Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Hydrogen-Bonding-Assisted α‑F Elimination from Cu−CF3 for in Situ Generation of R3N·HF Reagents: Reaction Design and Applications Song-Lin Zhang* and Jia-Jia Dong Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material Engineering, Jiangnan University, Wuxi, Jiangsu 214122, China
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S Supporting Information *
ABSTRACT: We report herein a strategy of ammonium hydrogen-bondingassisted α-F elimination from Cu−CF3 compounds that generates R3N·HF reagents in situ. Combining this strategy and Cu(III)−CF3 chemistry with alkynes, dual fluorination and trifluoromethylation of terminal alkynes is enabled by a single Cu(III)−CF3 compound assisted by a tertiary amine with excellent regioand stereoselectivity. This strategy also enables the development of other reaction types involving trapping of the in situ-formed R3N·HF reagents by other electrophilic groups and can be used for the late-stage functionalization of estrone derivatives.
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This strategy was designed during our development of Cu(III)−CF3 reactivity with terminal alkynes (Scheme 1c).12,13 The reaction was found to generate the Ar−CC− CF3 product in up to quantitative yield at 100 °C in DMF with the strong base NaOtBu.12c,13a Interestingly, when excess CsF was used to replace NaOtBu, selective alkyne fluorotrifluoromethylation was achieved, producing 3a in 81% yield, where CsF was a preferred fluoride source (Scheme 1c).13a From the reaction balance and mechanistic studies, a vinyl cation intermediate B and a [CuI(CF3)2]− anionic species D were proposed (Scheme 2).13 We reasoned that if a tertiary amine is used as the base,14 then a protonated ammonium ion would be generated. This ammonium ion would engage in substantial hydrogen bonding to the F atom of the bound CF3 ligand to weaken the C−F bond, and thus, C−F bond cleavage might occur under appropriate conditions, generating the crucial R3N·HF reagents (red box in Scheme 2) that may further be trapped by other electrophilic groups. This is synthetically attractive to avoid the use of stoichiometric toxic and corrosive R3N·HF reagents. DFT computational studies15 were performed to verify the feasibility of this hydrogen-bonding-assisted α-F elimination (Scheme 3 and Figure 1). The anionic intermediate D and Et3NH+ first combine to form an initial complex CP1 with a weak hydrogen bond, which is slightly exergonic by 5.9 kcal/ mol. In CP1 there is weak yet significant hydrogen bonding between the Et3NH+ hydrogen and one fluorine atom of one CF3 ligand, as reflected by the bond distances of 1.82 and 1.45 Å for the H−F and C−F bonds (Figure 1), indicating
he conversion of alkali-metal- or alkaline-earth-metalbound CF3 complexes to fluoride and difluorocarbene in solution has been observed under certain conditions in dynamic equilibrium, involving a formal α-F elimination (Scheme 1a). Such conversion has been utilized as an efficient strategy for the generation of difluorocarbene, which can be introduced into various organic compounds,1,2 in particular alkenes, alkynes,3 carbonyl compounds in the presence of phosphine,4 and nucleophiles (Nu−H, where Nu is a nucleophilic group, e.g., C, O, S, N, etc.),5,6 leading to the formation of important difluorinated structural motifs. In addition, α-F elimination of transition-metal-bound CF3 compounds is also known for Mo, Ru, etc.,7,8 but synthetically useful transformations remain very limited. Herein we report a strategy of hydrogen-bonding-assisted C−F bond cleavage of copper-bound CF3 for efficient in situ generation of R3N·HF reagents (Scheme 1b). Specifically, a protonated tertiary amine, HNR3+, can efficiently cleave the C−F bond of the copper-bound CF3 ligand, promoted by significant H···F hydrogen bonding between the ammonium ion and a fluorine atom. This leads to the in situ generation of the R3N·HF reagent, a classic nucleophilic fluoride reagent,9,10 which then undergoes known hydrofluorination with alkyne, aldehyde, and epoxide functionalities in a one-pot operation (Scheme 1d). The in situ generation and utilization of the R3N·HF reagent avoids the safety problem and inconvenience of manipulating highly toxic and erosive R3N·HF reagents. Our strategy combines the trifluoromethylation and hydrofluorination reactions of a substrate by a single Cu(III)−CF3 compound11,12 in one pot, which is a novel and challenging task. © XXXX American Chemical Society
Received: July 19, 2019
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DOI: 10.1021/acs.orglett.9b02516 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 1. Strategy of α-F Elimination of Organometallic M−CF3 Reagents
Scheme 3. Computational Rationalization of HydrogenBonding-Assisted C−F Bond Cleavagea
a
Values in parentheses are relative free energies in kcal/mol.
Scheme 2. Concept Design
Figure 1. Optimized key structures for ammonium-assisted α-F elimination to generate Et3N·HF. The values depicted are bond lengths in Å and bond angles and dihedral angles in degrees.
elimination to produce Et3N·HF in situ is in principle very facile in the presence of Et3NH+. Indeed, when Et3N, one of the simplest tertiary amines, was used instead of the inorganic salts, the desired reaction of path a (Scheme 2) occurred very efficiently to produce the fluorotrifluoromethylated product 3a (Scheme 4) without the need for an external f luoride salt/reagent.16 Other tertiary amines were also evaluated, and TMEDA and DABCO were also good organic bases for promoting this reaction (see the Supporting Information for more details about the screening of the reaction conditions). This strategy was found to be generally applicable to various terminal alkynes to achieve the dual fluorination−trifluoromethylation reaction (Scheme 4). A range of functional groups can be tolerated, including alkyl, alkoxy, chloro, bromo, nitro, carbonyl, ester, and even an unprotected amine group (3l). The halo, carbonyl, ester, and unprotected amine groups provide useful synthetic handles that can be further functionalized to broaden the diversity and scope of the products. Furthermore, 2-naphthylacetylene 2m and heteroaryl acetylenes, including 3-pyridyl- (2n) and 2-thiophenylacetylene
activation and elongation of the C−F bond. Then, a crucial αC−F bond cleavage occurs for the CF3 ligand with hydrogen bonding through the key transition state TS1 to generate CP2, which is a complex of (phen)CuI(CF2)(CF3) (E) and Et3N· HF (Figure 1). This α-C−F bond cleavage has an activation free energy of only 13.8 kcal/mol. Further dissociation of Et3N· HF from intermediate E releases an additional 5.1 kcal/mol, making the overall α-C−F elimination process to form Et3N· HF only slightly endergonic by 2.4 kcal/mol from D and ammonium. Subsequent trapping of Et3N·HF would provide additional thermodynamic driving force for the α-F cleavage. These results verify that the hydrogen-bonding-assisted α-F B
DOI: 10.1021/acs.orglett.9b02516 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 4. Dual Fluorination−Trifluoromethylation of an Alkyne Functionality by a Single Cu(III)−CF3 Compounda,b
Scheme 5. Dual Functionalization of Two Functional Groups
acetylene as substrates. The expected product 6 was produced in an excellent 98% NMR yield and an 82% isolated yield (Scheme 5b). This observation supports the mechanistic proposal in Scheme 5a. The reaction of o-epoxide-substituted phenylacetylene gave product 7 in a low yield of 18%, where a formal β-elimination occurs after the expected nucleophilic addition of benzyl oxide to the o-alkyne (Scheme 5c). Finally, the synthetic potential of the fluorination− trifluoromethylation chemistry was demonstrated by the triple functionalization of 1,3,5-tris(ethynyl)benzene (Scheme 6)
a
Method A: 1 (0.3 mmol), 2 (0.3 mmol), Et3N (0.6 mmol), and DMF (2.5 mL) stirred at 100 °C for 12 h under N2. Method B: using DABCO (0.6 mmol) and dicarbonyl A2 (0.3 mmol) instead of Et3N in method A. bBoth 19F NMR and isolated yields (in parentheses) are given if available. cReaction time of 18 h. dSee the Supporting Information for more details. eDicarbonyl A1 was used in place of A2.
Scheme 6. Triple syn-Fluorotrifluoromethylation of a Triyne
(2o), are also good substrates, producing the desired 3m−o in 76%, 63%, and 55% yield, respectively. Notably, the reaction is also amenable to aliphatic alkynes (3p). With the above success of this hydrogen-bonding-assisted αF elimination strategy, we next envisioned that if there were a second electrophilic group present on the alkyne substrate that is more reactive than the alkyne functionality, the in situgenerated R3N·HF might react preferentially with the second group instead, thus achieving dual functionalization of two functional groups (path b in Scheme 2). With this consideration in mind, we then tested the o-ethynylbenzaldehyde as the substrate because aldehyde is a preferred electrophilic group for reaction with R3N·HF. We were delighted to see that product 5 was obtained in 81% NMR yield, where both CF3 and F are incorporated into the product (Scheme 5a). The formation of 5 is attributed to nucleophilic addition to the o-alkyne by the benzyl oxide generated by nucleophilic fluoride addition to the aldehyde by in situgenerated R3N·HF.17 This result provides nice evidence supporting the strategy designed. Inspired by the reaction in Scheme 5a, we then directly used o-ethynylbenzyl alcohol and o-epoxide-substituted phenyl-
and late-stage modification of an estrone derivative (Scheme 7), producing star-shaped tristyrene 8 and functionalized estrone product 10 in 48% and 58% isolated yield, respectively. These results show that this hydrogen-bonding-assisted α-F elimination strategy is anticipated to find applications in materials science and pharmaceuticals. Scheme 7. Application to the Modification of Estrone
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DOI: 10.1021/acs.orglett.9b02516 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
X.-Y.; Lin, J.-H.; Zheng, J.; Xiao, J.-C. Chem. Commun. 2015, 51, 8805. (c) Li, L.; Wang, F.; Ni, C.; Hu, J. Angew. Chem., Int. Ed. 2013, 52, 12390. (d) Wang, F.; Huang, W.; Hu, J. Chin. J. Chem. 2011, 29, 2717. (7) For Mo α-F elimination, see: Reger, D. L.; Dukes, M. D. J. Organomet. Chem. 1978, 153, 67−72. (8) For Ru α-F elimination, see: Clark, G. R.; Hoskins, S. V.; Roper, W. R. J. Organomet. Chem. 1982, 234, C9−C12. (9) For a review of Et3N·HF, see: McClinton, M. A. Aldrichimica Acta 1995, 28, 31−35. (10) For hydrofluorination of alkynes by R3N·HF reagents, see: (a) Akana, J. A.; Bhattacharyya, K. X.; Muller, P.; Sadighi, J. P. J. Am. Chem. Soc. 2007, 129, 7736. (b) Compain, G.; Jouvin, K.; MartinMingot, A.; Evano, G.; Marrot, J.; Thibaudeau, S. Chem. Commun. 2012, 48, 5196. (c) Gorske, B. C.; Mbofana, C. T.; Miller, S. J. Org. Lett. 2009, 11, 4318. (d) He, G.; Qiu, S.; Huang, H.; Zhu, G.; Zhang, D.; Zhang, R.; Zhu, H. Org. Lett. 2016, 18, 1856. (e) Nahra, F.; Patrick, S. R.; Bello, D.; Brill, M.; Obled, A.; Cordes, D. B.; Slawin, A. M. Z.; O’Hagan, D.; Nolan, S. P. ChemCatChem 2015, 7, 240. (f) O’Connor, T. J.; Toste, F. D. ACS Catal. 2018, 8, 5947. (g) Pfeifer, L.; Gouverneur, V. Org. Lett. 2018, 20, 1576. (h) Yin, J.; Zarkowsky, D. S.; Thomas, D. W.; Zhao, M. M.; Huffman, M. A. Org. Lett. 2004, 6, 1465. (i) Zhu, G.; Qiu, S.; Xi, Y.; Ding, Y.; Zhang, D.; Zhang, R.; He, G.; Zhu, H. Org. Biomol. Chem. 2016, 14, 7746. (11) For related Cu(III)−CF3 compounds, see: (a) Willert-Porada, M. A.; Burton, D. J.; Baenziger, N. C. J. Chem. Soc., Chem. Commun. 1989, 1633. (b) Naumann, D.; Roy, T.; Tebbe, K.-F.; Crump, W. Angew. Chem., Int. Ed. Engl. 1993, 32, 1482. (c) Romine, A. M.; Nebra, N.; Konovalov, A. I.; Martin, E.; Benet-Buchholz, J.; Grushin, V. V. Angew. Chem., Int. Ed. 2015, 54, 2745. (d) Tan, X.; Liu, Z.; Shen, H.; Zhang, P.; Zhang, Z.; Li, C. J. Am. Chem. Soc. 2017, 139, 12430. (e) Lu, Z.; Liu, H.; Liu, S.; Leng, X.; Lan, Y.; Shen, Q. Angew. Chem., Int. Ed. 2019, 58, 8510. (12) (a) Zhang, S.-L.; Bie, W.-F. RSC Adv. 2016, 6, 70902. (b) Zhang, S.-L.; Bie, W.-F. Dalton Trans 2016, 45, 17588. (c) Zhang, S.-L.; Xiao, C.; Wan, H.-X. Dalton Trans 2018, 47, 4779. (d) Xiao, C.; Zhang, S.-L. Dalton Trans 2019, 48, 848. (13) (a) Zhang, S.-L.; Wan, H.-X.; Bie, W.-F. Org. Lett. 2017, 19, 6372. (b) Zhang, S.-L.; Xiao, C. J. Org. Chem. 2018, 83, 10908. (c) Xiao, C.; Wan, H.-X.; Zhang, S.-L. Asian J. Org. Chem. 2019, 8, 654. (d) Zhang, S.-L.; Xiao, C.; Wan, H.-X.; Zhang, X. Chem. Commun. 2019, 55, 4099. (14) Reaction of amine with metal−trifluoromethyl reagents, e.g., Zn−CF3 or Cd−CF3 reagents, was reported to produce [R3N− CF2H]+X− ammonium species from α-F elimination and consequent combination of the amine with the resulting difluorocarbene. See: (a) Pasenok, S. V.; Kirij, N. V.; Yagupolskii, Y. L.; Naumann, D.; Tyrra, W.; Fitzner, A. Z. Z. Anorg. Allg. Chem. 1999, 625, 834−838. (b) Kirij, N. V.; Pasenok, S. V.; Yagupolskii, Y. L.; Fitzner, A.; Tyrra, W.; Naumann, D. J. Fluorine Chem. 1999, 94, 207−212. (c) Zafrani, Y.; Amir, D.; Yehezkel, L.; Madmon, M.; Saphier, S.; Karton-Lifshin, N.; Gershonov, E. J. Org. Chem. 2016, 81, 9180. (d) Prakash, G. K. S.; Zhang, Z.; Wang, F.; Ni, C.; Olah, G. A. J. Fluorine Chem. 2011, 132, 792. (e) Prakash, G. K. S.; Weber, C.; Chacko, S.; Olah, G. A. Org. Lett. 2007, 9, 1863. (15) For more discussions on the computational details, see the Supporting Information and also: Zhang, S.-L.; Huang, L.; Sun, L.-J. Dalton Trans 2015, 44, 4613. (16) Qing et al. reported an example of alkene fluorotrifluoromethylation. See: (a) Yu, W.; Xu, X.-H.; Qing, F.-L. Adv. Synth. Catal. 2015, 357, 2039. (b) For fluorotrifluoromethylation of alkynes, see ref 13a. In both reactions, both external fluoride sources and CF3 reagents are required. (17) An alternative pathway was suggested by one referee to involve direct nucleophilic attack of the aldehyde oxygen to the vinyl cation from trifluoromethylation of the terminal alkyne, generating an oxonium-type intermediate that can be further attacked by fluoride to deliver product 5.
In conclusion, a novel reactivity of a Cu(III)−CF 3 compound has been developed to enable one-pot fluorination and trifluoromethylation of terminal alkynes and o-ethynylbenzaldehydes, assisted by a tertiary amine, without the need for external fluoride salts/reagents. A hydrogen-bondingassisted α-F elimination is involved to provide R3N·HF reagents in situ that can further be trapped by the substrates. This is advantageous to avoid the use of toxic and corrosive R3N·HF reagents. The synthetic potential of this strategy was demonstrated by the triple fluorotrifluoromethylation of a triyne and the late-stage functionalization of a complex estrone derivative.
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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.9b02516. Experimental details and spectroscopic characterization data (PDF)
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AUTHOR INFORMATION
Corresponding Author
*
[email protected] ORCID
Song-Lin Zhang: 0000-0002-5337-8600 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This study was supported by the National Natural Science Foundation of China (21472068). Financial support from MOE&SAFEA for the “111 Project” (B13025) and national first-class discipline program of Food Science and Technology (JUFSTR20180204) is also gratefully acknowledged.
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REFERENCES
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DOI: 10.1021/acs.orglett.9b02516 Org. Lett. XXXX, XXX, XXX−XXX
