Letter pubs.acs.org/OrgLett
Hypervalent-Iodine-Mediated Ring-Contraction Monofluorination Affording Monofluorinated Five-Membered Ring-Fused Oxazolines Yong-Chao Han, Yan-Dong Zhang, Qun Jia, Jian Cui, and Chi Zhang* State Key Laboratory of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering, College of Chemistry, Nankai University, Tianjin 300071, China S Supporting Information *
ABSTRACT: The first ring-contraction monofluorination reaction mediated by a hypervalent iodine reagent is reported, and the use of the reaction for the synthesis of monofluorinated five-membered ring-fused oxazolines is described. By means of this reaction, a fluorine atom can be selectively introduced either on the five-membered ring or external to it, depending on whether or not the substrate has C-4 alkyl substituents. The reaction was used for the further conversion of probenecid and isoxepac.
F
pounds that are otherwise difficult to obtain. To the best of our knowledge, only one example of a ring-contraction fluorination reaction mediated by a hypervalent iodine reagent has been reported: specifically, Hara et al. found that ringcontraction difluorination reactions of cyclic alkenes with piodotoluene difluoride and Et3N·5HF yield gem-difluorination products.12 However, ring-contraction monof luorination reactions mediated by hypervalent iodine reagents remain unexplored. Herein, we report the first such reaction, which we carried out with BF3·Et2O as the fluorine source and with readily accessible N-cyclohexenyl amides and their derivatives as substrates. The reaction afforded monofluorinated five-membered ringfused oxazolines as products. The five-membered ring-fused oxazoline moiety is present in a number of bioactive molecules, such as the pharmaceutical deflazacort, a glucocorticoid with anti-inflammatory and immunosuppressant activities (Figure 1, I).13 However, there have been only a few scattered reports on the formation of this moiety, and the methods used for this purpose can be divided into two categories (Scheme 1): (1) amidomercuration,14a amidoselenenylation,14b or amidotellurinylation14c of cyclopentene in the presence of nitriles, followed by intramolecular nucleophilic substitution, and (2) treatment of 2-amidocyclopentanols with sulfurous dichloride to afford the corresponding sulfurochloridite intermediate, which undergoes an intramolecular nucleophilic substitution reaction accompanied by the release of SO2 and HCl.15 However, the reagents used in amidomercuration, amidotellurinylation, and
luorine-containing organic compounds play important roles in the pharmaceutical1,2 and agrochemical industries:1,3 approximately 20% of pharmaceuticals and 30−40% of agrochemicals contain at least one fluorine atom.4 In addition, interactions between organic fluorine and various other chemical entities have received considerable attention from researchers involved in the systematic design of functional materials.1,5 Therefore, numerous methods for the introduction of a fluorine atom into organic compounds have been developed.6 Because nucleophilic fluorine reagents are usually stable and readily available, direct oxidative fluorination of organic compounds with such reagents, including alkali-metal fluorides (e.g., KF, CsF), HF-based reagents (e.g., HF-pyridine, Et3N·3HF), tetraalkylammonium fluorides (e.g., n-Bu4NF, Me4NF), and boron trifluoride etherate (BF3·Et2O), is an ideal method for introducing a fluorine atom into organic molecules.7 BF3·Et2O, a widely used Lewis acid, acts as the fluorine source in the Prins reaction, the carbofluorination reaction, and ring-opening fluorination reactions of strained rings including epoxides and aziridines.8 BF3·Et2O has also been reported to serve as the fluorine source in oxidative fluorination reactions.9 In these reactions, the oxidant must be carefully chosen. Because hypervalent iodine reagents are versatile, readily available, easy to handle, and environmentally friendly,10 they are the preferred organo-oxidants for this purpose. Among the various oxidative fluorination reactions mediated by hypervalent iodine reagents,11 oxidative ringcontraction fluorination reactions hold a special place because they can be used to manipulate the molecular skeleton and to introduce a fluorine atom in a single step, providing an efficient method for synthesizing fluorine-containing organic com© 2017 American Chemical Society
Received: August 22, 2017 Published: September 19, 2017 5300
DOI: 10.1021/acs.orglett.7b02479 Org. Lett. 2017, 19, 5300−5303
Letter
Organic Letters
Scheme 2. Ring-Contraction Monofluorination Reactions of 1 Mediated by Iodine(III) Reagent 2ba
Figure 1. Biologically active molecules containing a five-membered ring-fused oxazoline moiety.
Scheme 1. Methods for the Formation of Five-Membered Ring-Fused Oxazolines
a
The reaction was conducted on a 0.2 mmol scale.
(1d−1g) on the phenyl ring gave 52−72% yields of the corresponding monofluorinated oxazoline products (3b−3g) within 10 min. The halogen atoms on the phenyl rings of products such as 3e−3g can be expected to serve as handles for increasing molecular complexity by means of well-developed transition-metal-catalyzed coupling reactions. Other aromatic amides, including naphthyl, furyl, and thienyl amides, afforded the desired monofluorinated products (3h−3k) in 55−61% yields. Reactions of N-cyclohexenyl phenylacetamide and Ncyclohexenyl hexanamide also gave the corresponding monofluorinated products (3l and 3m) in 48% and 34% yields, respectively. Surprisingly, when N-(4,4-dimethylcyclohex-2-en-1-yl)benzamide (4a), which has two methyl groups at C-4 of the cyclohexenyl ring, was subjected to the optimized reaction conditions for 5 min, we obtained a quantitative yield of a different ring-contraction monofluorinated oxazoline product, that is, 6-(2-fluoropropan-2-yl)-2-phenyl-3a,5,6,6a-tetrahydro4H-cyclopenta[d]oxazole (5a), in which the fluorine atom was external to the five-membered ring (as indicated by X-ray crystallography). We then explored the reactions of numerous derivatives of 4a under the optimized conditions (Scheme 3). Aromatic amides with electron-donating or electron-withdrawing groups on the phenyl ring afforded the corresponding monofluorinated products (5b−5o) in good to excellent yields, which suggests that the electronic properties of the phenyl ring had little influence on the outcome of the reaction. Naphthyl, furyl, thienyl, and indolyl amides were compatible with the reaction conditions as well, yielding products 5p−5t in excellent yields. Moreover, the reaction of aliphatic amides 4v−4z proceeded smoothly to afford the desired monofluorinated products in 65−91% yields. In addition, the reaction of a substrate bearing two ethyl groups at C-4 instead of two methyl groups also proceeded well, affording corresponding monofluorinated oxazoline product 5aa in 90% yield. Similarly, a substrate
amidoselenenylation reactions are toxic, and none of the reported methods can be used to introduce a fluorine atom in a single step. Considering that the substitution of fluorine for hydrogen in bioactive molecules, including drug candidates, is a long-recognized, commonly used strategy in drug development,16 the new method described herein for the synthesis of monofluorinated five-membered ring-fused oxazolines represents a significant advance. We began by exploring the reaction of N-(cyclohex-2-en-1yl)benzamide (1a) as the substrate and iodosobenzene (2a) as the oxidant in the presence of 2.0 equiv of BF3·Et2O in CH2Cl2 at room temperature. Reaction for 20 min afforded a 35% yield of a ring-contraction monofluorinated oxazoline product, 5fluoro-6-methyl-2-phenyl-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]oxazole (3a), formed by the introduction of a fluorine atom onto the five-membered ring. The structure of 3a was confirmed by X-ray crystallography, which showed that the methyl group and fluorine atom on the five-membered ring were trans to each other. Variation of the reaction conditions revealed that the use of 1.5 equiv of 3,5-dichloroiodosobenzene (2b) and 2.0 equiv of BF3·Et2O in CHCl3 at room temperature afforded the highest yield of 3a (67%; for details, see the Supporting Information). We investigated the substrate scope of the reaction by subjecting various N-cyclohexenyl amides 1 to the optimized conditions (Scheme 2). Substituted benzamides bearing electron-donating (1b and 1c) or electron-withdrawing groups 5301
DOI: 10.1021/acs.orglett.7b02479 Org. Lett. 2017, 19, 5300−5303
Letter
Organic Letters
A proposed mechanism for the ring-contraction monofluorination reaction is shown in Scheme 5. First, activation of
Scheme 3. Ring-Contraction Monofluorination Reactions of 4 Mediated by Iodine(III) Reagent 2ba
Scheme 5. Proposed Mechanism for the Formation of 3a and 5a
a The reaction was conducted on a 0.2 mmol scale. bThe reaction was carried out in 18 mL of CHCl3. c2.0 equiv of 2b were used.
hypervalent iodine(III) reagent 2b by BF3·Et2O forms iodine(III) intermediate A, which activates the double bond of the substrate (1a or 4a) and reacts with it to afford iodonium intermediate B. Subsequent intramolecular nucleophilic attack of the oxygen atom of the amide group generates intermediate C, which undergoes reductive elimination to give carbocation intermediate D, along with release of a fluoride ion. The next step depends on the R group. If R is hydrogen, carbocation intermediate G forms via successive alkyl and double hydride shifts. Intermediate G reacts with a fluoride ion to give monofluorinated product 3a. We speculate that G is more stable than F because of the electron-withdrawing inductive effect of the oxygen atom, which may explain the transformation of tertiary carbocation intermediate F to secondary carbocation intermediate G.19 The formation of Ritter products i and ii confirms the intermediacy of carbocations D and G. If R is a methyl group, intermediate D undergoes an alkyl migration to form a more stable tertiary carbocation intermediate H. Carbocation H is then trapped by a fluoride ion to provide product 5a. And, the formation of the Ritter product iii confirms the intermediacy of carbocation H. In summary, we have developed a mild, efficient ringcontraction monofluorination reaction of N-cyclohexenyl amides, with BF3·Et2O as the fluorine source, to afford monofluorinated five-membered ring-fused oxazolines. This is the first report of a ring-contraction monofluorination reaction mediated by a hypervalent iodine(III) reagent. This mild, operationally simple, metal-free reaction provides an efficient method for generating fluorine-containing oxazolines that are
bearing a cyclohexyl group at C-4 provided a 74% yield of ringcontraction monofluorination product 5bb. The synthetic utility of this ring-contraction monofluorination reaction was evaluated (Scheme 4). Specifically, we Scheme 4. Further Conversion of Probenecid and Isoxepac
prepared compound 6a from probenecid, a commercial drug used to treat gout,17 and then we carried out the reaction of 6a with 2b and BF3·Et2O in CHCl3, which proceeded smoothly to afford 7a in 81% yield. The same strategy also worked for isoxepac, an anti-inflammatory compound that is a key intermediate in the synthesis of the pharmaceutical olopatadine;18 we obtained corresponding monofluorinated oxazoline product 7b in high yield. These two syntheses show that biologically active molecules, probenecid and isoxepac, constitute viable substrates for the present reaction. 5302
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Organic Letters
(8) Cresswell, A. J.; Davies, S. G.; Roberts, P. M.; Thomson, J. E. Chem. Rev. 2015, 115, 566−611. (9) (a) Cui, J.; Jia, Q.; Feng, R. Z.; Liu, S. S.; He, T.; Zhang, C. Org. Lett. 2014, 16, 1442−1445. (b) De Meio, G.; Morgan, J.; Pinhey, J. T. Tetrahedron 1993, 49, 8129−8138. (c) De Meio, G. V.; Pinhey, J. T. J. Chem. Soc., Chem. Commun. 1990, 1065−1066. (10) (a) Zhdankin, V. V. Hypervalent Iodine Chemistry: Preparation, Structure and Synthetic Application of Polyvalent Iodine Compounds; John Wiley & Sons Ltd.: New York, 2014. (b) Yoshimura, A.; Zhdankin, V. V. Chem. Rev. 2016, 116, 3328−3435. (c) Li, Y.; Hari, D. P.; Vita, M. V.; Waser, J. Angew. Chem., Int. Ed. 2016, 55, 4436−4454. (d) Duan, Y.; Jiang, S.; Han, Y.; Sun, B.; Zhang, C. Youji Huaxue 2016, 36, 1973−1984. (e) Zhang, X.; Cong, Y.; Lin, G.; Guo, X.; Cao, Y.; Lei, K.; Du, Y. Youji Huaxue 2016, 36, 2513−2529. (f) Chen, J.; Qu, H.-M.; Peng, J.; Chen, C. Youji Huaxue 2015, 35, 937−946. (g) Charpentier, J.; Früh, N.; Togni, A. Chem. Rev. 2015, 115, 650− 682. (h) Singh, F. V.; Wirth, T. Chem. - Asian J. 2014, 9, 950−971. (i) Brown, M.; Farid, U.; Wirth, T. Synlett 2013, 24, 424−431. (j) Duschek, A.; Kirsch, S. F. Angew. Chem., Int. Ed. 2011, 50, 1524− 1552. (k) Merritt, E. A.; Olofsson, B. Synthesis 2011, 2011, 517−538. (l) Brand, J. P.; Gonzalez, D. F.; Nicolai, S.; Waser, J. Chem. Commun. 2011, 47, 102−115. (m) Dohi, T.; Kita, Y. Chem. Commun. 2009, 2073−2085. (n) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299−5358. (o) Wirth, T. Angew. Chem., Int. Ed. 2005, 44, 3656− 3665. (p) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523− 2584. (11) (a) Kohlhepp, S. V.; Gulder, T. Chem. Soc. Rev. 2016, 45, 6270− 6288. (b) Xu, P.; Wang, F.; Fan, G.; Xu, X.; Tang, P. Angew. Chem., Int. Ed. 2017, 56, 1101−1104. (c) Banik, S. M.; Mennie, K.; Jacobsen, E. N. J. Am. Chem. Soc. 2017, 139, 9152−9155. (d) Ilchenko, N. O.; Hedberg, M.; Szabó, K. J. Chem. Sci. 2017, 8, 1056−1061. (e) Yang, B.; Chansaenpak, K.; Wu, H.; Zhu, L.; Wang, M.; Li, Z.; Lu, H. Chem. Commun. 2017, 53, 3497−3500. (f) Kitamura, T.; Miyake, A.; Muta, K.; Oyamada, A. J. J. Org. Chem. 2017, DOI: 10.1021/acs.joc.7b01266. (g) Banik, S. M.; Medley, J. W.; Jacobsen, E. N. Science 2016, 353, 51− 54. (h) Molnár, I. G.; Gilmour, R. J. Am. Chem. Soc. 2016, 138, 5004− 5007. (12) Hara, S.; Nakahigashi, J.; Ishii, K.; Fukuhara, T.; Yoneda, N. Tetrahedron Lett. 1998, 39, 2589−2592. (13) (a) Parente, L. BMC Pharmacol. Toxicol. 2017, 18, No. 1, DOI: 10.1186/s40360-016-0111-8. (b) Markham, A.; Bryson, H. M. Drugs 1995, 50 (2), 317−333. (14) (a) Kretchmer, R. A.; Daly, P. J. J. Org. Chem. 1976, 41, 192− 195. (b) Tiecco, M.; Testaferri, L.; Marini, F.; Temperini, A.; Bagnoli, L.; Santi, C. Synth. Commun. 1997, 27, 4131−4140. (c) Hu, N. X.; Aso, Y.; Otsubo, T.; Ogura, F. Tetrahedron Lett. 1988, 29, 1049−1052. (15) Bannard, R. A. B.; Gibson, N. C. C.; Parkkari, J. H. Can. J. Chem. 1971, 49 (12), 2064−2072. (16) (a) Wang, J.; Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem. Rev. 2014, 114, 2432−2506. (b) Ojima, I. J. Org. Chem. 2013, 78, 6358− 6383. (c) O’Hagan, D. J. Fluorine Chem. 2010, 131, 1071−1081. (d) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305−321. (e) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320−330. (17) (a) Perwitasari, O.; Yan, X.; Johnson, S.; White, C.; Brooks, P.; Tompkins, S. M.; Tripp, R. A. Antimicrob. Agents Chemother. 2013, 57, 475−483. (b) Mason, R. M. Ann. Rheum. Dis. 1954, 13 (2), 120−130. (18) Chavan, S. P.; Lasonkar, P. B. Synthesis 2013, 45, 3399−3403. (19) Prakash, G. K.; Mathew, T.; Panja, C.; Kulkarni, A.; Olah, G. A.; Harmer, M. A. Adv. Synth. Catal. 2012, 354, 2163−2171.
otherwise difficult to obtain. In addition, the regioselectivity of introduction of the fluorine atom could be controlled by changing the substituent at C-4 of the substrate. We propose a mechanism involving the intermediacy of various carbocations. Further conversions of probenecid and isoxepac indicate that the present reaction might be useful for substantially increasing the complexity of carboxyl-group-containing compounds.
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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.7b02479. Experimental details, characterization of new compounds, and copies of 1H, 13C, and 19F NMR spectra, HRMS, and crystallographic structure (PDF) Crystallographic data for 3a (CIF) Crystallographic data for 5a (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Chi Zhang: 0000-0001-9050-076X Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was financially supported by The National Natural Science Foundation of China (21472094, 21172110, 21421062) and The Tianjin Natural Science Foundation (17JCYBJC20300).
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REFERENCES
(1) (a) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, 2nd ed.; Wiley-VCH: Weinheim, 2013. (b) Hiyama, T. In Organofluorine Compounds; Chemistry and Applications; Yamamoto, H., Ed.; Springer: New York, 2000 and references therein. (2) (a) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. J. Med. Chem. 2015, 58, 8315−8359. (b) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359−4369. (c) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881−1886. (d) Böhm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637−643. (3) (a) Fujiwara, T.; O’Hagan, D. J. Fluorine Chem. 2014, 167, 16− 29. (b) Jeschke, P. Pest Manage. Sci. 2010, 66, 10−27. (c) Jeschke, P. ChemBioChem 2004, 5, 570−589. (4) Thayer, A. M. Chem. Eng. News 2006, 84, 15−24. (5) Berger, R.; Resnati, G.; Metrangolo, P.; Weber, E.; Hulliger, J. Chem. Soc. Rev. 2011, 40, 3496−3508. (6) (a) Champagne, P. A.; Desroches, J.; Hamel, J.-D.; Vandamme, M.; Paquin, J.-F. Chem. Rev. 2015, 115, 9073−9174. (b) Yang, X.; Wu, T.; Phipps, R. J.; Toste, F. D. Chem. Rev. 2015, 115, 826−870. (c) Campbell, M. G.; Ritter, T. Chem. Rev. 2015, 115, 612−633. (d) Chatalova-Sazepin, C.; Hemelaere, R.; Paquin, J.-F.; Sammis, G. M. Synthesis 2015, 47, 2554−2569. (e) Liang, T.; Neumann, C.; Ritter, T. Angew. Chem., Int. Ed. 2013, 52, 8214−8264. (f) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470−477. (g) Valero, G.; Companyó, X.; Rios, R. Chem. - Eur. J. 2011, 17, 2018−2037. (7) Ni, C. F.; Jiang, F. Z.; Zeng, Y. W.; Hu, J. B. J. Fluorine Chem. 2015, 179, 3−13. 5303
DOI: 10.1021/acs.orglett.7b02479 Org. Lett. 2017, 19, 5300−5303
