the preparation of different 3difluoromethyl benzoxazole-2-thione derivatives.
a
Reaction conditions: 1 (0.40 mmol), 2 (2.0 mmol), S8 (2.0 mmol), NaOt-Bu (1.5 mmol), DMF (6.0 mL), 4 Å molecular sieve (60 mg), 70 °C, 3 h, N2; Isolated yields bA mixture of NaOH (1.6 mmol) and NaIO4 (0.060 mmol) was used instead of NaOt-Bu. cNaOH was used instead of NaOt-Bu. d4-Amino-3-hydroxybenzoic acid was used as substrate. e19F NMR yield.
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ASSOCIATED CONTENT
S Supporting Information *
Scheme 3. Gram-Scale Reaction
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02713. Detailed experimental procedures, characterization data, and copies of 1H, 13C and 19F NMR spectra for all new compounds (PDF) Accession Codes
synthesis of 3-difluoromethyl benzoxazole-2-thiones from commercially available starting materials. To gain further insight into the mechanism of this transformation, a series of control experiments were carried out. Upon the addition of the radical scavenger 2,2,6,6tetramethyl-1-piperidinyloxy (TEMPO, 2.0 equiv) to the reaction mixture, the desired product 3a was isolated in good yield (52%), thereby suggesting that a radical intermediate may not be involved in this transformation (Scheme 4a). Under the standard reaction conditions, 2-benzoxazolinone 4 furnished its N-difluoromethylated product 5 instead of the desired product 3a (Scheme 4b). The observation suggests that the reaction does not involve the sulfurization of 2-benzoxazolinones with elemental sulfur under the present conditions. To examine the possibility that the reaction proceeds with a 2-mercaptobenzoxazole intermediate, compound 6 was subjected to the reaction,
CCDC 1843392 and 1852585 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Ding-Yah Yang: 0000-0002-3611-2042 Zhiqiang Weng: 0000-0001-6851-1841 6409
DOI: 10.1021/acs.orglett.8b02713 Org. Lett. 2018, 20, 6407−6410
Letter
Organic Letters Notes
(17) Zheng, J.; Cheng, R.; Lin, J.-H.; Yu, D.-H.; Ma, L.; Jia, L.; Zhang, L.; Wang, L.; Xiao, J.-C.; Liang, S. H. Angew. Chem., Int. Ed. 2017, 56, 3196. (18) (a) Scattolin, T.; Deckers, K.; Schoenebeck, F. Angew. Chem., Int. Ed. 2017, 56, 221. (b) Yu, J.; Lin, J. H.; Xiao, J. C. Angew. Chem., Int. Ed. 2017, 56, 16669. (19) Scattolin, T.; Deckers, K.; Schoenebeck, F. Org. Lett. 2017, 19, 5740. (20) Zhen, L.; Yuan, K.; Li, X.-y.; Zhang, C.; Yang, J.; Fan, H.; Jiang, L. Org. Lett. 2018, 20, 3109. (21) (a) Zhang, M.; Chen, S.; Weng, Z. Org. Lett. 2018, 20, 481. (b) Zhang, M.; Lu, J.; Weng, Z. Org. Biomol. Chem. 2018, 16, 4558. (22) Dolbier, W. R. Guide to Fluorine NMR for Organic Chemists; John Wiley & Sons, Inc.: New York, 2009.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (21772022).
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REFERENCES
(1) (a) Yamazaki, T.; Taguchi, T.; Ojima, I. Fluorine in Medicinal Chemistry and Chemical Biology; Wiley-Blackwell: Chichester, 2009. (b) Filler, R.; Kobayashi, Y.; Yugapolskii, L. M. Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications; Elsevier: Amsterdam, 1993. (c) Nakajima, T.; Groult, H. Fluorinated Materials for Energy Conversion; Elsevier: London, 2005. (2) (a) Chen, P.; Liu, G. Synthesis 2013, 45, 2919. (b) Zhang, C.-P.; Chen, Q.-Y.; Guo, Y.; Xiao, J.-C.; Gu, Y.-C. Coord. Chem. Rev. 2014, 261, 28. (c) Chen, B.; Vicic, D. A. Top. Organomet. Chem. 2014, 52, 113. (d) Ni, C.; Hu, J. Synthesis 2014, 46, 842. (e) Ni, C.; Hu, M.; Hu, J. Chem. Rev. 2015, 115, 765. (f) Krishnamoorthy, S.; Prakash, G. K. S. Synthesis 2017, 49, 3394. (3) (a) Hu, J.; Zhang, W.; Wang, F. Chem. Commun. 2009, 7465. (b) Xu, P.; Guo, S.; Wang, L.; Tang, P. Synlett 2014, 26, 36. (c) Rong, J.; Ni, C.; Hu, J. Asian J. Org. Chem. 2017, 6, 139. (d) Yerien, D. E.; BarataVallejo, S.; Postigo, A. Chem. - Eur. J. 2017, 23, 14676. (4) (a) Markovskij, L. N.; Pashinnik, V. E.; Kirsanov, A. V. Synthesis 1973, 1973, 787. (b) Middleton, W. J. J. Org. Chem. 1975, 40, 574. (5) (a) Prakash, G. K. S.; Ganesh, S. K.; Jones, J. P.; Kulkarni, A.; Masood, K.; Swabeck, J. K.; Olah, G. A. Angew. Chem., Int. Ed. 2012, 51, 12090. (b) Fier, P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 5524. (c) Fujiwara, Y.; Dixon, J. A.; Rodriguez, R. A.; Baxter, R. D.; Dixon, D. D.; Collins, M. R.; Blackmond, D. G.; Baran, P. S. J. Am. Chem. Soc. 2012, 134, 1494. (d) Jiang, X.-L.; Chen, Z.-H.; Xu, X.-H.; Qing, F.-L. Org. Chem. Front. 2014, 1, 774. (e) Matheis, C.; Jouvin, K.; Goossen, L. Org. Lett. 2014, 16, 5984. (f) Feng, Z.; Min, Q.-Q.; Fu, X.-P.; An, L.; Zhang, X. Nat. Chem. 2017, 9, 918. (g) Lu, C.; Lu, H.; Wu, J.; Shen, H. C.; Hu, T.; Gu, Y.; Shen, Q. J. Org. Chem. 2018, 83, 1077. (h) Serizawa, H.; Ishii, K.; Aikawa, K.; Mikami, K. Org. Lett. 2016, 18, 3686. (i) Levin, V. V.; Trifonov, A. L.; Zemtsov, A. A.; Struchkova, M. I.; Arkhipov, D. E.; Dilman, A. D. Org. Lett. 2014, 16, 6256. (6) (a) Prakash, G. K. S.; Krishnamoorthy, S.; Ganesh, S. K.; Kulkarni, A.; Haiges, R.; Olah, G. A. Org. Lett. 2014, 16, 54. (b) Thomoson, C. S.; Wang, L.; Dolbier, W. R. J. Fluorine Chem. 2014, 168, 34. (c) Mehta, V. P.; Greaney, M. F. Org. Lett. 2013, 15, 5036. (d) Heine, N. B.; Studer, A. Org. Lett. 2017, 19, 4150. (e) Xu, W.; Abboud, K. A.; Ghiviriga, I.; Dolbier, W. R.; Rapp, M.; Wnuk, S. F. Org. Lett. 2006, 8, 5549. (f) Ando, M.; Wada, T.; Sato, N. Org. Lett. 2006, 8, 3805. (7) Le Hiress, M.; Akagah, B.; Bernadat, G.; Tu, L.; Thuillet, R.; Huertas, A.; Phan, C.; Fadel, E.; Simonneau, G.; Humbert, M.; Jalce, G.; Guignabert, C. J. Med. Chem. 2018, 61, 2725. (8) Braun, S.; Botzki, A.; Salmen, S.; Textor, C.; Bernhardt, G.; Dove, S.; Buschauer, A. Eur. J. Med. Chem. 2011, 46, 4419. (9) Lim, H.; Lee, D. H.; Kim, S. O.; Yoo, S.-e.; Yi, K. Y.; Lee, S. K.; Suh, J. H.; Kim, N. J.; Hwang, S. K.; Kim, T. M.; Lee, B. H.; Seo, H.-w. Patent Appl. WO2004106331, 2004. (10) Varma, R. S.; Nobles, W. L. J. Pharm. Sci. 1972, 61, 112. (11) Singh, M. S.; Singh, P.; Singh, S. Indian J. Chem. 2007, 42B, 1666. (12) Deligeorgiev, T. G.; Kaloyanova, S. S.; Lesev, N. Y.; Vaquero, J. Monatsh. Chem. 2011, 142, 895. (13) Li, Z.; Liu, D.; Chen, Y.; Yin, Y.; Wang, Z.; Sun, X. J. Chem. Res. 2016, 40, 515. (14) Liu, X.; Liu, M.; Xu, W.; Zeng, M.-T.; Zhu, H.; Chang, C.-Z.; Dong, Z.-B. Green Chem. 2017, 19, 5591. (15) (a) Liu, J. B.; Xu, X. H.; Chen, Z. H.; Qing, F. L. Angew. Chem., Int. Ed. 2015, 54, 897. (b) Glenadel, Q.; Tlili, A.; Billard, T. Eur. J. Org. Chem. 2016, 2016, 1955. (c) Luo, J.-J.; Zhang, M.; Lin, J.-H.; Xiao, J.-C. J. Org. Chem. 2017, 82, 11206. (16) Liu, Y.-L.; Xu, X.-H.; Qing, F.-L. Tetrahedron 2018, 74, 5827. 6410
DOI: 10.1021/acs.orglett.8b02713 Org. Lett. 2018, 20, 6407−6410
