Chemo- and Regioselective Hydroarylation of Alkenes with Aromatic

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Chemo- and Regioselective Hydroarylation of Alkenes with Aromatic Amines Catalyzed by [Ph3C][B(C6F5)4] Wenguo Zhu,† Qiu Sun,†,‡ Yaorong Wang,† Dan Yuan,*,† and Yingming Yao*,† †

Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Dushu Lake Campus, Soochow University, Suzhou 215123, People’s Republic of China ‡ School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou 225002, People’s Republic of China S Supporting Information *

ABSTRACT: A nonmetal catalyst [Ph3C][B(C6F5)4] has been developed to catalyze hydroarylation reaction of alkenes with aromatic primary, secondary, and tertiary amines, which generated aniline derivatives in 32−98% yields. This method is applicable to a wide range of substrates, is highly chemo- and regioselective, and provides a simple and efficient approach for aniline derivative preparation.

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and regioselective approach is highly desirable. We herein report the development of simple and readily available borate [Ph3C][B(C6F5)4] as a metal-free catalyst for hydroarylation of alkenes with primary, secondary, and tertiary aromatic amines under relatively mild conditions. In a preliminary study, 10 mol % [Ph3C][B(C6F5)4] (TB) catalyzed the reaction between styrene 1a and 1,2,3,4tetrahydroquinoline 2a at 100 °C, which furnished Markovnikov addition product 3a with the ortho-C−H bond addition to styrene in 83% yield (Table S1, entry 2). The identity of 3a was confirmed by 1D and 2D NMR spectra in the Supporting Information (SI). Optimization of reaction conditions includes changing reaction temperatures, solvents, catalyst loadings, substrate ratios, and borate reagents (Table S1), and the best yield of 89% was obtained at 60 °C after 12 h reaction (Scheme 1). [PhNH3][B(C6F5)4] was reported to catalyze concurrent

niline derivatives have found widespread application in natural products, medicines, and organic functional materials. Tremendous efforts have been devoted to synthesizing compounds bearing aniline motifs.1 Catalytic C−H addition of anilines to alkenes is one of the most efficient and atomeconomical strategies to modify aniline skeletons. However, classical Friedel−Crafts alkylation conditions2,3 are generally not applicable in constructing aniline derivatives due to their coordination with Lewis acid catalysts.4,5 Moreover, Friedel− Crafts reactions usually furnish both ortho- and para-substitution and require electron-deficient alkenes. Hence, the development of suitable catalytic systems to promote direct and regioselective C−H alkylation of anilines is an important task. In the literature, some catalytic systems have been reported for direct C−H alkylation reactions of anilines with C−C unsaturated bonds.6,7 Transition metal catalysts include Rh,6a−c Ru,6d Ir,6e Zn,6f Au,6g Y,6h and Ti complexes,6i which are mainly precious metal based, and in general, require delicate design and synthesis. Coates et al. employed CF3SO3H to catalyze orthoalkylation of primary anilines with styrenes at 160 °C.7e Stephan et al. developed phosphonium cations as main group catalysts for hydroarylation of olefins with secondary/tertiary anilines, giving rise to para-substituted anilines.7i Arnold and Bergman reported proton-catalyzed reactions of primary aniline and alkenes, which afforded mixtures of hydroamination (N-alkylation) and hydroarylation (C-alkylation) products in varying ratios.7d Although several catalysts have been developed for this important transformation, current strategies suffer from some limitations: (1) substrate scopes are limited to primary anilines,6a,b,e,f,i,7a−h while reports on more basic secondary and tertiary amines are rare;6c,d,g,h,7i−l (2) many protocols result in a mixture of hydroamination (N-alkylation) and hydroarylation (C-alkylation) products, and the latter often consist of ortho- and paraisomers;6a−c,e,f,i,7d−i (3) either aromatic alkenes7i or strong electron-withdrawing groups on CC double bonds are required for higher yields.7j−l Development of a highly chemo© XXXX American Chemical Society

Scheme 1. Optimal Conditions of Hydroarylation of Styrene (1a) with 1,2,3,4-Tetrahydroquinoline (2a)

hydroamination and hydroarylation reactions of primary anilines with alkenes.7d In our study, a low yield (31%) of hydroarylation product was obtained in [PhNH3][B(C6F5)4]-catalyzed reactions of secondary amines (Table S1, entry 13). Overall, [Ph3C][B(C6F5)4] represents a most simple, active, and Received: April 12, 2018

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DOI: 10.1021/acs.orglett.8b01158 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters chemo- and regioselective nonmetal catalyst that promotes ortho-position reaction of secondary amines with simple alkenes. Different secondary amines and styrene were studied under optimized conditions, and results are summarized in Scheme 2.

Scheme 3. Hydroarylation of Various Primary and Tertiary Amines and Styrene Catalyzed by TBa

Scheme 2. Hydroarylation of Various Secondary Amines and Styrene Catalyzed by TBa

a

Conditions: amines (0.5 mmol), styrene (1 mmol), TB (46 mg, 0.05 mmol), PhCl (2 mL), 80 °C, 24 h. Isolated yields based on amines. b 3.0 equiv of styrene. c130 °C reaction temperature.

a

Conditions: amines (0.5 mmol), styrene (1 mmol), TB (46 mg, 0.05 mmol), PhCl (2 mL), 60 °C, 12 h. Isolated yields based on amines. b 80 °C reaction temperature.

Table 1. Hydroarylation of 6-Methyl-1,2,3,4tetrahydroquinoline 2h and Styrene Derivatives Catalyzed by TBa

The reaction of N-methylaniline afforded desired product 3b in 80% yield, while that of N-ethylaniline gave a lower yield of 44%, possibly due to increased steric hindrance.8 Similarly, diphenyl amine resulted in 38% isolated yield of 3d. Substituted1,2,3,4-tetrahydroquinoline with either α- or aryl-substituent gave rise to addition products 3e−h in 75−96% yields. Reactions with indoline (2i) or indoline derivative (2j−m) were less efficient and afforded products 3i and 3j−m in 45−73% yields. No product was isolated from reactions of 1,2,3,4-tetrahydroisoquinoline or N-methyl-1-phenylmethanamine. In addition to secondary amines, reactions of primary and tertiary amines with styrene also proceeded at elevated temperatures of 80−130 °C in the presence of TB and generated hydroarylation products in 58−97% yields (Scheme 3). Dialkylation reaction occurred to p-toluidine and generated product 3n almost exclusively in 97% yield, while reaction of aniline yielded trialkylation product 3o in a good yield of 82%. In comparison, CF3SO3H-catalyzed alkylation of anilines required high temperature of 160 °C.7e Tertiary anilines N,N-dimethylaniline 2p and N,N,3-trimethylaniline 2q also reacted smoothly with styrene, affording mixtures of mono- and dialkylated products with high ortho-regioselectivity. This result is different with the phosphonium cations-catalyzed alkylation of N,N-dimethylaniline, which generated para-alkylation products.7i These two methods thus complement each other. para-Substituted N,Ndimethylaniline derivatives (2r−u) reacted efficiently at the ortho-position in 80−90% yields, while reactions of orthosubstituted N,N,2-trimethylaniline occurred at the other orthoposition and afforded product 3v in a lower yield of 58%. Reactions between 6-methyl-1,2,3,4-tetrahydroquinoline 2h and a series of styrene derivatives were studied, and the results are summarized in Table 1. Generally good yields of 89−99% were

a Conditions: 1 (1 mmol), 2h (74 mg, 0.5 mmol), TB (46 mg, 0.05 mmol) in PhCl (2 mL) for 12 h, 60 °C, isolated yield. b1b/2h (1:1). c 100 °C. d80 °C. e120 °C.

obtained with o-, m-, or p-substituted styrene. Reactions of electron-rich styrenes proceeded at lower temperatures of 60−80 B

DOI: 10.1021/acs.orglett.8b01158 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters °C (products 4b,c,e,i,m), while those of electron-deficient styrenes required higher temperature of 100−120 °C (products 4f−h,j−l,n−p). For instance, 4-methoxystyrene 1b reacted with 2h in 97% yield at 60 °C, while no reaction occurred to 4nitrostyrene even at 130 °C. In addition, different positions of the substituent seem to have some influence on the reaction outcome. ortho-Substituted styrenes required elevated temperatures as compared to para-analogue (entry 1 vs 3). 1,1Disubstituted aromatic alkene α-methylstyrene 1q also worked straightforwardly and led to a good yield of 96% (entry 4). Hydroarylation of 1,2,3,4-tetrahydroquinoline with aliphatic olefins, i.e., norbornene, cyclohexadiene, and linear alkenes, were explored under established conditions, and the results are summarized in Table 2. Good yields of 95 and 74% were isolated

Figure 1. Plot of ([amine]02 − [amine]2)/2 versus time (h) for the hydroarylation reaction of styrene 1a and 6-methyl-1,2,3,4-tetrahydroquinoline 2h. Conditions: [1a]0 = 1.6665 mol·L−1, [2h]0 = 0.3333 mol·L−1, 10 mol % of TB, PhCl, 100 °C, detected by GC with nhexadecane as internal standard. R2 = 0.9963 (black ■); plot of [amine]0 − [amine] versus time (h). Conditions: [1a]0 = 1.25 mol·L−1, [2h]0 = 0.25 mol·L−1, 10 mol % of TB, PhCl, 100 °C. R2 = 0.9986 (red ●).

Table 2. Hydroarylation Reactions of 1,2,3,4Tetrahydroquinoline and Aliphatic/Internal Olefins Catalyzed by TBa

To gain more insight into the mechanism of the hydroarylation reaction, monitoring by 11B and 19F NMR spectroscopy was conducted, which revealed no change of the [B(C6F5)4] anion signals, and rules out the participation of borate in the catalytic process.7i Moreover, kinetic study of N-methyl aniline and d5-N-methyl aniline was conducted in parallel. The kinetic isotope effect was determined to be 2.3 (Figure S3), suggesting C−H bond cleavage as the rate-determining step. Two possible mechanisms are proposed for the [Ph3C][B(C6F5)4]-catalyzed hydroarylation reaction. The trityl cation may first react with the aromatic amine substrate to form an anilinium salt (Scheme S1), followed by protonation of alkenes to generate a carbocation.9 This mechanism, however, does not explain reactions of tertiary amines. Alternatively, the trityl cation may first activate the alkene (Scheme 4).7i In both pathways, Scheme 4. Plausible Mechanism

a

Conditions: 1 (1 mmol), 2h (74 mg, 0.5 mmol), TB (46 mg, 0.05 mmol) in PhCl (2 mL) 12 h. Isolated yield. bOlefin/1,2,3,4tetrahydroquinoline = 5:1, 24 h.

from reactions of cyclic alkenes norbornene and cyclohexadiene (entry 1 and 2), respectively, while lower yields of 40 and 32% were obtained from linear alkenes 1-octene and 1-hexene (entry 3 and 4), respectively, albeit with a higher ratio of alkene to amine. Acyclic internal alkene β-methylstyrene reacted straightforwardly at 130 °C and generated product 4v in 90% yield (entry 5), while the bulkier substrate stilbene did not react (entry 6). A linear plot of ln([1a]0/[1a]) versus time reveals a first-order dependence on styrene concentration (Figure S2). The order of amine 2h was found to be fractional, as the plots suggest reversefirst-order at a higher concentration of 0.33 mol·L−1, whereas zero-order at a lower concentration of 0.25 mol·L−1 (Figure 1). Overall, the rate law is deduced as ν ≈ [styrene]1[amine]n (n = −1−0).

nucleophilic addition leads to C−C bond formation,10 and subsequent proton transfer regenerates aryl rings, as well as trityl cations. High concentration amine may interact with trityl cations, decreasing their nucleophilicity, which slows the reaction. Both mechanisms are plausible, and further confirmation cannot be made based on the current results. In conclusion, nonmetal catalyst [Ph3C][B(C6F5)4] has been developed for hydroarylation of a wide range of alkenes with aromatic primary, secondary, and tertiary amines. One hundred C

DOI: 10.1021/acs.orglett.8b01158 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

(7) (a) Stroh, R.; Ebersberger, J.; Haberland, H.; Hahn, W. Angew. Chem. 1957, 69, 124. (b) Ecke, G. G.; Napolitano, J. P.; Kolka, A. J. J. Org. Chem. 1956, 21, 711. (c) Hart, H.; Kosak, J. R. J. Org. Chem. 1962, 27, 116. (d) Anderson, L. L.; Arnold, J.; Bergman, R. G. J. Am. Chem. Soc. 2005, 127, 14542. (e) Cherian, A. E.; Domski, G. J.; Rose, J. M.; Lobkovsky, E. B.; Coates, G. W. Org. Lett. 2005, 7, 5135. (f) Lapis, A. A. M.; Dasilveira Neto, B. A.; Scholten, J. D.; Nachtigall, F. M.; Eberlin, M. N.; Dupont, J. Tetrahedron Lett. 2006, 47, 6775. (g) Marcsekova, K.; Doye, S. Synthesis 2007, 1, 145. (h) Seshu Babu, N.; Mohan Reddy, K.; Sai Prasad, P. S.; Suryanarayana, I.; Lingaiah, N. Tetrahedron Lett. 2007, 48, 7642. (i) Pérez, M.; Mahdi, T.; Hounjet, L. J.; Stephan, D. W. Chem. Commun. 2015, 51, 11301. (j) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 7894. (k) Takenaka, N.; Sarangthem, R. S.; Seerla, S. K. Org. Lett. 2007, 9, 2819. (l) Halimehjani, A. Z.; Farvardin, M. V.; Zanussi, H. P.; Ranjbari, M. A.; Fattahi, M. J. Mol. Catal. A: Chem. 2014, 381, 21. (8) (a) Sun, Q.; Wang, Y.; Yuan, D.; Yao, Y.; Shen, Q. Chem. Commun. 2015, 51, 7633. (b) Sun, Q.; Wang, Y.; Yuan, D.; Yao, Y.; Shen, Q. Dalton Trans. 2015, 44, 20352. (9) Damico, R.; Broaddus, C. D. J. Org. Chem. 1966, 31, 1607. (10) Mosaferi, E.; Ripsman, D.; Stephan, D. W. Chem. Commun. 2016, 52, 8291.

percent Markovnikov products with ortho-substituents formed in good yields of 32−98%. A kinetic study revealed a fractionalorder dependence on amine concentration, while first-order on alkene concentration. This method provides a simple and efficient method to prepare aniline derivatives, and the work complements the literature methods. Further development of catalytic C−H bond functionalization is in progress.

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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.8b01158. Characterization of hydroarylation products, 1H and 13C NMR spectra, and details of kinetic study (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail:[email protected]. *E-mail: [email protected]. ORCID

Yingming Yao: 0000-0001-9841-3169 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge financial support from the National Natural Science Foundation of China (Grants 21402135 and 21674070), the Project of Scientific and Technologic Infrastructure of Suzhou (SZS201708), and PAPD.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b01158 Org. Lett. XXXX, XXX, XXX−XXX