Letter Cite This: Org. Lett. 2017, 19, 5976-5979
pubs.acs.org/OrgLett
Visible-Light-Mediated Radical Arylation of Anilines with AcceptorSubstituted (Hetero)aryl Halides Leyre Marzo, Shun Wang, and Burkhard König* Institute of Organic Chemistry, University of Regensburg, D-93040 Regensburg, Germany S Supporting Information *
ABSTRACT: A visible-light-mediated, catalyst-free, direct (hetero)arylation of anilines with mild reaction conditions has been developed. The formation of a donor−acceptor complex between electron-withdrawing substituted (hetero)aryl halides and anilines allows, under blue LED irradiation, the synthesis of ortho and para (hetero)arylated anilines in moderate to good yields. The reaction has a high functional group tolerance. Spectroscopic studies confirmed the donor−acceptor complex formation between aniline and aryl halide.
A
Scheme 1. Metal-Mediated and Photochemical Arylation of Anilines
niline is a frequent structural motif of antibacterial compounds, analgesics, antifungal agents, or compounds used as treatment for noninfectious diseases, such us tranquilizers or anesthetics. In industry, anilines are used as starting material or key intermediates for the synthesis of pigments, dyestuffs, rubber products, or explosives, among other uses.1 A typical approach for the arylation of aniline derivatives is the Suzuki cross-coupling reaction, starting from aryl halides or triflates and aniline boronic acids or boronates.2 Other approaches use the Stille cross-coupling reaction3 from stannane derivatives or the Ullmann reaction4 from the corresponding halides. These methods are well developed and yield, in many cases, excellent results, but require transition metals as catalyst and a prefunctionalization of the aniline. More atom economic is the direct C−H functionalization of anilines. However, only a small number of examples of this kind of transformation have been reported so far. Greaney et al. reported the direct C−H arylation of anilines via a benzyne intermediate from 2-(trimethylsilyl)phenyl trifluoromethanesulfonate, as the benzyne precursor, and trityl aniline5a or Nsubstituted arylsulfonamides.5b High temperatures are necessary to obtain ortho-substituted anilines. Heinrich and coworkers reported the radical ortho- and meta-arylation of parasubstituted anilines with aryldiazonium salts6a and arylhydrazines6b as precursors of a transient aryl radical, which is trapped by aniline present in the reaction mixture. In both examples, stoichiometric amounts of a reducing or oxidizing agent (TiCl3 and MnO2, respectively) are required. To overcome this limitation,6c−e they developed a method starting from aryl hydrazines as the radical source and dioxygen as the oxidant under basic conditions (eq 1, Scheme 1).6d Using arylhydrazines as starting materials, Zou and co-workers have reported the CoPc-catalyzed radical arylation of anilines (eq 2, Scheme 1).7 The reaction afforded good results when using 10 mol % of the transition metal catalyst at 80 °C. We report here a practical alternative method for the arylation of anilines at room temperature starting from commercially available (hetero)aryl bromides or chlorides and anilines using visible light as a traceless reagent (eq 3, Scheme 1). © 2017 American Chemical Society
Based on our experience in the photoreduction of aryl8 and heteroaryl halides9 with rhodamine 6G (Rh-6G), we investigated the reaction between bromothiophene 1A and aniline 2a using the previously reported9 catalytic system and obtained product 3Aa in 66% yield (entry 1, Table 1). However, control experiments revealed that the photocatalyst is not necessary (entry 2, Table 1). Irradiation with 455 nm light is crucial for the reaction (entry 3, Table 1). To understand this result, we measured the absorption spectra of 1A (see Supporting Information (SI), Figure S1). At the concentration of the reaction mixture, 1A absorbs visible light until 600 nm, which allows the initiation of the observed reaction. The reaction proceeds in the absence of DIPEA (entry 4, Table 1), but its presence accelerates the initial reaction (see kinetic measurements in the SI, Figure S4), resulting in higher product yields. Further experiments using different solvents as well as equivalents of DIPEA and aniline revealed as the optimal Received: September 25, 2017 Published: October 24, 2017 5976
DOI: 10.1021/acs.orglett.7b03001 Org. Lett. 2017, 19, 5976−5979
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Organic Letters Table 1. Optimization of the Reaction Conditions for the Direct Heteroarylation of Anilinesa
entry
solvent
DIPEA (equiv)
2a (equiv)
yield 3Aa (%)b
1c 2 3d 4 5 6 7 8 9 10 11 12
CH3CN CH3CN CH3CN CH3CN DMSO DMF THF CH2Cl2 EtOH CH3CN CH3CN CH3CN
1.2 1.2 1.2 − 1.2 1.2 1.2 1.2 1.2 0.5 0.2 0.5
3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 5.0
66 60 0 62 0 0 0 50 0 70 64 77
Scheme 2. Scope of Aniline Derivatives 2 under Optimal Reaction Conditions with 1Aa
a Reaction conditions: 0.1 mmol of 1A, in 1 mL of CH3CN, 20 h, under N2 at room temperature and 455 nm LED irradiation. b Determined by GC analysis with benzophenone as internal standard. c Using 10 mol % Rh-6G. dNo light.
reaction conditions the use of 0.5 equiv of DIPEA, 5.0 equiv of the aniline derivative in acetonitrile (0.1 M) under nitrogen atmosphere, 25 °C, and 455 nm irradiation (for further details see SI, Table S1). With the optimized conditions in hand, we studied the reaction of different anilines with 1A (Scheme 2). Aniline 2a and N-substituted anilines 2b and 2c afforded a mixture of the ortho and para regioisomers in high yields (3Aa, 3Ab, 3Ac, Scheme 2), while para-substituted anilines (2d, 2e, 2f) gave the ortho adducts as single regioisomers in moderate yields (3Ad, 3Ae, 3Af, Scheme 2). With 2g, bearing bulky alkyl groups in the two ortho positions, 3 equiv of the aniline are enough to obtain the para adduct in good yield (3Ag, Scheme 2). However, the presence of double bonds in the molecule diminishes the reactivity.10 Thus, with 2h a 32% yield of the two possible regioisomers was obtained (3Ah, Scheme 2). Benzene diamine derivative 2i afforded 3Ai in 76% yield as a single regioisomer. The steric hindrance by the dimethylated amines blocks position C-2, forcing the substitution reaction to position C-4 (3Ai, Scheme 2). The reaction tolerates para-halogenated anilines. Thus, 2j and 2k gave the ortho-substituted products as single regioisomers in moderate yields (3Aj, 3Ak, Scheme 2).11 However, halogens in the ortho position and electronwithdrawing groups at the nitrogen atom completely suppress the reactivity by diminishing the electron density (3Al, 3Am, Scheme 2). Anilines bearing ester substituents (2n and 2o) show low reactivity, but the expected regioselectivity. Thus, 3An was obtained as a mixture of regioisomers in moderate yield, while benzocaine 2o, an aniline derivative employed as a topical anesthetic,12 affords the ortho adduct 3Ap in low yield (Scheme 2). Naphthalene-2-amine 2p gave 3Ap in 54% yield, but 2q did not react, due to low solubility and overlapping absorption in the visible region of 2q and 1A.13 Next, we investigated the (hetero)aryl halide scope of the reaction (Scheme 3). 2-Bromothiophene 1B and the electrondeficient 2-bromopyridine 1C did not react with 2c (3Bc, 3Cc, Scheme 3), suggesting that the presence of an electronwithdrawing substituent in 1 is essential for the reaction. 1D
a
Reaction conditions: 0.1 mmol of 1A, 0.5 mmol of 2, 0.05 mmol of DIPEA, 1 mL of CH3CN, blue LED irradiation (455 nm), under nitrogen atmosphere and 25 °C. b0.2 equiv of DIPEA were used instead of 0.5 equiv. c3.0 equiv of 2 were used. d8.0 equiv of 2 were used. e10.0 equiv of 2 were used.
Scheme 3. Scope of Brominated (Hetero)Arenes 1 Reacting with Diphenylamine 2ca
a Reaction conditions: 0.1 mmol of 1, 0.5 mmol of 2c, 0.05 mmol DIPEA, 1 mL of CH3CN, blue LED irradiation (455 nm), under nitrogen atmosphere and 25 °C. bThe reaction was carried out with the chlorinated starting material and under 400 nm LED irradiation.
and 1E, bearing an aldehyde or a nitrile group, react smoothly affording 3Dc and 3Ec as a mixture of regioisomers in excellent 5977
DOI: 10.1021/acs.orglett.7b03001 Org. Lett. 2017, 19, 5976−5979
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Organic Letters
6, 7, and 8 for Job plots, association constants, and NMR titration experiments of EDA complexes 1D/2c and 1G/2c). To elucidate the role of DIPEA as a base or as a sacrificial electron donor, we ran the reaction in the presence of other bases that cannot act as sacrificial electron donors.20 The reaction in standard conditions with DBU and K2CO3 afforded 3Aa in 75% and 76% yield, respectively (measured by GC), similar to the yield observed for the standard reaction conditions using 0.5 equiv of DIPEA (77%), thus suggesting that DIPEA is acting as a base and not as a sacrificial electron donor, and that DIPEA is able to accelerate the process by neutralizing the HBr formed in the reaction. Our proposed mechanistic model starts with the formation of the excited donor−acceptor complex I* by absorption of one photon under blue LED irradiation (Scheme 4). Single electron
yields (Scheme 3). However, in the presence of a nitro substituent (1F) the reaction does not take place, due to the ability of the nitro group to strongly stabilize the radical anion intermediate inhibiting the C−Br bond scission (3Fc, Scheme 3). Chlorinated thiophenes 1G and 1H afforded a mixture of the ortho/para adducts in moderate to good yields under 400 nm LED irradiation (3Gc, 3Hc, Scheme 3).14 2-Bromofurfural 1I also reacts under these conditions affording 3Ic in 78% yield.15 The reaction was also applied to aryl bromides 1J and 1K, which afforded 3Jc and 3Kc as a single regioisomer in low yield due to lower reactivity. 4-Bromobenzonitrile 1L gave 3Lc as an ortho/para mixture in 66% yield (Scheme 3). The reaction mixture turns yellow upon mixing of the starting materials (Figure 1a, picture). Compounds 1D−1L
Scheme 4. Mechanism of the Visible-Light-Mediated Direct (Hetero)Arylation of Anilines
transfer (SET), followed by C−Br bond scission, affords the radical intermediate II.21 Next, the radical intermediate II reacts with 2, generating the radical intermediate III. Final hydrogen atom transfer (HAT) regenerates the aromaticity and yields compound 3. The quantum yield of the reaction was determined to be Φ = 1%, indicating that the mechanism does not contain significant radical chains. In addition, we illuminated the reaction with successive intervals of light and dark periods (see SI, Figure S12). The experiment showed complete interruption of the reaction in the dark periods and restart of the reaction under irradiation, thus confirming light as an indispensable parameter of the reaction. In conclusion, we have developed the first catalyst-free, visible-light-mediated approach for the direct radical (hetero)arylation of aniline derivatives. The reaction proceeds smoothly under blue LED irradiation at room temperature, affording the final products in good to very good yields. The scope of the reaction comprises anilines bearing electron-withdrawing or electron-donating substituents in the arene, but N-acetylated or ortho-halogenated anilines do not react. On the other hand, a variety of electron-poor substituted (hetero)arenes were converted with good results. The arylation products are obtained as a mixture of regioisomers or a single isomer depending on the starting aniline. Mechanistic investigations support the formation of a donor−acceptor complex to be responsible for the observed reactivity.
Figure 1. Experimental observations supporting the EDA complex formation: (a) Visible appearance of starting materials and reaction mixture; (b) Comparison of the UV−vis absorption spectra of solutions of CH3CN containing 1A, 2a, and the mixture of 1A + 5.0 equiv of 2a; (c) Job plot of ratio between 1A and 2a; (d) NMR titration experiment between 1A and 2a.
absorb only slightly in the visible region (see SI, Figure S2). However, when 5 equiv of 2a were added to the solution of 1A, a significant extinction in the visible part of the spectrum arises, which indicates the formation of a donor−acceptor complex16 (Figure 1b; see also SI Figure S3 for changes in the absorption spectra of compounds 1D, 1G, and 1L in the presence of 5 equiv of 2c).17 The emission intensity of compound 1A is quenched upon addition of compound 2c (see SI, Figure S5). However, its emission lifetime was determined to be shorter than 1 ns; therefore, diffusion controlled quenching of the singlet state of 1A is unlikely, and an interaction between the two molecules via the formation of a donor−acceptor complex is more probable. NMR titration experiments showed that the H1 NMR resonance signal of the proton α to the electron-withdrawing group in 1A shifts downfield upon addition of 2a (Figure 1d). The stoichiometry of the donor−acceptor complex was investigated by a Job plot analysis of UV−vis and NMR data.18 The Job plot analysis of the EDA complex 1A/2a yields a 1:1 ratio of the two components (Figure 1c), and the association constant KEDA was derived to be 0.18 M−1 in CH3CN by the Benesi−Hildebrand method19 (see SI sections
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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.7b03001. 5978
DOI: 10.1021/acs.orglett.7b03001 Org. Lett. 2017, 19, 5976−5979
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Organic Letters
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(13) Zeng, K.; Hwang, H.-M.; Dong, S.; Shi, X.; Wilson, K.; Green, J.; Jiao, Y.; Yu, H. Environ. Toxicol. Chem. 2004, 23, 1400. (14) The reaction under blue LED (455 nm) also worked, but in lower conversion than under 400 nm irradiation. (15) Although other heterocycles were studied in the reaction, the scope is limited to furane and thiophene derivatives. (16) (a) Rosokha, S. V.; Kochi, J. K. Acc. Chem. Res. 2008, 41, 641. (b) Arceo, E.; Jurberg, I. D.; Á lvarez-Fernández, A.; Melchiorre, P. Nat. Chem. 2013, 5, 750. (17) In the case of 1C and 1K this complex is able to absorb at 455 nm irradiation. However, in the case of 1F, the complex shows little absorption at 455 nm vs 400 nm, explaining the better conversion observed with 400 nm LED irradiation. (18) MacCarthy, P. Anal. Chem. 1978, 50, 2165. (19) Benesi, H. A.; Hildebrand, J. H. J. Am. Chem. Soc. 1949, 71, 2703. (20) The reaction was carried out with DBU and K2CO3 under the optimized reaction conditions (entry 12, Table 1). (21) To probe the radical character of the reaction, we ran the reaction of 1A with 2a in the standard reaction conditions, adding 10 equiv of TEMPO after 1 h of irradiation, and irradiating for an additional 20 h. Compound 3Aa was obtained with a 26% yield, which means that the reaction was suppressed by the addition of TEMPO, confirming the radical character of the reaction.
Full experimental data (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Burkhard König: 0000-0002-6131-4850 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the Deutsche Forschungsgemeinschaft DFG GRK 1626, Chemical Photocatalysis. L.M. thanks the Alexander von Humboldt Foundation for a postdoctoral fellowship. S.W. thanks the China Scholarship Council (CSC) for a predoctoral fellowship. We thank Dr. Rudolf Vasold (University of Regensburg) for his assistance in GC−MS measurements and Ms. Regina Hoheisel (University of Regensburg) for her assistance in cyclic voltammetry measurements.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b03001 Org. Lett. 2017, 19, 5976−5979
