Letter pubs.acs.org/OrgLett
Silver-Catalyzed Regioselective Fluorination of Carbonyl Directed Alkynes: Synthesis of α‑Fluoroketones Fang-Hui Li, Zhong-Jian Cai, Ling Yin, Jian Li, Shun-Yi Wang,* and Shun-Jun Ji* Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science & Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou 215123, China S Supporting Information *
ABSTRACT: A novel silver-catalyzed fluorination reaction of carbonyl directed alkynes in the presence of N-fluorobenzenesulfonimide and water with high regioselectivities has been developed. The established protocol provides an alternative method for rapid assembly of α-fluoroketone derivatives under simple and mild reaction conditions. The reaction pathway involves a ring closure and opening process for the construction of new C−O and C−F bonds. In addition, a fluorinecontaining indanone was observed through further N-heterocyclic carbene catalyzed intramolecular crossed-benzoin reaction of α-fluoroketone.
F
Meanwhile, Yang’s group developed a metal-free, efficient, and direct approach to access α-fluoroketones via olefin difunctionalization. This green acylfluorination protocol could furnish α-fluoroketones in moderate yields with a broad substrate scopes.11 Recently, Liu et al. reported a novel fluorination of vinyl azides to construct α-fluoroketones under mild conditions. It was found that a single-electron transfer and a fluorine atom transfer are involved in the reaction.12 The difunctionalization of alkynes has emerged as a powerful and versatile synthetic strategy that can be widely applied in the construction of complex organic molecules via using simple alkynes as building blocks.13 In the last two decades, the oalkynylaryl aldehydes/ketones and the corresponding condensation derivatives were used as handy building blocks to construct carbo- or heterocycles through the domino inter-/ intramolecular nucleophilic addition cyclization.14 Herein, we report a silver-catalyzed fluorination of carbonyl-directed alkynes in the presence of NSFI to afford α-fluoroketone derivatives in moderate to good yields under simple and mild reaction conditions (Scheme 1). The reaction pathway involves a ring-closure and -opening process for the construction of new C−O and C−F bonds. At the outset of this study, the fluorination reaction of 2(phenylethynyl)benzaldehyde (1a) was carried out in 2 mL of DMA, at 60 °C, using a catalytic amount of AgNO3 as the promoter. Gratifyingly, the targeted α-fluoroketone 3a was obtained in 71% GC yield after 8 h (Table 1, entry 1). Next, this fluorination reaction of 1a and N-fluorobenzenesulfonimide 2a was used as a model reaction to optimize the reaction conditions (for detailed information, see the Supporting Information). It was found that the desired α-fluoroketones 3a was obtained in good yields in the presence of other silver
luorinated organic compounds have an integral role in agrochemicals,1pharmaceuticals,2 imaging agents,3 and material science4 due to the unique properties of the fluorine atom (high electronegativity and small size).5 According to a survey, approximately 30% of agrochemicals and 20% of medicinal compounds contain a fluorine atom.2a As a result, the development of efficient and mild methods to incorporate fluorine into diverse molecules has received increasing attention in organic synthesis.6 α-Fluoroketones are considered useful compounds in medicinal and biological chemistry,7 and αfluoroketones have important uses in organic chemistry since the keto group, the α-carbon, and the aromatic ring can be transformed into a number of fluorine-containing intermediates.8 The traditional approach for the preparation of αfluoroketones is the direct fluorination of α-haloketones, hydroxy-substituted ketones, or phenylketones.9 Nevado and co-workers found that disubstituted alkynes can be transformed into a regioisomeric mixture of acetals or ketones in the presence of Selectfluor and gold catalyst (Scheme 1).10 Scheme 1. Construction of α-Fluoroketones
Received: February 14, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00453 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Screening of Reaction Conditionsa
Scheme 2. Substrate Scope of o-Alkynylaryl Aldehydesa
entry
cat. (20 mol %)
solvent (2 mL)
temp (°C)
yieldb (%)
1 2 3 4 5 6 7 8 9 10d 11e 12f 13g 14h
AgNO3 AgOTf Ag2CO3 AgF AgOAc AgSbF6 AgF AgF AgF AgF AgF AgF AgF AgF
DMA DMA DMA DMA DMA DMA DMA DMA DMA DMA DMA DMA DMA DMA
60 60 60 60 60 60 rt 50 80 50 50 50 50 50
71 80 80 83 75 83 53 86 (83)c 71 trace 76 80 79 81
a
Reaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), and cat. (20 mol %), DMA (commercial sources without further purification, 2.0 mL) was stirred at the corresponding temperature for 8 h. bThe yields were determined by GC analysis using benzophenone as the internal standard. cIsolated yield. dExtra dry DMA (2 mL) was used. eExtra dry DMA (2 mL) and 2 equiv of H2O were added. fExtra dry DMA (2 mL) and 4 equiv of H2O were added. gExtra dry DMA (2 mL) and 10 equiv of H2O were added. hExtra dry DMA (2 mL) and 20 equiv of H2O were added. a
Reaction conditions: 1 (0.5 mmol), NFSI (0.75 mmol), DMA (2 mL). The reaction was stirred at 50 °C with AgF (0.1 mmol) for 12 h.
salts (such as AgOTf, Ag2CO3, AgF, AgOAc, and AgSbF6), and AgF and AgSbF6 gave the best result (83% GC yield, entries 4 and 6). Notably, a moderate yield (53%) was observed when the reaction was carried out at room temperature (Table 1, entry 7). Moreover, the yield was decreased when the temperature was raised (Table 1, entry 9), and a satisfactory yield was obtained when the reaction was carried out under milder conditions (Table 1, entry 8). It was found that a trace amount of α-fluoroketone 3a was observed when the raction was carried out in 2 mL of extra dry DMA (Table 1, entry 10). However, 76−81% yields were obtained when 2−20 equiv of H2O was added to the reaction (Table 1, entries 11−14). These results were similar to those for the reaction in commercially available DMA (nonanhydrous) (Table 1, entry 8). Therefore, the conditions shown in entry 8 were chosen as the optimized conditions. With the optimal conditions in hand, we next examined the scope of this fluorination reaction, and the results are shown in Scheme 2. A good yield of 3b (87%) was obtained when methyl-substituted o-alkynylaryl aldehyde was used. Furthermore, the current method was applied for halogen-containing oalkynylaryl aldehydes, affording the desired α-fluoroketones 3c, 3d, and 3e in 77%, 78%, and 72% yields, respectively. Meanwhile, the ortho-substituted aryl group also performed well, and product 3f was isolated in 62% yield. Although the electron-withdrawing group on the aryl ring reduced the yield to some extent, 57% yield of 3g was still obtained. Pleasingly, substrates bearing heterocyclic rings were proven to be appropriate candidates, affording the corresponding products 3h and 3i in excellent yields. Notably, the reaction successfully converted the compounds into the α-fluoro-substituted alkyl ketones 3j−m (47−88%) when the aromatic alkynes were changed to aliphatic alkynes. In addition, it was found that
methyl- and chlorine-substituted aldehydes were also compatible with the reaction conditions, delivering the desired products 3n and 3o in 59% and 66% yields, respectively. To gain further insight into this silver-promoted direct fluorination reaction, o-alkynylaryl ketones were used, and the results are shown in Scheme 3. To our delight, the desired αScheme 3. Substrate Scope of o-Alkynylaryl Ketonesa
a
Reaction conditions: 4 (0.5 mmol), NFSI (0.75 mmol), DMA (2 mL). The reaction was stirred at 50 °C with AgF (0.1 mmol) for 12 h.
fluoroketone 5a could be obtained in an acceptable yield under the optimal conditions. Similar to the o-alkynylaryl aldehydes, the o-alkynylaryl ketones bearing methyl- and brominesubstituted aromatic alkynes or aliphatic alkyne could react smoothly to generate the corresponding products in moderate to good yields 5b−d (57−71%). Meanwhile, fluorineB
DOI: 10.1021/acs.orglett.7b00453 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters containing diphenyl ketone 5e could be obtained in 74% yield under the standard conditions. In order to further explore the diversity application of our new reactions, we chose the α-fluoroketone 3k to achieve the further transformation. To our delight, a fluorine-containing indanone 3ka was obtained in an excellent yield (89%) through intramolecular crossed-benzoin reaction catalyzed by a Nheterocyclic carbene (Scheme 4).15
Scheme 6. Possible Mechanism
Scheme 4. Transformation of α-Fluoroketones
Some control experiments were carried out to clarify the possible pathway of this transformation (Scheme 5). It was Scheme 5. Control Experiments In summary, we have reported a novel silver-catalyzed direct fluorination reaction for rapid assembly of α-fluoroketone derivatives from carbonyl-directed alkynes with commercially available fluorine-containing block (NFSI). The transformation could be accomplished under simple and mild conditions with high regioselectivities, which provides chemists an alternative method for designing α-fluoroketones. Meanwhile, the fluorinecontaining 1,5-dicarbonyl compounds may also be further applied to construct other synthetic units. Control experiments indicate that this transformation involves a ring closure and opening process, and H2O used as H and O sources is an important reagent for the generation of α-fluoroketones. Further investigations to study the mechanism of this reaction and its applications in other organic reactions are ongoing in our laboratory.
■
ASSOCIATED CONTENT
S Supporting Information *
found that no α-fluoroketone products 7 and 9 were observed when the reactions were carried out with carbonyl-removed substrate 6 or p-alkynylaryl aldehyde 8 under the standard conditions (Scheme 5, eq 1−2). These results suggested that an o-carbonyl-substituent is necessary for the fluorination process. Next, we examined the silver-promoted fluorination reaction of o-alkynylaryl aldehyde 1b with D2O. It was found that the deuterated product 3b′ was obtained in 63% yield when 10 equiv of D2O was added to the extra dry DMA system (Scheme 5, eq 3). Moreover, major 18O-α-fluoroketone 3b″ and minor 3b‴ were observed when H218O was added to the extra dry DMA system (Scheme 5, eq 4). These results indicate that H2O used as H and O sources is an important reagent for the generation of α-fluoroketones. On the basis of the above results, a plausible mechanism for the silver-promoted direct fluorination reaction is illustrated in Scheme 6. The alkyne π-bond is attacked by the carbonyl oxygen to afford benzopyrylium intermediate A, which undergoes a subsequent nucleophilic attack of D2O to generate cyclic ketal species B. Then the Ag enol intermediate C is formed via a proton-catalyzed opening of ketal species. Next, the fluorination occurs to provide a enol compound D. The desired α-fluoroketone product 3b′ is formed through a enol− keto tautomerism of D.
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00453. Detailed experimental procedures and characterization data (PDF)
■
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Shun-Yi Wang: 0000-0002-8985-8753 Shun-Jun Ji: 0000-0002-4299-3528 Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS We gratefully acknowledge the National Natural Science Foundation of China (21542015, 21672157), PAPD, the Major Basic Research Project of the Natural Science Foundation of the Jiangsu Higher Education Institutions (No.16KJA150002), Soochow University, and the State and C
DOI: 10.1021/acs.orglett.7b00453 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Local Joint Engineering Laboratory for Novel Functional Polymeric Materials for financial support.
■
REFERENCES
(1) Jeschke, P. ChemBioChem 2004, 5, 570. (2) (a) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (3) (a) Ametamey, S. M.; Honer, M.; Schubiger, P. A. Chem. Rev. 2008, 108, 1501. (b) Patterson, J. C.; Mosley, M. L. Mol. Imaging Biol. 2005, 7, 197. (4) Hung, M. H.; Farnham, W. B.; Feiring, A. E.; Rozen, S. Fluoropolymers 2002, 1, 51. (5) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308. (6) (a) Chambers, R. D. Fluorine in Organic Chemistry; Blackwell, 2004. (b) Furuya, T.; Kuttruff, C. A.; Ritter, T. Curr. Opin. Drug. Discovery Dev. 2008, 11, 803. (7) (a) Welch, J. T.; Eswarakrishnan, S. Fluorine in Bioorganic Chemistry; Wiley, 1991 (b) Filler, R.; Kobayashi, Y.; Yagupolskii, L. M. Organofluorine Compounds in Medicinal Chemistry and Biomedical Application; Elsevier, 1993. (8) (a) Heinrich, M. R. Tetrahedron Lett. 2007, 48, 3895. (b) KatochRouse, R.; Pavlova, O. A.; Caulder, T.; Hoffman, A. F.; Mukhin, A. G.; Horti, A. G. J. J. Med. Chem. 2003, 46, 642. (c) Yoon, S. C.; Cho, J.; Kim, K. J. J. Chem. Soc., Perkin Trans. 1 1998, 1, 109. (d) Zajc, B.; Zupan, M. J. Org. Chem. 1990, 55, 1099. (e) Elke, F.-L. DE Patent 4328761, 1993. (f) Leroy, J. J. Org. Chem. 1981, 46, 206. (9) (a) Kim, K.-Y.; Kim, B. C.; Lee, H. B.; Shin, H. J. Org. Chem. 2008, 73, 8106. (b) Middleton, W. J.; Bingham, E. M. J. Am. Chem. Soc. 1980, 102, 4845. (c) Fuglseth, E.; Thvedt, T. H. K.; Møll, M. F.; Hoff, B. H. Tetrahedron 2008, 64, 7318. (d) Chen, Z.; Zhu, W.; Zheng, Z.; Zou, X. J. J. Fluorine Chem. 2010, 131, 340. (e) Stavber, S.; Zupan, M. Tetrahedron Lett. 1996, 37, 3591. (f) Stavber, S.; Jereb, M.; Zupan, M. Chem. Commun. 2000, 46, 1323. (g) Tenza, K.; Northen, J. S.; O’Hagan, D.; Slawin, A. M. Z. J. J. Fluorine Chem. 2004, 125, 1779. (h) Fuglseth, E.; Sundby, E.; Hoff, B. H. J. J. Fluorine Chem. 2009, 130, 600. (10) de Haro, T.; Nevado; de, C. Adv. Synth. Catal. 2010, 352, 2767. (11) Yang, Q.; Mao, L.-L.; Yang, B.; Yang, S.-D. Org. Lett. 2014, 16, 3460. (12) Wu, S.-W.; Liu, F. Org. Lett. 2016, 18, 3642. (13) (a) Wang, C.-Y.; Hsieh, Y.-F.; Liu, R.-S. Adv. Synth. Catal. 2014, 356, 144. (b) Liang, Z.-Q.; Ma, S.-M.; Yu, J.-H.; Xu, R.-R. J. Org. Chem. 2007, 72, 9219. (c) Nakamura, I.; Mizushima, Y.; Yamamoto, Y. J. J. Am. Chem. Soc. 2005, 127, 15022. (d) Nakamura, I.; Mizushima, Y.; Gridnev, I. D.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 9844. (e) Nakamura, I.; Bajracharya, G. B.; Wu, H.-Y.; Oishi, K.; Mizushima, Y.; Gridnev, I. D.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 15423. (f) Iwai, T.; Fujihara, T.; Terao, J.; Tsuji, Y. J. Am. Chem. Soc. 2009, 131, 6668. (g) Hirner, J. J.; Faizi, D. J.; Blum, S. A. J. Am. Chem. Soc. 2014, 136, 4740. (h) Nakamura, I.; Mizushima, Y.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 15022. (i) Chen, Q.; Zhao, J.; Ishikawa, Y.; Asao, N.; Yamamoto, Y.; Jin, T. Org. Lett. 2013, 15, 5766. (j) Nakamura, I.; Sato, T.; Terada, M.; Yamamoto, Y. Org. Lett. 2008, 10, 2649. (k) Nakamura, I.; Sato, T.; Terada, M.; Yamamoto, Y. Org. Lett. 2007, 9, 4081. (l) Zhang, Q.-W.; An, K.; He, W. Angew. Chem., Int. Ed. 2014, 53, 5667. (m) Fielding, M. R.; Grigg, R.; Urch, C. J. Chem. Commun. 2000, 22, 2239. (n) Janreddy, D.; Kavala, V.; Kuo, C.-W.; Kuo, T.-S.; He, C.-H.; Yao, C.-F. Tetrahedron 2013, 69, 3323. (14) For reviews, see: (a) Asao, N. Synlett 2006, 2006, 1645. (b) Wang, H.; Kuang, Y.; Wu, J. Asian J. Org. Chem. 2012, 1, 302. (c) Tanaka, K.; Tajima, Y. Eur. J. Org. Chem. 2012, 2012, 3715. (15) Enders, D.; Niemeier, O.; Balensiefer, T. Angew. Chem., Int. Ed. 2006, 45, 1463.
D
DOI: 10.1021/acs.orglett.7b00453 Org. Lett. XXXX, XXX, XXX−XXX
