Cu-Catalyzed/mediated synthesis of N-fluoroalkylanilines from arylboronic acids: fluorine effect on the reactivity of fluoroalkylamines

Hui Wang , Yuan-Hong Tu , De-Yong Liu and Xiang-Guo Hu *
National Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang, 330022, China. E-mail: huxiangg@iccas.ac.cn

Received 5th July 2018 , Accepted 3rd August 2018

First published on 3rd August 2018


An oxidative coupling reaction of fluoroalkylamines with arylboronic acids has been achieved for the first time. Fluorine has profound influence on the reactivity and fluoroalkylated amines have the following reactivity trend: difluoroethylamine > trifluoroethylamine > pentafluoropropylamine ≈ heptafluorobutylamine.


Anilines are structural components of a large and increasing number of bioactive natural and unnatural compounds. Anilines attached with electron-withdrawing groups (EWGs) are more important than the corresponding parent molecules in drug development, as aerobic or metabolic degradation, common problem encountered by anilines, can be significantly mitigated by the introduction of EWGs.1 Among various EWGs, the 2,2,2-trifluoroethyl group is very appealing because it usually endows the drug candidates with better pharmacokinetic and pharmacodynamic properties, such as lipophilicity, membrane permeability and metabolic stability.2 Notable examples of N-trifluoroethylanilines are shown in Fig. 1.
image file: c8ob01581c-f1.tif
Fig. 1 Selected examples of drugs and drug candidates bearing ArNHCH2CF3.

Conventional methods for the synthesis of N-trifluoroethylanilines involve SNAr reaction,3 reductive amination4 and N-trifluoroethylation using a hypervalent-iodine reagent.5 Recently, the synthesis of N-trifluoroethylanilines has also been achieved with 2,4,6-tris(2,2,2-trifluoroethoxy)-1,3,5-triazine6a and trifluoroacetic acid,6b respectively.

Among various newly developed methods, transition-metal catalyzed synthesis of N-trifluoroethylanilines is attractive (Scheme 1). In 2015, Hartwig and co-workers reported a palladium catalyzed coupling reaction of trifluoroethylamine with arylbromides and arylchlorides, providing an efficient approach to N-trifluoroethylanilines with a broad substrate scope and excellent functional group compatibility.7a In the same context, the research groups of Wang7b and Gouverneur7c have independently developed a silver and copper-catalyzed insertion reaction for the synthesis of N-trifluoroethylanilines. However, these methods usually require the use of expensive transition-metal catalysts and ligands, complex reaction setting (air and moisture extrusion), and/or non-commercially available reagents (CF3CHN2).


image file: c8ob01581c-s1.tif
Scheme 1 Strategies to access N-trifluoroethylated anilines.

In 1998, the research groups of Chan,8a Lam8b and Evans8c simultaneously developed the Cu-mediated oxidative cross-coupling of arylboronic acids with amines. Due to the mild conditions and use of an inexpensive copper promoter, this reaction has received great attention in the organic community. Although many different types of amines have been successfully employed in Chan–Lam–Evans reactions,9 to the best of our knowledge, the Cu-mediated/catalyzed oxidative cross-coupling of arylboronic acids with trifluoroethylamine has not been reported.

In continuation of our interest in utilizing fluoroalkylated amines for the synthesis of high-value compounds,10 we report herein the first copper catalyzed/mediated oxidative coupling of trifluoroethylamine and three other fluoroalkylamines with arylboronic acids (Scheme 1). This reaction has the advantages of using an inexpensive transition metal catalyst [Cu(OAc)2], readily available reagents and operational simplicity. An interesting reactivity trend of different fluoroalkylated amines is also disclosed in this work.

In the initial stage of this study, we chose 4-biphenylboronic acid 1a and 2,2,2-trifluoroethylamine 2a with a stoichiometric amount of copper acetate for the reaction optimization, based on the study by the research groups of Chan and Lam.8a,b The reaction in dichloromethane at room temperature after 24 hours left large amounts of starting materials (not shown), while increasing the temperature to 80 °C only afforded the desired product in 17% yield (entry 1, Table 1), thus reflecting the difficulty associated with transitional-metal catalyzed fluoroalkylated amines. Indeed, it has been reported that fluoroalkylated amines gave low yields under conventional Buchwald–Hartwig conditions possibly due to the low nucleophilicity and elimination reactions of fluoride.7a We next examined different solvents, such as dichloromethane, dioxane, and methanol, and found that dry acetonitrile gave the product in 70% yield (entries 2–7). It should be pointed out that when methanol was used as the solvent, 4 was obtained in 83% yield.11 Screening of the base showed that triethylamine was the optimal base (entries 8–12). Although other copper salts such as CuCl11 and CuBr12 were reported as effective promoters in Chan–Lam–Evans reactions, our work showed that only copper acetate worked for this reaction (entries 13–15). The amount of copper acetate could be reduced to a catalytic amount with three equivalents of triethylamine (entries 16–18). Pyridine-derived ligands were also explored (entries 19 and 20), and a slightly increased yield compared to that in entry 16 was obtained when a catalytic amount of pyridine was used (entry 19).13 The addition of 4 Å molecular sieves is important, because the side product phenol 5 could be obtained in up to 20% yield if it is not used (not shown). A comparison experiment showed that the ambient atmosphere was better than an oxygen atmosphere, and thus selected as the oxidant owing to the ease of handling and safety concern (entry 21). It should be noted that protodeboronation was an inevitable side reaction and product 6 was observed in every reaction tested.14 However, 6 did not complicate the isolation of the final product owing to its non-polar property. The elegant work by Batey suggests that N-dealkylation is a serious problem for alkylamines in the Chan–Lam reaction.15 However, we did not isolate diarylamine 7, which indicates a significant difference between fluoroalkylated amines and other ordinary alkylamines in this transformation.

Table 1 Reaction optimization for the oxidative coupling of 1a and 2a

image file: c8ob01581c-u1.tif

Entry Cu salt (equiv.) Base (equiv.)/solvent Yielda (%)
image file: c8ob01581c-u2.tifConditions: 4-Biphenylboronic acid 1a (0.1 mmol, 1 equiv.), CF3CH2NH2 (0.2 mmol, 2 equiv.), Cu salt (X equiv.), base (X equiv.), solvents (2.0 mL, dried with 4 Å molecular sieves overnight), 80 °C, 4 Å MS, overnight.a Yields are determined by 19F-NMR spectroscopy using benzotrifluoride as an internal standard.b Py (0.1 mmol, 1 equiv.) was used.c Py (0.02 mmol, 0.2 equiv.) was used.d 2,2′-Bipyridine (0.1 mmol, 1 equiv.) was used.e O2 was used instead of air.
1 Cu(OAc)2(1.0) TEA (2.0)/CH2Cl2 17%
2 Cu(OAc)2 (1.0) TEA (2.0)/dioxane 48%
3 Cu(OAc)2 (1.0) TEA (2.0)/MeOH 0
4 Cu(OAc)2 (1.0) TEA (2.0)/DMF 65%
5 Cu(OAc)2 (1.0) TEA (2.0)/toluene 41%
6 Cu(OAc)2 (1.0) TEA (2.0)/DCE 35%
7 Cu(OAc) 2 (1.0) TEA (2.0)/CH 3 CN 70%
8 Cu(OAc)2 (1.0) Na2CO3 (2.0)/CH3CN 47%
9 Cu(OAc)2 (1.0) Pyridine (2.0)/CH3CN 52%
10 Cu(OAc)2 (1.0) DIPEA (2.0)/CH3CN 63%
11 Cu(OAc)2 (1.0) K3PO4 (2.0)/CH3CN 58%
12 Cu(OAc)2 (1.0) NaOAc (2.0)/CH3CN 58%
13 CuCl (1.0) TEA (2.0)/CH3CN Trace
14 CuBr2 (1.0) TEA (2.0)/CH3CN Trace
15 CuCN (1.0) TEA (2.0)/CH3CN 0
16 Cu(OAc)2 (0.2) TEA (2.0)/CH3CN 60%
17 Cu(OAc) 2 (0.2) TEA (3.0)/CH 3 CN 71%
18 Cu(OAc)2 (0.2) TEA (4.0)/CH3CN 63%
19 Cu(OAc)2 (0.2) TEA (2.0)/CH3CN 54%b (65%)c
20 Cu(OAc)2 (0.2) TEA (2.0)/CH3CN 5%d
21 Cu(OAc)2 (0.2) TEA (3.0)/CH3CN 57%e


With the optimized reaction conditions in hand (entry 17, Table 1), we then investigated the generality and limitation of this copper-catalyzed oxidative coupling reaction of trifluoroethylamine 2a with arylboronic acids. Both electron-deficient (3e–h) and electron-rich (3i–j) arylboronic acids can be coupled with 2a in moderate to good yields. The conditions tolerated a large range of functional groups, such as aryl (3a), alkyl (3b), bromo (3d), nitro (3e), cyano (3f), ester (3g), keto (3h) and ether groups (3i–j). It is noteworthy that the arylboronic acid bearing bromo (3d) group was intact under the reaction conditions, which is complementary to the palladium-catalyzed reaction.7a Furthermore, the keto-group (3h) was well tolerated and no imine side product was observed. One limitation of this reaction is that it is not suitable for heteroaryl-substrates, and 3k was obtained in a quite low yield.

Having successfully obtained a range of N-trifluoroethylanilines, we next turned our attention to the reaction with the difluoroethylamine 2b. To our delight, this transformation is more effective than that with their trifluorinated counterparts, and most of the products were obtained in 10%–15% higher yields (8a–k). Overall, it appeared to us that the strong electronegativity of fluorine has a “negative effect” on this transformation,16,17 which might be due to the reduced nucleophilicity of trifluoroethylamine 2a relative to difluoroethylamine 2b. The structure of 3f was confirmed unambiguously by means of X-ray crystallographic analysis (Fig. 2).18 Finally, it is important to note that the removal of the solvent should be conducted with great care for some of the compounds (e.g., 3c, 8c, 3j and 8j) because of the volatile property of these products.


image file: c8ob01581c-f2.tif
Fig. 2 X-ray crystal structures of 3f and 11b.

To further explore the substrate scope of this oxidative coupling reaction, we then selected three representative boric acids to react with fluoroalkylamines 9 and 10. It is interesting to note that the negative impact imparted by fluorine becomes more apparent. The reaction appeared to be very sluggish and the corresponding products could only be obtained in low yields (e.g., 40% for 11b) under previously established optimized conditions (Scheme 3). Nevertheless, all the products could be obtained in 60–70% yields when copper acetate was increased to one equivalent. Again, this reaction is not sensitive to the electron properties of arylboronic acids as 11a–c and 12a–c were obtained in similar yields. The structure of 11b was confirmed unambiguously by means of X-ray crystallographic analysis (Fig. 2).19


image file: c8ob01581c-s2.tif
Scheme 2 Cu-Catalyzed coupling of arylboronic acids with XCF2CH2NH22a and 2b. Conditions: arylboronic acid (0.25 mmol, 1 equiv.), 2a or 2b (0.5 mmol, 2 equiv.), Cu(OAc)2 (0.2 equiv.), base (3 equiv.), solvents (2.5 mL), 80 °C, 4 Å MS, overnight.

image file: c8ob01581c-s3.tif
Scheme 3 Reaction of fluoroalkylated amines 9 and 10 with arylboronic acids. Conditions: arylboronic acid (0.25 mmol, 1 equiv.), 9 or 10 (0.5 mmol, 2 equiv.), Cu(OAc)2 (1 equiv.), base (3 equiv.), solvents (2.5 mL), 80 °C, 4 Å MS, overnight; a[thin space (1/6-em)]yield obtained under catalytic conditions.

In the above-mentioned work, we observed an intriguing trend that fluorine had an effect on the efficacy of the coupling reaction. This fluorine effect was further proved in the following competitive reactions that are shown in Scheme 4. For example, the reaction of 1 with an equal amount of difluoroethylamine 2b and trifluoroethylamine 2a yielded the fluoroalkylated anilines in a 3.5[thin space (1/6-em)]:[thin space (1/6-em)]1.0 ratio, with the difluorinated product 8a being favored (Scheme 4A); Scheme 4B indicates that 2a is more reactive than pentafluoropropylamine 9, while Scheme 4C suggests that pentafluoropropylamine 9 and heptafluorobutylamine 10 basically have the same reactivity. This series of competitive reactions, along with the results obtained in Schemes 2 and 3, indicates that the fluoroalkylated amines exhibit the following reactivity: 2b > 2a > 9 = 10. Overall, the reactivity of these fluoroalkylated amines seems to correlate well with the nucleophilicity of these fluoroalkylated amines. It is known that the nucleophilicity is parallel to the basicity when the atom forming the new bond is the same over a range of nucleophiles.20 The pKaH values of 2a (5.47) and 2b (7.09) indicate that the former is less nucleophilic than the latter. As the pKaH values of 9 and 10 are both 5.89, similar to that of 2a, their decreased reactivity relative to 2a may be due to the increased steric hindrance. However, as the mechanism of Chan–Lam–Evans coupling is rather complicated,14,21 it is not clear to us at this moment how the nucleophilicity affects the behavior of these fluoroalkylated amines in the oxidative coupling.


image file: c8ob01581c-s4.tif
Scheme 4 Comparison of the reactivities of different fluoroalkylamines with 4-biphenylboronic acid. Standard conditions are the ones used in Scheme 2; all the reaction ratios were determined by 19F-NMR spectroscopy.

Conclusions

In summary, we have achieved for the first time the oxidative (Chan–Lam–Evans) coupling reaction of fluoroalkylamines with arylboronic acids. The reaction has the following features such as operational simplicity, inexpensive copper acetate as either a catalyst or a promoter, air as an oxidant and good functional group tolerance, which should make it an important alternative method to other transition-metal catalyzed syntheses of fluoroalkylated anilines.7 Furthermore, we observed an interesting trend of reactivity of the four different fluoroalkylated amines, that is, difluoroethylamine > trifluoroethylamine > pentafluoropropylamine ≈ heptafluorobutylamine. This could serve as a clear example of how the introduction of fluorine could affect the reactivity of a nucleophile.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank the National Natural Science Foundation of China (21502076) the Natural Science Foundation of Jiangxi Province (20161BAB213068), and the Outstanding Young Talents Scheme of Jiangxi Province (20171BCB23039) for funding this research.

Notes and references

  1. The Chemistry of Anilines, ed. Z. Rappoport, Wiley, New York, 2007, vol. 1 Search PubMed.
  2. (a) S. Purser, P. R. Moore, S. Swallow and V. Gouverneur, Chem. Soc. Rev., 2008, 37, 320–330 RSC; (b) E. P. Gillis, K. J. Eastman, M. D. Hill, D. J. Donnelly and N. A. Meanwell, J. Med. Chem., 2015, 58, 8315–8359 CrossRef PubMed.
  3. P. Francotte, E. Goffin, P. Fraikin, P. Lestage, J. C. Van Heugen, F. Gillotin, L. Danober, J. Y. Thomas, P. Chiap, D. H. Caignard, B. Pirotte and P. de Tullio, J. Med. Chem., 2010, 53, 1700–1711 CrossRef PubMed.
  4. H. Mimura, K. Kawada, T. Yamashita, T. Sakamoto and Y. Kikugawa, J. Fluorine Chem., 2010, 131, 477–486 CrossRef.
  5. T. Umemoto and Y. Gotoh, J. Fluorine Chem., 1986, 31, 231–236 CrossRef.
  6. (a) F. Haghighi, F. Panahi, M. G. Haghighi and A. Khalafi-Nezhad, Chem. Commun., 2017, 53, 12650–12653 RSC; (b) K. G. Andrews, R. Faizova and R. M. Denton, Nat. Commun., 2017, 8, 15913 CrossRef PubMed.
  7. (a) A. T. Brusoe and J. F. Hartwig, J. Am. Chem. Soc., 2015, 137, 8460–8468 CrossRef PubMed; (b) H. Q. Luo, G. J. Wu, Y. Zhang and J. B. Wang, Angew. Chem., Int. Ed., 2015, 54, 14503–14507 CrossRef PubMed; (c) S. Hyde, J. Veliks, B. Liegault, D. Grassi, M. Taillefer and V. Gouverneur, Angew. Chem., Int. Ed., 2016, 55, 3785–3789 CrossRef PubMed.
  8. (a) D. M. T. Chan, K. L. Monaco, R.-P. Wang and M. P. Winters, Tetrahedron Lett., 1998, 39, 2933–2936 CrossRef; (b) P. Y. S. Lam, C. G. Clark, S. Saubern, J. Adams, M. P. Winters, D. M. T. Chan and A. Combs, Tetrahedron Lett., 1998, 39, 2941–2944 CrossRef; (c) D. A. Evans, J. L. Katz and T. R. West, Tetrahedron Lett., 1998, 39, 2937–2940 CrossRef.
  9. J. X. Qiao and P. Y. S. Lam, Synthesis, 2011, 829–856 CrossRef.
  10. (a) S. Q. Peng, X. W. Zhang, L. Zhang and X. G. Hu, Org. Lett., 2017, 19, 5689–5692 CrossRef PubMed; (b) X.-W. Zhang, W.-L. Hu, S. Chen and X.-G. Hu, Org. Lett., 2018, 20, 860–863 CrossRef PubMed.
  11. S.-Y. Moon, J. Nam, K. Rathwell and W.-S. Kim, Org. Lett., 2014, 16, 338–341 CrossRef PubMed.
  12. S. A. Rossi, K. W. Shimkin, Q. Xu, L. M. Mori-Quiroz and D. A. Watson, Org. Lett., 2013, 15, 2314–2317 CrossRef PubMed.
  13. K. Zhang, X.-H. Xu and F.-L. Qing, J. Fluorine Chem., 2017, 196, 24–31 CrossRef.
  14. J. C. Vantourout, H. N. Miras, A. Isidro-Llobet, S. Sproules and A. J. B. Watson, J. Am. Chem. Soc., 2017, 139, 4769–4779 CrossRef PubMed.
  15. T. D. Quach and R. A. Batey, Org. Lett., 2003, 5, 4397–4400 CrossRef PubMed.
  16. For the negative fluorine effect on fluoroalkylation: (a) C. F. Ni and J. B. Hu, Chem. Soc. Rev., 2016, 45, 5441–5545 RSC; (b) W. Zhang, C. Ni and J. Hu, Top. Curr. Chem., 2012, 308, 25–44 CrossRef PubMed.
  17. For review of the properties of the C–F bond: (a) D. O'Hagan, Chem. Soc. Rev., 2008, 37, 308–319 RSC. For review of the fluorine effect on the basicity of alkylamines: (b) M. Morgenthaler, E. Schweizer, A. Hoffmann-Röder, F. Benini, R. E. Martin, G. Jaeschke, B. Wagner, H. Fischer, S. Bendels, D. Zimmerli, J. Schneider, F. Diederich, M. Kansy and K. Müller, ChemMedChem, 2007, 2, 1100–1115 CrossRef PubMed.
  18. CCDC 1853090(3f) contains the crystallographic data for this paper.
  19. CCDC 1853088(11b) contains the crystallographic data for this paper.
  20. J. Clayden, N. Greeves and S. Warren, Organic Chemistry, Oxford University Press, New York, 2nd edn, 2001 Search PubMed.
  21. A. E. King, T. C. Brunold and S. S. Stahl, J. Am. Chem. Soc., 2009, 131, 5044–5045 CrossRef PubMed.

Footnote

Electronic supplementary information (ESI) available. CCDC 1853090 and 1853088. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c8ob01581c

This journal is © The Royal Society of Chemistry 2018