Letter pubs.acs.org/OrgLett
syn-Fluoro- and -Oxy-trifluoromethylation of Arylacetylenes Song-Lin Zhang,* Hai-Xing Wan, and Wen-Feng Bie Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material Engineering, Jiangnan University, Wuxi, Jiangsu 214122, China S Supporting Information *
ABSTRACT: One-step concurrent fluoro-trifluoromethylation across the triple bond of arylacetylenes in a syn mode is enabled by the collaboration of (phen)CuIII(CF3)3 and CsF that produces chemo-, regio-, and stereoselectively (Z)-α-fluoro-β-CF3 styrenes. This method can be extended to achieve syn-oxy-trifluoromethylation and syn-aryl-trifluoromethylation of alkynes using phenoxides, alkoxides, or phenylboronic acid in place of CsF. It opens up new opportunities for preparing various functionalized trifluoromethylated Z-alkenes and demonstrates the potential of Cu(III)−CF3 complexes in organic synthesis.
D
Recently, direct one-step difunctionalization of alkynes involving trifluoromethylation, such as iodo-, amino-, oxy-, and aryl-trifluoromethylation of alkynes, has been developed that enables access to a range of trifluoromethylated alkenes (Scheme 1b).3 These reactions typically rely on the use of preformed Togni’s or Umemoto’s reagents as the CF3 source and sometimes require an additional photosensitizer under irradiation conditions. Notably, anti-addition of CF3 and a nucleophilic group (Nu−) across the triple bond of alkynes is generally achieved to produce (E)-Nu-trifluoromethylated olefins (Scheme 1b). As far as we know, selective one-step syn-addition of CF3 and a Nu across alkyne triple bond has never been documented. Moreover, the selectivity of the reported methods remains unsatisfying because a mixture of regio- and stereoisomers were often obtained. Finally, diverse sets of reaction conditions were developed for different types of nucleophiles. A general methodology is still lacking that can accommodate several types of nucleophilic groups. Herein, we report an efficient, one-step, regio- and stereoselective method for syn-fluoro- and -oxy-trifluoromethylation of terminal arylalkynes (Scheme 1c). The key point to this reaction is the use of a bench-stable phenCuIII(CF3)3 (1) as the highly reactive CF3 source (phen denotes phenanthroline), in combination with readily available fluoride, phenoxides, and alkoxides (as well as a phenylboronic acid) as the nucleophilic reagents. As far as we know, this method represents the first general method for syn-Nu-trifluoromethylation of alkynes. This study was inspired by our recent study on the isolation and reactivity of several stable high-valent Cu(III) CF 3 complexes (L)CuIII(CF3)3 and [(L)2CuI]+[CuIII(CF3)4]− (L: a bidentate N,N or P,P ligand).8,9 In an attempt to broaden the chemistry of the CuIII CF3 complexes, we set out to investigate the reaction of phenCuIII(CF3)3 (1) with p-methoxyphenylacetylene (2a) (Table 1). When a strong base such as NaOtBu was used, the reaction occurred cleanly (with the complete
ifunctionalization of alkynes by the concurrent introduction of CF3 and another functional group represents one attractive, step- and atom-economical method for the construction of multiple functionalized trifluoromethylated alkenes with widespread applications in pharmaceuticals, agrochemicals, and materials science.1−5 This strategy shows superior advantages to methods relying on cascade crosscoupling of volatile polyhalogenated olefins with organometallic reagents (such as organolithium, Grignard reagents, organoboron) or other nucleophiles (such as amines, carboxylates) (Scheme 1a).6 It is also more attractive than stepwise methods involving Ar−CC−CF3 preparation/nucleophilic addition where separation and purification of Ar−CC−CF3 intermediates is required that adds synthetic steps and reduces atomand step-efficiency of the methods (Scheme 1a).7 Scheme 1. Nu-trifluoromethylation across Triple Bond of Alkynes
Received: October 16, 2017 Published: November 20, 2017 © 2017 American Chemical Society
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DOI: 10.1021/acs.orglett.7b03229 Org. Lett. 2017, 19, 6372−6375
Letter
Organic Letters
Next, various terminal alkynes were studied under the optimized conditions to show the synthetic compatibility of this method (Scheme 2). All of the arylacetylenes with either
Table 1. Optimization Study for Fluoro-trifluoromethylation Reaction of Alkynea
Scheme 2. Scope of syn-Fluoro-trifluoromethylationa yieldb (%) entry
additive
solvent
temp (°C)
3a
4a
1 2 3 4 5 6
NaOtBu KF CsF AgF CsF CsF
DMF DMF DMF DMF DMF toluene
100 100 100 100 50 or rt 100
0 44 81 0 0 0
99 29 trace 0 99 75
a
Reaction conditions: 1 (0.1 mmol), 2a (0.1 mmol), additive (0.5 mmol), 4,4′-biphenyl (0.1 mmol, internal standard), and solvent (2 mL) stirred for 6 h under N2. bDetermined by 19F NMR spectroscopy based on 2a.
disappearance of 19F NMR signals at −24.4 (septet) and −37.4 (quartet) ppm for phenCuIII(CF3)3),8a and a new 19F resonance at ca. −50 ppm (singlet) was produced quantitatively (Table 1, entry 1, and Figure S1). The product is assigned to be the Ar− CC−CF3 (4a) (Table 1) arising from trifluoromethylation of alkyne C−H bond promoted by a base.10 It is exciting to see that when fluoride salt (KF) was used in place of basic NaOtBu, in addition to the −50 ppm resonance, two new 19F NMR signals at ca. −56 (doublet) and −102 (quartet) ppm appeared with both coupling constants of 16.3 Hz (Figure S2). The signals at −56 and −102 ppm are in an approximately 3:1 molar ratio with the signal at −56 ppm being the major one. These data imply the generation of a new product with vinylic CF3 and F. Fortunately, this product was able to be isolated in pure form after workup and column chromatography, and extensive efforts confirmed the new product to be (Z)-(Ar)(F)CC(CF3)(H) (3a) (Table 1).11 Notably, the vinylic proton appearing at 5.57 ppm is characteristic with a doublet of quartet splitting (coupling constants of 33.9 and 7.5 Hz), indicating a vicinal transconfiguration of H and F and a geminal position of H and CF3 on the double bond. Therefore, a formal one-step syn-addition of F and CF3 across the triple bond is achieved. As far as we know, there is no precedent for such reactivity of fluorotrifluoromethylation of alkynes in the literature. Most importantly, this reaction occurs in a regio- and stereoexclusive way, without the detectable formation of other potential regioor stereoisomers.11 The syn-addition mode of the reaction is unprecedented and particularly significant because general antiaddition across triple bond was accomplished as aforementioned.3 Further optimization of the reaction conditions show that CsF performed better than KF, selectively giving 3a in 81% yield (Table 1, entry 3, and Figure S3), while AgF gave no significant yield of 3a or 4a (entry 4). Varying the solvent from DMF to nonpolar toluene led to the selective formation of 4a instead (entry 6). The temperature is also crucial to this reaction; lowering the reaction temperature to 50 °C or room temperature (rt) gave the selective formation of 4a, without appreciable amounts of 3a detected (entry 5). Therefore, the reaction conditions shown in entry 3 are found to be optimal for this fluoro-trifluoromethylation reaction.
a
Both 19F NMR and isolated yields (in parentheses) are given if available. bKF was used instead. c18 h. dC−H trifluoromethylation product in 60% yield. e1 (0.2 mmol) was used. f10 h.
electron-donating or electron-withdrawing substituents are good substrates, selectively giving (Z)-α-F-β-CF3 styrenes in moderate to quantitative yields as determined by 19F NMR spectroscopy. A broad range of functional groups can be tolerated for this reaction, including alkyl, alkoxy, phenyl, chloro, bromo, nitro, amino, acetyl, ester, and even aldehyde. Substitution patterns with either meta- or para-substituents are all compatible, showing no appreciable differences in reactivity. However, a dramatic ortho-steric effect was observed for ochlorophenyl acetylene (2p) which gave the desired 3p in only 22% yield, while the major product was C−H trifluoromethylation product (60% yield). Interestingly, benzene-1,3-bisacetylene can produce 3q from double syn-fluoro-trifluoromethylation of both alkynyl groups. Furthermore, naphthyl acetylene 2r and heteroaryl acetylenes including 3-pyridyl and 2-thiophenyl acetylenes (2s, 2t) are also good substrates, producing the desired 3r, 3s, and 3t in 98%, 84%, and 42% yields. Notably, the Z-products from syn-fluoro-trifluoromethylation were selectively obtained in all cases, without appreciable amounts of other regio- or stereoisomers. It shows complementary stereoselectivity to the general E-selectivity observed previously for the Nu-trifluoromethylation of alkynes.3 As a further example showcasing the potential application of this fluoro-trifluoromethylation reaction for large complex molecule functionalization, a spirobifluorene 2u decorated with four acetylene groups was subjected to reaction with 4 equiv of 1. Quadruple syn-fluoro-trifluoromethylation of 2u was 6373
DOI: 10.1021/acs.orglett.7b03229 Org. Lett. 2017, 19, 6372−6375
Letter
Organic Letters
Scheme 5. syn-Oxy-trifluoromethylation of 2a Using Various Phenoxides and Alkoxides
achieved to produce 3u in a good yield of 55% (isolated in 40% as a yellow solid) (Scheme 3). Scheme 3. Quadruple syn-Fluoro-trifluoromethylation of 2u
In an effort to broaden this syn-Nu-trifluoromethylation chemistry, we were pleased to find that when sodium phenoxide was used in place of CsF under otherwise identical conditions, the desired syn-oxy-trifluoromethylation occurred in excellent yields (Scheme 4). Arylacetylenes with substituents such as Scheme 4. syn-Oxy-trifluoromethylation of Arylacetylenesa,b
Scheme 6. syn-Aryl-trifluoromethylation of Arylacetylenes
or in nonpolar toluene, as shown in entries 5 and 6 in Table 1. These results confirm that the formation of 4a should be kinetically facile and 3a should be produced from the reaction of 4a with fluoride at a slower rate. Thus, direct subjection of 4a in place of 2a under the optimized reaction conditions gave 3a in trace amounts with 4a recovered (Scheme 7, eq 1), which
a
Both 19F NMR and isolated yields (in parentheses) are given. bFor the synthesis of 5h, 0.2 mmol of 1 was used.
Scheme 7. Control Experiments and Radical-Trapping Study alkoxy, alkyl, phenyl, and halides all selectively gave syn-oxytrifluoromethylation styrenes as the dominant products. Interestingly, benzene-1,3-bisalkyne 2h gave the mono synoxy-trifluoromethylation product 5h in a good yield of 83%. Naphthyl and heteroaryl acetylenes can also produce the desired 5i and 5j in excellent yields. It should be emphasized that this represents the first examples of one-step syn-oxy-trifluoromethylation of alkynes and also the first use of phenoxides in such alkyne oxy-trifluoromethylation reactions. On the other hand, a range of phenoxides can be tolerated in the syn-oxy-trifluoromethylation of alkynes (Scheme 5). Methoxide and ethoxide are also applicable oxy-nucleophiles. All of the phenoxides and alkoxides examined selectively gave the desired products 5 in good to excellent yields. Finally, phenyl boronic acid was also found to be applicable as a carbon nucleophile to engage in a similar syn-carbotrifluoromethylation of 2a to give 7 in 78% yield (Scheme 6).12 To shed mechanistic insights, particularly regarding the high regio- and stereoselectivity, extensive control experiments were done for the fluoro-trifluoromethylation reaction. First, 19F NMR monitoring of the crude mixtures of the model reaction in Table 1 in 5 min, 30 min, 2 h, 4 h, and 6 h clearly shows initial dominant formation of 4a and the gradual consumption of 4a and concurrent accumulation of the desired 3a (see Figure S4). Moreover, the reactions selectively gave 4a at lower temperature
indicates that the proton of terminal alkynes is crucial to the formation of 3a. To prove this, the explicit addition of 2 equiv of tertbutanol as a proton source to the reaction solutions did give the desired 3a in 62% yield (eq 2). Finally, radical trapping experiments show that the reaction yield was significantly diminished in the presence of stoichiometric radical scavenger BHT (2,6-di-tert-butyl-4-methylphenol), and the reaction was almost completely inhibited with TEMPO (2,2,6,6-tetramethylpiperidinyloxy) (eq 3), which suggests that radical species might be involved. 6374
DOI: 10.1021/acs.orglett.7b03229 Org. Lett. 2017, 19, 6372−6375
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On the basis of the above mechanistic results, a plausible mechanism involves the initial generation of CF3 radical from 113 and addition to alkyne triple bond to form a vinyl radical (A) (Scheme 8). Upon single-electron transfer (SET) from A to
Cu(II), the vinyl radical (A) is transformed to vinyl cation B that produces 4a after deprotonation.14 Then, fluoride attacks at the electrophilic Cα position to give a syn-α-F-β-CF3 styryl carbanion (C).15 Protonation of C produces the desired 3. By this mechanism, both the regio- and stereoselectivity are determined by a common step of nucleophilic addition of fluoride to 4a. The more electrophilic Cα of 4a reacts preferentially with fluoride to introduce the fluoride at the Cα position. The Z-stereoselectivity with cis-orientation of F and CF3 in intermediate C may stem from the presence of stabilizing secondary orbital interaction of π orbital of vinyl fluoride moiety with π*(CF3), parallel to the proposal for the reaction of ArC C−CF3 with phenoxide to produce the (Z)-oxy-trifluoromethylated styrenes.15a,b Nevertheless, more efforts are required to fully clarify the mechanistic details of this fluoro-trifluoromethylation reaction. Thus, a general method is developed to achieve syn-fluoro-, -oxy-, and -aryl-trifluoromethylation across triple bond of alkynes. It is attractive for preparing various trifluoromethylated Z-alkenes and shows the potential of CuIII−CF3 in organic synthesis.16
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03229. Experimental details; characterization data (PDF)
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REFERENCES
(1) (a) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH: Weinheim, Germany, 2004. (b) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (c) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (2) For general reviews, see: (a) Schlosser, M. Angew. Chem., Int. Ed. 2006, 45, 5432. (b) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1. (c) Grushin, V. V. Acc. Chem. Res. 2010, 43, 160. (d) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470. (e) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem., Int. Ed. 2013, 52, 8214. (3) Iodo-trifluoromethylation: (a) Iqbal, N.; Jung, J.; Park, S.; Cho, E. J. Angew. Chem., Int. Ed. 2014, 53, 539. (b) Hang, Z.; Li, Z.; Liu, Z.-Q. Org. Lett. 2014, 16, 3648. (c) Xu, T.; Cheung, C. W.; Hu, X. Angew. Chem., Int. Ed. 2014, 53, 4910. Oxy-trifluoromethylation: (f) Tomita, R.; Koike, T.; Akita, M. Angew. Chem., Int. Ed. 2015, 54, 12923. (g) Janson, P. G.; Ghoneim, I.; Ilchenko, N. O.; Szabó, K. J. Org. Lett. 2012, 14, 2882. (h) Egami, H.; Shimizu, R.; Sodeoka, M. Tetrahedron Lett. 2012, 53, 5503. Amino-trifluoromethylation: (i) Xiang, Y.; Kuang, Y.; Wu, J. Org. Chem. Front. 2016, 3, 901. (j) Ge, G.-C.; Huang, X.-J.; Ding, C.-H.; Wan, S.-L.; Dai, L.-X.; Hou, X.-L. Chem. Commun. 2014, 50, 3048. (k) Wang, F.; Zhu, N.; Chen, P.; Ye, J.; Liu, G. Angew. Chem., Int. Ed. 2015, 54, 9356. Aryl-trifluoromethylation: (l) Li, Z.; GarciaDominguez, A.; Nevado, C. J. Am. Chem. Soc. 2015, 137, 11610. (4) (a) Egami, H.; Sodeoka, M. Angew. Chem., Int. Ed. 2014, 53, 8294. (b) Merino, E.; Nevado, C. Chem. Soc. Rev. 2014, 43, 6598. (5) (a) Xu, T.; Wu, Y.; Yuan, Z.; Guan, H.; Liu, G. Organometallics 2016, 35, 1347. (b) Zeng, X.; Liu, S.; Shi, Z.; Liu, G.; Xu, B. Angew. Chem., Int. Ed. 2016, 55, 10032. (c) Li, S.; Li, Z.; Yuan, Y.; Li, Y.; Zhang, L.; Wu, Y. Chem. - Eur. J. 2013, 19, 1496. (6) (a) Begue, J.-P.; Bonnet-Delpon, D.; Bouvet, D.; Rock, M. H. J. J. Chem. Soc., Perkin Trans. 1 1998, 1797. (b) Goldberg, A. A.; Muzalevskiy, V. M.; Shastin, A. V.; Balenkova, E. S.; Nenajdenko, V. G. J. J. Fluorine Chem. 2010, 131, 384. (c) Zhao, Y.; Zhou, Y.; Liu, J.; Yang, D.; Tao, L.; Liu, Y.; Dong, X.; Liu, J.; Qu, J. J. J. Org. Chem. 2016, 81, 4797. (7) For a review of functionalization of Ar−CC−CF3, see: (a) Konno, T. Synlett 2014, 25, 1350. (8) (a) Zhang, S.-L.; Bie, W.-F. RSC Adv. 2016, 6, 70902. (b) Zhang, S.-L.; Bie, W.-F. Dalton Trans. 2016, 45, 17588. (9) (a) Willert-Porada, M. A.; Burton, D. J.; Baenziger, N. C. J. 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.; BenetBuchholz, J.; Grushin, V. V. Angew. Chem., Int. Ed. 2015, 54, 2745. (10) (a) Chu, L.; Qing, F.-L. J. J. Am. Chem. Soc. 2010, 132, 7262. (b) Luo, D.-F.; Xu, J.; Fu, Y.; Guo, Q.-X. Tetrahedron Lett. 2012, 53, 2769. (11) (a) Everett, T. S.; Purrington, S. T.; Bumgardner, C. L. J. J. Org. Chem. 1984, 49, 3702. For related isomers, see: (b) Reference 6b. (c) Yamada, S.; Takahashi, T.; Konno, T.; Ishihara, T. Chem. Commun. 2007, 3679. (12) Other nucleophiles, e.g., enolates, were also found to give low to moderate NMR yields and are still under study. (13) Evidence supporting the generation of CF3 radical from 1 is the observation of significant 19F signal at ca. −53 ppm from heating DMF solution of 1 in the presence of TEMPO at 100 °C, assigned to the formation of TEMPO−CF3 adduct. See Figure S9. (14) For a similar proposal, see: (a) Ji, Y.-L.; Luo, J.-J.; Lin, J.-H.; Xiao, J.-C.; Gu, Y.-C. Org. Lett. 2016, 18, 1000. (b) See also refs 3f and 3i.. (c) Maji, A.; Hazra, A.; Maiti, D. Org. Lett. 2014, 16, 4524. (d) Deb, A.; Manna, S.; Modak, A.; Patra, T.; Maity, S.; Maiti, D. Angew. Chem., Int. Ed. 2013, 52, 9747. (15) (a) Bumgardner, C. L.; Bunch, J. E.; Whangbo, M.-H. Tetrahedron Lett. 1986, 27, 1883. (b) Bumgardner, C. L.; Bunch, J. E.; Whangbo, M.-H. J. J. Org. Chem. 1986, 51, 4082. (c) Muzalevskiy, V. M.; Nenajdenko, V. G.; Shastin, A. V.; Balenkova, E. S.; Haufe, G. Synthesis 2009, 2009, 2249. (16) For a recent related study, see: Shen, H.; Liu, Z.; Zhang, P.; Tan, X.; Zhang, Z.; Li, C. J. J. Am. Chem. Soc. 2017, 139, 9843.
Scheme 8. Proposed Mechanism
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Letter
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[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 (No. 21472068). Financial support from MOE & SAFEA for the 111 Project (B13025), is gratefully acknowledged. 6375
DOI: 10.1021/acs.orglett.7b03229 Org. Lett. 2017, 19, 6372−6375
