Source: https://pubs.rsc.org/en/content/articlehtml/2019/sc/c8sc04892d
Timestamp: 2019-04-26 15:37:50+00:00

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Herein, we report a protocol for direct visible-light-mediated Minisci C–H alkylation of heteroarenes with unactivated alkyl halides using molecular oxygen as an oxidant at room temperature. This mild protocol is compatible with a wide array of sensitive functional groups and has a broad substrate scope. Notably, functionalization of (iso)quinolines, pyridines, phenanthrolines, quinazoline, and other heterocyclic compounds with unactivated primary, secondary, and tertiary alkyl halides proceeds smoothly under the standard conditions. The robustness of this protocol is further demonstrated by the late-stage functionalization of complex nitrogen-containing natural products and drugs.
Heteroaryl motifs are present in a wide variety of natural products, organic materials, small-molecule drugs, and ligands for metal catalysts.1 Substituted heteroarenes can be readily accessed by direct functionalization of the C–H bonds of unsubstituted heteroarenes.2 A useful tool for this purpose is the Minisci reaction, in which a protonated N-heteroarene is attacked by an alkyl radical under oxidative conditions.3 Classic Minisci reactions, which involve carboxylic acids as the alkyl radical sources, often require the use of excess oxidant (e.g., peroxide), excess acid, and high temperature.3,4 Recently, there have been several reports of visible-light-mediated Minisci C–H alkylation reactions of N-heteroarenes with alkyl peroxides, primary alcohols, aliphatic carboxylic acids, boronic acids, alkyltrifluoroborates, and alkyl iodides as the alkyl radical sources (Scheme 1A).5 In addition, Barriault and co-workers described a protocol for direct alkylation of heteroarenes with alkyl bromides in the presence of a gold photoredox catalyst (Scheme 1B).6 However, the protocol employs a high catalyst loading and high-energy UVA (365 nm) irradiation, which can narrow the functional group tolerance and limit the substrate scope.
Scheme 1 Photoredox-mediated Minisci C–H alkylation of N-heteroarenes.
Halogen abstraction from alkyl bromides by tris(trimethylsilyl)silyl radical for thermal generation of alkyl radicals has been widely studied, and photomediated processes have also been reported.9 However, halogen abstraction by a silyl radical under Minisci reaction conditions has not been explored. In this study, we focused our attention on developing a practical method for Minisci-type reactions using alkyl bromides as the alkyl radical sources and tris(trimethylsilyl)silane (TTMS) as the halogen-abstraction agent under photoredox conditions. Specifically, we herein report a protocol for visible-light-mediated Minisci C–H alkylation of heteroarenes with unactivated primary, secondary, and tertiary alkyl halides (Scheme 1C). The high efficiency, broad substrate scope, excellent functional group tolerance, and mildness of this protocol make it particularly suitable for late-stage functionalization of complex nitrogen-containing natural products and drugs.
As a model reaction, we investigated the alkylation of lepidine (1, 1.0 equiv.) with bromocyclohexane (2, 2.0 equiv.) under various conditions (Table 1). First, a number of silanes were screened with 1 mol% of Ir[dF(CF3)ppy]2(dtbbpy)PF6 as the photocatalyst, trifluoroacetic acid as the proton source, molecular oxygen as the oxidant, and acetone as the solvent under irradiation with a 36 W blue LED (see the ESI‡). To our delight, desired product 3 was obtained in excellent yield when TTMS was used as a silyl radical precursor (entry 1). Using the above-described conditions, we then varied the photocatalyst (entries 2–4). However, [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 proved to be the most effective catalyst. Other solvents (acetonitrile, methanol, and dimethylformamide) gave lower yields (entries 5–7). Control experiments showed that the reaction failed to proceed in the absence of light, photocatalyst, TTMS, or molecular oxygen (entries 8–11).
a General conditions, unless otherwise noted: 1 (0.2 mmol), 2 (0.4 mmol), photocatalyst (0.002 mmol), TTMS (0.4 mmol), trifluoroacetic acid (TFA, 0.4 mmol), and acetone (2 mL) under O2 atmosphere. NR = no reaction. b Isolated yields are given. c Reaction performed in the absence of light. d Reaction performed in the absence of TTMS. e Reaction performed under argon atmosphere.
With the optimized reaction conditions in hand, we studied the scope of the reaction with respect to the alkyl bromide (Table 2). The reaction was found to be amenable to a wide range of primary alkyl bromides, which gave the desired products in good to excellent yields. For example, linear alkyl bromides afforded the corresponding alkylated heteroarenes (5–7) in 45–84% yields. Minisci reactions of primary alkyl radicals are more challenging than reactions of secondary alkyl radicals, owing to the lower stability and nucleophilicity of the former.10 However, we were pleased to observe that primary alkyl substituents carrying various functional groups (e.g., a terminal alkyne, a terminal alkene, an ester, an acetal, or a phenoxy group; 8–12, respectively) could be incorporated in good yields. Phenylethyl bromide and benzyl bromide were also suitable substrates, giving 13 and 14 in 78 and 85% yields. Alkylation reactions of secondary bromoalkanes also proceeded under the standard conditions to afford the corresponding alkylated heteroarenes in moderate to excellent yields (15–20, 22–24). Notably, ether, amine, and tert-butyl carbamate groups were also tolerated. Finally, tertiary-bromoalkane-functionalized lepidine derivatives 25 and 26 could be obtained in good to excellent yields, and the protocol was amenable to scale up; 26 was isolated in 77% yield when the reaction was carried out on a 6 mmol scale.
a Reactions were performed on a 0.3 mmol scale. Isolated yields are given.
Next, we explored alkylation reactions with alkyl iodides (Table 2). Gratifyingly, we found that unactivated primary, secondary, and tertiary iodoalkanes underwent the desired reaction, and the corresponding products were obtained in moderate to good yields. Although in each case the yield was lower than that obtained with the corresponding alkyl bromide, the ability to use alkyl iodides broadens the scope of the reaction with respect and would be helpful when the alkyl bromide is not available. Unfortunately, unactivated primary, secondary, and tertiary alkyl chlorides showed no reactivity.
Finally, we tested this new alkylation protocol with various N-heteroarenes (Table 3). Electron-deficient heteroarenes were readily alkylated at the most electrophilic position with bromocyclohexane (2) in fair to excellent yields. Specifically, quinoline was selectively alkylated with 2 at the C2 position to afford 27 in 45% yield. The use of 4-chloro- and 4-bromo-quinoline and 2-methyl-quinoline resulted in selective alkylation with 2 at C2 for the halogenated substrates and at C4 for the methylated substrate (28–30, 41–84% yields). Reactions of 2 with 4-methoxycarbonyl-substituted isoquinolines afforded products of selective α-aminoalkylation at C2 position (31, 81% yield). Alkylation of 2,6-dimethylpyridine afforded a fair yield (50%) of C4-functionalized product 32. When nicotinonitrile was used, dialkylated product 33 (40%) was the major product. The scope of the reaction was further extended to phthalazine (34, 46%), 2-chloroquinazoline (35, 56%), 6-chloroimidazo[1,2-b]pyridazine (36, 48%), and benzothiazole (37, 44%). Notably, the reaction could be used to modify commercially available phenanthroline ligands, as demonstrated by the selective monoalkylation with 2 at the C2 position to afford fair to good yields of 38–40. The selective monoalkylation of these phenanthroline ligands suggests that this protocol may find applications in the synthesis of ligands for catalysis.
a Reactions were performed on a 0.3 mmol scale. Isolated yields are given. b Steride (0.2 mmol) and lepidine (0.4 mmol) were used.
Having explored the substrate scope and utility of the reaction, we turned our attention to the mechanism (Scheme 2). When a radical scavenger, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or 1,1-diphenylethylene, was present in a reaction mixture containing 1 and 2, the formation of 3 was completely inhibited. When benzyl acrylate (48) was used as a radical scavenger, benzyl 3-(1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilan-2-yl)propanoate (49) was isolated in 5% yield, which suggests that a silyl radical was generated.9f In addition, the product of cyclohexyl radical trapping, benzyl 3-cyclohexylpropanoate (50), was observed by mass spectrometry.9f To lend additional support to our proposed mechanism, we carried out a radical clock experiment.6,13 Alkylation of 1 with 6-bromohex-1-ene (51) resulted in 5-exo trig cyclization prior to heteroarene addition and afforded a 14 : 1 mixture of 52a and 52b. Alkylation of 1 with (bromomethyl)cyclopropane (53) under the standard conditions gave ring-opened product 54 in 45% yield. (Bromomethyl)cyclobutane 55 remained mostly unopened, affording 56a and 56b in a 14 : 1 ratio. These experiments clearly point to a radical pathway. Moreover, we conducted a light/dark experiment, which showed that coupling product 3 formed only under continuous irradiation (see ESI‡). This result suggests that radical chain propagation was not involved in the reaction.
Scheme 3 Proposed mechanism for direct C–H alkylation of heteroarenes.
In conclusion, we have achieved visible-light-mediated Minisci C–H alkylation of heteroarenes by using readily available, inexpensive alkyl halides as the alkyl radical sources. A broad range of cyclic and acyclic unactivated primary, secondary, and tertiary alkyl groups can be efficiently incorporated into N-heteroarenes under mild conditions, and the protocol is scalable to the gram level. Its high efficiency, broad substrate scope, excellent functional group tolerance, and mild operation conditions make it particularly suitable for late-stage functionalization of complex nitrogen-containing natural products and drugs.
We are grateful to the National Natural Science Foundation of China (21732002, 21672117) and the Tianjin Natural Science Foundation (16JCZDJC32400) for generous financial support for our programs.
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† Dedicated to the 100th anniversary of Nankai University.

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