Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
α‑Aminoalkyl Radical Addition to Maleimides via Electron Donor− Acceptor Complexes Chien-Wei Hsu and Henrik Sundén* Department of Chemistry and Chemical Engineering, Chalmers University of Technology, Kemivägen 10, 41296 Göteborg, Sweden S Supporting Information *
ABSTRACT: A catalyst-free, photochemical oxidative annulation reaction between dialkylanilines and maleimides to generate tetrahydroquinolines is presented. The reaction is driven by the photochemical activity of an electron donor−acceptor (EDA) complex and has a broad substrate scope with the corresponding products isolated in good to excellent yields. Photochemical characterization of the EDA complex and a mechanistic rational is provided. Scheme 1. Light-Induced α-Aminoalkyl Radical Addition to Maleimides
C(sp3)−H bond functionalization through the generation of αaminoalkyl radicals has emerged as a key synthetic strategy for several important reactions, such as cross-dehydrogenative couplings (CDCs)1 and radical addition to alkenes,2 imines,3 and isocyanates.4 Due to the ease of generating radicals with light, recent progress in photoredox catalysis has dramatically expanded the usage of α-aminoalkyl substrates in synthesis.2d,e,5 Photochemically, α-aminoalkyl radicals can be generated through desilylation of α-silylamine,6 decarboxylation of amino acids, 7 or by single electron oxidation of an alkylamine.2b,c,5a,8 The latter process involves a single electron transfer (SET) from an amine to an excited state photosensitizer. In the next step, the amine cation radical is transformed, via a facile deprotonation, into an α-aminoalkyl radical (I) that can react with a double bond. In this context, the oxidative addition of N,N-dimethylanilines to maleimides is particularly interesting as intermediate II can cyclize and, under oxidative conditions, yield the tetrahydroquinoline (III), a motif prevalent in many natural products and biologically active compounds.9 In the field of photoredox catalysis, the oxidative annulation reaction between N,N-dimethylanilines and maleimides to furnish tetrahydroquinolines has therefore rendered considerable attention, and the reaction has been reported with both metal-based and organic photosensitizers (Scheme 1).10 In addition to the photomediated processes, there are several reports with nonradiative conditions,11 for example, the groups of Miura and Antonchick have shown that the amine cation radicals can be generated in the presence of tert-butyl hydroperoxide (TBHP) as the oxidant and a copper(II) or tetrabutylammonium iodide (TBAI) as the catalyst, respectively.11b,c In the process of investigating a new photoredox catalyst, we observed a high degree of background reaction and that the reaction mixture changed color upon mixing two colorless reagents N,N-dimethylaniline and N-methylmaleimide (Figure 1A). These observations prompted the idea that the αaminoalkyl radical is generated via an electron donor−acceptor © XXXX American Chemical Society
(EDA) complex and that the reaction could be performed without any catalyst. An EDA complex12 is characterized by a weak absorption band or a charge-transfer band in the absorption spectrum and/ or can be seen as a color change when mixing two colorless substrates. Excitation of the EDA complex leads to electron transfer (ET) from donor to acceptor producing a charge separated state. If the electron transfer has a sufficiently long lifetime, the charge separated species can react in a variety of ways.13 In the context of α-aminoalkyl radical chemistry, a few reports exist where the α-aminoalkyl radicals have been photochemically generated in the presence of an EDA complex. For example, Melchiorre and co-workers have shown that EDA complexes drive the alkylation of both indoles and enamines.14 Furthermore, the notion that the reaction could be promoted by an EDA complex was also supported in a report by Mariano and co-workers that showed the N,N-dimethylaniline can react with unsaturated ketones in the absence of a photosensitizer.15 Received: February 19, 2018
A
DOI: 10.1021/acs.orglett.8b00597 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
the lifetime of the excited charge transfer complex compared to other polar solvents such as acetonitrile.16 The reaction could be improved further when performed without any cap on the reaction vial (Table 1, entry 5). This prompted us to investigate the role of oxygen. Indeed, the desired reaction performs poorly without the oxygen present (Table 1, entry 6), while 2 forms a polymeric product signifying the importance of an external oxidant. Performing the reactions in the presence of a black bulb (UV-light bulb, λmax at 366 nm14c) instead of the compact fluorescent lamp (CFL) light source increased the efficiency of the reaction from 55% to 60% yield (Table 1, entry 8). The absorption spectrum (Figure 1) provides an explanation to this improvement as the charge transfer band of EDA complex fits with the wavelength of the UV-light source leading to a more efficient excitation of the EDA complex at shorter wavelengths. No product was observed when no light source was applied (Table 1, entry 9). Furthermore, it was discovered that the reagent stoichiometry was important for product formation, and we could observe a steady increase in yield on 3 when increasing the 1/2 ratio (Table 1, entries 10−14). A reasonable explanation can be found when looking at the association constant KEDA of 1 and 2, which is 0.12 M−1 in 1,4-dioxane as calculated by using the Benesi−Hildebrand method17 (see Supporting Information, SI). Consequently, a higher concentration of the EDA complex, the key reaction intermediate, can be accomplished when increasing the loading of 1. Having found the optimal reaction conditions, we set out to probe the substrate scope (Scheme 2). The combination of N,N-dimethylaniline with different aliphatic substituted maleimides gives the products 3−7 and 11 in high reaction yields (83−92%). Steric hindrance introduced by N-alkyl substituents plays little role, and both methyl and t-butyl groups are well accommodated by the reaction, and the corresponding tetrahydroquinolines 3 and 6 were isolated in 87% and 85% yields, respectively. However, the reaction efficiency drops when aromatic maleimides are used as substrates, 47−66% yield (compounds 8−10). The lower reactivity for the aromatic maleimides might be due to the overlap of UV−vis absorption of N-aryl substituted maleimides and their EDA complexes (see SI for the absorption spectra), resulting in a competition of light absorption events. This problem can be solved by prolonging the reaction time from 18 to 40 h, which improved the yield from 66% to 85% (compound 8). Substituent effects on the N,N-dimethylaniline were also investigated in compounds 12−17. For instance, halogen substituents were well tolerated providing the bromo- and fluoro-substituted analogues in 69% and 85% yield (compounds 13 and 15). Substrates such as o- and p-methylaniline were also compatible with this reaction giving 12 and 16 in 89% and 61% yield, respectively. A decrease in yield was observed for the pmethoxyaniline, which provided 14 in a poor yield. Interestingly, there was a clear substituent effect when reacting N-phenylmaleimide with para-substituted anilines. The yield was significantly lower depending on the para-substituent of the N,N-dimethylaniline; p-H (8), 66%, to p-F (21), 52%, to pMe (20), 8%,18 and finally, there was no reaction when p-Br substituted aniline (26) was employed. This could be due to a steric effect, which is further supported by the fact that there was no product observed in the case of o-methyl- or mdimethyl-N,N-dimethylaniline (25 and 27). Previous studies have shown that the bulky groups on the EDA complex will decrease the electron transfer rate (kET) due to the decrease of π-overlap of donor and acceptor.19
Here, we report an EDA-mediated, catalyst-free, direct photochemically mediated synthesis of tetrahydroquinolines from alkylanilines and maleimides using molecular oxygen as the terminal oxidant. Our study commenced with investigating the mechanism behind the color change when mixing N,N-dimethylaniline (1) and N-methylmaleimide (2). The UV−vis absorption spectra of 1 and 2 were measured separately and combined (Figure 1B). Accordingly, 0.05 M solutions of compounds 1 and 2 and a mixture of the two were prepared in 1,4-dioxane and analyzed. When mixing 1 and 2, a new tailing band from 380 to 475 nm appeared (Figure 1B, inset shows deconvoluted absorbance spectrum), which is attributed to the EDA complex arising from charge transfer from 1 to 2.
Figure 1. (A) Photos of 1, 2, and 1 + 2 in 1,4-dioxane (0.05 M). (B) UV−vis absorption spectra of 1 (N,N-dimethylaniline, 0.05 M), 2 (Nmethylmaleimide, 0.05 M), and their mixture (1 + 2) in 1,4-dioxane. Insert: the charge transfer band of (1 + 2) EDA complex.
Initial optimization studies showed that the best reaction solvent was 1,4-dioxane providing the corresponding cis-fused tetrahydroquinoline 3 in 36% (Table 1, entry 3). These results correlate well with previous studies that have shown that 1,4dioxane may have a beneficial effect due to the formation of a solvent cage that can avoid the ionic dissociation and increase Table 1. Screen of the Reaction Conditionsa
entry
1 (mmol)
solvent
light source
3 yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14
0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.75 1.0 1.25 1.5 1.75
acetonitrile acetone 1,4-dioxane toluene 1,4-dioxane 1,4-dioxane acetonitrile 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane
CFL CFL CFL CFL CFL CFL blue LED UV-CFL dark UV-CFL UV-CFL UV-CFL UV-CFL UV-CFL
19c 16c 36c 14c 55d 17e 16c 60d 0f 65d 76d 81d 86d 87d
a
Three milliliters of solvent was used. bIsolated yield. cIn a sealed tube. Under ambient atmosphere. eUnder N2. fNo product observed on TLC. d
B
DOI: 10.1021/acs.orglett.8b00597 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Scheme 2. Substrate Scope of Anilines with Maleimidesa,b
Surprisingly, when we applied a more bulky group on the maleimide (N-tert-butylmaleimide), there was no significant difference between N,N-dimethylaniline (85%) and N,Ndimethyl-p-toluidine (74%) (compound 6 and 24, respectively). Thus, the phenyl substituted maleimide might be affecting the donor−acceptor structure in such a manner that the reaction becomes sensitive to aniline substituents. A quantum yield of 0.61 was obtained for this photochemical reaction (see SI for details), indicating that a radical chain reaction is not dominating the reaction mechanism.20 When illumination of the reaction mixture cycled on and off several times, product formation was only observed during the irradiation periods, and no product formation was evident when light was excluded. This is further supporting the fact that light is an essential parameter for this photochemical reaction and that any propagation step is of little importance (see SI, Figure S5). The proposed reaction mechanism (Scheme 3) Scheme 3. Proposed Reaction Mechanism
begins with the formation of an EDA complex between the aniline and maleimide. Under irradiation, a photon-induced electron transfer from aniline to maleimide occurs, followed by a proton transfer to generate the α-aminoalkyl radical (IV) and the maleimide radical (V). Radical V is quenched by oxygen. Next, radical IV attacks maleimide 2 forming VI, which rapidly cyclizes to intermediate VII. In the next step, VII is intercepted by a hydroperoxyl radical to yield the desired product 3 and hydrogen peroxide (H2O2). The formation of hydrogen peroxide was verified by adding the reaction mixture to a solution of KI/starch indicator (see SI, Figure S4). In summary, tetrahydroquinolines have been synthesized in a photochemical process that requires no catalyst. In place of a catalyst, it is the formation of an EDA complex between the N,N-dialkylaniline and the maleimide that drives this photochemical reaction. Optimization has shown that the wavelength of light source must overlap with the absorption spectrum of the EDA complex, that ambient oxygen functions as an external oxidant, and that the concentration of the EDA complex is crucial for high reaction turnovers. The transformative power of other types of EDA complexes is currently being explored in the laboratory.
a
Isolated yield. bThree milliliters of solvent was used. cReaction time 40 h. dFour equiv of 4-methoxy-N,N-dimethylaniline was used. eNo product observed on TLC. C
DOI: 10.1021/acs.orglett.8b00597 Org. Lett. XXXX, XXX, XXX−XXX
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5925. (c) Liang, Z.; Xu, S.; Tian, W.; Zhang, R. Beilstein J. Org. Chem. 2015, 11, 425−430. (d) Tang, J.; Grampp, G.; Liu, Y.; Wang, B.-X.; Tao, F.-F.; Wang, L.-J.; Liang, X.-Z.; Xiao, H.-Q.; Shen, Y.-M. J. Org. Chem. 2015, 80, 2724−2732. (e) Nicholls, T. P.; Constable, G. E.; Robertson, J. C.; Gardiner, M. G.; Bissember, A. C. ACS Catal. 2016, 6, 451−457. (f) Guo, J.-T.; Yang, D.-C.; Guan, Z.; He, Y.-H. J. Org. Chem. 2017, 82, 1888−1894. (g) Yadav, A. K.; Yadav, L. D. S. Tetrahedron Lett. 2017, 58, 552−555. (11) (a) Roy, R. B.; Swan, G. A. Chem. Commun. 1968, 1446−1447. (b) Nishino, M.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2011, 76, 6447−6451. (c) Song, Z.; Antonchick, A. P. Tetrahedron 2016, 72, 7715−7721. (d) Yadav, A. K.; Yadav, L. D. S. Tetrahedron Lett. 2016, 57, 1489−1491. (e) Sakai, N.; Matsumoto, S.; Ogiwara, Y. Tetrahedron Lett. 2016, 57, 5449−5452. (12) Foster, R. J. Phys. Chem. 1980, 84, 2135−2141. (13) For relevant reviews, see: (a) Rathore, R.; Kochi, J. K. Adv. Phys. Org. Chem. 2000, 35, 193−318. (b) Mori, T.; Inoue, Y. Chem. Soc. Rev. 2013, 42, 8122−8133. (c) Lima, C. G. S.; de M. Lima, T.; Duarte, M.; Jurberg, I. D.; Paixão, M. W. ACS Catal. 2016, 6, 1389−1407. For examples of EDA complexes in organic synthesis, see: (d) Masnovi, J. M.; Kochi, J. K. J. Org. Chem. 1985, 50, 5245−5255. (e) Miyashi, T.; Kamata, M.; Mukai, T. J. Am. Chem. Soc. 1987, 109, 2780−2788. (f) Sankararaman, S.; Haney, W. A.; Kochi, J. K. J. Am. Chem. Soc. 1987, 109, 5235−5249. (g) Sankararaman, S.; Haney, W. A.; Kochi, J. K. J. Am. Chem. Soc. 1987, 109, 7824−7838. (h) Gotoh, T.; Padias, A. B.; Hall, H. K. J. Am. Chem. Soc. 1991, 113, 1308−1312. (i) Davies, J.; Booth, S. G.; Essafi, S.; Dryfe, R. A. W.; Leonori, D. Angew. Chem., Int. Ed. 2015, 54, 14017−14021. (j) Spell, M. L.; Deveaux, K.; Bresnahan, C. G.; Bernard, B. L.; Sheffield, W.; Kumar, R.; Ragains, J. R. Angew. Chem., Int. Ed. 2016, 55, 6515−6519. (k) Cheng, Y.; Yu, S. Org. Lett. 2016, 18, 2962−2965. (l) Fawcett, A.; Pradeilles, J.; Wang, Y.; Mutsuga, T.; Myers, E. L.; Aggarwal, V. K. Science 2017, 357, 283. (m) Zhang, J.; Li, Y.; Xu, R.; Chen, Y. Angew. Chem., Int. Ed. 2017, 56, 12619−12623. (n) Marzo, L.; Wang, S.; König, B. Org. Lett. 2017, 19, 5976−5979. (14) (a) Arceo, E.; Jurberg, I. D.; Á lvarez-Fernández, A.; Melchiorre, P. Nat. Chem. 2013, 5, 750−756. (b) Arceo, E.; Bahamonde, A.; Bergonzini, G.; Melchiorre, P. Chem. Sci. 2014, 5, 2438−2442. (c) Kandukuri, S. R.; Bahamonde, A.; Chatterjee, I.; Jurberg, I. D.; Escudero-Adán, E. C.; Melchiorre, P. Angew. Chem., Int. Ed. 2015, 54, 1485−1489. (15) Zhang, X. M.; Mariano, P. S. J. Org. Chem. 1991, 56, 1655− 1660. (16) Sun, D.; Hubig, S. M.; Kochi, J. K. J. Org. Chem. 1999, 64, 2250−2258. (17) Benesi, H. A.; Hildebrand, J. H. J. Am. Chem. Soc. 1949, 71, 2703−2707. (18) The lower reactivity of 1-phenyl-1H-pyrrole-2,5-dione provides a reasonable explanation as to why this reaction is commonly performed with a photosensitizer in the literature. In several photomediated reactions between maleimides and N,N-dimethylanilines (ref 10), the optimization work has been performed with 1phenyl-1H-pyrrole-2,5-dione and 4-N,N-trimethylaniline, a combination of substrates that performs very poorly under our conditions, thus affording a low reactivity when investigating the background reaction. (19) (a) Hubig, S. M.; Rathore, R.; Kochi, J. K. J. Am. Chem. Soc. 1999, 121, 617−626. (b) Luo, P.; Dinnocenzo, J. P.; Merkel, P. B.; Young, R. H.; Farid, S. J. Org. Chem. 2012, 77, 1632−1639. (20) Another factor that may influence the quantum yield is the competition of light absorption between N-methylmaleimide and EDA complex.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00597. Photophysical measurements, synthesis procedures, and NMR characterization data (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Henrik Sundén: 0000-0001-6202-7557 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We gratefully acknowledge the Swedish Research council (VR and Formas) for funding and Carl-Tryggers foundation for providing a postdoc fellowship for C.-W.H.
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DOI: 10.1021/acs.orglett.8b00597 Org. Lett. XXXX, XXX, XXX−XXX
