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Sterically Controlled Ru(II)-Catalyzed Divergent Synthesis of 2‑Methylindoles and Indolines through a C−H Allylation/Cyclization Cascade Manash Kumar Manna,†,‡ Gurupada Bairy,†,‡ and Ranjan Jana*,†,‡ †

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Organic and Medicinal Chemistry Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata, 700032 West Bengal, India ‡ Academy of Scientific and Innovative Research (AcSIR), Kolkata, 700032 West Bengal, India S Supporting Information *

ABSTRACT: A ruthenium-catalyzed synthesis of 2-methylindole was accomplished via a C−H allylation/oxidative cyclization cascade. Strategically, β-hydride elimination from the σ-alkyl-Ru intermediate has been suppressed by steric hindrance from a remote position. Hence, 2-methylindolines from the corresponding ortho-substituted anilines were achieved via protodemetalation in lieu of β-hydride elimination under a modified reaction condition. This mild intermolecular annulation cascade proceeds smoothly by a redox-neutral ruthenium catalyst without stoichiometric metal oxidants, such as silver(I) or copper(II) salts, providing excellent functional group tolerance.

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INTRODUCTION Indole and indoline core structures are ubiquitously found in medicinal scaffolds, natural products, agrochemicals, and functionalized materials.1 By taking advantage of facile electrophilic ortho-metalation of protected anilines,2 an impressive array of a C−H activation methodology has been developed for the synthesis of indoles.3 Direct synthesis of the indoline nucleus was also achieved with norbornene that lacks syn-β-hydrogen,4 π-allyl stabilization,5 nucleophilic addition of Rh-alkyl species to the NN bond,6 or intramolecular C−H amination.7 However, divergent synthesis of the indole and indoline from aniline derivatives via C−H activation is underdeveloped. Hypothetically, it is plausible by intercepting the incipient Heck intermediate which is formed through migratory alkene insertion. In this vein, previously, we reported a palladium-catalyzed divergent synthesis of 2- arylindole and indolines merging the C−H activation and alkene difunctionalization manifolds (Scheme 1a).8 Recently, we have also demonstrated the synthesis of indoline with electronically unbiased styrenes by a Ru-catalyst, which is reluctant to undergo β-hydride elimination compared to the palladium catalyst.9 Although, synthesis of 2arylindoles via C−H activation has been studied extensively, the synthesis of 2-alkylindoles is less attended. The Saá group has reported an expensive Rh(III)-catalyzed synthesis of 2© XXXX American Chemical Society

methylindoles where shoichiometric copper(II) was used as an oxidant (Scheme 1b).10 To the best of our knowledge, there is no report for the direct intermolecular synthesis of 2methylindolines. We report herein a ruthenium(II)-catalyzed synthesis of 2-methylindole from 2-pyridine-protected aniline and allyl acetate via a C−H allylation/oxidative cyclization cascade. Furthermore, a hitherto unknown sterically controlled indoline formation for ortho-substituted anilines was also achieved via protodemetalation in lieu of β-hydride elimination (Scheme 1c). Besides an inexpensive ruthenium(II)-catalyst, no stoichiometric copper, silver salt, or base was essential since an unprecedented redox-neutral catalytic cycle has been explored for this reaction manifold.

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RESULTS AND DISCUSSION We chose an inexpensive ruthenium-catalyst, N-arylpyrimidine, and an allyl acetate for initial screening (entry 1, Table 1). To our delight, after heating the reaction mixture at 120 °C in DCE, the desired 2-methylindole (3a) was obtained in 22% yield along with 7% C-3 allylation of the 2-methylindole (3a′) product as an inseparable mixture (entry 1, Table 1). Although the yield of 3a Received: April 24, 2018 Published: June 6, 2018 A

DOI: 10.1021/acs.joc.8b01034 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry Scheme 1. Divergent Synthesis of Indole and Indoline

Table 1. Optimization of the Reaction Conditionsa

entry

X

Ag(I) salts

additive

solvent

yieldb 3a/3a′

1 2 3 4 5 6 7 8 9 10 11 12c 13d

N N N N CH CH CH CH CH CH CH CH CH

AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgBF4 AgOTf AgSbF6 AgSbF6 AgSbF6 AgSbF6

NaOAc PivOH NaOAc NaOAc PivOH NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc

DCE DCE DCE TFE DCE DCE TFE DCE DCE toluene 1,4-dioxane DCE DCE

22/7 43/13 36/11 22/53 82/0 67/0 79/0 43/0 48/0 45/0 ND 56/0 37/0

a

All reactions were carried out in 0.1 mmol scale. bYields referred to here are overall isolated yields, and the product distribution was measured from NMR. cAllyl methyl carbonate was used instead of allyl acetate. dAllyl alcohol was used instead of allyl acetate.

to generate the active catalyst. Since an acetate ion is required to generate an active catalyst, several acetate ion sources, such as LiOAc, NaOAc, KOAc, CsOAc, AgOAc, and Cu(OAc)2, were examined, and among them NaOAc was found to be optimal. Finally, 5 mol % [Ru(p-cymene)Cl2]2, 20 mol % AgSbF6, and 50 mol % NaOAc in DCE at 120 °C provided 82% yield of the desired indole (Table 1).

increased to 43% with the addition of NaOAc, the yield of 3a′ was also increased commensurately (entry 2, Table 1). Gratifyingly, by changing the directing group from pyrimidine to pyridine, the formation of unexpected 3-allyl-2-methylindole (3a′) was suppressed completely, and the desired 2-methylindole (3a) was obtained exclusively in 82% yield (entry 5, Table 1). Among various silver salts, such as AgSbF6, AgBF4, AgOTf, and AgNTf2, AgSbF6 (20 mol %) was found to be most effective B

DOI: 10.1021/acs.joc.8b01034 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Table 2. Substrate Scope of Indolesa,b

a All reactions were carried out in 0.2 mmol scale. bYields refer to the average of isolated yields of at least two experiments. cFrom meta-methoxy aniline.

place regioselectively at the ortho-position of the −NHPy group, while −NHPiv (3e) remained inert, suggesting that a strong, electron-rich directing group is necessary for electrophilic orthometalation. Other weakly coordinating groups, such as −CO 2 Me (3d), −NO 2 (3j), −CH 2 CO 2 Me (3k), and

A wide variety of anilines containing functional groups, such as methoxy (3q, 3v, and 3v′), OTBDMS (3u), trifluoromethoxy (3t), methyl (3f, 3l, 3p, and 3q), tert-butyl (3s), trifluoromethyl (3h, 3n, and 3o), aryl (3m), etc., were compatible under these mild reaction conditions. Notably, the annulation reaction took C

DOI: 10.1021/acs.joc.8b01034 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry Table 3. Optimization of the Reaction Conditionsa

entry

X

Ag(I) salts

additive

solvent

yieldb 5c/5c′

1 2 3 4 5

CH2 CH2 N N N

AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6

NaOAc NaOAc NaOAc NaOAc

DCE TFE DCE TFE TFE

36/17 54/8 43/26 82/trace 82/trace

a

All reactions were carried out in a 0.1 mmol scale. bYields referred to here are overall isolated yields, and the product distribution was measured from NMR.

Table 4. Substrate Scope of Indolinesa,b

a

All reactions were carried out in a 0.2 mmol scale. bYields refer to the average of isolated yields of at least two experiments.

−COMe (3r), that have the potential to competitively direct ortho-C−H activation were found to compatible and did not direct C−H allylation under these conditions. Halogens, such as fluoro (3b and 3g) and chloro (3c, 3o, and 3p), are compatible under the reaction conditions. Interestingly, electron-deficient para-nitro aniline also produced the desired product with a good yield (3j). Electron-rich meta-methoxy aniline furnished a mixture of two regio-isomeric products through ortho-metalation from both ortho-positions (3v, 3v′). Electron withdrawing and neutral functional groups give a single product through ortho-metalation from the sterically less hindered side. Reaction with α-methyl allyl acetate furnished 2-ethylindole in a lower

yield (3w). Interestingly, no double allylation followed by singular cyclization to provide 7-allyl,2-methylindole was observed (Table 2). During the synthesis of 2-methylindoles, we observed that ortho-methyl anilines furnished a mixture of 2-methylindoles and indolines in 17% and 36% yield, respectively. We assumed that the β-hydride elimination of the ruthenium-alkyl species, which leads to the indole formation, may be perturbed in the case of ortho-substituted aniline, furnishing the corresponding indoline product through protodemetalation. Although sterically controlled remote C−H functionalization is reported,11 to the best of our knowledge, steric-induced scaffold diversification D

DOI: 10.1021/acs.joc.8b01034 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 2. Control Experiments

through C−H activation is unknown. Being encouraged by this exciting result, we started further optimization to get the indoline product exclusively. As expected, indoline formation was favored in protic solvent via protodemetalation. Therefore, when the solvent was changed from DCE to TFE, the yield of the indoline product increased to 54% with a trace amount of indole product. Switching from the pyridine to pyrimidine directing group, the yield of the reaction was further improved to 82%. Since no effect of NaOAc was observed, it was omitted to simplify the reaction condition further (Table 3). Although sterically less hindered fluorine substitution at the ortho-position of aniline yielded an indole as the predominant product (3g), other larger halogens, such as ortho-chloro (5a) and bromo (5b)-substituted anilines, provided exclusive indoline products in high yields (Table 4). Besides halogen, methyl (5c, 5d, and 5e)-, methoxy (5f)-, and isopropyl (5g)-substituted anilines at the ortho-position produce the corresponding indoline products in good yield. Presumably, syn-β-hydrogen may not be accessible for elimination, instead protoderuthenation occurs in a protic solvent to furnish indoline. This is an unprecedented example of divergent indole and indoline synthesis, where steric hindrance from a remote position inhibits the β-hydride elimination. As expected, even larger ortho-substituents on aniline, such as tert-butyl (6a) and phenyl

(6b), provided a C−H allylation product which did not undergo further cyclization due to steric hindrance. When deuterated 1a-d5 was subjected under standard reaction conditions in the absence of olefin, 70% ortho-D-H exchange was observed (Scheme 2a). Whereas, in the absence of a metal catalyst, no D-H exchange was observed, suggesting the involvement of a reversibly directed ortho-metalation step. A similar experiment in the presence of allyl acetate provided the desired product in 80% yield with a 83% D-H exchange at the C7 position (Scheme 2b). This suggests that, although a reversible ortho-metalation is feasible at both ortho-positions, allylationcyclization takes place exclusively in one of the ortho-positions. From a competitive experiment taking an equimolecular mixture of 1a and 1a-d5, kH/kD = 1.2 was determined from 1H NMR (Scheme 2c). This low value indicates that the C−H activation may not be involved in the rate-determining step. To know the role of NaOAc, when the annulation was performed with a combination of Ru(p-cymene)(OAc)2 and NaSbF6, the desired product was isolated in 76% yield (Scheme 2d), and no product formation was observed in the absence of NaSbF6. This experiment suggests that the catalytic silver ion is necessary to remove the chloride ion, and NaOAc and SbF6− ions are necessary to generate the active catalyst. A preformed allylation product was separately prepared and subjected to the standard E

DOI: 10.1021/acs.joc.8b01034 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 3. Plausible Catalytic Cycle

presumably by the formation of hydrogen gas reacting with AcOH generated in the reaction medium (Scheme 3).13 Finally, to remove the pyridine directing group, the indole was treated with MeOTf followed by alkali to furnish the deprotected 2-methylindole in 87% yield.13 However, all of our attempts to deprotect pyrimidine from the indoline moiety were in vain.7

reaction condition to form the annulation product in 84% yield (Scheme 2e). This experiment indicates that C−H allylation take place during the course of the reaction. No indoline to indole oxidation was observed under the standard reaction condition with a preformed indoline substrate, indicating that protodemetalation followed by oxidation may not be involved. Instead, a concerted β-hydride elimintion/isomerization sequence may be involved for the indole formation (Scheme 2e). When 4c was subjected to the indoline formation in DCE in the presence of 10 equiv of D2O, 32% deuterium incorporation was observed at the 2-methyl group (Scheme 2f), suggesting a protodemetalation step is involved for the indoline formation. From the control experiments and previous reports,12 the active catalyst is generated from [Ru(p-cymene)Cl2]2 in the presence of AgSbF6 and NaOAc through the removal of silver chloride which undergoes directed ortho-metalation to the substrate in a reversible manner to generate the intermediate B. Migratory insertion of the intermediate B to alkene generates an alkyl ruthenium intermediate C which undergoes rapid βacetoxy elimination to generate the C−H allylation intermediate D. The ruthenium catalyst further coordinates with the aniline nitrogen atom and undergoes a migratory alkene insertion to the allyl group that results in the intermediate F through an intramolecular C−N bond formation. In the case of orthounsubstituted anilines, the intermediate F undergoes a rapid βhydride elimination and double bond isomerization to produce the desired indole product. But in the case of ortho-substituted anilines, the β-hydride elimination is perturbed due to steric interaction with the directing pyrimidine group which stabilizes the alkyl-Ru species through coordination. Thus, it prefers a protodemetalation in protic solvent, e.g., TFE, to produce the indoline product. The active catalyst is regenerated for subsequent runs from the generated ruthenium hydride species

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CONCLUSION

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EXPERIMENTAL SECTION

In conclusion, we have developed an unprecedented sterically controlled synthesis of 2-methylindoles and indolines. Mechanistically, the 2-methylindole nucleus is obtained through a C− H allylation/carboamination/β-hydride elimination/double bond isomerization cascade, whereas for ortho-substituted sterically hindered anilines, the indolines are obtained through a C−H allylation/carboamination/protodemetalation cascade in protic solvent. This mild intermolecular annulation cascade proceeds smoothly by a redox-neutral ruthenium catalyst without stoichiometric metal oxidants, such as silver(I) or copper(II) salts, with exceptional functional group tolerance. This divergent synthetic approach through a C−H activation cascade will be a valuable tool in organic and medicinal chemistry.

General Information. All manipulations with air-sensitive reagents were carried out under a dry nitrogen atmosphere. Unless otherwise stated, all commercial reagents were used without additional purification. Solvents were dried using standard methods and distilled before use. The starting material N-arylpyridines,14,15 N-aryl pyrimidines,3g and deuterated N-phenylpyridine (1a-d5)15 were prepared using a literature reported method. TLC was performed on silica gel plates (Merck silica gel 60, f254), and the spots were visualized with UV light (254 and 365 nm) or by charring the plate dipped in F

DOI: 10.1021/acs.joc.8b01034 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry KMnO4 or vanillin charring solution. 1H NMR was recorded at 300 MHz (Bruker-DPX), 400 MHz (JEOL-JNM-ECZ400S/L1), and 600 MHz (Bruker-Avance) frequencies, and 13C NMR spectra were recorded at 75 MHz (Bruker-DPX) and 150 MHz (Bruker-Avance) frequencies in CDCl3 solvent using TMS as the internal standard. 19F NMR spectra were recorded in CDCl3 solvent using hexafluorobenzene as the internal standard. Chemical shifts were measured in parts per million (ppm) referenced to 0.0 ppm for tetramethylsilane. The following abbreviations were used to explain multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad. Coupling constants, J, were reported in Hertz (Hz). HRMS (m/z) were measured using EI and ESI techniques (JEOL-JMS 700 and Q-Tof Micro mass spectrometer, respectively). Infrared (IR) spectra were recorded on a Fourier transform infrared spectrometer (Bruker Tensor 27), only intense peaks were reported. General Experimental Procedure for Ruthenium-Catalyzed 2-Methylindole Synthesis from the Corresponding N-Arylpyridines and Allyl acetates. A mixture of N-arylpyridine (0.2 mmol), [Ru(p-cymene)Cl2]2 (0.01 mmol, 5 mol %), AgSbF6 (0.04 mmol, 20 mol %), and NaOAc (0.1 mmol, 0.5 equiv) was taken in a 15 mL pressure tube. To this reaction mixture, DCE (2.0 mL) and the corresponding allyl acetate (0.4 mmol) were added via micro syringe, and the closed reaction mixture was allowed to stir at 120 °C for 16 h. After completion, as indicated by TLC, the reaction the reaction mixture was cooled to ambient temperature. After dilution with dichloromethane, the reaction mixture was completely transferred to a RB flask and concentrated under reduced pressure. The crude product was purified by column chromatography using ethyl acetate/hexane as the eluent to afford the desired indole product. 2-Methyl-1-(pyridin-2-yl)-1H-indole 3a, Table 2. Column chromatography (SiO2, eluting with 19:1 hexane/ethyl acetate) afforded the desired product as a colorless liquid (34 mg, 82%). The same reaction was performed in an 1.0 mmol scale, and the desired product was obtained in 68% yield. 1H NMR (600 MHz, CDCl3, δ): 8.69 (dd, J1 = 4.8 Hz, J2 = 1.8 Hz, 1H), 7.90 (td, J1 = 7.2 Hz, J2 = 1.8 Hz, 1H), 7.58− 7.60 (m, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.41−7.42 (m, 1H), 7.32−7.34 (m, 1H), 7.15−7.17 (m, 2H), 6.46 (s, 1H), 2.50 (s, 3H). 13C NMR (150 MHz, CDCl3, δ): 151.4, 149.6, 138.2, 137.1, 136.8, 128.7, 121.9, 121.5, 120.8, 120.6, 119.7, 110.2, 103.3, 14.0. IR (neat) υmax: 2922, 1691, 1582, 1461, 742 cm−1. HRMS (ESI, m/z): [M + H]+ calcd. for C14H13N2, 209.1079; found, 209.1075. 5-Fluoro-2-methyl-1-(pyridin-2-yl)-1H-indole 3b, Table 2. Column chromatography (SiO2, eluting with 19:1 hexane/ethyl acetate) afforded the desired product as a yellow liquid (29 mg, 64%). 1H NMR (600 MHz, CDCl3, δ): 8.68 (dd, J1 = 4.8 Hz, J2 = 1.8 Hz, 1H), 7.90 (td, J1 = 7.8 Hz, J2 = 1.8 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.30−7.35 (m, 2H), 7.21 (dd, J1 = 9.6 Hz, J2 = 3.0 Hz, 1H), 6.87 (td, J1 = 9.0 Hz, J2 = 3.0 Hz, 1H), 6.40 (s, 1H), 2.47 (s, 3H). 13C NMR (150 MHz, CDCl3, δ): 158.4 (d, J = 233.4 Hz), 151.2, 149.6, 138.4, 138.3, 133.6, 129.1 (d, J = 10.4 Hz), 122.0, 120.7, 110.0 (d, J = 9.5 Hz), 109.4 (d, J = 25.7 Hz), 140.7 (d, J = 23.4 Hz), 103.2 (d, J = 4.1 Hz), 14.1. 19F NMR (376 MHz, CDCl3, δ): −124.0 (s, 1F). IR (neat) υmax: 2921, 1585, 1466, 1179, 780 cm−1. HRMS (ESI, m/z): [M + H]+ calcd. for C14H12N2F, 227.0985; found, 227.0979. 5-Chloro-2-methyl-1-(pyridin-2-yl)-1H-indole 3c, Table 2. Column chromatography (SiO2, eluting with 19:1 hexane/ethyl acetate) afforded the desired product as a yellow liquid (39 mg, 80%).1H NMR (600 MHz, CDCl3, δ): 8.67 (dd, J1 = 4.8 Hz, J2 = 1.8 Hz, 1H), 7.90 (td, J1 = 7.8 Hz, J2 = 1.8 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.33−7.36 (m, 1H), 7.30 (d, J = 9.0 Hz, 1H), 7.08 (dd, J1 = 9.0 Hz, J2 = 2.4 Hz, 1H), 6.38 (s, 1H), 2.46 (s, 3H). 13C NMR (150 MHz, CDCl3, δ): 151.0, 149.6, 138.4, 138.2, 135.5, 129.8, 126.1, 122.2, 121.6, 120.7, 119.1, 111.3, 102.8, 14.0. IR (neat) υmax: 2923, 1582, 1455, 1378, 786 cm−1. HRMS (ESI, m/z): [M + H]+ calcd. for C14H12N2Cl, 243.0689; found, 243.0693. Methyl 2-methyl-1-(pyridin-2-yl)-1H-indole-5-carboxylate 3d, Table 2. Column chromatography (SiO2, eluting with 9:1 hexane/ ethyl acetate) afforded the desired product as a white solid (50 mg, 94%). mp 64−66 °C. 1H NMR (600 MHz, CDCl3, δ): 8.70 (dd, J1 = 4.8 Hz, J2 = 1.8 Hz, 1H), 8.32 (d, J = 1.8 Hz, 1H), 7.94 (td, J1 = 7.8 Hz, J2 =

1.8 Hz, 1H), 7.84 (dd, J1 = 9.0 Hz, J2 = 1.8 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.38−7.40 (m, 1H), 7.36 (d, J = 9.0 Hz, 1H), 6.52 (s, 1H), 3.94 (s, 3H), 2.47 (s, 3H). 13C NMR (150 MHz, CDCl3, δ): 168.1, 150.9, 149.7, 139.6, 138.5, 138.4, 128.2, 123.1, 122.6, 122.5, 122.4, 121.0, 110.0, 104.1, 51.8, 13.9. IR (neat) υmax: 2923, 1712, 1578, 1441, 1299, 775 cm−1. HRMS (EI, m/z): [M]+ calcd. for C16H14N2O2, 266.1055; found, 266.1055. N-(2-Methyl-1-(pyridin-2-yl)-1H-indol-5-yl)pivalamide 3e, Table 2. Column chromatography (SiO2, eluting with 7:3 hexane/ethyl acetate) afforded the desired product as a yellow solid (39 mg, 64%). mp 128−130 °C. 1H NMR (600 MHz, CDCl3, δ): 8.66 (dd, J1 = 5.4 Hz, J2 = 1.8 Hz, 1H), 7.89 (td, J1 = 7.8 Hz, J2 = 1.8 Hz, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.31−7.33 (m, 2H), 7.16 (dd, J1 = 9.0 Hz, J2 = 2.4 Hz, 1H), 6.38 (s, 1H), 2.46 (s, 3H), 1.35 (s, 9H). 13C NMR (150 MHz, CDCl3, δ): 176.4, 151.3, 149.5, 138.2, 137.7, 134.3, 131.4, 129.0, 121.8, 120.6, 115.3, 111.6, 110.3, 103.5, 39.4, 27.7, 14.1. IR (neat) υmax: 3338, 2920, 1655, 1584, 1471, 1208 cm−1. HRMS (EI, m/ z): [M]+ calcd. for C19H21N3O, 307.1685; found, 307.1684. 2,6-Dimethyl-1-(pyridin-2-yl)-1H-indole 3f, Table 2. Column chromatography (SiO2, eluting with 19:1 hexane/ethyl acetate) afforded the desired product as a yellow liquid (28 mg, 63%). 1H NMR (300 MHz, CDCl3, δ): 8.69 (dd, J1 = 4.2 Hz, J2 = 1.8 Hz, 1H), 7.91 (td, J1 = 7.5 Hz, J2 = 1.8 Hz, 1H), 7.42−7.47 (m, 2H), 7.30−7.35 (m, 1H), 7.21 (s, 1H), 6.99 (dd, J1 = 8.1 Hz, J2 = 1.5 Hz, 1H), 6.39 (s, 1H), 2.46 (s, 3H), 2.44 (s, 3H). 13C NMR (75 MHz, CDCl3, δ): 151.5, 149.5, 138.2, 137.5, 136.0, 131.3, 126.5, 122.2, 121.7, 120.9, 119.3, 110.3, 10−3.1, 21.8, 13.9. IR (neat) υmax: 2921, 1692, 1582, 1467, 773 cm−1. HRMS (EI, m/z): [M]+ calcd. for C15H14N2, 222.1157; found, 222.1134. 7-Fluoro-2-methyl-1-(pyridin-2-yl)-1H-indole 3g, Table 2. Column chromatography (SiO2, eluting with 19:1 hexane/ethyl acetate) afforded the desired product as a yellow liquid (26 mg, 58%). 1H NMR (600 MHz, CDCl3, δ): 8.63 (dd, J1 = 5.4 Hz, J2 = 2.4 Hz, 1H), 7.87 (td, J1 = 7.8 Hz, J2 = 1.8 Hz, 1H), 7.36−7.41 (m, 2H), 7.34 (d, J = 7.8 Hz, 1H), 7.02−7.05 (m, 1H), 6.81−6.85 (m, 1H), 6.45 (s, 1H), 2.36 (s, 3H). 13C NMR (150 MHz, CDCl3, δ): 151.7, 149.3 (d, J = 243.8 Hz), 148.7, 138.6, 137.8, 132.5 (d, J = 4.8 Hz), 124.7 (d, J = 8.7 Hz), 122.7, 122.2 (d, J = 4.4 Hz), 120.5 (d, J = 6.9 Hz), 115.5 (d, J = 3.5 Hz), 107.5 (d, J = 18.0 Hz), 103.0 (d, J = 1.5 Hz), 13.5. 19F NMR (376 MHz, CDCl3, δ): −129.2 (s, 1F). IR (neat) υmax: 2924, 1576, 1471, 1174, 767 cm−1. HRMS (EI, m/z): [M]+ calcd. for C14H11N2F, 226.0906; found, 226.0901. 2-Methyl-1-(pyridin-2-yl)-6-(trifluoromethyl)-1H-indole 3h, Table 2. Column chromatography (SiO2, eluting with 19:1 hexane/ethyl acetate) afforded the desired product as a colorless liquid (34 mg, 62%). 1 H NMR (600 MHz, CDCl3, δ): 8.71 (dd, J1 = 5.4 Hz, J2 = 2.4 Hz, 1H), 7.95 (td, J1 = 7.8 Hz, J2 = 2.4 Hz, 1H), 7.63−7.65 (m, 2H), 7.43 (d, J = 8.4 Hz, 1H), 7.38−7.42 (m, 2H), 6.50 (s, 1H), 2.49 (s, 3H). 13C NMR (150 MHz, CDCl3, δ): 150.7, 149.8, 139.7, 138.6, 136.1, 131.1, 125.2 (q, J = 269.7 Hz), 123.5 (q, J = 31.7 Hz), 122.6, 120.9, 119.9, 117.4 (q, J = 3.6 Hz), 107.8 (q, J = 4.4 Hz), 103.3, 14.0. 19F NMR (376 MHz, CDCl3, δ): −60.3 (s, 3F). IR (neat) υmax: 2924, 1585, 1443, 1331, 1114, 823 cm−1. HRMS (ESI, m/z): [M + H]+ calcd. for C15H12F3N2, 277.0953; found, 277.0951. 2-Methyl-1-(pyridin-2-yl)-1H-indol-5-yl acetate 3i, Table 2. Column chromatography (SiO2, eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a white solid (46 mg, 87%). mp 74−76 °C. 1H NMR (300 MHz, CDCl3, δ): 8.66 (d, J = 4.8 Hz, 1H), 7.89 (td, J1 = 7.8 Hz, J2 = 2.1 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.30−7.35 (m, 2H), 7.24 (d, J = 2.4 Hz, 1H), 6.83 (dd, J1 = 8.7 Hz, J2 = 2.4 Hz, 1H), 6.40 (s, 1H), 2.45 (s, 3H), 2.31 (s, 3H). 13C NMR (75 MHz, CDCl3, δ): 170.4, 151.2, 149.6, 145.0, 138.3, 138.2, 135.0, 129.1, 122.1, 120.7, 115.3, 111.9, 110.7, 103.4, 21.2, 14.1. IR (neat) υmax: 2922, 1753, 1585, 1465, 1216, 754 cm−1. HRMS (EI, m/z): [M]+ calcd. for C16H14N2O2, 266.1055; found, 266.1052. 2-Methyl-5-nitro-1-(pyridin-2-yl)-1H-indole 3j, Table 2. Column chromatography (SiO2, eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a yellow liquid solid (37 mg, 74%). mp 142−144 °C. 1H NMR (300 MHz, CDCl3, δ): 8.71 (dd, J1 = 5.4 Hz, J2 = 2.1 Hz, 1H), 8.50 (d, J = 2.1 Hz, 1H), 7.94−8.05 (m, 2H), 7.41−7.45 (m, 2H), G

DOI: 10.1021/acs.joc.8b01034 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry

754 cm−1. HRMS (EI, m/z): [M]+ calcd. for C15H13ClN2, 256.0767; found, 256.0766. 6-Methoxy-2,5-dimethyl-1-(pyridin-2-yl)-1H-indole 3q, Table 2. Column chromatography (SiO2, eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a white solid (28 mg, 55%). mp 88−90 °C. 1H NMR (600 MHz, CDCl3, δ): 8.69 (dd, J1 = 4.8 Hz, J2 = 1.8 Hz, 1H), 7.90 (td, J1 = 7.8 Hz, J2 = 2.4 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.31−7.33 (m, 1H), 7.29 (s, 1H), 6.90 (s, 1H), 6.30 (s, 1H), 3.80 (s, 3H), 2.43 (s, 3H), 2.32 (s, 3H). 13C NMR (150 MHz, CDCl3, δ): 154.6, 151.8, 149.5, 138.2, 136.2, 134.8, 122.1, 121.6, 120.73, 120.66, 120.5, 102.8, 92.8, 55.6, 16.7, 14.0. IR (neat) υmax: 2920, 1583, 1471, 1376, 1202, 779 cm−1. HRMS (EI, m/z): [M]+ calcd. for C16H16N2O, 252.1263; found, 252.1259. 1-(2-Methyl-1-(pyridin-2-yl)-1H-indol-5-yl)ethanone 3r, Table 2. Column chromatography (SiO2, eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a colorless liquid (37 mg, 74%). 1H NMR (600 MHz, CDCl3, δ): 8.69 (d, J = 3.6 Hz, 1H), 8.22 (s, 1H), 7.93 (t, J = 7.8 Hz, 1H), 7.80 (d, J = 9.0 Hz, 1H), 7.42 (dd, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H), 7.36−7.39 (m, 2H), 6.53 (s, 1H), 2.67 (s, 3H), 2.46 (s, 3H). 13C NMR (150 MHz, CDCl3, δ): 198.3, 150.8, 149.7, 139.7, 138.6, 138.5, 130.6, 128.2, 122.5, 122.0, 121.7, 120.9, 110.1, 104.3, 26.7, 14.0. IR (neat) υmax: 2921, 1669, 1588, 1469, 1364, 786 cm−1. HRMS (ESI, m/z): [M + Na]+ calcd. for C16H14N2ONa, 273.1004; found, 273.1010. 5-(tert-Butyl)-2-methyl-1-(pyridin-2-yl)-1H-indole 3s, Table 2. Column chromatography (SiO2, eluting with 19:1 hexane/ethyl acetate) afforded the desired product as a yellow liquid (38 mg, 72%). 1H NMR (600 MHz, CDCl3, δ): 8.66 (dd, J1 = 4.8 Hz, J2 = 1.8 Hz, 1H), 7.88 (td, J1 = 7.8 Hz, J2 = 1.8 Hz, 1H), 7.58 (d, J = 1.8 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.29−7.31 (m, 1H), 7.23 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 6.41 (s, 1H), 2.48 (s, 3H), 1.41 (s, 9H). 13C NMR (150 MHz, CDCl3, δ): 151.6, 149.5, 143.6, 138.1, 136.8, 135.2, 128.5, 121.5, 120.4, 119.6, 115.8, 109.7, 103.4, 34.5, 31.9, 14.1. IR (neat) υmax: 2954, 1583, 1473, 1375, 783 cm−1. HRMS (ESI, m/z): [M + Na]+ calcd. for C18H20N2Na, 287.1524; found, 287.1525. 2-Methyl-1-(pyridin-2-yl)-5-(trifluoromethoxy)-1H-indole 3t, Table 2. Column chromatography (SiO2, eluting with 9:1 hexane/ ethyl acetate) afforded the desired product as a colorless liquid (34 mg, 58%). 1H NMR (600 MHz, CDCl3, δ): 8.68 (dd, J1 = 5.4 Hz, J2 = 1.8 Hz, 1H), 7.92 (td, J1 = 7.8 Hz, J2 = 1.8 Hz, 1H), 7.40−7.42 (m, 2H), 7.34−7.37 (m, 2H), 7.00 (dd, J1 = 8.4 Hz, J2 = 1.8 Hz, 1H), 6.44 (s, 1H), 2.47 (s, 3H). 13C NMR (150 MHz, CDCl3, δ): 151.0, 149.7, 143.6, 138.7, 138.4, 135.4, 128.9, 122.3, 120.8 (q, J = 253.7 Hz), 120.7, 115.2, 112.1, 110.9, 103.3, 14.0. 19F NMR (376 MHz, CDCl3, δ): −58.0 (s, 3F). IR (neat) υmax: 2924, 1585, 1466, 1262, 1163, 782 cm−1. HRMS (EI, m/z): [M]+ calcd. for C15H11F3N2O, 292.0823; found, 292.0822. 5-((tert-Butyldimethylsilyl)oxy)-2-methyl-1-(pyridin-2-yl)-1H-indole 3u, Table 2. Column chromatography (SiO2, eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a colorless liquid (41 mg, 60%). 1H NMR (600 MHz, CDCl3, δ): 8.65 (dd, J1 = 7.8 Hz, J2 = 1.8 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.26−7.31 (m, 2H), 7.00 (d, J = 1.8 Hz, 1H), 6.69 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 6.33 (s, 1H), 2.46 (s, 3H), 1.02 (s, 9H), 0.21 (s, 6H). 13C NMR (150 MHz, CDCl3, δ): 151.6, 150.0, 149.4, 138.1, 137.2, 132.7, 129.4, 121.5, 120.4, 115.3, 110.6, 109.6, 103.1, 25.8, 18.2, 14.1, −4.4. IR (neat) υmax: 2929, 1583, 1466, 1261, 1198, 864 cm−1. HRMS (EI, m/z): [M]+ calcd. for C20H26N2OSi, 338.1814; found, 338.1804. 4-Methoxy-2-methyl-1-(pyridin-2-yl)-1H-indole 3v, Table 2. Column chromatography (SiO2, eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a yellow liquid (18 mg, 37%). 1H NMR (300 MHz, CDCl3, δ): 8.66 (dd, J1 = 4.8 Hz, J2 = 1.2 Hz, 1H), 7.87 (td, J1 = 7.5 Hz, J2 = 1.8 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.28−7.33 (m, 1H), 6.98−7.08 (m, 2H), 6.57 (dd, J1 = 7.2 Hz, J2 = 1.2 Hz, 1H), 6.53 (s, 1H), 3.97 (s, 3H), 2.45 (s, 3H). 13C NMR (150 MHz, CDCl3, δ): 152.5, 151.5, 149.5, 138.4, 138.2, 135.2, 122.2, 121.9, 120.9, 119.0, 103.8, 100.8, 100.3, 55.4, 13.9. IR (neat) υmax: 2926, 1583, 1447, 1254, 1098, 766 cm−1. HRMS (EI, m/z): [M]+ calcd. for C15H14N2O, 238.1106; found, 238.1104. 6-Methoxy-2-methyl-1-(pyridin-2-yl)-1H-indole 3v′, Table 2. Column chromatography (SiO2, eluting with 9:1 hexane/ethyl acetate)

7.35 (d, J = 9.3 Hz, 1H), 6.58 (s, 1H), 2.46 (s, 3H). 13C NMR (75 MHz, CDCl3, δ): 150.2, 149.9, 142.3, 140.4, 140.0, 138.7, 128.0, 123.1, 121.0, 117.2, 116.6, 110.2, 104.6, 13.9. IR (neat) υmax: 2917, 1577, 1512, 1464, 1334, 777 cm−1. HRMS (EI, m/z): [M]+ calcd. for C14H11N3O2, 253.0851; found, 253.0855. Methyl 2-(2-methyl-1-(pyridin-2-yl)-1H-indol-5-yl)acetate 3k, Table 2. Column chromatography (SiO2, eluting with 8:2 hexane/ ethyl acetate) afforded the desired product as a colorless liquid (45 mg, 81%). 1H NMR (600 MHz, CDCl3, δ): 8.66 (dd, J1 = 4.8 Hz, J2 = 1.8 Hz, 1H), 7.88 (td, J1 = 7.8 Hz, J2 = 1.8 Hz, 1H), 7.47 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.30−7.32 (m, 1H), 7.06 (dd, J1 = 8.4 Hz, J2 = 1.8 Hz, 1H), 6.40 (s, 1H), 3.73 (s, 2H), 3.70 (s, 3H), 2.47 (s, 3H). 13C NMR (150 MHz, CDCl3, δ): 172.8, 151.4, 149.5, 138.2, 137.3, 136.3, 129.0, 126.2, 122.8, 121.8, 120.6, 120.3, 110.3, 103.2, 51.9, 41.3, 14.0. IR (neat) υmax: 2920, 1735, 1582, 1470, 1155, 786 cm−1. HRMS (EI, m/z): [M]+ calcd. for C17H16N2O2, 280.1212; found, 280.1218. 2,5-Dimethyl-1-(pyridin-2-yl)-1H-indole 3l, Table 2. Column chromatography (SiO2, eluting with 19:1 hexane/ethyl acetate) afforded the desired product as a colorless liquid (34 mg, 76%). 1H NMR (600 MHz, CDCl3, δ): 8.67 (dd, J1 = 4.8 Hz, J2 = 1.8 Hz, 1H), 7.88 (td, J1 = 7.8 Hz, J2 = 1.8 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.37 (s, 1H), 7.29−7.31 (m, 2H), 6.97 (dd, J1 = 8.4 Hz, J2 = 1.8 Hz, 1H), 6.37 (s, 1H), 2.48 (s, 3H), 2.46 (s, 3H). 13C NMR (150 MHz, CDCl3, δ): 151.6, 149.5, 138.1, 136.8, 135.4, 129.9, 129.0, 122.9, 121.6, 120.5, 119.5, 109.9, 103.0, 21.4, 14.1. IR (neat) υmax: 2926, 1586, 1378, 1175, 773 cm−1. HRMS (EI, m/z): [M]+ calcd. for C15H14N2, 222.1157; found, 222.1157. 2-Methyl-5-phenyl-1-(pyridin-2-yl)-1H-indole 3m, Table 2. Column chromatography (SiO2, eluting with 19:1 hexane/ethyl acetate) afforded the desired product as a colorless solid (45 mg, 80%). mp 116−118 °C. 1H NMR (600 MHz, CDCl3, δ): 8.70 (dd, J1 = 4.8 Hz, J2 = 1.8 Hz, 1H), 7.93 (t, 1H), 7.80 (d, J = 1.8 Hz, 1H), 7.66−7.68 (m, 2H), 7.44−7.48 (m, 4H), 7.39−7.40 (m, 1H), 7.31−7.36 (m, 2H), 6.49 (s, 1H), 2.51 (s, 3H). 13C NMR (150 MHz, CDCl3, δ): 151.4, 149.5, 142.4, 138.3, 137.5, 136.6, 134.1, 129.2, 128.6, 127.3, 126.3, 121.9, 121.3, 120.7, 118.3, 110.5, 103.7, 14.1. IR (neat) υmax: 2919, 1581, 1466, 1375, 756 cm−1. HRMS (EI, m/z): [M]+ calcd. for C20H16N2, 284.1313; found, 284.1311. 2-Methyl-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-indole 3n, Table 2. Column chromatography (SiO2, eluting with 19:1 hexane/ethyl acetate) afforded the desired product as a colorless liquid (40 mg, 65%). 1 H NMR (600 MHz, CDCl3, δ): 8.70 (dd, J1 = 4.8 Hz, J2 = 1.8 Hz, 1H), 7.93 (td, J1 = 7.8 Hz, J2 = 1.8 Hz, 1H), 7.86 (s, 1H), 7.36−7.43 (m, 4H), 6.51 (s, 1H), 2.48 (s, 3H). 13C NMR (150 MHz, CDCl3, δ): 150.8, 149.8, 138.8, 138.48, 138.46, 128.1, 125.3 (q, J = 270.0 Hz), 122.9 (q, J = 31.4 Hz), 122.5, 120.9, 118.3 (q, J = 3.6 Hz), 117.3 (q, J = 4.1 Hz), 110.4, 103.6, 13.9. 19F NMR (376 MHz, CDCl3, δ): −60.3 (s, 3F). IR (neat) υmax: 2921, 1582, 1467, 1217, 775 cm−1. HRMS (EI, m/z): [M]+ calcd. for C15H11N2F3, 276.0874; found, 276.0872. 5-Chloro-2-methyl-1-(pyridin-2-yl)-6-(trifluoromethyl)-1H-indole 3o, Table 2. Column chromatography (SiO2, eluting with 9:1 hexane/ ethyl acetate) afforded the desired product as a yellow solid (38 mg, 62%). mp 86−88 °C. 1H NMR (600 MHz, CDCl3, δ): 8.71 (s, 1H), 7.96 (td, J1 = 7.2 Hz, J2 = 1.8 Hz, 1H), 7.67 (s, 1H), 7.65 (s, 1H), 7.39− 7.43 (m, 2H), 6.42 (s, 1H), 2.48 (s, 3H). 13C NMR (150 MHz, CDCl3, δ): 150.3, 149.9, 141.2, 138.7, 134.4, 131.7, 123.8 (q, J = 270.5 Hz), 123.3, 122.9, 121.9, 120.8, 120.7 (q, J = 30.8 Hz), 110.0 (q, J = 7.35 Hz), 102.7, 14.0. 19F NMR (376 MHz, CDCl3, δ): −60.6 (s, 3F). IR (neat) υmax: 2922, 1585, 1437, 1288, 1128, 760 cm−1. HRMS (EI, m/z): [M]+ calcd. for C15H10ClF3N2, 310.0485; found, 310.0486. 6-Chloro-2,5-dimethyl-1-(pyridin-2-yl)-1H-indole 3p, Table 2. Column chromatography (SiO2, eluting with 19:1 hexane/ethyl acetate) afforded the desired product as a colorless liquid (32 mg, 62%). 1H NMR (600 MHz, CDCl3, δ): 8.66 (dd, J1 = 4.8 Hz, J2 = 1.8 Hz, 1H), 7.89 (td, J1 = 7.8 Hz, J2 = 2.1 Hz, 1H), 7.30−7.40 (m, 4H), 6.32 (s, 1H), 2.44 (s, 3H), 2.44 (s, 3H). 13C NMR (150 MHz, CDCl3, δ): 151.1, 149.6, 138.4, 137.4, 136.1, 128.1, 127.9, 127.6, 122.0, 120.9, 120.5, 110.7, 102.8, 20.3, 14.0. IR (neat) υmax: 2921, 1584, 1465, 1376, H

DOI: 10.1021/acs.joc.8b01034 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry afforded the desired product as a yellow liquid (13 mg, 28%). 1H NMR (300 MHz, CDCl3, δ): 8.67 (dd, J1 = 5.1 Hz, J2 = 1.5 Hz, 1H), 7.89 (td, J1 = 7.5 Hz, J2 = 1.8 Hz, 1H), 7.40−7.43 (m, 2H), 7.29−7.34 (m, 1H), 6.92 (d, J = 2.4 Hz, 1H), 6.79 (dd, J1 = 8.7 Hz, J2 = 2.4 Hz, 1H), 6.34 (s, 1H), 3.79 (s, 3H), 2.41 (s, 3H). 13C NMR (150 MHz, CDCl3, δ): 156.1, 151.5, 149.6, 138.2, 137.8, 135.6, 122.9, 121.8, 120.7, 120.1, 109.6, 103.0, 94.9, 55.8, 14.0. IR (neat) υmax: 2922, 1579, 1440, 1203, 1029, 775 cm−1. HRMS (EI, m/z): [M]+ calcd. for C15H14N2O, 238.1106; found, 238.1084. 2-Ethyl-1-(pyridin-2-yl)-1H-indole 3w, Table 2. Column chromatography (SiO2, eluting with 19:1 hexane/ethyl acetate) afforded the desired product as a colorless liquid (12 mg, 28%). 1H NMR (600 MHz, CDCl3, δ): 8.68 (dd, J1 = 5.4 Hz, J2 = 1.8 Hz, 1H), 7.90 (td, J1 = 7.2 Hz, J2 = 1.8 Hz, 1H), 7.59−7.61 (m, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.33−7.36 (m, 2H), 7.13−7.16 (m, 2H), 6.48 (s, 1H), 2.88 (q, J = 7.8 Hz, 2H), 1.25 (t, 3H). 13C NMR (150 MHz, CDCl3, δ): 151.5, 149.6, 143.2, 138.2, 137.3, 128.6, 122.0, 121.5, 121.1, 120.5, 119.9, 110.0, 101.2, 20.9, 12.8. IR (neat) υmax: 2922, 1585, 1458, 1374, 756 cm−1. HRMS (EI, m/z): [M]+ calcd. for C15H14N2, 222.1157; found, 222.1157. General Experimental Procedure for Ruthenium-Catalyzed 2Methylindoline Synthesis from the Corresponding N-Aryl Pyrimidines and Allyl Acetates. A mixture of N-aryl pyrimidine (0.2 mmol), [Ru(p-cymene)Cl2]2 (0.01 mmol, 5 mol %), and AgSbF6 (0.04 mmol, 20 mol %) was taken in a 15 mL pressure tube. To this reaction mixture, trifluoroethanol (TFE) (2.0 mL) and the corresponding allyl acetate (0.4 mmol) were added via micro syringe, and the closed reaction mixture was allowed to stir at 120 °C for 16 h. After completion as indicated by TLC, the reaction mixture was cooled to ambient temperature. After dilution with dichloromethane, the reaction mixture was completely transferred to a RB flask and concentrated under reduced pressure. The crude product was purified by column chromatography using ethyl acetate/hexane as the eluent to afford the desired indoline product. 7-Chloro-2-methyl-1-(pyrimidin-2-yl)indoline 5a, Table 4. Column chromatography (SiO2, eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a white solid (40 mg, 82%). mp 100− 102 °C. 1H NMR (600 MHz, CDCl3, δ): 8.49 (d, J = 4.8 Hz, 2H), 7.25 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 6.99 (t, J = 9.1 Hz, 1H), 6.77 (t, J = 4.8 Hz, 1H), 4.89−4.94 (m, 1H), 3.54 (dd, J1 = 15.6 Hz, J2 = 8.4 Hz, 1H), 2.57 (d, J = 15.6 Hz, 1H), 1.44 (d, J = 6.6 Hz, 3H). 13C NMR (150 MHz, CDCl3, δ): 160.3, 157.4, 140.2, 135.7, 128.9, 124.5, 124.1, 123.4, 113.2, 61.3, 37.3, 21.6. IR (neat) υmax: 2976, 1568, 1458, 1050, 770 cm−1. HRMS (EI, m/z): [M]+ calcd. for C13H12N3Cl, 245.0720; found, 245.0721. 7-Bromo-2-methyl-1-(pyrimidin-2-yl)indoline 5b, Table 4. Column chromatography (SiO2, eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a white solid (45 mg, 78%). mp 118− 120 °C. 1H NMR (600 MHz, CDCl3, δ): 8.50 (d, J = 4.8 Hz, 2H), 7.43 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 7.2 Hz, 1H), 6.91 (t, J = 8.4 Hz, 1H), 6.78 (t, J = 4.8 Hz, 1H), 4.90−4.94 (m, 1H), 3.55 (dd, J1 = 15.0 Hz, J2 = 7.8 Hz, 1H), 2.57 (d, J = 15.6 Hz, 1H), 1.44 (d, J = 6.6 Hz, 3H). 13C NMR (150 MHz, CDCl3, δ): 160.1, 157.4, 142.0, 135.9, 131.9, 124.8, 124.0, 113.3, 113.2, 61.4, 37.4, 21.6. IR (neat) υmax: 2972, 1564, 1415, 1215, 1049, 769 cm−1. HRMS (EI, m/z): [M]+ calcd. for C13H12BrN3, 289.0215; found, 289.0215. 2,7-Dimethyl-1-(pyrimidin-2-yl)indoline 5c, Table 4. Column chromatography (SiO2, eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a white solid (37 mg, 82%). mp 94−96 °C. 1H NMR (300 MHz, CDCl3, δ): 8.43 (d, J = 4.5 Hz, 2H), 6.96−7.10 (m, 3H), 6.68 (t, J = 4.5 Hz, 1H), 4.91−5.00 (m, 1H), 3.47 (dd, J1 = 15.3 Hz, J2 = 8.1 Hz, 1H), 2.50 (d, J = 15.3 Hz, 1H), 2.19 (s, 3H), 1.38 (d, J = 6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3, δ): 160.8, 157.6, 141.4, 133.1, 129.5, 128.5, 123.9, 122.4, 112.1, 60.5, 37.0, 21.3, 20.8. IR (neat) υmax: 2922, 1577, 1429, 1189, 760 cm−1. HRMS (EI, m/z): [M]+ calcd. for C14H15N3, 225.1266; found, 225.1245. 6-Chloro-2,7-dimethyl-1-(pyrimidin-2-yl)indoline 5d, Table 4. Column chromatography (SiO2, eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a white solid (41 mg, 80%). mp 56−58 °C. 1H NMR (300 MHz, CDCl3, δ): 8.43 (d, J = 4.8 Hz, 2H), 7.09 (d, J

= 8.1 Hz, 1H), 7.00 (d, J = 7.8 Hz, 1H), 6.71 (t, J = 4.8 Hz, 1H), 4.94− 5.03 (m, 1H), 3.43 (dd, J1 = 15.6 Hz, J2 = 8.4 Hz, 1H), 2.47 (d, J = 15.6 Hz, 1H), 2.14 (s, 3H), 1.39 (d, J = 6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3, δ): 160.9, 157.6, 143.0, 133.6, 131.7, 127.0, 124.6, 122.7, 112.6, 61.2, 36.7, 21.4, 18.6. IR (neat) υmax: 2967, 1572, 1448, 1176, 788 cm−1. HRMS (EI, m/z): [M]+ calcd. for C14H14N3Cl, 259.0876; found, 259.0871. 2,5,7-Trimethyl-1-(pyrimidin-2-yl)indoline 5e, Table 4. Column chromatography (SiO2, eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a white solid (27 mg, 56%). mp 78−80 °C. 1H NMR (600 MHz, CDCl3, δ): 8.43 (d, J = 4.8 Hz, 2H), 6.92 (s, 1H), 6.90 (s, 1H), 6.67 (t, J = 4.8 Hz, 1H), 4.94−4.99 (m, 1H), 3.45 (dd, J1 = 15.6 Hz, J2 = 8.4 Hz, 1H), 2.46 (d, J = 15.6 Hz, 1H), 2.32 (s, 3H), 2.18 (s, 3H), 1.39 (d, J = 6.6 Hz, 3H). 13C NMR (150 MHz, CDCl3, δ): 161.0, 157.6, 139.0, 133.5, 133.2, 130.0, 128.2, 123.1, 111.9, 60.6, 37.0, 21.3, 21.0, 20.6. IR (neat) υmax: 2951, 1579, 1426, 1191, 793 cm−1. HRMS (ESI, m/z): [M + H]+ calcd. for C15H18N3, 240.1501; found, 240.1494. 7-Methoxy-2-methyl-1-(pyrimidin-2-yl)indoline 5f, Table 4. Column chromatography (SiO2, eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a white solid (34 mg, 72%). mp 142− 144 °C. 1H NMR (300 MHz, CDCl3, δ): 8.42 (d, J = 4.8 Hz, 2H), 7.01−7.06 (m, 1H), 6.87−6.90 (m, 2H), 6.68 (t, J = 4.8 Hz, 1H), 4.85− 4.94 (m, 1H), 3.84 (s, 3H), 3.50 (dd, J1 = 15.3 Hz, J2 = 8.4 Hz, 1H), 2.52 (dd, J1 = 15.3 Hz, J2 = 1.2 Hz, 1H), 1.07 (d, J = 6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3, δ): 160.7, 157.3, 150.2, 134.7, 131.4, 124.7, 117.7, 112.3, 112.2, 60.9, 55.9, 37.3, 21.5. IR (neat) υmax: 2941, 1561, 1430, 1271, 1078, 768 cm−1. HRMS (EI, m/z): [M]+ calcd. for C14H15N3O, 241.1215; found, 241.1218. 7-Ethyl-2-methyl-1-(pyrimidin-2-yl)indoline 5g, Table 4. Column chromatography (SiO2, eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a colorless liquid (30 mg, 63%). 1H NMR (300 MHz, CDCl3, δ): 8.42 (d, J = 4.8 Hz, 2H), 7.02−7.15 (m, 3H), 6.67 (t, J = 4.8 Hz, 1H), 4.94−5.04 (m, 1H), 3.46 (dd, J1 = 15.0 Hz, J2 = 8.1 Hz, 1H), 2.61 (q, J = 7.5 Hz, 2H), 2.48 (d, J = 15.3 Hz, 1H), 1.37 (d, J = 6.6 Hz, 3H), 1.13 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3, δ): 160.9, 157.5, 140.5, 134.5, 133.3, 127.3, 124.2, 122.4, 112.2, 60.4, 36.8, 26.6, 21.0, 13.3. HRMS (ESI, m/z): [M + H]+ calcd. for C15H18N3, 240.1501; found, 240.1496. 2-Methyl-7-propyl-1-(pyrimidin-2-yl)indoline 5h, Table 4. Column chromatography (SiO2, eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a colorless liquid (18 mg, 35%). 1H NMR (300 MHz, CDCl3, δ): 8.42 (d, J = 4.8 Hz, 2H), 6.99−7.11 (m, 3H), 6.67 (t, J = 4.8 Hz, 1H), 4.94−5.04 (m, 1H), 3.44 (dd, J1 = 15.3 Hz, J2 = 8.1 Hz, 1H), 2.45−2.70 (m, 3H), 1.52−1.64 (m, 2H), 1.36 (d, J = 6.6 Hz, 3H), 0.77 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3, δ): 157.7, 140.9, 133.6, 133.3, 128.5, 124.4, 122.7, 112.3, 100.1, 60.6, 37.0, 36.2, 22.2, 21.1, 14.2. HRMS (ESI, m/z): [M + H]+ calcd. for C16H20N3, 254.1657; found, 254. 1627. 7-Isopropyl-2-methyl-1-(pyrimidin-2-yl)indoline 5i, Table 4. Column chromatography (SiO2, eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a colorless liquid (33 mg, 65%). 1H NMR (600 MHz, CDCl3, δ): 8.42 (d, J = 4.8 Hz, 2H), 7.21−7.28 (m, 1H), 7.10−7.13 (m, 2H), 6.69 (t, J = 4.8 Hz, 1H), 5.02−5.07 (m, 1H), 3.44 (dd, J1 = 15.6 Hz, J2 = 8.4 Hz, 1H), 2.93 (m, 1H), 2.49 (d, J = 15.0 Hz, 1H), 1.42 (d, J = 6.6 Hz, 3H), 1.39 (d, J = 6.6 Hz, 3H), 1.02 (d, J = 6.6 Hz, 3H). 13C NMR (150 MHz, CDCl3, δ): 161.5, 157.5, 140.0, 139.8, 133.5, 124.8, 124.5, 122.4, 112.3, 60.4, 37.0, 30.1, 24.9, 21.4, 21.1. IR (neat) υmax: 2966, 1580, 1435, 1186, 787 cm−1. HRMS (EI, m/ z): [M]+ calcd. for C16H19N3, 253.1579; found, 253.1578. N-(2-Allyl-6-(tert-butyl)phenyl)pyrimidin-2-amine 6a, Table 4. Column chromatography (SiO2, eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a colorless liquid (35 mg, 65%). 1H NMR (300 MHz, CDCl3, δ): 8.30 (d, J = 5.1 Hz, 2H), 7.41 (dd, J1 = 7.8 Hz, J2 = 1.8 Hz, 1H), 7.20−7.29 (m, 2H), 7.07 (br, s, 1H), 6.57 (t, J = 4.8 Hz, 1H), 5.85−5.98 (m, 1H), 4.93−5.04 (m, 2H), 3.22−3.29 (m, 2H), 1.38 (s, 9H). 13C NMR (75 MHz, CDCl3, δ): 162.1, 158.7, 158.3, 148.3, 140.7, 136.9, 135.1, 128.3, 127.9, 125.5, 116.0, 111.2, 36.8, 35.6, 31.2. HRMS (ESI, m/z): [M + H]+ calcd. for C17H22N3, 268.1814; found, 268. 1807. I

DOI: 10.1021/acs.joc.8b01034 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry N-(3-Allyl-[1,1′-biphenyl]-2-yl)pyrimidin-2-amine 6b, Table 4. Column chromatography (SiO2, eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a colorless liquid (17 mg, 35%). 1H NMR (300 MHz, CDCl3, δ): 8.23 (d, J = 4.8 Hz, 2H), 7.22−7.34 (m, 8H), 6.54 (t, J = 4.8 Hz, 1H), 6.46 (br, s, 1H), 5.93−6.06 (m, 1H), 5.03−5.11(m, 2H), 3.40−3.43 (m, 2H). 13C NMR (75 MHz, CDCl3, δ): 161.5, 158.1, 140.1, 140.0, 138.3, 136.6, 133.8, 129.3, 128.9, 128.8, 128.0, 127.2, 127.0, 116.2, 111.5, 36.7. HRMS (ESI, m/z): [M + H]+ calcd. for C19H18N3, 288.1501; found, 288. 1496. Deprotection of the Directing Group of Indole. Methyl trifluoromethanesulfonate (0.24 mmol, 1.2 equiv) was added dropwise to a solution of 3a (0.20 mmol, 1.0 equiv) in CH2Cl2 (5 mL) at 0 °C, and the resulting solution was stirred for 24 h at room temperature. Then, the solvent was removed under reduced pressure, and the residue was dissolved in MeOH (2.0 mL). A 2 M aq. NaOH solution (2.0 mL) was added to it, and stirring was continued at 60 °C for 10 h. Then, the solvents were removed under reduced pressure, and the resulting residue was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and again concentrated under reduced pressure. The residue was purified by column chromatography to afford the desired indole 7a. 2-Methyl-1H-indole 7a.16 Column chromatography (SiO2, eluting with 19:1 hexane/ethyl acetate) afforded the desired product as a white solid (23 mg, 87%). 1H NMR (300 MHz, CDCl3, δ): 7.77 (br, s, 1H), 7.55 (dd, J1 = 6.9 Hz, J2 = 2.1 Hz, 1H), 7.27−7.30 (m, 1H), 7.08−7.18 (m, 2H), 6.25 (s, 1H), 2.44 (s, 3H). 13C NMR (150 MHz, CDCl3, δ): 135.9, 135.1, 128.9, 120.8, 119.5, 110.2, 100.2, 13.5.

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T.; Abela, A. R.; Lipshutz, B. H. Room Temperature C-H Activation and Cross-Coupling of Aryl Ureas in Water. Angew. Chem., Int. Ed. 2010, 49, 781−784. (d) Nishikata, T.; Abela, A. R.; Huang, S.; Lipshutz, B. H. Cationic Palladium(II) Catalysis: C-H Activation/SuzukiMiyaura Couplings at Room Temperature. J. Am. Chem. Soc. 2010, 132, 4978−4979. (e) Houlden, C. E.; Hutchby, M.; Bailey, C. D.; Ford, J. G.; Tyler, S. N. G.; Gagné, M. R.; Lloyd-Jones, G. C.; BookerMilburn, K. I. Room-Temperature Palladium-Catalyzed C-H Activation: ortho-Carbonylation of Aniline Derivatives. Angew. Chem., Int. Ed. 2009, 48, 1830−1833. (f) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. Selective Pd-Catalyzed Oxidative Coupling of Anilides with Olefins through C-H Bond Activation at Room Temperature. J. Am. Chem. Soc. 2002, 124, 1586−1587. (3) For review, see: (a) Agasti, S.; Dey, A.; Maiti, D. Palladiumcatalyzed benzofuran and indole synthesis by multiple C-H functionalizations. Chem. Commun. 2017, 53, 6544−6556. For selected examples, see: (b) Lu, Q.; Vásquez-Céspedes, S.; Gensch, T.; Glorius, F. Control over Organometallic Intermediate Enables Cp*Co(III) Catalyzed Switchable Cyclization to Quinolines and Indoles. ACS Catal. 2016, 6, 2352−2356. (c) Liu, B.; Song, C.; Sun, C.; Zhou, S.; Zhu, J. Rhodium(III)-Catalyzed Indole Synthesis Using N-N Bond as an Internal Oxidant. J. Am. Chem. Soc. 2013, 135, 16625−16631. (d) Wang, C.; Sun, H.; Fang, Y.; Huang, Y. General and Efficient Synthesis of Indoles through Triazene-Directed C-H Annulation. Angew. Chem., Int. Ed. 2013, 52, 5795−5798. (e) Zhao, D.; Shi, Z.; Glorius, F. Indole Synthesis by Rhodium(III)-Catalyzed HydrazineDirected C-H Activation: Redox-Neutral and Traceless by N-N Bond Cleavage. Angew. Chem., Int. Ed. 2013, 52, 12426−12429. (f) Ackermann, L.; Lygin, A. V. Cationic Ruthenium(II) Catalysts for Oxidative C−H/N−H Bond Functionalizations of Anilines with Removable Directing Group: Synthesis of Indoles in Water. Org. Lett. 2012, 14, 764−767. (g) Chen, J.; Song, G.; Pan, C.-L.; Li, X. Rh(III)-Catalyzed Oxidative Coupling of N-Aryl-2-aminopyridine with Alkynes and Alkenes. Org. Lett. 2010, 12, 5426−5429. (h) Stuart, D. R.; BertrandLaperle, M.; Burgess, K. M. N.; Fagnou, K. Indole Synthesis via Rhodium Catalyzed Oxidative Coupling of Acetanilides and Internal Alkynes. J. Am. Chem. Soc. 2008, 130, 16474−16475. (4) Gao, Y.; Huang, Y.; Wu, W.; Huang, K.; Jiang, H. Pd-Catalyzed CH activation/oxidative cyclization of acetanilide with norbornene: concise access to functionalized indolines. Chem. Commun. 2014, 50, 8370−8373. (5) Houlden, C. E.; Bailey, C. D.; Ford, J. G.; Gagné, M. R.; LloydJones, G. C.; Booker-Milburn, K. I. Distinct Reactivity of Pd(OTs)2: The Intermolecular Pd(II)-Catalyzed 1,2-Carboamination of Dienes. J. Am. Chem. Soc. 2008, 130, 10066−10067. (6) Zhao, D.; Vásquez-Céspedes, S.; Glorius, F. Rhodium(III)Catalyzed Cyclative Capture Approach to Diverse 1-Aminoindoline Derivatives at Room Temperature. Angew. Chem., Int. Ed. 2015, 54, 1657−1661. (7) (a) Takamatsu, K.; Hirano, K.; Satoh, T.; Miura, M. Synthesis of Indolines by Copper-Mediated Intramolecular Aromatic C-H Amination. J. Org. Chem. 2015, 80, 3242−3249. (b) Mei, T. S.; Leow, D.; Xiao, H.; Laforteza, B. N.; Yu, J. Q. Synthesis of Indolines via Pd(II)Catalyzed Amination of C-H Bonds Using PhI(OAc)2 as the Bystanding Oxidant. Org. Lett. 2013, 15, 3058−3061. (c) Li, J.-J.; Mei, T.-S.; Yu, J.-Q. Synthesis of Indolines and Tetrahydroisoquinolines from Arylethylamines by PdII-Catalyzed C-H Activation Reactions. Angew. Chem., Int. Ed. 2008, 47, 6452−6455. (8) Manna, M. K.; Hossian, A.; Jana, R. Merging C−H Activation and Alkene Difunctionalization at Room Temperature: A PalladiumCatalyzed Divergent Synthesis of Indoles and Indolines. Org. Lett. 2015, 17, 672−675. (9) Manna, M. K.; Bhunia, S. K.; Jana, R. Ruthenium(II)-catalyzed intermolecular synthesis of 2-arylindolines through C-H activation/ oxidative cyclization cascade. Chem. Commun. 2017, 53, 6906−6909. (10) Cajaraville, A.; López, S.; Varela, J. A.; Saá, C. Rh(III)-Catalyzed Tandem C-H Allylation and Oxidative Cyclization of Anilides: A New Entry to Indoles. Org. Lett. 2013, 15, 4576−4579.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01034. Mechanistic study, spectral data of 3a′, crystallographic data of 3m and 5c, and 1H and 13C NMR spectra for all synthesized compounds (PDF) X-ray crystallographic data for compound 3m (CIF) X-ray crystallographic data for compound 5c (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Ranjan Jana: 0000-0002-5473-0258 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by DST, SERB, Govt. of India, Ramanujan fellowship (award SR/S2/RJN-97/2012), and extra mural research grant (EMR/2014/000469). M.K.M. and G.B. thank UGC for their fellowships.

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REFERENCES

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DOI: 10.1021/acs.joc.8b01034 J. Org. Chem. XXXX, XXX, XXX−XXX