Letter Cite This: Org. Lett. 2018, 20, 7257−7260
pubs.acs.org/OrgLett
Silver-Promoted Synthesis of 5‑[(Pentafluorosulfanyl)methyl]-2oxazolines Audrey Gilbert, Xavier Bertrand, and Jean-François Paquin* CGCC, PROTEO, Département de chimie, Université Laval, 1045 Avenue de la Médecine, Québec, Québec G1V 0A6, Canada
Downloaded via UNIV OF SOUTH DAKOTA on November 16, 2018 at 11:28:26 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
S Supporting Information *
ABSTRACT: The synthesis of 5-[(pentafluorosulfanyl)methyl]-2-oxazolines is reported. The use of a silver promoter allows the intramolecular cyclization of N-[2-chloro-3(pentafluorosulfanyl)propyl]amide to occur without elimination of the chlorine atom, a reaction pathway typically observed for β-chloro-SF5-alkyl compounds. The products, potentially valuable SF5-containing heterocycles, are obtained in up to 97% yield.
he fluorine atom and its simple related fluorinated substituents (i.e., CF2 and CF3) have been used extensively in various fields1−3 due to the unique properties brought by the fluorine atom.4 The search for a larger structural diversity has led over the past years to the invention/ discovery of novel fluorinated substituents,5 with one of them being the pentafluorosulfanyl group (SF5).6,7 This fluorinated substituent, often viewed as an alternative for the CF3 group (hence the surname “super CF3”),8 possesses interesting properties such as a high lipophilicity combined with a strong electron-withdrawing capacity, a large dipole moment, and a high hydrolytic stability.7,9 As such, the SF5 has become a valuable substituent in drug development,10 agrochemistry11 and material sciences.12 2-Oxazolines are an important N-containing five-membered ring. This heterocyclic construction is exploited in medicinal chemistry,13 in catalysis,14 in synthetic organic chemistry,15 and in material sciences.16 In this context, we envisioned that 5-(pentafluorosulfanyl)methyl-2-oxazolines (3) could represent valuable SF5-containing heterocycles17 as the corresponding CF3-containing oxazolines have been recently described (Scheme 1, eq 1).18 Regarding the synthetic approach, we envisioned starting with readily available N-allylamides 1 (Scheme 1, eq 2). Radical addition of pentafluorosulfanyl chloride (SF5Cl)19 should provide N-(2-chloro-3-(pentafluorosulfanyl)propyl)amides 2 that could undergo an intramolecular cyclization to provide the targeted heterocycles 3. Such cyclization has been exploited previously on a nonfluorinated substrate under basic conditions.20 Herein, we report the use of silver salt to promote this intramolecular cyclization. Notably, this reaction occurs without elimination of the chlorine atom, a reaction pathway typically observed for β-chloro-SF5-alkyl compounds.7 The reactivity was initially investigated using N-(2-chloro-3(pentafluorosulfanyl)propyl)benzamide (2a), which was easily obtained from N-allylbenzamide using Dolbier’s protocol (Scheme 2, eq 1).15,21 Unfortunately, under all conditions
T
© 2018 American Chemical Society
Scheme 1. Target and Envisioned Approach
tested for the cyclization, the desired product 3a was never observed and only starting materials and/or the SF5-vinyl product 4a were obtained (Scheme 2, eq 2). Though disappointing, these results were not unexpected as a dehydrohalogenation reaction of β-halo-SF5-alkyl compounds is the major approach used to prepare SF5-containing alkenes.7 Winter and Gard reported the use of silver salts of various nucleophiles to avoid elimination and favor the substitution on (2-bromoethyl)pentafluorosulfane (Scheme 2, eq 3).22 Given this precedent (even though only a brominated substrate was used), we wondered, in our case, if the use of silver additive could favor the cyclization over the elimination. Key optimization results are presented in Table 1. Inspired by Received: October 4, 2018 Published: October 29, 2018 7257
DOI: 10.1021/acs.orglett.8b03170 Org. Lett. 2018, 20, 7257−7260
Letter
Organic Letters Scheme 3. Scope of the Cyclizationa,b
Scheme 2. Synthesis of the Precursor, Initial Results, and Inspiration
Table 1. Key Optimization Results for the Silver-Promoted Cyclization of 2aa
entry
Ag salt (equiv)
solvent
temp (°C)
time (h)
yieldb (%)
1 2 3 4 5 6 7 8 9 10
AgNO3 (4) AgBF4 (4) AgOAc (4) AgOTf (4) AgOTf (4) AgOTf (2) AgOTf (1.5) AgOTf (1.1) AgOTf (1.0) AgOTf (0.5)
CH3CN CH3CN CH3CN CH3CN toluene toluene toluene toluene toluene toluene
80 80 80 80 110 110 110 110 110 110
20 20 20 20 3 3 3 3 3 3
13 37 5 59 98 100 100 100 (97)c 94 56
a See the Supporting Information for the detailed experimental procedures. bYield of 3a determined by 19F NMR analysis of the crude mixture after workup using 2-fluoro-4-nitrotoluene as an internal standard. cIsolated yield of 3a.
Gard’s conditions, we initially screened a range of silver salts in CH3CN at 80 °C (Table 1, entries 1−4). Gratifyingly, in all cases, the desired product23 was formed and the best result was obtained when 4 equiv of AgOTf (Table 1, entry 4) was used. It is worth noting that the elimination side product 4a was only observed when AgOAc was used as the silver salt (86% yield by NMR). Switching to toluene allowed the reaction to proceed at a higher temperature. This change not only resulted in a significantly shorter reaction time (3 h) but also in a higher yield of 98% (Table 1, entry 5). The generous excess of AgOTf was then determined to be unnecessary as 1.1 equiv was enough to give a 100% NMR yield, with an isolated yield of 97% (Table 1, entry 8). Using a lesser amount (1 or 0.5 equiv) gave 3a in lower yield (Table 1, entries 9 and 10). As such, the conditions of Table 1, entry 8 were chosen as the optimal ones. We next evaluated the reactivity of various N-(2-chloro-3(pentafluorosulfanyl)propyl)amide (2) under the optimized conditions (Scheme 3). The benzamides 2b−f with a substituent at the para position all performed well, regardless of the nature of the substituent. Hence, oxazolines 3b−f were isolated with yields between 76 and 97%. Notably, an aryl
a
See the Supporting Information for the detailed experimental procedures. bIsolated yield. cReaction was performed on a 1 mmol scale. dThe product was contaminated with ca. 4% of a fluorinated inseparable side product. eReaction time was 1 h. fdr ∼1:1. gReaction time was 17 h.
bromide is well tolerated, thus opening the door to further functionalization of the product (vide infra). Replacement of the phenyl ring for a thiophene or a furan was possible, and the corresponding heterocycles24 were obtained in good yields (66−86%). Substrates bearing a substituent at the ortho position could be used, although the corresponding products 3g−j were obtained in slightly lower yields (55−83%). Cinnamyl derivative 2m performed well, and the cyclized product 3m was isolated in 92% yield. The alkynyl substrate proved more problematic. Indeed, under the standard reaction conditions, an incomplete conversion was observed, and the 7258
DOI: 10.1021/acs.orglett.8b03170 Org. Lett. 2018, 20, 7257−7260
Letter
Organic Letters Accession Codes
product 3n was isolated in a moderate 40% yield. Further optimization (nature and number of equivalent of the silver salt, reaction time and temperature, solvent and additive) was attempted for this particular substrate, but without success.25 Finally, the use of various aliphatic substrates (2o−s) was investigated. While the reaction proceeded well, the isolated yields for those substrates were moderate to good (52−75%). Nonetheless, somewhat functionalized substrates such as a lithocholic acid derivatives and a Cbz-protected piperidine could be employed and provided the corresponding oxazolines. Finally, to further extend the utility of these new SF5containing oxazolines, we investigated potential transformations (Scheme 4). For instance, palladium-catalyzed Suzuki−
CCDC 1870013 contains 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.
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Jean-François Paquin: 0000-0003-2412-3083
Scheme 4. Further Transformations of 5(Pentafluorosulfanyl)methyl-2-oxazolinesa
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS This work was supported by the Natural Sciences and Engineering Research Council of Canada, the Fonds de recherche du Quebec−Nature et technologies and the Université Laval. We thank Thierry Maris (Département de chimie, Université de Montréal) for the crystallographic analysis.
■
a
See the Supporting Information for the detailed experimental procedures.
Miyaura cross-coupling of 3f with 4-methoxyphenylboronic acid under the standard conditions provided the desired product 5 in 84% yield. It is interesting to note that the pentafluorosulfanyl group is stable under the basic conditions used, even though elimination of a SF5 group has been observed by others.26 Also, acid-promoted opening of oxazoline 3a with water27 followed by a treatment with acetyl chloride gave the fully protected SF5-containing amino alcohol 6 in 83% yield over two steps. Considering the vast chemistry of amino alcohol, this new SF5-containing derivative may be viewed as a versatile building block. In summary, we have reported the silver-promoted synthesis of 5-(pentafluorosulfanyl)methyloxazolines. This transformation represents the first report, to the best of our knowledge, of a substitution of the chlorine atom on β-chloro-SF5-alkyl compounds. Notably, under the reaction conditions, no elimination of the chlorine atom is observed. Finally, it provides access to potentially useful SF5-containing oxazolines. Extension of a similar strategy for the preparation of other SF5containing heterocycles is currently underway and will be reported in due course.
■
REFERENCES
(1) Review: Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. Applications of Fluorine in Medicinal Chemistry. J. Med. Chem. 2015, 58, 8315−8359. (2) Reviews: (a) Jeschke, P. The unique role of halogen substituents in the design of modern agrochemicals. Pest Manage. Sci. 2010, 66, 10−27. (b) Fujiwara, T.; O’Hagan, D. Successful fluorine-containing herbicide agrochemicals. J. Fluorine Chem. 2014, 167, 16−29. (3) Reviews: (a) Berger, R.; Resnati, G.; Metrangolo, P.; Weber, E.; Hulliger, J. Organic fluorine compounds: a great opportunity for enhanced materials properties. Chem. Soc. Rev. 2011, 40, 3496−3508. (b) Ragni, R.; Punzi, A.; Babudri, F.; Farinola, G. M. Organic and Organometallic Fluorinated Materials for Electronics and Optoelectronics: A Survey on Recent Research. Eur. J. Org. Chem. 2018, 2018, 3500−3519. (4) Review: O’Hagan, D. Understanding organofluorine chemistry. An introduction to the C-F bond. Chem. Soc. Rev. 2008, 37, 308−319. (5) Review: Manteau, B.; Pazenok, S.; Vors, J.-P.; Leroux, F. R. New trends in the chemistry of α-fluorinated ethers, thioethers, amines and phosphines. J. Fluorine Chem. 2010, 131, 140−158. (6) Silvey, G. A.; Cady, G. H. Trifluoromethylsulfur Pentafluoride. J. Am. Chem. Soc. 1950, 72, 3624−3626. (7) Reviews: (a) Kirsch, P. The Pentafluorosulfuranyl Group and Related Structures. In Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications; Wiley-VCH: Weinheim, 2004; pp 146−156. (b) Altomonte, S.; Zanda, M. Synthetic chemistry and biological activity of pentafluorosulphanyl (SF5) organic molecules. J. Fluorine Chem. 2012, 143, 57−93. (c) Savoie, P. R.; Welch, J. T. Preparation and Utility of Organic Pentafluorosulfanyl-Containing Compounds. Chem. Rev. 2015, 115, 1130−1190. (8) Sowaileh, M. F.; Hazlitt, R. A.; Colby, D. A. Application of the Pentafluorosulfanyl Group as a Bioisosteric Replacement. ChemMedChem 2017, 12, 1481−1490. (9) Bowden, R. D.; Comina, P. J.; Greenhall, M. P.; Kariuki, B. M.; Loveday, A.; Philp, D. A New Method for the Synthesis of Aromatic Sulfurpentafluorides and Studies of the stability of the Sulfurpentafluoride Group in Common Synthetic Transformations. Tetrahedron 2000, 56, 3399−3408. (10) For selected recent examples, see: (a) Alverez, C.; Arkin, M. R.; Bulfer, S. L.; Colombo, R.; Kovaliov, M.; LaPorte, M. G.; Lim, C.; Liang, M.; Moore, W. J.; Neitz, R. J.; Yan, Y.; Yue, Z.; Huryn, D. M.;
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03170. Detailed experimental procedures and full spectroscopic data for all new compounds (PDF) 7259
DOI: 10.1021/acs.orglett.8b03170 Org. Lett. 2018, 20, 7257−7260
Letter
Organic Letters Wipf, P. Structure-Activity Study of Bioisosteric Trifluoromethyl and Pentafluorosulfanyl Indole Inhibitors of the AAA ATPase p97. ACS Med. Chem. Lett. 2015, 6, 1225−1230. (b) Hendriks, C. M. M.; Penning, T. M.; Zang, T.; Wiemuth, D.; Gründer, S.; Sanhueza, I. A.; Schoenebeck, F.; Bolm, C. Pentafluorosulfanyl-containing flufenamic acid analogs: syntheses, properties and biological activities. Bioorg. Med. Chem. Lett. 2015, 25, 4437−4440. (c) Kanishchev, O. S.; Dolbier, W. R., Jr. Synthesis of 6-SF5-indazoles and an SF5-analog of Gamendazole. Org. Biomol. Chem. 2018, 16, 5793−5799. (11) For selected examples, see: (a) Lim, D. S.; Choi, J. S.; Pak, C. S.; Welch, J. T. Synthesis and herbicidal activity of a pentafluorosulfanyl analog of trifluralin. J. Pestic. Sci. 2007, 32, 255−259. (b) Kanishchev, O. S.; Dolbier, W. R., Jr. Ni/Ir-Catalyzed Photoredox Decarboxylative Coupling of S-Substituted Thiolactic Acids with Heteroaryl Bromides: Short Synthesis of Sulfoxalor and Its SF5 Analog. Chem. - Eur. J. 2017, 23, 7677−7681. (12) For selected examples, see: (a) Ponomarenko, M. V.; Kalinovich, N.; Serguchev, Y. A.; Bremer, M.; Röschenthaler, G.-V. Synthesis of pentafluoro-λ6-sulfanyl substituted acetylenes for novel liquid crystals. J. Fluorine Chem. 2012, 135, 68−74. (b) Martinez, H.; Zheng, Z.; Dolbier, W. R., Jr. Energetic materials containing fluorine. Design, synthesis and testing of furazan-containing energetic bearing a pentafluorosulfanyl group. J. Fluorine Chem. 2012, 143, 112−122. (c) Iida, N.; Tanaka, K.; Tokunaga, E.; Mori, S.; Saito, N.; Shibata, N. Synthesis of Phthalocyanides with a Pentafluorosulfanyl Substituent at Peripheral Positions. ChemistryOpen 2015, 4, 698−702. (d) Kenyon, P.; Mecking, S. Pentafluorosulfanyl Substituents in Polymerization Catalysis. J. Am. Chem. Soc. 2017, 139, 13786−13790. (13) For selected recent examples, see: (a) Li, X.; Taechalertpaisarn, J.; Xin, D.; Burgess, K. Protein-Protein Interface Mimicry by an Oxazoline Piperidine-2,4-dione. Org. Lett. 2015, 17, 632−635. (b) Yoshida, M.; Onda, Y.; Masuda, Y.; Doi, T. Potent oxazoline analog of apratoxin C: Synthesis, biological evaluation, and conformational analysis. Biopolymers 2016, 106, 404−414. (c) Avalos-Alanís, F. G.; Hernández-Fernández, E.; Carranza-Rosales, P.; López-Cortina, S.; Hernández-Fernández, J.; Ordóñez, M.; Guzmán-Delgado, N. E.; Morales-Vargas, A.; Velázquez-Moreno, V. M.; Santiago-Mauricio, M. G. Synthesis, antimycobacterial and cytotoxic activity of α,βunsaturated amides and 2,4-disubstituted oxazoline derivatives. Bioorg. Med. Chem. Lett. 2017, 27, 821−825. (14) Hargaden, G. C.; Guiry, P. J. Recent Applications of OxazolineContaining Ligands in Asymmetric Catalysis. Chem. Rev. 2009, 109, 2505−2550. (15) Wong, G. S. K.; Wu, W. In Oxazoles: Synthesis, Reactions, and Spectroscopy. Part B; Palmer, D. C., Ed.; John Wiley & Sons: Hoboken, 2004; pp 331−528. (16) Riobé, F.; Avarvari, N. Electroactive oxazoline ligands. Coord. Chem. Rev. 2010, 254, 1523−1533. (17) For recent reviews on synthetic approaches to other SF5containing heterocycles, see: (a) Kanishchev, O. S.; Dolbier, W. R., Jr. SF5-Substituted Aromatic Heterocycles. Adv. Heterocycl. Chem. 2016, 120, 1−42. (b) Das, P.; Tokunaga, E.; Shibata, N. Recent advancements in the synthesis of pentafluorosulfanyl (SF5)-containing heteroaromatic compounds. Tetrahedron Lett. 2017, 58, 4803−4815. (18) (a) Yu, J.; Yang, H.; Fu, H. Transition Metal-Free Trifluoromethylation of N-Allylamides with Sodium Trifluoromethanesulfinate: Synthesis of Trifluoromethyl-Containing Oxazolines. Adv. Synth. Catal. 2014, 356, 3669−3675. (b) Kawamura, S.; Sekine, D.; Sodeoka, M. Synthesis of CF3-containing oxazolines via trifluoromethylation of allylamides with Togni reagent in the presence of alkali metal iodides. J. Fluorine Chem. 2017, 203, 115−121. (19) Aït-Mohand, S.; Dolbier, W. R., Jr. New and Convenient Method for Incorporation of Pentafluorosulfanyl (SF5) Substituents Into Aliphatic Organic Compounds. Org. Lett. 2002, 4, 3013−3015. (20) Roush, D. M.; Patel, M. M. A Mild Procedure for the Preparation of 2-Oxazolines. Synth. Commun. 1985, 15, 675−679. (21) All of the N-(2-chloro-3-(pentafluorosulfanyl)propyl)amides used herein have been prepared using a similar route. See the Supporting Information for details.
(22) Winter, R. W.; Gard, G. L. Halogen displacement chemistry with silver and alkali metal salts: Preparation of SF5-esters, alcohols, aliphatic olefins, acids and an iodide. J. Fluorine Chem. 2006, 127, 1188−1894. (23) Suitable crystals of compound 3a were obtained for X-ray diffraction, and the analysis confirmed the structure. (24) The synthesis of a pyridyl derivative was attempted, but the corresponding N-(2-chloro-3-(pentafluorosulfanyl)propyl)amide could never be obtained. (25) In some cases, an unidentified side product was formed in significant amounts. (26) For example, see: (a) Huang, Y.; Gard, G. L.; Shreeve, J. M. One-pot syntheses of 1,2,3-triazoles containing a pentafluorosulfanylalkyl group via click chemistry. Tetrahedron Lett. 2010, 51, 6951− 6954. (b) Dudziński, P.; Matsnev, A. V.; Thrasher, J. S.; Haufe, G. Synthesis of SF5CF2-Containing Enones and Instability of This Group in Specific Chemical Environments and Reaction Conditions. J. Org. Chem. 2016, 81, 4454−4463. (27) Wappes, E. A.; Nakafuku, K. M.; Nagib, D. A. Directed β C−H Amination of Alcohols via Radical Relay Chaperones. J. Am. Chem. Soc. 2017, 139, 10204−10207.
7260
DOI: 10.1021/acs.orglett.8b03170 Org. Lett. 2018, 20, 7257−7260
