Letter pubs.acs.org/OrgLett
Visible Light Promoted Synthesis of Indoles by Single Photosensitizer under Aerobic Conditions Wen-Qiang Liu,†,‡ Tao Lei,†,‡ Zi-Qi Song,†,‡ Xiu-Long Yang,†,‡ Cheng-Juan Wu,†,‡ Xin Jiang,†,‡ Bin Chen,†,‡ Chen-Ho Tung,†,‡ and Li-Zhu Wu*,†,‡ †
Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, The Chinese Academy of Sciences, Beijing 100190, P. R. China ‡ University of Chinese Academy of Sciences, Beijing 100049, P. R. China S Supporting Information *
ABSTRACT: The construction of substituted indole skeletons is always an important concern of synthetic chemists because of its prevalent structure found in natural products and biological molecules. Here, we succeeded in preparing indoles and their derivatives from a wide variety of simple enamines via radical cyclization only with catalytic amounts of an iridium(III) photosensitizer (PS) in DMSO solution under air atmosphere. The mechanistic investigation suggests that the reaction involves a radical course to accomplish the conversion of enamines to indoles under visible light irradiation.
I
Taking advantage of visible light as a renewable energy source, photoredox catalysis has recently made significant progress in organic synthesis.9 Rueping and our group combined a photosensitizer with metal palladium10 or cobalt catalysts11 to achieve a range of indoles synthesis (Scheme 1b). In contrast to the previous work, we report herein a new strategy for the synthesis of indoles, which relies on a single photosensitizer in DMSO to afford multisubstituted indoles via radical cyclization of enamines in air without adding any metal catalysts and bases (Scheme 1). We started our investigations with the easily prepared N-aryl enamine 1a as the substrate. When dissolving the mixture of facIr(ppy)3 (tris(2-phenylpyridine)iridium(III)) and enamine substrate in DMSO under blue LEDs irradiation for 5 h at room temperature in air, the desired indole compound was obtained in a yield of 81% monitored by 1H NMR analysis (Table 1, entry 1). In order to improve the reaction efficiency, we studied the effect of reaction temperature, photosensitizers, and solvents and achieved an excellent yield of 99% at the reaction temperature of 75 °C (Table 1, entry 2). Among a series of common photosensitizers, fac-Ir(ppy)3 had the best catalytic efficiency (Table 1, entries 3−7), and the amount of photosensitizer showed no much effect on the yields (Table 1, entries 8−9). The most striking observation is that DMSO is the best solvent among the tested solvents like DMF, MeCN, MeOH, and ClCH2CH2Cl (Table 1, entries 10−13), even at higher concentration (Table 1, entry 14). Control experiments confirmed that the photosensitizer and visible light were essential to the reaction (Table 1, entries 15−16) and that the presence of air greatly enhanced the yield of 16% under inert argon to 99% (Table 1, entry 17). Under the optimized conditions, i.e.,
ndoles are an important kind of heterocyclic compounds, which widely exist in pharmaceuticals, agrochemicals, natural products, and materials science.1 The traditional indole synthesis is mainly based on annulation reactions of anilines with alkynes,2 cyclization reactions of o-alkynylanilines,3 or vinylanilines,4 cyclization reactions via C−N bond formation,5 and so on.6 However, most of these approaches suffer from the lack of starting material availability and functional group tolerance. In 2008, Glorius7 and co-workers were the first to disclose a direct oxidative synthesis of indoles, employing N-aryl enamines as the starting materials with the help of Pd(OAc)2 as the catalyst (Scheme 1a). The availability of raw materials and the tolerance Scheme 1. Representative Synthesis of Indoles via Intramolecular Cyclization of Enamines
of functional groups make the reaction better.8 Nonetheless, the use of stoichiometric amounts of metal salts as the oxidants leads to undesirable byproducts and residual metals. Developing green and sustainable reaction systems is essential for indole synthesis in chemistry and pharmaceuticals. © 2017 American Chemical Society
Received: May 7, 2017 Published: May 26, 2017 3251
DOI: 10.1021/acs.orglett.7b01367 Org. Lett. 2017, 19, 3251−3254
Letter
Organic Letters Table 1. Optimization of the Reaction Conditionsa
Scheme 2. Substrates of Enaminesa,b
entry
PS
solvent
yield (%)b
c
fac-Ir(ppy)3 fac-Ir(ppy)3 Ir(ppy)2(dtbpy)PF6 (Ir[dF(CF3)ppy]2(dtbpy))PF6 Ru(bpy)3Cl2 Ru(bpy)3(PF6)2 Acr+-Mes·ClO4− fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 − fac-Ir(ppy)3 fac-Ir(ppy)3
DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMF MeCN MeOH DCE DMSO DMSO DMSO DMSO
81 >99 23 68 17 15 0 >99 >99 0 0 0 0 66 0 0 16
1 2 3 4 5 6 7 8d 9e 10 11 12 13 14f 15 16g 17h
a Reaction conditions (unless otherwise specified): a mixture of 1a (0.1 mmol) and photosensitizer (2 mol %) in solvent (2 mL) irradiated with 3 W blue LEDs for 5 h at 75 °C in air. bYields detected by 1H NMR. cAt room temperature. d1 mol % of fac-Ir(ppy)3. e3 mol % of fac-Ir(ppy)3. f1 mL of DMSO. gIn the absence of light. hIn argon. a
Reaction conditions: a mixture of 1 (0.1 mmol) and fac-Ir(ppy)3 (1 mol %) in DMSO (2 mL) irradiated with 3 W blue LEDs for 5 h at 75 °C in air. bIsolated yields. cScale up to 1.0 mmol for 6 h.
enamine 1 (0.1 mmol) with 1 mol % fac-Ir(ppy)3 in DMSO (2 mL), irradiated by blue LEDs for 5 h at 75 °C in air (Table 1, entry 8), the reaction proceeded efficiently. With the optimized conditions in hand, we attempted to explore the scope of the reaction (Table 1, 8). Most of the N-aryl enamines bearing electron-donating or electron-withdrawing groups could afford their corresponding indoles in high yields under optimized conditions. Incorporation of electron-donating (−OMe, −SMe) groups of N-aryl enamine was tolerated affording the products in high yields (2b−2c, 89−99%). Trimethoxy-substituted N-aryl enamine could also give the indole in a yield of 78% (2d). It was noteworthy that highly reactive hydroxyl substituted N-aryl enamine produced the product in 69% yield (2e). Substrate with naphthyl group afforded the desired product in a moderate 58% yield (2f). When replacing ethoxycarbonyl to butoxycarbonyl (2g), we achieved an excellent yield of 86%. As shown in Scheme 2, the N-aryl enamines with a strong electron-withdrawing trifluoromethyl group and cyano-group could yield the indoles in 78% and 82% yield, respectively (2h−2i). The N-aryl enamines with an estergroup and acetyl group could successfully produce the indoles in 89−97% yields (2j−2k). The N-aryl enamines with −F, −Cl, and −Br enabled to have their indoles up to 85% yield (2l−2n), which would be conducive to further modification of indoles. Despite the steric hindrance of the substituents, methylmonosubstituted enamines could produce their corresponding indoles in high yields. N-Aryl enamines bearing the methyl group at the ortho (2o)-, para (2p)-, and meta-position (2q and 2q′) afforded the indoles in a yield of 95%, 88%, and 96%, respectively. In addition, meta-methyl-substituted N-aryl enamine 1q gave two regioisomers (2q and 2q′) at the ratio of 2.6:1. In the case of Naryl enamine with two meta-methyl-substituents, the indole product was obtained (2r) only in 71% yield. With the large steric
hindrance tert-butyl at the para-position of N-aryl enamine, 93% yield could be achieved (2s). Moreover, a good yield of 78% was obtained when the template reaction scaled up to 1.0 mmol under the irradiation of blue LEDs for 6 h. Next, we examined the ethyl benzoylacetate moiety with different substituents of the N-aryl enamines (Scheme 3). The Naryl enamine containing methoxy group gave the desired indole in 68% yield (2t), and the N-aryl enamines with electronwithdrawing groups such as −F and −Cl also performed well with good yields (2u−2v, 83−85%). However, the enamine bearing a strong electron-withdrawing group of −NO2 did not Scheme 3. Substrates of Enaminesa,b
a Reaction conditions: a mixture of 1 (0.1 mmol) and fac-Ir(ppy)3 (1 mol %) in DMSO (2 mL) irradiated with 3 W blue LEDs for 5 h at 75 °C in air. bIsolated yields.
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DOI: 10.1021/acs.orglett.7b01367 Org. Lett. 2017, 19, 3251−3254
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Organic Letters
dioxetane intermediate, which subsequently decomposes into two carbonyl fragments.14 This is consistent with the fact that substrate 1a decomposed completely after 5 h of irradiation in DMF, MeOH, MeCN, and ClCH2CH2Cl. In DMSO when the typical 1O2 photosensitizer Eosin Y or Rose Bengal was used, no desired indole 2 could be detected, but the above reaction proceeded smoothly in the presence of a strong physical quencher of 1O2, 1,4-diazabicyclo[2.2.2]-octane (DABCO) (Scheme 4).15 All of the results clearly demonstrate that 1O2 was not involved in the formation of indoles, and the real active oxygen species is the superoxide radical anion (O2•−) in DMSO.
produce any desired product due to substrate decomposition detected by TLC (2w). In addition, we examined the reactivity of N-methyl substituted enamine 2x and obtained its corresponding indole in a yield of 70% under the template reaction conditions. This result suggested that the presence of the N−H bond is not imperative for the synthesis of indoles from enamines under this reaction condition. To understand the reaction process of the system, we carefully designed a number of control experiments and found that when DMF, MeOH, MeCN, or ClCH2CH2Cl was the solvent under standard reaction conditions, enamine substrate 1a decomposed completely after irradiation with blue LEDs for 5 h. Only with catalytic amounts of fac-Ir(ppy)3 in DMSO solution could we produce the indole skeleton from simple enamines under air atmosphere, indicating that DMSO might serve as the oxidant in this reaction. However, this assumption is not the case because emission of fac-Ir(ppy)3 was not quenched by DMSO (Figure S1), and the sulfur free radical was not captured by electron spin resonance (ESR) (Figure S8). Notably, the solution color changed from bright yellow to brown except for DMSO during the reaction process. To monitor the reaction in different solvents, steady-state spectroscopy was subsequently employed (Figure S2−5). With respect to the absorption spectral changes as a function of illumination time, the use of only DMSO as the reaction solvent enabled the reaction system to be stable. To clarify the role of DMSO solvent, we determined the oxidation/reduction potentials of fac-Ir(ppy)3 and substrate in different solvents. It was surprising to note that the oxidation/ reduction potentials of fac-Ir(ppy)3 and enamine substrate changed a lot in different solvents, especially in DMSO (Table S1). The oxidation potential of substrate 1a was dramatically increased to 0.90 V vs SCE. As a result, the excited fac-Ir(ppy)3* and resulting IrIV are unable to oxidize enamine 1a but react with oxygen yielding a superoxide radical anion (O2•−), which reacts with enamine 1a for the following transformation. Indeed, we could trap the superoxide radical anion (O2•−)12 (Figure 1b) and carbon radical13 (Figure 1f) signals. At the same time, the signal of singlet oxygen (1O2) was also detected (Figure S10). It is wellknown that enamines with an electron-rich double bond are easy to react with 1O2 under visible light irradiation and to yield
Scheme 4. Mechanistic Experiments
On the basis of previous work and the above results, we proposed a plausible mechanism for this transformation. As shown in Scheme 5, fac-Ir(ppy)3 is initially pumped to reach its Scheme 5. Proposed Mechanism
excited state *IrIII by visible light. The electron-transfer *IrIII to molecular oxygen (O2) leads to the formation of O2•− and IrIV. Because *IrIII and IrIV are not oxidative enough to abstract an electron from N-aryl enamine 1 in DMSO (Table S1), the generated O2•− is the most likely species in charge of oxidation of 1a to produce the radical intermediate A, with the generation of HOO−. The resulting radical intermediate A undergoes radical cyclization to afford B, which is further oxidized by IrIV and deprotonated to give the desired indole 2 with the completion of the photocatalytic cycle. The fact that the introduction of a radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) into the reaction solution resulted in no conversion of substrate 1a to indole 2a (Scheme 4) further confirmed that radicals are involved in our reaction system. No hydrogen peroxide (H2O2) was detected by in situ 1H NMR analysis after irradiation of the reaction mixture in DMSO-d6 for 5 h in air at
Figure 1. Electron spin resonance (ESR) spectrum: a solution of DMPO and fac-Ir(ppy)3 in air-saturated DMSO (a) without irradiation and (b) upon irradiation with blue LEDs for 10 s; a solution of enamine 1a, DMPO, and fac-Ir(ppy)3 in deaerated DMSO (c) without irradiation and (d) upon irradiation with blue LEDs for 30 s; a solution of enamine 1a, DMPO, and fac-Ir(ppy)3 in air-saturated DMSO (e) without irradiation and (f) upon irradiation with blue LEDs for 30 s. 3253
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room temperature (Figure S14), while the water peak (H2O) increased suggesting that the molecular oxygen was finally converted to H2O rather than H2O2. The generated H2O2 could participate in the catalytic cycle and ultimately convert to H2O as the byproduct (see details in Figure S13−15). In summary, we have developed a straightforward strategy for indole synthesis via radical intramolecular cyclization in DMSO solution under extremely mild reaction conditions, using facIr(ppy)3 as the single photosensitizer in air without any additives. Investigations of the mechanism demonstrates that the superoxide radical anion (O2•−) generated by single electron transfer from the photosensitizer to molecular oxygen is essential to initiate the cyclization of enamines. Among various solvents used in this work, DMSO is unique because it enhances the oxidation potential of enamines, thus facilitating the electron transfer process to generate O2•− and simultaneously preventing the enamines from destruction by 1O2 to keep the stability of the reaction system. Because of these attributes, various N-aryl enamines can be successfully converted to their corresponding indoles in good to excellent yields. Compared with traditional methods, our strategy is a simple, mild, green, and practical tool for the synthesis of an indole skeleton that is widely pursued in chemistry and pharmaceutical industries.
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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.7b01367. Experimental procedures, methods, and product characterizations (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Xin Jiang: 0000-0002-7836-1784 Bin Chen: 0000-0003-0437-1442 Chen-Ho Tung: 0000-0001-9999-9755 Li-Zhu Wu: 0000-0002-5561-9922 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support for this research from the Ministry of Science and Technology of China (2013CB834804, 2014CB239402, and 2013CB834505), the National Natural Science Foundation of China (21390404 and 91427303), the Strategic Priority Research Program of the Chinese Academy of Science (XDB17030400), and the Chinese Academy of Sciences is gratefully acknowledged.
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