Letter pubs.acs.org/OrgLett
Azidofluoroalkylation of Alkenes with Simple Fluoroalkyl Iodides Enabled by Photoredox Catalysis Xiaoyu Geng,† Fengguirong Lin,† Xiaoyang Wang,† and Ning Jiao*,†,‡ †
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Xue Yuan Road 38, Beijing 100191 China ‡ Shanghai Key Laboratory of Green Chemistry and Chemical Processes, East China Normal University, Shanghai 200062, China S Supporting Information *
ABSTRACT: A mild and efficient protocol for photoredoxcatalyzed azidofluoroalkylation of simple alkenes is described with readily available fluoroalkyl iodides. This method allows for a direct and regioselective formation of C−RF and C−N3 bonds from the CC moiety. A variety of fluoroalkyl groups including the CF3 group can be selectively introduced to olefins to afford a series of β-fluoroalkylated azides.
O
Scheme 1. Synthesis of Fluoroalkyl Azides
rgano azides including alkyl azides are versatile intermediates and building blocks for the synthesis of numerous useful chemicals such as amines, amides, and heterocycles.1 The azide moiety has been investigated in the design of fundamental compounds for drug discovery and applied as prodrugs of primary amine.2 Recently, azides have been utilized as a point of attachment for various probes in bioconjugation with click chemistry,3 and such reactions have been developed to visualize biochemical processes in living cells and organisms.4 Therefore, much attention has been paid to the mild and efficient introduction of azido groups into organic molecules.5 Fluoroalkylated compounds are widely used in materials science, argochemistry, and medicinal chemistry owing to their unique biological properties.6 In this regard, olefin difunctionalization represents the ideal and most straightforward way for the introduction of functional groups.7 We envisaged that the simultaneous introduction of both azide and RF groups into organic molecules could allow for the efficient synthesis of fluoroalkylated azides, thus providing an opportunity to prepare fluoroalkylated fundamental compounds and probes to improve their bioactivities. However, the synthesis of fluoroalkylated organoazides is rare, and such processes suffer from harsh conditions and multistep operations (Scheme 1a, (i)).8 Significant work by Liu and co-workers realized the direct azidotrifluoromethylation of alkenes using the Togni-CF3 reagent and copper catalysis, but the RF group was limited to CF3 (Scheme1a, (ii)).9 Later, Masson et al. reported similar azidotrifluoromethylation of alkenes with photoredox catalysis.9b Recently, the use of inexpensive and readily available fluoroalkyl iodides has attracted considerable attention.10,11 Using mild and environmentally friendly visible-light photocatalysis,12 the groups of Stephenson et al.12a,b and Noël et al.12e realized olefin iodofluoroalkylations and hydrofluoroalkylation, respectively. To date, despite the importance of these studies, the efficient and versatile installation of both fluoroalkyl and azido groups onto a wide range of alkenes is still undiscovered. Herein, we report the © 2017 American Chemical Society
visible-light photocatalysis enabled azidofluoroalkylation of olefins using inexpensive and readily available RFI as both CF3 and perfluoroalkylating reagents (Scheme 1b). Challenging issues such as the regioselectivity and potential side reactions including unproductive dimerization13 and competitive elimination14 were successfully overcome in the present protocol. As a continuation of our interest in nitrogenation15 and oxygenation reactions,16 we hypothesize triggering a radical addition/nitrogenation sequence by investigating the reaction of C4F9I (2a) and 2-vinylnaphthalene (1a) using a catalytic amount of Ru(bpy)3Cl2·6H2O under blue LED irradiation. To our delight, 19% of target product 3a was detected by NMR analysis when NaN3 was used as an azide source. (Table 1, entry 1). Other azido compounds, such as TMSN3, TosN3, and Zhdankin Received: July 9, 2017 Published: September 6, 2017 4738
DOI: 10.1021/acs.orglett.7b02056 Org. Lett. 2017, 19, 4738−4741
Letter
Organic Letters Table 1. Screening of Azidofluoroalkylation Parametersa
entry 1 2c 3 4 5 6 7 8 9 10d 11e 12 13 14f 15f,g 16f,g 17f,g 18f,g 19f,g 20f−h 21f,g,i
solvent DMF DMF DMSO toluene DMF DMF DMF/CH3CN (1:1) DMF/DCM (1:1) DMF/dioxane (1:1) DMF/dioxane (1:1) DMF/dioxane (1:1) DMF/dioxane (1:1) DMF/dioxane (1:1) DMF/dioxane (1:1) DMF/dioxane (1:1) DMF/dioxane (1:1) DMF/dioxane (1:1) DMF/dioxane (1:1) DMF/dioxane (1:1) DMF/dioxane (1:1) DMF/dioxane (1:1)
ratio (1a/2a)
additive (equiv)
1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 2:1 1:2 2:1 2:1 2:1 2:1 2:1 2:1 2:1 2:1
Bu4NBr (0.1) BnEt3NBr (0.1) BnEt3NBr (0.1) BnEt3NBr (0.1) BnEt3NBr (0.1) BnEt3NBr (0.1) BnEt3NBr (0.1) BnEt3NBr (0.1) BnEt3NBr (0.1) BnEt3NBr (0.1) BnEt3NBr (0.1) BnEt3NBr (0.MgI2 (0.2) BnEt3NBr (0.1)/LiI (0.2) BnEt3NBr (0.1)/NaI (0.2) BnEt3NBr (0.1)/NaI (0.6) BnEt3NBr (0.1)/NaI (0.6) BnEt3NBr (0.1)/NaI (0.6)
yieldb (%) 19 0 17 0 21 26 26 27 40 27 25 41 30 42 50 66 36 70 72 (68) 0 0
General reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol), NaN3 (0.1 mol), Ru(bpy)3Cl2·6H2O (0.001 mmol), additive in solvent (1 mL, 0.1 M) at 30 °C for 12 h under Ar. bYield of crude NMR analysis with 1,3,5-trimethoxybenzene as internal standard; isolated yield in parentheses. cTMSN3, TosN3, Ph2P(O)N3, or Zhdankin reagent were used instead of NaN3 dRu(bpy)3(PF6)2 was used instead of Ru(bpy)3Cl2·6H2O. eIr(ppy)3 (1 mol %) was used instead of Ru(bpy)3Cl2·6H2O. fRu(bpy)3Cl2·6H2O (5 mol %) was used. gNaN3(0.2 mmol) was used. hThe reaction was conducted under dark. iNo Ru(bpy)3Cl2·6H2O was added. Np = naphthalen-2-yl a
Scheme 2. Scope of Alkenes of Azidofluoroalkylationa
reagent, were not effective (Table 1, entry 2). After an intense screening of the solvents, we found that DMF provided higher efficiency, while the reaction conducted in toluene did not give any detectable product. We found that NaN3 would not totally dissolve in DMF, and thus, a catalytic amount of the phasetransfer catalyst was introduced to the reaction. When BnEt3NBr was employed as a catalyst, the reaction proceeded with a slightly higher yield (26%, entry 6) and other salts showed lower efficiencies. To further improve the yield, an additional portion of solvent was added as a cosolvent. These results illuminated that the reaction performed in DMF and dioxane (1:1) as a cosolvent gave target product 3a in 40% yield in the presence of the phasetransfer catalyst BnEt3NBr (Table 1, entry 9). Employing other photoredox catalysts did not improve the yield (Table 1, entries 10 and 11). Further optimization of the reactant ratio of 1a/2a (2:1) gave a slightly higher yield compared to the result in entry 9. Applying a reactant ratio of 1a/2a (2:1) with 5 mol % catalyst provided 3a in 50% yield (Table 1, entry 15). The optimal results were obtained by adding 60 mol % NaI in DMF/dioxane furnishing the β-fluoroalkylated azide in 72% NMR yield and 68% isolated yield (Table 1, entry 19). Control experiments showed that no reactions occurred in the absent of either blue light or the photocatalyst (Table 1, entries 20 and 21). With the optimal reaction conditions in hand, we set out to investigate the scope of alkenes in the azidofluoroalkylation. Our protocol accommodated a variety of styrenes (Scheme 2). A range of functional groups such as Cl, Br, and CN remained intact, which provides the opportunity for further synthetic transformations (3d, 3e, 3g). Indene also proved to be a suitable substrate and selectively gave trans-isomer 3h as a single product.
a
Reaction conditions: 1 (0.4 mmol), 2 (0.2 mmol), NaN3 (0.4 mol), Ru(bpy)3Cl2·6H2O (5 mol %), BnEt3NBr (10 mol %), NaI (60 mol %), DMF/dioxane (0.1 M, 1:1), 30 °C, 12 h. Isolated yields. b Determined by crude 1H NMR analysis. c1 (0.2 mmol), 2a (0.4 mmol) were used. dRu(bpy)3(PF6)2 (5 mol %) was used instead of Ru(bpy)3Cl2·6H2O, DME was used instead of dioxane. DME = 1,2dimethoxyethane.
A meta-substituted styrene was tolerated, leading to products 3i in 68% yield. Furthermore, the azidofluoroalkylation reaction was 4739
DOI: 10.1021/acs.orglett.7b02056 Org. Lett. 2017, 19, 4738−4741
Letter
Organic Letters also examined using aliphatic alkenes. Simple olefins worked well under slightly modified conditions and furnished the desired products (3k, 3l, 3m) in moderate yields. Furthermore, fluoroalkyl iodides including CF 3I were successfully transformed to the corresponding azides in a regioselective fashion (Scheme 3). This is a considerable
Scheme 4. Further Transformations
Scheme 5. Preliminary Mechanism Studiesa
Scheme 3. Scope of Fluoroalkyl Iodides of Azidofluoroalkylationa
a Reaction conditions: 1c (0.4 mmol), 2 (0.2 mmol), NaN3 (0.4 mol), Ru(bpy)3Cl2·6H2O (5 mol %), BnEt3NBr (10 mol %), NaI (60 mol %), DMF/Et2O (0.1 M, 1:1), 30 °C, 12 h. Isolated yields.
a
All the reactions were conducted on a 0.2 mmol scale. Isolated yields.
Furthermore, a radical clock experiment suggested that a radical addition/ring-opening sequence was involved (Scheme 5b). The reaction of alkene 1a with C4F9I did not occur and no iodofluoroalkylated product was detected in the absence of NaN3 with the recovery of 1a (Scheme 5c). This result indicated that the azidofluoroalkylation product was not produced by the relay of iodofluoroalkylation and subsequent substitution with the azido N3 anion. Therefore, a direct addition of the N3 group to a benzyl intermediate may be involved in the mechanism of the azidofluoroalkylation reactions. To probe the detailed interaction of the catalyst with substrates, a series of experiments were conducted (see the Supporting Information). Our first attempt at evaluating the oxidative quenching ability of the C4F9I to Ru catalyst showed a weak quenching effect even under high concentration of the C4F9I. In contrast, the addition of either NaN3 or NaI to the excited Ru-catalyst resulted in a strongly enhanced quenching effect. These results indicated that a reductive quenching of RuII* by either NaN3 or NaI was involved in the mechanism. A plausible mechanism was proposed according to the above preliminary studies (Scheme 6). The reductive quenching of
advantage of the current method, as the perfluoroalkyl analogues of other fluoroalkylating reagents are expensive or not commercially available. Most importantly, the efficient azidoperfluoroalkylation of alkenes represents a closed gap between alkene azidation and perfluoroalkylation, which was not reported in previous studies. Next, a complex bioactive molecule containing an alkenyl group was selected for this transformation. The estrone derivative 4 afforded the corresponding azide 5 in 52% yield (eq 1). This
Scheme 6. Plausible Mechanism compound may have potential applications in medical chemistry. In order to demonstrate the potential synthetic utility of this reaction, a large-scale experiment was performed, which produced 3 in 39% yield with a 35 W lamp (eq 2). Further transformations of azidofluoroalkylation products were explored. It is noteworthy that fluoroalkyl azides were successfully applied in the efficient synthesis of many molecules as useful building blocks. The click reaction of 3a with phenylacetylene gave β-fluoroalkyl triazole which may be applied as a druglike candidate molecule (Scheme 4).17 Furthermore, βfluoroalkyl amine was prepared from 3a after a simple reduction reaction (Scheme 4). Preliminary experiments of the reaction mechanism indicated that the azidofluoroalkylation reactions likely involved a C4F9 radical intermediate. Under the standard condition, no azide product was detected in the presence of TEMPO (Scheme 5a).
excited RuII catalyst by NaN3 and NaI generates N3 and iodide radicals along with a RuI complex. Then, the RuI complex was oxidized by RFI, delivering electrophilic RF radical as well as the RuII catalyst. The RF radical undergoes addition to the alkene to provide the RF adduct, which was further captured by the N3 radical to afford the azide product. 4740
DOI: 10.1021/acs.orglett.7b02056 Org. Lett. 2017, 19, 4738−4741
Letter
Organic Letters
Wadepohl, H.; Gade, L. H. J. Am. Chem. Soc. 2013, 135, 5356. (c) Xie, F.; Qi, Z.; Li, X. Angew. Chem., Int. Ed. 2013, 52, 11862. (d) Ren, R.; Zhao, H.; Huan, L.; Zhu, C. Angew. Chem., Int. Ed. 2015, 54, 12692. (e) Li, Z.; Zhang, C.; Zhu, L.; Liu, C.; Li, C. Org. Chem. Front. 2014, 1, 100. (f) Li, P.; Zhao, J.; Xia, C.; Li, F. Org. Chem. Front. 2015, 2, 1313. (g) Li, X.; Shi, Z.-J. Org. Chem. Front. 2016, 3, 1326. (h) Karimov, R. R.; Sharma, A.; Hartwig, J. F. ACS Cent. Sci. 2016, 2, 715. (i) Peng, H.; Yuan, Y.; Chen, P.; Liu, G. Chin. J. Chem. 2017, 35, 876. (6) For recent reviews, see: (a) Smart, B. E. J. Fluorine Chem. 2001, 109, 3. (b) Special issue on “Fluorine in the Life Sciences”: ChemBioChem 2004, 5, 557. (c) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (d) Hird, M. Chem. Soc. Rev. 2007, 36, 2070. (e) Mueller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (f) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (g) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359. (h) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Acena, J. L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Chem. Rev. 2016, 116, 422. (7) For selected reviews on alkene functionalization, see: (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483. (b) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285. (c) Jensen, K. H.; Sigman, M. S. Org. Biomol. Chem. 2008, 6, 4083. (d) Heinrich, M. R. Chem. - Eur. J. 2009, 15, 820. (e) Cardona, C.; Goti, A. Nat. Chem. 2009, 1, 269. (f) McDonald, R. I.; Liu, G.; Stahl, S. S. Chem. Rev. 2011, 111, 2981. (g) Wolfe, J. P. Angew. Chem., Int. Ed. 2012, 51, 10224. (h) Chemler, S. R.; Bovino, M. T. ACS Catal. 2013, 3, 1076. (i) Merino, E.; Nevado, C. Chem. Soc. Rev. 2014, 43, 6598. (8) For limited reports for the multistep synthesis of fluoroalkylated azides, see: (a) Larsson, U.; Carlson, R.; Leroy, J. Acta Chem. Scand. 1993, 47, 380. (b) Jiang, Z.; Liu, X.; Qiu, X.; Qing, F.-L. J. Fluorine Chem. 2005, 126, 497. (c) Yajima, T.; Nagano, H. Org. Lett. 2007, 9, 2513. (9) For direct azidotrifluoromethylation of alkenes, see: (a) Wang, F.; Qi, X.; Liang, Z.; Chen, P.; Liu, G. Angew. Chem., Int. Ed. 2014, 53, 1881. (b) Dagousset, G.; Carboni, A.; Magnier, E.; Masson, G. Org. Lett. 2014, 16, 4340. (10) For selected examples, see: (a) Itoh, Y.; Houk, K. N.; Mikami, K. J. Org. Chem. 2006, 71, 8918. (b) Kino, T.; Nagase, Y.; Ohtsuka, Y.; Yamamoto, K.; Uraguchi, D.; Tokuhisa, K.; Yamakawa, T. J. Fluorine Chem. 2010, 131, 98. (11) For a review, see: Zhang, C.; Chen, Q.; Guo, Y.; Xiao, J.; Gu, Y. Chem. Soc. Rev. 2012, 41, 4536. (12) For visible-light catalyzed alkene fluoroalkylation with RFI, see: (a) Nguyen, J. D.; Tucker, J. W.; Konieczynska, M. D.; Stephenson, C. R. J. J. Am. Chem. Soc. 2011, 133, 4160. (b) Wallentin, C. J.; Finkbeiner, J. D. P.; Stephenson, C. R. J. J. Am. Chem. Soc. 2012, 134, 8875. (c) Kim, E.; Choi, S.; Kim, H.; Cho, E. J. Chem. - Eur. J. 2013, 19, 6209. (d) Li, L.; Huang, M.; Liu, C.; Xiao, J.; Chen, Q.; Guo, Y.; Zhao, Z. Org. Lett. 2015, 17, 4714. (e) Straathof, N.; Cramer, S.; Hessel, V.; Noël, T. Angew. Chem., Int. Ed. 2016, 55, 15549. (13) (a) Tommasino, J.-B.; Brondex, A.; Medebielle, M.; Thomalla, M.; Langlois, B. R.; Billard, T. Synlett 2002, 1697. (b) Yoshida, M.; Iizuka, M.; Okuno, K.; Sawada, H. J. Fluorine Chem. 2016, 184, 82. (14) Choi, W. J.; Choi, S.; Ohkubo, K.; Fukuzumi, S.; Cho, E. J.; You, Y. Chem. Sci. 2015, 6, 1454. (15) For reviews, see: (a) Wang, T.; Jiao, N. Acc. Chem. Res. 2014, 47, 1137. (b) Liang, Y.; Liang, Y.-F.; Jiao, N. Org. Chem. Front. 2015, 2, 403. For a recent example, see: (c) Song, S.; Feng, P.; Zou, M.; Jiao, N. Chin. J. Chem. 2017, 35, 845. (16) (a) Zhang, C.; Jiao, N. J. Am. Chem. Soc. 2010, 132, 28. (b) Xu, Z.; Zhang, C.; Jiao, N. Angew. Chem., Int. Ed. 2012, 51, 11367. (c) Wang, T.; Jiao, N. J. Am. Chem. Soc. 2013, 135, 11692. (d) Su, Y.; Sun, X.; Wu, G.; Jiao, N. Angew. Chem., Int. Ed. 2013, 52, 9808. (e) Yan, Y.; Feng, P.; Zheng, Q.; Liang, Y.; Lu, J.; Cui, Y.; Jiao, N. Angew. Chem., Int. Ed. 2013, 52, 5827. (f) Shen, T.; Zhang, Y.; Liang, Y.; Jiao, N. J. Am. Chem. Soc. 2016, 138, 13147. (17) Kumar, A.; Ahmad, I.; Chhikara, B. S.; Tiwari, R.; Mandal, D. Bioorg. Med. Chem. Lett. 2011, 21, 1342.
In summary, we developed a simple and practical protocol for the azidofluoroalkylation of alkenes utilizing mild visible-light photocatalysis. Using inexpensive and readily available fluoroalkyl iodides as the fluoroalkyl radical precursors, the azido and fluoroalkyl groups were successfully incorporated into simple olefins. The reactions featured excellent selectivity and mild reaction conditions and tolerated both styrene and aliphatic alkenes. The application of this photoredox strategy in other azidation reactions is underway in our laboratory.
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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.7b02056. Research details, experimental procedures, full characterization of products, and NMR spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Ning Jiao: 0000-0003-0290-9034 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the National Basic Research Program of China (973 Program) (No. 2015CB856600), the National Natural Science Foundation of China (No. 21325206, 21632001), National Young Top-notch Talent Support Program, and Peking University Health Science Center (No BMU20160541) for financial support of this work. We thank Dr. Xuzhe Wang and Pro. Li-Zhu Wu from the Technical Institute of Physics and Chemistry for the help with the emission quenching experiments. We thank Hao Wu in this group for reproducing the results of 3k.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b02056 Org. Lett. 2017, 19, 4738−4741
