Manganese(I)-Catalyzed Direct C–H Allylation of Arenes with Allenes

and Biomimetic Drugs, Peking University, Beijing, 100191, China. J. Org. Chem. , 2017, 82 (20), pp 11173–11181. DOI: 10.1021/acs.joc.7b02220. Pu...
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Manganese(I)-Catalyzed Direct C−H Allylation of Arenes with Allenes Shi-Yong Chen,† Qingjiang Li,*,†,‡ and Honggen Wang*,† †

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China

‡

S Supporting Information *

ABSTRACT: Polysubstituted allyl groups, for example, the prenyl group, are valuable synthetic handles and widely encountered in bioactive compounds. Reported herein is a manganese(I)-catalyzed direct C−H coupling with allenes for the efficient assembly of allylated arenes. The protocol offers an extremely high level of atom-economy and is particularly suited for the introduction of 1,1-disubstitiuted allyl groups, as exemplified by the quantitative syntheses of a variety of prenylated indoles. The practicality of this method was evidenced by a gram-scale synthesis with a lower catalyst loading of manganese(I) (2.5 mol %, 95% yield). Experimental mechanistic studies were conducted, and a possible reaction mechanism was proposed.

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INTRODUCTION The introduction of an allyl group into a molecule is of significant interest due to its ample synthetic utilities1 and widespread occurrence in bioactive compounds. For instance, the prenyl motif is present as a key pharmacophore element in numerous bioactive natural products, particularly in indole alkaloids.2 Synthetically, the assembly of prenylarenes has been fulfilled by Lewis acid-catalyzed or mediated Friedel−Craftstype prenylation of electron-rich arenes,2b,3 transition-metalcatalyzed cross-coupling reactions of prefunctionalized arenes,4 and Claisen rearrangement of allyl ethers.5 With the ongoing pursuit of allylation reactions in our group,6 we recently disclosed a synthesis of prenylated heteroarenes through a cascade Minisci reaction and acid-promoted dehydration sequence.7 Though elegant, the application of the above methods may suffer from drawbacks such as low atomeconomy, harsh reaction conditions, the use of noble-metal catalyst, poor regioselectivity, potential olefinic isomerization, and/or tedious preparation of the starting materials. Therefore, the development of new prenylation methodology is still highly desirable. Recently, the transition-metal-catalyzed C−H bond activation reaction8 has provided straightforward and atomeconomical9 strategies for the introduction of allyl groups.10 Nevertheless, examples for the introduction of the 1,1disubstitiuted allyl group, for instance, the prenyl group, are still limited. The coupling reaction with the corresponding electrophilic allyl halide and allyl alcohol or its derivatives has been shown to be effective for such a reaction, but generally high catalyst loadings, harsh reaction conditions, and moderate reaction efficiency were found (Scheme 1a).11 The use of 1,1disubstituted allenes as a coupling partner provided a more efficient alternative for their assemblies, wherein noble metal catalysts such as IrI, PdII, AuI, and RhIII were commonly used (Scheme 1b).12 © 2017 American Chemical Society

Scheme 1. Transition-Metal-Catalyzed C−H Prenylation

From the viewpoint of sustainable (green) chemistry,13 the use of inexpensive metals in lieu of noble metals in catalysis is advantageous not only because of their cost-efficiency but also because of their potential unique reactivities. In this regard, Mn has been recently recognized as an efficient catalyst for a number of C−H activation reactions on the basis of seminal works from the groups of Kuninobu and Takai,14 Wang,15 and Ackermann11c,16 among others.17 Very recently, Ackermann and co-workers disclosed an elegant Mn(I)-catalyzed C−H allylation by using allyl carbonates as a coupling partner.11c Received: September 7, 2017 Published: September 26, 2017 11173

DOI: 10.1021/acs.joc.7b02220 J. Org. Chem. 2017, 82, 11173−11181

Article

The Journal of Organic Chemistry

3fa), and ether (3da, 3ia, 3ma) highlighted the versatility of the transformation. The 7-chlorinated indole gave relatively lower yield due to incomplete conversion, presumably for steric reasons (3oa). In contrast, however, a methyl substituted at the C3 position did not hamper the reactivity (3pa). In addition to 2-pyrimidinyl, 2-pyridyl was also an effective directing group for this reaction, giving the corresponding product in almost quantitative yield (3qa, 99%). The manganese(I)-catalyzed prenylation reaction was not limited to indoles; N-pyrimidylpyrrole was amenable for prenylation, giving a diprenylated product in 73% yield (3ra). Interestingly, when an estersubstituted pyrrole was used, only the monoprenylated product, favoring the reaction at the sterically more congested position, was found, indicating a secondary directing effect (3sa).18 Furthermore, with the aid of a pyridine or pyrimidine directing group, isoquinolin-1(2H)-one (3ta), pyridin-2(1H)-one (3ua), thiophene (3va), benzothiophene (3wa), benzofuran (3xa), dibenzothiophene (3ya), and 1H-benzo[d]imidazole (3za) were prenylated in moderate to high yields. The functionalization of 2-arylpyrimidines (3aaa, 3aba) or 2-arylpyridine (3aca) was also realizable. It is noted that there is a slight influence for the mono- and diprenylation selectivity of 3aaa and 3aba by using different equivalents of 2a (see Supporting Information). In addition, tryptamine- and tropisetron-derived substrates were subjected to the reaction, which furnished the corresponding analogues 3ada and 3aea in 90% and 76% yields, respectively. With the C−H prenylation with 1,1-dimethylallene extablished, we set to explore the applicability of other allenes (Scheme 3). As expected, 1,1-dialkyl substituted allenes proved to be efficient participants for the transformation (3ab, 3ac). When 1-methyl-1-phenylallene was applied, a mixture of stereoisomers (Z:E = 3:1) were isolated (3ad). With monosubstituted allenes, the desired allylation products were observable, along with significant amount of regioisomer(s) derived from unselective migratory insertion (3ae and 3af). Disappointedly, the use of tri- (2g, 2h) or tetrasubstituted (2i, 2j) allenes completely shut down the reaction, probably due to the steric hindrance of allenes. The practicality of this method was evidenced by a gramscale synthesis with a low catalyst loading of 2.5 mol %. Still, very high efficiency was observed, with an excellent yield of 95% obtained and no column chromatography purification of the product needed (eq 1).

Unfortunately, in their studies, only two examples of prenylation reaction were demonstrated in moderate efficiency with catalyst loading as high as 20 mol %. We have recently disclosed that Mn(I) is an effective catalyst for the alkenylation of indoles17e and allylation of ketimines17f with allenes. To further extend the substrates scope, we report herein our realization of a Mn(I)-catalyzed direct C−H allylation with allenes. The protocol is well suited for the introduction of 1,1disubstituted allyl groups, as exemplified by the quantitative syntheses of a variety of prenylated indoles wherein 100% atom-economy, high yields, and excellent functional group tolerance were observed (Scheme 1c).

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RESULTS AND DISCUSSION We initiated our studies by reacting N-pyrimidylindole 1a with commercially available 1,1-dimethylallene 2a (1.5 equiv) under the reaction conditions of [Mn2(CO)10] (10 mol %), NaOAc (40 mol %), 1,4-dioxane, 120 °C, 24 h (Table 1, entry 1). Table 1. Optimization of Mn(I)-Catalyzed C−H Prenylation Conditionsa entry

[Mn] (x mol %)

solvent

temp (°C)

yield (%)b

1 2 3 4 5 6 7 8 9 10 11

[Mn2(CO)10] (10) [Mn2(CO)10] (10) [Mn2(CO)10] (10) [Mn2(CO)10] (10) [Mn2(CO)10] (10) [MnBr(CO)5] (20) [MnBr(CO)5] (10) − [MnBr(CO)5] (10) [MnBr(CO)5] (10) [MnBr(CO)5] (10)

dioxane toluene MeOH DCE DMF dioxane dioxane dioxane dioxane dioxane dioxane

120 120 120 120 120 120 100 100 100 100 100

59 50 48 59 trace 98 98 0 56c 87d 98e

a

Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2a (0.3 mmol, 1.5 equiv), [Mn] (x mol %), NaOAc (40 mol %), solvent (1.0 mL), N2, 24 h. bIsolated yield. cNo NaOAc added. d2a (1.0 equiv) was employed. e 2a (2.5 equiv) was employed.

Gratifyingly, the desired C2-prenylated indole 3aa was formed in 59% isolated yield. Further screening demonstrated that, in addition to 1,4-dioxane, solvents such as toluene, MeOH, and DCE were also effective (entries 2−5). Interestingly, the simple switching of the catalyst from [Mn2(CO)10] to [MnBr(CO)5] led to almost quantitative isolation of the product (98% yield, entry 6). Of note, the same yield was maintained while lowering both the catalyst loading (to 10 mol %, entry 7) and temperature (to 100 °C, entry 7). Control experiments showed that both the catalyst and the additive NaOAc were important for this transformation. The omission of catalyst resulted in no formation of the desired product (entry 8), whereas the exclusion of NaOAc led to significantly lower yield (entry 9). In addition, the use of 1.0 equiv of 2a gave slightly lower yield. (entries 7, 10, 11). Then, the scope of this transformation was investigated. First, the generality of Mn(I)-catalyzed prenylation of indoles was examined. As shown in Scheme 2, a variety of diversely substituted indoles bearing both electron-withdrawing and electron-donating substituents at different positions underwent reaction smoothly, giving the corresponding products in generally excellent to quantitative yields. The survival of commonly encountered functional groups such as ester (3ca, 3la), cyano (3ea), formyl (3na), halide (3ba, 3fa, 3ga, 3ha, 3ja,

To elucidate the mechanism of the transformation, several experiments were conducted (Scheme 4). First, an intermolecular kinetic isotope effect studies revealed a small kH/kD value of 1.1, indicating that the C−H bond cleavage is not involved in the turnover-limiting process (Scheme 4a). Second, H/D scrambling experiments demonstrated that the C−H metalation step is reversible, and the proton of the newly formed olefinic C−H bond should come from the solvent or the in situ-generated conjugated acid HOAc (Scheme 4b). In addition, by using a literature procedure, we were able to prepare the cyclometalated complex 4 by reacting 1q with 11174

DOI: 10.1021/acs.joc.7b02220 J. Org. Chem. 2017, 82, 11173−11181

Article

The Journal of Organic Chemistry Scheme 2. Mn(I)-Catalyzed Direct C−H Prenylationa,b,c

a

With [MnBr(CO)5] (20 mol %), 2a (2.5 equiv), 40 h. bMono:di ratio. cWith [Mn2(CO)10] (10 mol %) in TFE, 120 °C, 24 h.

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stoichiometric amount of manganese.11c,16a In both stoichiometric and catalytic reaction, complex 4 showed good reactivity, indicating it might be a catalytic intermediate in the C−H prenylation reaction (Scheme 4c and 4d). Finally, an intermolecular competition experiment between differently substituted indoles 1d and 1f concluded that electron-rich indole reacted preferentially (Scheme 4e). Based on the above results and literature precedents,15−17,19 a plausible mechanism was proposed (Scheme 5). Initially, a pyrimidine-assisted C−H activation of 1a takes place to yield intermediate B and HOAc. This process is not turnoverlimiting and is reversible, and it presumably follows a baseassisted deprotonation mechanism20 or an σ-CAM mechanism.21 Thereafter, allene coordination and migratory insertion of the terminal double bond provides D. The protonation of the resulting C−Mn bond with HOAc and release of manganese catalyst then delivers the prenylation product 3aa.

CONCLUSIONS In summary, by using allenes as a coupling partner, the Mn(I)catalyzed C−H activation/functionalization allowed the efficient assembly of allyl arenes in an atom- and stepeconomical manner. The prenyl group and other densely substituted allyl groups could be introduced in good to excellent efficiency. The practicality of the protocol was evidenced by a gram-scale synthesis with a lower catalyst loading of manganese(I) (2.5 mol %, 95% yield). Preliminary mechanistic studies have been conducted and a plausible mechanism was proposed accordingly. Given the prevalence of the prenyl motif in bioactive natural products and medicinal chemistry, we anticipate that this protocol will find applications.

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EXPERIMENTAL SECTION

General Experimental Methods. The solvents used were dried by distillation over the drying agents indicated in parentheses and were transferred under argon: toluene (Na-benzophenone), diethyl ether (Na-benzophenone), and tetrahydrofuran (Na-benzophenone). Anhydrous 1,4-dioxane was purchased from Energy-chemical and stored 11175

DOI: 10.1021/acs.joc.7b02220 J. Org. Chem. 2017, 82, 11173−11181

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The Journal of Organic Chemistry Scheme 3. Mn(I)-Catalyzed Direct C−H Allylation of Indole with Allenesa,b

a

With [Mn2(CO)10] (10 mol %) in TFE, 100 °C, 24 h. bZ:E ratio.

under argon. Commercially available chemicals were obtained from commercial suppliers and used without further purification unless otherwise stated. Proton (1H), fluorine (19F), and carbon (13C) NMR spectra were recorded at 400, 376, and 101 MHz, respectively. The following abbreviations are used for the multiplicities: s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, br s: broad singlet for proton spectra. Coupling constants (J) are reported in hertz (Hz). High-resolution mass spectra (HRMS) were recorded on a Bruker VPEXII spectrometer with EI and ESI modes unless otherwise stated, and the mass analysis mode of HRMS was TOF. Analytical thin layer chromatography was performed on Polygram SIL G/UV254 plates. Visualization was accomplished with short-wave UV light, or KMnO4 staining solutions followed by heating. Flash column chromatography was performed using silica gel (200−300 mesh) with solvents distilled prior to use. The substrates 1 (1-(pyrimidin-2-yl)-1H-indoles, 2-arylpyridines, and 2-arylpyrimidines) were prepared according to the procedure reported by Wang22a,b or purchased from commercial suppliers. The substrates isoquinolin-1(2H)-one 1t and pyridin-2(1H)-one 1u were prepared according to the procedure reported by Miura and Hirano.22c The allenes 2c,22d 2d,22d 2e22e and 2f22d were prepared according to the literature procedures. Spectral data for the prepared substrates 1 and 2 showed good agreement with the literature data, and no attempts were made to optimize yields for substrate synthesis. Analytical Characterization Data of Substrate 1ae. (1R,3R,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 1-(Pyrimidin-2yl)-1H-indole- 3-carboxylate (1ae). Following the reported procedure,22a the product 1ae was obtained in 45% yield (1.63 g) as a colorless solid after column chromatography (DCM/MeOH = 8/1; DCM/ MeOH = 6/1, RF ≈ 0.3). 1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 8.83 (d, J = 8.0 Hz, 1H), 8.78 (d, J = 4.8 Hz, 2H), 8.30 (d, J = 7.5 Hz, 1H), 7.39 (p, J = 7.1 Hz, 2H), 7.18 (t, J = 4.9 Hz, 1H), 5.30 (t, J = 5.5 Hz, 1H), 3.19 (s, 2H), 2.34 (s, 3H), 2.26 (dd, J = 12.0, 7.7 Hz, 2H), 2.21−2.04 (m, 4H), 1.94 (d, J = 15.0 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 163.9, 158.5, 157.3, 135.9, 131.7, 128.6, 124.8, 123. 8, 121.4, 117. 7, 116. 5, 112.0, 66.7, 60.4, 40.1, 36.2, 25.8. HRMS (ESI-TOF): m/z calculated for C21H23N4O2 [M + H]+: 363.1816, found: 363.1817. General Procedure for Manganese-Catalyzed C−H Allylation of Arenes. Arenes 1 (0.2 mmol), NaOAc (6.6 mg, 40 mol %),

MnBr(CO)5 (5.5 mg, 10 mol %), 1,4-dioxane (1.0 mL), and allenes 2 (0.3 mmol, 1.5 equiv) were added to a 15 mL Schlenk tube under N2. The mixture was stirred at 100 °C for 24 h. After being cooled to ambient temperature, the reaction mixture was diluted with EtOAc (10 mL) and H2O (5 mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford the desired products 3. Analytical Characterization Data of Products. 2-(3-Methylbut2-en-1-yl)-1-(pyrimidin-2-yl)-1H-indole (3aa).11a Following the general procedure, the product 3aa was obtained in 98% yield (51.6 mg) as a colorless oil after column chromatography (PE/EA = 40/1; PE/ EA = 32/1, RF ≈ 0.3). 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 4.8 Hz, 2H), 8.23 (d, J = 8.0 Hz, 1H), 7.55−7.50 (m, 1H), 7.24−7.11 (m, 3H), 6.46 (s, 1H), 5.38−5.25 (m, 1H), 3.87 (d, J = 7.1 Hz, 2H), 1.72 (s, 3H), 1.69 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 158.4, 158.2, 141.3, 137.3, 133.6, 129.5, 122.5, 121.8, 119.8, 117.1, 113.8, 105.9, 28.8, 25.8, 18.0. 5-Bromo-2-(3-methylbut-2-en-1-yl)-1-(pyrimidin-2-yl)-1H-indole (3ba). Following the general procedure, the product 3ba was obtained in 91% yield (62.1 mg) as a yellow oil after column chromatography (PE/EA = 32/1; PE/EA = 20/1, RF ≈ 0.3). 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 4.8 Hz, 2H), 8.11 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 1.9 Hz, 1H), 7.28 (dd, J = 9.3, 2.4 Hz, 1H), 7.17 (t, J = 4.8 Hz, 1H), 6.36 (d, J = 17.3 Hz, 1H), 5.47−5.14 (m, 1H), 3.86 (d, J = 7.1 Hz, 2H), 1.72 (s, 3H), 1.67 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 157.3, 157.2, 141.8, 134.9, 133.1, 130.2, 124.2, 121.3, 119.8, 116.4, 114.4, 114.0, 104.2, 27.9, 24.8, 17.0. HRMS (ESI-TOF): m/z calculated for C17H17N3Br [M + H]+: 342.0600, found: 342.0611. Methyl 2-(3-Methylbut-2-en-1-yl)-1-(pyrimidin-2-yl)-1H-indole-5carboxylate (3ca). Following the general procedure, the product 3ca was obtained in 98% yield (62.9 mg) as a yellow oil after column chromatography (PE/EA = 32/1; PE/EA = 16/1, RF ≈ 0.3). 1H NMR (400 MHz, CDCl3) δ 8.88−8.87 (m, 1H), 8.84 (d, J = 4.8 Hz, 2H), 7.87 (dd, J = 8.2, 1.5 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.20 (t, J = 4.8 Hz, 1H), 6.50 (d, J = 0.9 Hz, 1H), 5.36−5.27 (m, 1H), 3.92 (s, 3H), 3.88 (d, J = 7.1 Hz, 2H), 1.72 (d, J = 1.0 Hz, 3H), 1.68 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 168.4, 158.5, 158.0, 145.0, 136.6, 134.3, 11176

DOI: 10.1021/acs.joc.7b02220 J. Org. Chem. 2017, 82, 11173−11181

Article

The Journal of Organic Chemistry Scheme 4. Mechanistic Studies

2-(3-Methylbut-2-en-1-yl)-1-(pyrimidin-2-yl)-1H-indole-5-carbonitrile (3ea). Following the general procedure, the product 3ea was obtained in 98% yield (56.5 mg) as a yellow oil after column chromatography (PE/EA = 50/1; PE/EA = 32/1, RF ≈ 0.3). 1H NMR (400 MHz, CDCl3) δ 8.86 (d, J = 4.8 Hz, 2H), 8.26 (dt, J = 8.7, 0.7 Hz, 1H), 7.86 (dd, J = 1.6, 0.6 Hz, 1H), 7.46 (dd, J = 8.7, 1.7 Hz, 1H), 7.29−7.27 (m, 1H), 6.53 (d, J = 0.8 Hz, 1H), 5.32 (dddd, J = 8.6, 5.7, 2.8, 1.4 Hz, 1H), 3.88 (d, J = 7.1 Hz, 2H), 1.75 (d, J = 1.0 Hz, 3H), 1.70 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 158.5, 157.9, 144.1, 139.0, 134.6, 129.3, 125.7, 124.8, 120.6, 120.3, 118.2, 114.5, 105.6, 104.9, 28.7, 25.8, 18.0. HRMS (ESI-TOF): m/z calculated for C18H17N4 [M + H]+: 289.1448, found: 289.1457. 5-Fluoro-2-(3-methylbut-2-en-1-yl)-1-(pyrimidin-2-yl)-1H-indole (3fa). Following the general procedure, the product 3fa was obtained in 90% yield (50.6 mg) as a colorless oil after column chromatography (PE/EA = 64/1; PE/EA = 64/1, RF ≈ 0.2). 1H NMR (400 MHz,

133.3, 124.1, 123.1, 120.5, 119.4, 117.7, 115.8, 105.8, 52.1, 28.8, 25.8, 18.1. HRMS (ESI-TOF): m/z calculated for C19H20N3O2 [M + H]+: 322.1550, found: 322.1556. 5-Methoxy-2-(3-methylbut-2-en-1-yl)-1-(pyrimidin-2-yl)-1H-indole (3da). Following the general procedure, the product 3da was obtained in 97% yield (56.8 mg) as a colorless oil after column chromatography (PE/EA = 64/1; PE/EA = 64/1, RF ≈ 0.3). 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J = 4.8 Hz, 2H), 8.20 (d, J = 9.0 Hz, 1H), 7.09 (t, J = 4.8 Hz, 1H), 7.00 (d, J = 2.5 Hz, 1H), 6.90−6.76 (m, 1H), 6.39 (d, J = 0.8 Hz, 1H), 5.38−5.27 (m, 1H), 3.88 (d, J = 7.0 Hz, 2H), 3.86 (s, 3H), 1.72 (d, J = 1.0 Hz, 3H), 1.69 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 158.5, 158.1, 155.6, 142.2, 133.6, 132.2, 130.3, 121.3, 116.8, 115.0, 111.4, 106.1, 102.5, 55.9, 29.2, 25.8, 18.0. HRMS (ESI-TOF): m/z calculated for C18H20N3O [M + H] +: 294.1601, found: 294.1609. 11177

DOI: 10.1021/acs.joc.7b02220 J. Org. Chem. 2017, 82, 11173−11181

Article

The Journal of Organic Chemistry

1.68 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 158.3, 158.1, 142.2, 137.5, 134.0, 128.3, 128.0, 122.3, 120.8, 120.4, 117.4, 114.1, 105.7, 28.9, 25.8, 18.0. HRMS (ESI-TOF): m/z calculated for C17H17N3Cl [M + H]+: 298.1106, found: 298.1117. 4-Methyl-2-(3-methylbut-2-en-1-yl)-1-(pyrimidin-2-yl)-1H-indole (3ka). Following the general procedure, the product 3ka was obtained in 96% yield (53.2 mg) as a yellow oil after column chromatography (PE/EA = 64/1; PE/EA = 32/1, RF ≈ 0.4). 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 4.8 Hz, 2H), 8.04 (d, J = 8.3 Hz, 1H), 7.11 (dt, J = 14.2, 5.8 Hz, 2H), 7.04−6.93 (m, 1H), 6.47 (s, 1H), 5.32 (q, J = 7.2 Hz, 1H), 3.88 (d, J = 7.1 Hz, 2H), 2.54 (s, 3H), 1.72 (s, 3H), 1.69 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 158.5, 158.2, 140.7, 137.0, 133.6, 129.1, 129.0, 122.6, 122.2, 121.3, 117.1, 111.2, 104.3, 28.8, 25.9, 18.8, 18.1. HRMS (ESI-TOF): m/z calculated for C18H20N3 [M + H]+: 278.1652, found: 278.1657. Methyl 2-(3-Methylbut-2-en-1-yl)-1-(pyrimidin-2-yl)-1H-indole-4carboxylate (3la). Following the general procedure, the product 3la was obtained in 98% yield (62.9 mg) as a yellow oil after column chromatography (PE/EA = 32/1; PE/EA = 32/1, RF ≈ 0.2). 1H NMR (400 MHz, CDCl3) δ 8.73 (d, J = 4.8 Hz, 2H), 8.30 (d, J = 8.3 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.16 (dd, J = 12.6, 4.6 Hz, 1H), 7.10 (dd, J = 8.6, 3.5 Hz, 2H), 5.24 (t, J = 7.1 Hz, 1H), 3.90 (s, 3H), 3.82 (d, J = 7.1 Hz, 2H), 1.62 (s, 3H), 1.60 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 168.1, 158.4, 158.0, 143.8, 137.9, 133.9, 129.5, 124.8, 121.7, 120.8, 120.6, 118.2, 117.7, 106.5, 51.9, 28.7, 25.9, 18.1. HRMS (ESITOF): m/z calculated for C19H20N3O2 [M + H]+: 322.1550, found: 322.1551. 4-(Benzyloxy)-2-(3-methylbut-2-en-1-yl)-1-(pyrimidin-2-yl)-1H-indole (3ma). Following the general procedure, the product 3ma was obtained in 86% yield (63.5 mg) as a white solid powder after column chromatography (PE/EA = 32/1; PE/EA = 32/1, RF ≈ 0.2). 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 4.8 Hz, 2H), 7.84 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 7.3 Hz, 2H), 7.42 (t, J = 7.4 Hz, 2H), 7.34 (t, J = 7.3 Hz, 1H), 7.17−7.08 (m, 2H), 6.71 (t, J = 8.6 Hz, 1H), 6.63 (d, J = 6.8 Hz, 1H), 5.33 (t, J = 7.1 Hz, 1H), 5.24 (s, 2H), 3.86 (d, J = 7.1 Hz, 2H), 1.71 (s, 3H), 1.69 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 158.5, 158.2, 151.6, 139.8, 138.6, 137.7, 133.5, 128.6, 127.9, 127.5, 123.2, 121.2, 120.0, 117.2, 107.3, 103.8, 102.9, 70.2, 28.7, 25.9, 18.0. HRMS (ESI-TOF): m/z calculated for C24H24N3O [M + H]+: 370.1914, found: 370.1924. 2-(3-Methylbut-2-en-1-yl)-1-(pyrimidin-2-yl)-1H-indole-4-carbaldehyde (3na). Following the general procedure, the product 3na was obtained in 98% yield (57.1 mg) as a yellow oil after column chromatography (PE/EA = 32/1; PE/EA = 16/1, RF ≈ 0.3). 1H NMR (400 MHz, CDCl3) δ 10.26 (s, 1H), 8.83 (d, J = 4.8 Hz, 2H), 8.44 (d, J = 8.3 Hz, 1H), 7.67 (d, J = 7.3 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.29 (s, 1H), 7.22 (t, J = 4.8 Hz, 1H), 5.32 (t, J = 7.1 Hz, 1H), 3.91 (d, J = 7.1 Hz, 2H), 1.71 (s, 3H), 1.68 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 193.1, 158.5, 158.0, 145.5, 138.0, 134.2, 128.4, 128.0, 127.4, 122.0, 120.5, 119.6, 117.9, 105.4, 28.8, 25.9, 18.1. HRMS (ESI-TOF): m/z calculated for C18H18N3O [M + H] +: 292.1444, found: 292.1452. 7-Chloro-2-(3-methylbut-2-en-1-yl)-1-(pyrimidin-2-yl)-1H-indole (3oa). Following the general procedure A, the product 3oa was obtained in 51% yield (30.3 mg) as a colorless oil after column chromatography (PE/EA = 100/1; PE/EA = 32/1, RF ≈ 0.4). 1H NMR (400 MHz, CDCl3) δ 8.87 (d, J = 4.8 Hz, 2H), 7.46 (d, J = 7.7 Hz, 1H), 7.34 (t, J = 4.8 Hz, 1H), 7.11 (d, J = 7.7 Hz, 1H), 7.04 (t, J = 7.7 Hz, 1H), 6.40 (s, 1H), 5.19 (tq, J = 7.1, 1.5 Hz, 1H), 3.39 (d, J = 7.1 Hz, 2H), 1.66 (s, 3H), 1.55 (s, 3H). 13C NMR (101 MHz, CDCl3) δ = 158.5, 158.2, 142.6, 134.3, 133.8, 131.7, 123.4, 121.7, 119.8 (2C), 118.9, 117.0, 102.9, 26.6, 25.7, 17.9. HRMS (ESI-TOF): m/z calculated for C17H17N3Cl [M + H]+: 298.1106, found: 298.1107. 3-Methyl-2-(3-methylbut-2-en-1-yl)-1-(pyrimidin-2-yl)-1H-indole (3pa). Following the general procedure, the product 3pa was obtained in 95% yield (52.7 mg) as a colorless oil after column chromatography (PE/EA = 50/1; PE/EA = 32/1, RF ≈ 0.3). 1H NMR (400 MHz, CDCl3) δ 8.77 (d, J = 4.8 Hz, 2H), 8.17 (dd, J = 6.3, 2.4 Hz, 1H), 7.59−7.42 (m, 1H), 7.25−7.15 (m, 1H), 7.10 (t, J = 4.8 Hz, 1H), 5.11−4.97 (m, 1H), 3.91 (d, J = 6.5 Hz, 2H), 2.31 (s, 3H), 1.65 (s, 3H), 1.55 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 158.5, 158.2,

Scheme 5. Proposed Mechanism

CDCl3) δ 8.78 (d, J = 4.8 Hz, 2H), 8.19 (dd, J = 9.1, 4.7 Hz, 1H), 7.15 (dd, J = 6.0, 3.4 Hz, 2H), 6.92 (td, J = 9.2, 2.6 Hz, 1H), 6.41 (s, 1H), 5.31 (t, J = 7.2 Hz, 1H), 3.86 (d, J = 7.1 Hz, 2H), 1.72 (s, 3H), 1.68 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.1 (d, J = 236.6 Hz), 158.3, 158.3, 143.2, 134.0, 133.6, 130.2 (d, J = 10.1 Hz), 120.9, 117.3, 114.8 (d, J = 9.1 Hz), 110.1 (d, J = 25.0 Hz), 105.8 (d, J = 4.0 Hz), 105.0 (d, J = 23.6 Hz), 29.0, 25.8, 18.0. HRMS (ESI-TOF): m/z calculated for C17H17N3F [M + H] +: 282.1401, found: 282.1399. 5-Chloro-2-(3-methylbut-2-en-1-yl)-1-(pyrimidin-2-yl)-1H-indole (3ga). Following the general procedure, the product 3ga was obtained in 97% yield (57.6 mg) as a yellow oil after column chromatography (PE/EA = 64/1; PE/EA = 32/1, RF ≈ 0.5). 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 4.8 Hz, 2H), 8.16 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 1.9 Hz, 1H), 7.20−7.09 (m, 2H), 6.39 (s, 1H), 5.30 (t, J = 7.1 Hz, 1H), 3.86 (d, J = 7.1 Hz, 2H), 1.72 (s, 3H), 1.67 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 158.3, 158.2, 142.9, 135.6, 134.1, 130.7, 127.3, 122.6, 120.8, 119.3, 117.4, 115.0, 105.3, 28.9, 25.8, 18.0. HRMS (ESITOF): m/z calculated for C17H17N3Cl [M + H]+: 298.1106, found: 298.1111. 6-Fluoro-2-(3-methylbut-2-en-1-yl)-1-(pyrimidin-2-yl)-1H-indole (3ha). Following the general procedure, the product 3ha was obtained in 95% yield (53.2 mg) as a white solid powder after column chromatography (PE/EA = 64/1; PE/EA = 32/1, RF ≈ 0.3). 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 4.8 Hz, 2H), 8.03 (dd, J = 11.1, 2.4 Hz, 1H), 7.40 (dd, J = 8.5, 5.6 Hz, 1H), 7.15 (t, J = 4.8 Hz, 1H), 6.97− 6.88 (m, 1H), 6.41 (d, J = 0.8 Hz, 1H), 5.31 (dddd, J = 7.2, 5.8, 2.8, 1.4 Hz, 1H), 3.86 (d, J = 7.1 Hz, 2H), 1.72 (d, J = 0.9 Hz, 3H), 1.68 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.2 (d, J = 236.5 Hz), 158.4, 158.3, 141.9 (d, J = 3.8 Hz), 137.4 (d, J = 12.8 Hz), 133.8, 125.9, 121.1, 120.1 (d, J = 9.9 Hz), 117.3, 110.0 (d, J = 24.2 Hz), 105.8, 101.4 (d, J = 28.7 Hz), 29.0, 25.8, 18.0. HRMS (ESI-TOF): m/z calculated for C17H17N3F [M + H]+: 282.1401, found: 282.1393. 6-Methoxy-2-(3-methylbut-2-en-1-yl)-1-(pyrimidin-2-yl)-1H-indole (3ia). Following the general procedure, the product 3ia was obtained in 98% yield (57.5 mg) as a colorless oil after column chromatography (PE/EA = 64/1; PE/EA = 64/1, RF ≈ 0.2). 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 4.8 Hz, 2H), 7.88 (d, J = 2.1 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.11 (t, J = 4.8 Hz, 1H), 6.84 (dd, J = 8.5, 2.3 Hz, 1H), 6.38 (s, 1H), 5.38−5.22 (m, 1H), 3.87 (s, 3H), 3.84 (d, J = 7.2 Hz, 2H), 1.71 (s, 3H), 1.68 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 158.5, 158.2, 156.7, 140.3, 138.0, 133.5, 123.6, 121.4, 120.1, 117.0, 110.5, 105.7, 98.9, 55.9, 28.9, 25.8, 18.0. HRMS (ESI-TOF): m/ z calculated for C18H20N3O [M + H]+: 294.1601, found: 294.1614. 6-Chloro-2-(3-methylbut-2-en-1-yl)-1-(pyrimidin-2-yl)-1H-indole (3ja). Following the general procedure, the product 3ja was obtained in 97% yield (57.6 mg) as a colorless oil after column chromatography (PE/EA = 100/1; PE/EA = 32/1, RF ≈ 0.4). 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J = 4.8 Hz, 2H), 8.29 (d, J = 1.7 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.15 (dt, J = 8.3, 3.4 Hz, 2H), 6.42 (s, 1H), 5.30 (dd, J = 4.9, 3.6 Hz, 1H), 3.85 (d, J = 7.1 Hz, 2H), 1.71 (d, J = 9.2 Hz, 3H), 11178

DOI: 10.1021/acs.joc.7b02220 J. Org. Chem. 2017, 82, 11173−11181

Article

The Journal of Organic Chemistry

(400 MHz, CDCl3) δ 8.70 (d, J = 4.8 Hz, 1H), 7.85 (dd, J = 6.5, 2.4 Hz, 1H), 7.74 (ddd, J = 7.7, 6.2, 2.0 Hz, 2H), 7.62 (d, J = 7.9 Hz, 1H), 7.37 (tt, J = 7.2, 5.5 Hz, 2H), 7.27−7.16 (m, 1H), 5.39−5.19 (m, 1H), 3.83 (d, J = 6.2 Hz, 2H), 1.83 (s, 3H), 1.73 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 153.5, 149.9, 141.1, 139.9, 138.6, 136.6, 133.5, 133.0, 125.1, 124.2, 123.3, 122.9, 122.5, 122.2, 122.1, 26.7, 25.8, 18.3. HRMS (ESI-TOF): m/z calculated for C18H18NS [M + H]+: 280.1154, found: 280.1140. 2-(3-(3-Methylbut-2-en-1-yl)benzofuran-2-yl)pyridine (3xa). Following the general procedure, the product 3xa was obtained in 61% yield (32.1 mg) as a yellow oil after column chromatography (PE/EA = 40/1; PE/EA = 32/1, RF ≈ 0.3). 1H NMR (400 MHz, CDCl3) δ 8.72−8.65 (m, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.76 (td, J = 7.8, 1.8 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.37−7.30 (m, 1H), 7.28−7.25 (m, 1H), 7.20 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 5.45− 5.36 (m, 1H), 4.06 (d, J = 7.0 Hz, 2H), 1.88 (s, 3H), 1.72 (d, J = 1.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 154.2, 151.3, 149.6, 148.8, 136.5, 132.5, 130.5, 125.3, 122.6, 122.3, 122.1, 121.1, 120.7, 119.7, 111.4, 25.9, 23.6, 18.3. HRMS (ESI-TOF): m/z calculated for C18H18NO [M + H]+: 264.1383, found: 264.1365. 2-(3-(3-Methylbut-2-en-1-yl)dibenzo[b,d]thiophen-4-yl)pyridine (3ya). Following the general procedure, the product 3ya was obtained in 46% yield (30.3 mg) as a yellow oil after column chromatography (PE/EA = 32/1; PE/EA = 32/1, RF ≈ 0.3). 1H NMR (400 MHz, CDCl3) δ 8.82 (d, J = 4.8 Hz, 1H), 8.12 (t, J = 8.6 Hz, 2H), 7.84 (t, J = 7.7 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.48− 7.31 (m, 4H), 5.29−5.02 (m, 1H), 3.43 (d, J = 7.1 Hz, 2H), 1.67 (s, 3H), 1.53 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 158.3, 150.1, 140.5, 140.0, 138.6, 136.7, 135.8, 134.6, 134.1, 132.4, 126.8, 126.4, 125.0, 124.4, 123.5, 122.7, 122.7, 121.5, 121.4, 32.2, 25.8, 17.9. HRMS (ESI-TOF): m/z calculated for C22H20NS [M + H]+: 330.1311, found: 330.1296. 2-(3-Methylbut-2-en-1-yl)-1-(pyrimidin-2-yl)-1H-benzo[d]imidazole (3za). Following the general procedure, the product 3za was obtained in 75% yield (39.6 mg) as a yellow oil after column chromatography (PE/EA = 16/1; PE/EA = 8/1, RF ≈ 0.3). 1H NMR (400 MHz, acetone-d6) δ 9.00 (d, J = 4.8 Hz, 2H), 8.23−8.12 (m, 1H), 7.68−7.60 (m, 1H), 7.52 (t, J = 4.8 Hz, 1H), 7.32−7.21 (m, 2H), 5.45 (dddd, J = 7.0, 5.5, 2.9, 1.5 Hz, 1H), 4.11 (d, J = 6.9 Hz, 2H), 1.70 (s, 3H), 1.64 (s, 3H). 13C NMR (101 MHz, Acetone-d6) δ 159.8, 157.7, 155.5, 143.9, 135.2, 134.3, 123.9, 123.9, 120.3, 119.8, 119.8, 115.0, 30.7, 25.8, 18.2.HRMS (ESI-TOF): m/z calculated for C16H17N4 [M + H]+: 265.1448, found: 265.1437. 2-(2-(3-Methylbut-2-en-1-yl)phenyl)pyrimidine (3aaa). Following the general procedure, the product 3aaa was obtained in 53% yield (23.5 mg) as a yellow oil after column chromatography (PE/EA = 64/ 1; PE/EA = 32/1, RF ≈ 0.2). 1H NMR (400 MHz, CDCl3) δ 8.84 (d, J = 4.9 Hz, 2H), 7.76−7.67 (m, 1H), 7.43−7.27 (m, 3H), 7.21 (t, J = 4.9 Hz, 1H), 5.18 (dddd, J = 8.5, 5.6, 2.8, 1.4 Hz, 1H), 3.66 (d, J = 7.1 Hz, 2H), 1.63 (d, J = 1.0 Hz, 3H), 1.60 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 168.1, 157.0, 140.8, 138.2, 132.1, 130.6, 130.2, 129.6, 126.1, 123.7, 118.6, 32.3, 25.8, 18.0. HRMS (ESI-TOF): m/z calculated for C15H17N2 [M + H]+: 225.1386, found: 225.1381. 2-(2,6-Bis(3-methylbut-2-en-1-yl)phenyl)pyrimidine (3aaa’). Following the general procedure, the product 3aaa’ was obtained in 26% yield (15.2 mg) as a yellow oil after column chromatography (PE/EA = 64/1; PE/EA = 32/1, RF ≈ 0.2). 1H NMR (400 MHz, CDCl3) δ 8.85 (d, J = 4.9 Hz, 2H), 7.25 (dt, J = 12.8, 4.8 Hz, 2H), 7.13 (d, J = 7.6 Hz, 2H), 5.11−5.02 (m, 2H), 3.12 (d, J = 7.2 Hz, 4H), 1.59 (s, 6H), 1.43 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 168.5, 157.1, 139.3, 132.1, 128.8, 127.0, 123.1, 118.9, 100.1, 32.4, 25.8, 17.8. HRMS (ESI-TOF): m/z calculated for C20H25N2 [M + H]+: 293.2012, found: 293.2020. 2-(4-Methyl-2-(3-methylbut-2-en-1-yl)phenyl)pyrimidine (3aba). Following the general procedure, the product 3aba was obtained in 48% yield (22.8 mg) as a yellow oil after column chromatography (PE/EA = 64/1; PE/EA = 32/1, RF ≈ 0.3). 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 4.9 Hz, 2H), 7.65 (d, J = 8.3 Hz, 1H), 7.17 (t, J = 4.9 Hz, 1H), 7.11 (m, 2H), 5.18 (m, 1H), 3.66 (d, J = 7.1 Hz, 2H), 2.38 (s, 3H), 1.64 (d, J = 1.1 Hz, 3H), 1.61 (s, 3H). 13C NMR (101

136.5, 136.3, 131.9, 130.7, 122.8, 122.2, 121.5, 118.1, 116.8, 113.3, 112.9, 25.7, 25.6, 18.1, 9.0. HRMS (ESI-TOF): m/z calculated for C18H20N3 [M + H]+: 278.1652, found: 278.1655. 2-(3-Methylbut-2-en-1-yl)-1-(pyridin-2-yl)-1H-indole (3qa).11c Following the general procedure, the product 3qa was obtained in 99% yield (51.9 mg) as a yellow oil after column chromatography (PE/EA = 64/1; PE/EA = 64/1, RF ≈ 0.3). 1H NMR (400 MHz, CDCl3) δ 8.66 (dd, J = 5.0, 1.8 Hz, 1H), 7.88 (td, J = 7.7, 2.0 Hz, 1H), 7.56 (m, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.32 (p, J = 4.7 Hz, 2H), 7.13− 7.09 (m, 2H), 6.44 (s, 1H), 5.24 (m, 1H), 3.55 (d, J = 7.1 Hz, 2H), 1.67 (s, 3H), 1.56 (s, 3H). 13C NMR (101 MHz, CDCl3) δ = 151.7, 149.8, 140.8, 138.3, 137.5, 133.7, 128.8, 122.1, 121.7, 121.3, 120.7 (2C), 120.1, 110.2, 102.6, 26.9, 25.8, 17.9. 2-(2,5-Bis(3-methylbut-2-en-1-yl)-1H-pyrrol-1-yl)pyrimidine (3ra). Following the general procedure, the product 3ra was obtained in 73% yield (41.1 mg) as a yellow oil after column chromatography (PE/EA = 64/1; PE/EA = 50/1, RF ≈ 0.3). 1H NMR (400 MHz, CDCl3) δ 8.77 (d, J = 4.8 Hz, 2H), 7.17 (t, J = 4.8 Hz, 1H), 5.92 (s, 2H), 5.10 (m, 2H), 3.44 (d, J = 7.1 Hz, 4H), 1.59 (s, 6H), 1.53 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 158.38 (2C), 133.6, 132.4, 121.9, 118.2, 107.9, 27.1, 25.7, 17.8. HRMS (ESI-TOF): m/z calculated for C18H24N3 [M + H]+: 282.1965, found: 282.1959. 2-(3-Methylbut-2-en-1-yl)-1-(pyrimidin-2-yl)-1H-pyrrole-3-carboxylate (3sa). Following the general procedure, the product 3sa was obtained in 60% yield (32.5 mg) as a yellow oil after column chromatography (PE/EA = 25/1; PE/EA = 6/1, RF ≈ 0.3). 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 4.8 Hz, 2H), 7.55 (d, J = 3.5 Hz, 1H), 7.17 (t, J = 4.8 Hz, 1H), 6.65 (d, J = 3.5 Hz, 1H), 5.08 (ddd, J = 6.6, 5.3, 1.3 Hz, 1H), 4.34 (d, J = 6.5 Hz, 2H), 3.83 (s, 3H), 1.71 (s, 3H), 1.58 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 165.7, 158.4, 157.6, 141.0, 132.2, 121.9, 120.8, 118.3, 115.7, 111.4, 51.2, 25.9, 25.9, 18.2. HRMS (ESI-TOF): m/z calculated for C15H18N3O2 [M + H] +: 272.1394, found: 272.1396. 3-(3-Methylbut-2-en-1-yl)-2-(pyridin-2-yl)isoquinolin-1(2H)-one (3ta). Following the general procedure, the product 3ta was obtained in 93% yield (54.5 mg) as a white solid after column chromatography (PE/EA = 4/1; PE/EA = 4/1, RF ≈ 0.3). 1H NMR (400 MHz, acetone) δ = 8.64 (d, J = 4.2, 1H), 8.24 (d, J = 8.0, 1H), 8.01 (td, J = 7.7, 1.9, 1H), 7.73−7.66 (m, 1H), 7.60 (d, J = 7.9, 1H), 7.54−7.38 (m, 3H), 6.50 (s, 1H), 5.14−4.98 (m, 1H), 3.03 (d, J = 6.9, 2H), 1.65 (s, 3H), 1.38 (s, 3H). 13C NMR (101 MHz, acetone) δ 164.1, 153.8, 150.8, 143.9, 139.4, 138.9, 136.3, 134.1, 128.8, 127.4, 127.2, 126.7, 126.4, 125.2, 120.6, 105.3, 33.3, 26.2, 18.2. HRMS (ESI-TOF): m/z calculated for C19H19N2O [M + H]+: 291.1492, found: 291.1505. 4-(Benzyloxy)-6-(3-methylbut-2-en-1-yl)-2H-[1,2′-bipyridin]-2one (3ua). Following the general procedure, the product 3ua was obtained in 91% yield (63.0 mg) as a colorless oil after column chromatography (PE/EA = 1/1; PE/EA = 1/1, RF ≈ 0.2). 1H NMR (400 MHz, acetone) δ 8.60 (d, J = 4.3 Hz, 1H), 7.95 (br s, 1H), 7.55− 7.31 (m, 7H), 5.88 (s, 1H), 5.84 (br s, 1H), 5.13 (s, 2H), 5.01 (t, J = 7.0 Hz, 1H), 2.93 (d, J = 5.7 Hz, 2H), 1.63 (s, 3H), 1.36 (s, 3H). 13C NMR (101 MHz, acetone) δ 168.2, 152.9, 150.3, 150.0, 138.9, 137.2, 136.4, 129.5, 129.1 (2C), 128.9, 126.1, 124.7, 119.3, 100.2, 96.5, 70.8, 32.6, 25.7, 17.7. HRMS (ESI-TOF): m/z calculated for C22H23N2O2 [M + H]+: 347.1754, found: 347.1756. 2-(3-(3-Methylbut-2-en-1-yl)thiophen-2-yl)pyridine (3va). Following the general procedure, the product 3va was obtained in 56% yield (25.6 mg) as a yellow oil after column chromatography (PE/EA = 32/ 1; PE/EA = 32/1, RF ≈ 0.3). 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 4.2 Hz, 1H), 7.69 (td, J = 7.7, 1.9 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 5.2 Hz, 1H), 7.16 (ddd, J = 7.5, 4.9, 1.1 Hz, 1H), 6.96 (d, J = 5.1 Hz, 1H), 5.32 (ddd, J = 8.5, 4.4, 1.6 Hz, 1H), 3.59 (d, J = 7.0 Hz, 2H), 1.74 (s, 3H), 1.71 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 153.5, 149.7, 139.6, 137.9, 136.5, 132.8, 130.9, 125.9, 122.7, 122.1, 121.5, 28.7, 25.8, 18.1. HRMS (ESI-TOF): m/z calculated for C14H16NS [M + H]+: 230.0998, found: 230.0982. 2-(3-(3-Methylbut-2-en-1-yl)benzo[b]thiophen-2-yl)pyridine (3wa). Following the general procedure, the product 3wa was obtained in 94% yield (52.5 mg) as a yellow oil after column chromatography (PE/EA = 32/1; PE/EA = 32/1, RF ≈ 0.3). 1H NMR 11179

DOI: 10.1021/acs.joc.7b02220 J. Org. Chem. 2017, 82, 11173−11181

Article

The Journal of Organic Chemistry MHz, CDCl3) δ 168.2, 156.9, 140.9, 139.6, 135.4, 131.8, 131.0, 130.8, 126.9, 124.0, 118.4, 32.4, 25.8, 21.5, 18.0. HRMS (ESI-TOF): m/z calculated for C16H19N2 [M + H]+: 239.1543, found: 239.1533. 2-(4-Methyl-2,6-bis(3-methylbut-2-en-1-yl)phenyl)pyrimidine (3aba’). Following the general procedure, the product 3aba’ was obtained in 30% yield (18.4 mg) as a yellow oil after column chromatography (PE/EA = 64/1; PE/EA = 32/1, RF ≈ 0.3). 1H NMR (400 MHz, CDCl3) δ 8.83 (d, J = 4.9 Hz, 2H), 7.20 (t, J = 4.9 Hz, 1H), 6.93 (s, 2H), 5.06 (ddt, J = 7.2, 5.8, 1.5 Hz, 2H), 3.10 (d, J = 7.1 Hz, 4H), 2.33 (s, 3H), 1.59 (s, 6H), 1.43 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 168.7, 157.0, 139.3, 138.4, 135.8, 131.8, 127.8, 123.3, 118.7, 32.4, 25.8, 21.5, 17.8. HRMS (ESI-TOF): m/z calculated for C21H27N2 [M + H]+: 307.2169, found: 307.2169. 2-(4-Methoxy-2-(3-methylbut-2-en-1-yl)phenyl)pyridine (3aca). Following the general procedure, the product 3aca was obtained in 70% yield (36.0 mg) as a yellow oil after column chromatography (PE/EA = 50/1; PE/EA = 32/1, RF ≈ 0.3). 1H NMR (400 MHz, CDCl3) δ 8.70−8.63 (m, 1H), 7.70 (td, J = 7.7, 1.8 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.20 (ddd, J = 7.5, 4.9, 0.9 Hz, 1H), 6.85 (d, J = 2.6 Hz, 1H), 6.81 (dd, J = 8.4, 2.6 Hz, 1H), 5.21− 5.13 (m, 1H), 3.84 (s, 3H), 3.42 (d, J = 7.1 Hz, 2H), 1.66 (s, 3H), 1.54 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.0, 159.8, 149.3, 141.4, 136.1, 133.3, 132.5, 131.2, 124.4, 123.5, 121.4, 115.4, 111.1, 55.4, 32.2, 25.8, 17.9. HRMS (ESI-TOF): m/z calculated for C17H20NO [M + H]+: 254.1539, found: 254.1536. 2-(2-(2-(3-Methylbut-2-en-1-yl)-1-(pyrimidin-2-yl)-1H-indol-3 yl)ethyl)isoindoline-1,3-dione (3ada). Following the general procedure, the product 3ada was obtained in 90% yield (78.5 mg) as a yellow solid after column chromatography (PE/EA = 6/1; PE/EA = 6/1, RF ≈ 0.2). 1H NMR (400 MHz, chloroform-d) δ 8.78 (d, J = 4.8 Hz, 2H), 8.15−8.10 (m, 1H), 7.85 (dt, J = 7.0, 3.5 Hz, 2H), 7.76 (dd, J = 6.4, 2.7 Hz, 1H), 7.71 (dd, J = 5.4, 3.0 Hz, 2H), 7.25−7.18 (m, 2H), 7.13 (t, J = 4.8 Hz, 1H), 5.14−4.83 (m, 1H), 4.03−3.83 (m, 4H), 3.22− 3.04 (m, 2H), 1.68 (s, 3H), 1.51 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 168.4, 158.3, 158.3, 137.6, 136.6, 135.1, 132.7, 132.4, 132.3, 129.5, 123.3, 123.0, 122.0, 121.9, 118.3, 117.2, 113.3, 113.2, 38.2 25.7, 25.5, 23.9, 18.2. HRMS (ESI-TOF): m/z calculated for C27H25N4O2 [M + H]+: 437.1972, found: 437.1965. (1R,3R,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(3-methylbut-2-en-1-yl)-1-(pyrimidin-2-yl)-1H-indole-3-carboxylate (3aea). Following the general procedure, the product 3aea was obtained in 76% yield (65.7 mg) as a colorless oil after column chromatography (DCM/MeOH = 6/1; DCM/MeOH = 6/1, RF ≈ 0.2). 1H NMR (400 MHz, CDCl3) δ 8.89 (d, J = 4.8 Hz, 2H), 8.21 (d, J = 7.4 Hz, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.31 (t, J = 4.8 Hz, 1H), 7.29 (dd, J = 7.7, 1.0 Hz, 1H), 7.26−7.21 (m, 1H), 5.29 (t, J = 5.7 Hz, 1H), 4.89 (t, J = 6.6 Hz, 1H), 4.37 (d, J = 6.5 Hz, 2H), 3.18 (s, 2H), 2.38−2.28 (m, 5H), 2.14−1.94 (m, 6H), 1.48 (s, 3H), 1.45 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 165.6, 158.8, 157.6, 148.2, 136.4, 133.4, 127.1, 123.5, 122.9, 121.4, 120.8, 119.1, 112.1, 108.3, 67.3, 59.9, 40.4, 36.9, 25.9, 25.6, 18.1. HRMS (ESI-TOF): m/z calculated for C26H31N4O2 [M + H] +: 431.2442, found: 431.2458. 2-(2-Cyclohexylideneethyl)-1-(pyrimidin-2-yl)-1H-indole (3ab). Following the general procedure, the product 3ab was obtained in 96% yield (58.2 mg) as a yellow oil after column chromatography (PE/EA = 100/1; PE/EA = 100/1, RF ≈ 0.3). 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 4.8 Hz, 2H), 8.23 (d, J = 8.0 Hz, 1H), 7.54 (dd, J = 6.6, 1.4 Hz, 1H), 7.25−7.16 (m, 2H), 7.13 (t, J = 4.8 Hz, 1H), 6.49 (s, 1H), 5.39−5.15 (m, 1H), 3.89 (d, J = 7.2 Hz, 2H), 2.26−2.15 (m, 2H), 2.15−2.04 (m, 2H), 1.60−1.46 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 158.4, 158.2, 141.8, 141.6, 137.3, 129.5, 122.5, 121.8, 119.8, 117.7, 117.1, 113.7, 106.0, 37.2, 29.0, 28.7, 27.9, 27.9, 27.0. HRMS (ESI-TOF): m/z calculated for C20H22N3 [M + H]+: 304.1808, found: 304.1812. 2-(3-Butylhept-2-en-1-yl)-1-(pyrimidin-2-yl)-1H-indole (3ac). Following the general procedure, the product 3ac was obtained in 90% yield (62.5 mg) as a yellow oil after column chromatography (PE/EA = 100/1; PE/EA = 100/1, RF ≈ 0.3). 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 4.8 Hz, 2H), 8.22 (d, J = 7.7 Hz, 1H), 7.53 (dd, J = 6.7, 1.4 Hz, 1H), 7.25−7.15 (m, 2H), 7.13 (t, J = 4.8 Hz, 1H), 6.47 (s, 1H),

5.29 (t, J = 7.0 Hz, 1H), 3.90 (d, J = 7.0 Hz, 2H), 2.08 (t, J = 7.4 Hz, 2H), 1.99 (t, J = 7.5 Hz, 2H), 1.42−1.17 (m, 8H), 0.90 (dt, J = 10.7, 7.0 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 158.4, 158.2, 141.9, 141.7, 137.3, 129.5, 122.5, 121.8, 121.0, 119.8, 117.1, 113.6, 106.0, 36.7, 30.8, 30.6, 30.0, 28.4, 23.0, 22.6, 14.2, 14.2. HRMS (ESI-TOF): m/z calculated for C23H30N3 [M + H]+: 348.2434, found: 348.2429. (Z)-2-(3-Phenylbut-2-en-1-yl)-1-(pyrimidin-2-yl)-1H-indole (3ad). Following the general procedure, the product 3ad was obtained in 84% yield (54.6 mg, E/Z = 3:1) as a yellow oil after column chromatography (PE/EA = 100/1; PE/EA = 64/1, RF ≈ 0.2). 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 4.8 Hz, 2H), 8.25 (dd, J = 8.5, 0.8 Hz, 1H), 7.55 (dd, J = 6.7, 1.8 Hz, 1H), 7.35−7.30 (m, 2H), 7.26− 7.16 (m, 5H), 7.07 (t, J = 4.8 Hz, 1H), 6.54 (d, J = 1.0 Hz, 0H), 5.71 (td, J = 7.4, 1.5 Hz, 1H), 3.89 (d, J = 7.4 Hz, 2H), 2.08 (d, J = 1.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 158.3, 158.2, 141.6, 141.3, 138.0, 137.2, 129.5, 128.3, 128.0, 126.9, 124.0, 122.7, 121.9, 119.9, 117.1, 113.8, 106.2, 30.0, 25.6. HRMS (ESI-TOF): m/z calculated for C22H20N3 [M + H]+: 326.1652, found: 326.1646. (Z)-2-(3-Phenylallyl)-1-(pyrimidin-2-yl)-1H-indole (3ae).11a Following the general procedure, the product 3ae was obtained in 69% yield (42.9 mg) as a yellow oil after column chromatography (PE/EA = 100/1; PE/EA = 64/1, RF ≈ 0.3). 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 4.8 Hz, 2H), 8.22 (dd, J = 8.2, 1.1 Hz, 1H), 7.49 (dd, J = 6.8, 1.3 Hz, 1H), 7.27 (d, J = 5.9 Hz, 3H), 7.21−7.10 (m, 4H), 7.00 (t, J = 4.8 Hz, 1H), 6.54 (s, 1H), 6.49 (d, J = 11.5 Hz, 1H), 5.81 (d, J = 11.5 Hz, 1H), 4.17 (d, J = 7.5 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 158.25, 158.16, 140.20, 137.28, 130.61, 129.37, 129.04, 128.84, 128.38, 126.95, 122.85, 121.98, 120.01, 117.08, 113.95, 106.42, 29.60. HRMS (ESI-TOF): m/z calculated for C21H18N3 [M + H]+: 312.1495, found: 312.1499. 2-(3-Phenylprop-1-en-2-yl)-1-(pyrimidin-2-yl)-1H-indole (3ae’).23 Following the general procedure, the product 3ae’ was obtained in 28% yield (17.5 mg) as a yellow oil after column chromatography (PE/EA = 100/1; PE/EA = 64/1, RF ≈ 0.2). 1H NMR (400 MHz, CDCl3) δ 8.83 (d, J = 4.8 Hz, 2H), 8.22 (dd, J = 8.3, 1.0 Hz, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.25−7.13 (m, 8H), 6.56 (s, 1H), 5.24 (d, J = 1.4 Hz, 1H), 5.02 (d, J = 1.5 Hz, 1H), 3.57 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 158.4(3C), 142.4, 141.4, 139.3, 137.7, 129.3, 128.4, 126.3, 123.7, 122.2, 120.7, 117.5, 116.3, 113.6, 108.5, 42.8. HRMS (ESITOF): m/z calculated for C21H18N3 [M + H]+: 312.1495, found: 312.1503. (Z)-2-(3-Cyclohexylallyl)-1-(pyrimidin-2-yl)-1H-indole (3af). Following the general procedure, the product 3af was obtained in 25% yield (15.8 mg) as a yellow oil after column chromatography (PE/EA = 50/1; PE/EA = 50/1, RF ≈ 0.3). 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J = 4.8 Hz, 2H), 8.24 (d, J = 8.0 Hz, 1H), 7.53 (dd, J = 7.3, 1.6 Hz, 1H), 7.26−7.15 (m, 2H), 7.15 (t, J = 4.8 Hz, 1H), 6.49 (s, 1H), 5.51−5.41 (m, 1H), 5.35 (dd, J = 10.9, 9.2 Hz, 1H), 3.94 (d, J = 7.2 Hz, 2H), 2.43−2.31 (m, 1H), 1.74−1.61 (m, 4H), 1.33−1.04 (m, 6H). 13 C NMR (101 MHz, CDCl3) δ 158.4, 158.3, 141.0, 137.9, 137.3, 129.4, 124.3, 122.7, 121.9, 119.9, 117.2, 113.8, 106.2, 36.4, 33.4, 28.2, 26.2, 26.1. HRMS (ESI-TOF): m/z calculated for C21H24N3 [M + H] + : 318.1965, found: 318.1959. Following the general procedure, the product 3af’ was obtained in 68% yield (43.5 mg) as a yellow oil after column chromatography (PE/EA = 50/1; PE/EA = 50/1, RF ≈ 0.2). 3af’ is a mixture of regioisomers.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02220. Mechanistic study, copies of spectra for compounds 1ae, 4 and the products, and related compounds S1, S2, and S3 (PDF) 11180

DOI: 10.1021/acs.joc.7b02220 J. Org. Chem. 2017, 82, 11173−11181

Article

The Journal of Organic Chemistry

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AUTHOR INFORMATION

Corresponding Authors

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

Shi-Yong Chen: 0000-0003-1824-5404 Qingjiang Li: 0000-0001-5535-6993 Honggen Wang: 0000-0002-9648-6759 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for the support of this work by National Natural Science Foundation of China (nos. 21502242, 21472250, and 81402794), the State Key Laboratory of Natural and Biomimetic Drugs (K20150215), the Key Project of Chinese National Programs for Fundamental Research and Development (2016YFA0602900), “1000-Youth Talents Plan”, and a Start-up Grant from Sun Yat-sen University.

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DOI: 10.1021/acs.joc.7b02220 J. Org. Chem. 2017, 82, 11173−11181