Sterically Controlled Ru(II)-Catalyzed Divergent Synthesis of 2

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Sterically Controlled Ru(II)-Catalyzed Divergent Synthesis of 2Methylindoles and Indolines through a C-H Allylation/Cyclization Cascade Manash Kumar Manna, Gurupada Bairy, and Ranjan Jana J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01034 • Publication Date (Web): 06 Jun 2018 Downloaded from http://pubs.acs.org on June 6, 2018

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The Journal of Organic Chemistry

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*†,‡ †

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 R=H DCE -hydride elimination

H N R

X

H N

RuII R

X

N

RuIILn

N OAc

Me N

N

R = FG TFE steric-controlled protodemetalation

H

C-H allylation/ cyclization cascade steric-controlled chemoselectivity redox-neutral Ru(II)-catalyst no stoichiometric metal oxidant

N FG

N

N

ABSTRACT: A Ruthenium-catalyzed synthesis of 2-methylindole was accomplished via 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 2methylindolines 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 redox-neutral ruthenium catalyst without stoichiometric metal oxidants such as silver(I) or copper(II) salts providing excellent functional group tolerance. 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 C-H activation methodology has been developed for the synthesis of indoles.3 Direct synthesis of indoline nucleus was also achieved with norbornene that lacks syn β-hydrogen,4 π-allyl stabilization,5

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nucleophilic addition of Rh-alkyl species to N=N bond,6 or intramolecular C-H amination.7 However, divergent synthesis of 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 2arylindole and indolines merging C-H activation and alkene difunctionalization manifolds (Scheme 1a).8 Recently, we have also demonstrated the synthesis of indoline with electronically unbiased styrenes by Ru-catalyst which is reluctant to undergo β-hydride elimination compared to palladium catalyst.9 Although, synthesis of 2-arylindoles via C-H activation has been studied extensively, the synthesis of 2-alkylindoles are less attended. The Saá group has reported an expensive Rh(III)-catalyzed synthesis of 2-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 2-methylindolines. We report herein, a ruthenium(II)-catalyzed synthesis of 2-methylindole from 2-pyridine-protected aniline and allyl acetate via 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, 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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Scheme 1. Divergent Synthesis of Indole and Indoline RESULTS AND DISCUSSION We chose an inexpensive ruthenium-catalyst, N-arylpyrimidine and allyl acetate for initial screening (entry 1, Table 1). To our delight, after heating the reaction mixture at 120 oC in DCE, the desired 2-methylindole (3a) was obtained in 22% yield along with 7% C-3 allylation of 2methylindole (3a’) product as an inseparable mixture (entry 1, table 1). Although, yield of 3a 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, AgNTf2, AgSbF6 (20 mol %) was found to be most effective to generate the active catalyst. Since acetate ion is required to generate active catalyst, several acetate ion sources such as LiOAc, NaOAc, KOAc, CsOAc, AgOAc, Cu(OAc)2 were examined and among them NaOAc was found to be optimal. Finally, 5



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mol % [Ru(p-cymene)Cl2]2, 20 mol % AgSbF6 and 50 mol % NaOAc in DCE at 120 oC provided 82% yield of the desired indole (Table 1). Table 1. Optimization of the Reaction Conditionsa

entry X

Ag(I)

additive solvent

salts

yieldb 3a/3a’

1

N

AgSbF6

-

DCE

22/7

2

N

AgSbF6

NaOAc

DCE

43/13

3

N

AgSbF6

PivOH

DCE

36/11

4

N

AgSbF6

NaOAc

TFE

22/53

5

CH AgSbF6 NaOAc DCE

82/0

6

CH

AgSbF6

PivOH

DCE

67/0

7

CH

AgSbF6

NaOAc

TFE

79/0

8

CH

AgBF4

NaOAc

DCE

43/0

9

CH

AgOTf

NaOAc

DCE

48/0

10

CH

AgSbF6

NaOAc

Toluene 45/0

11

CH

AgSbF6

NaOAc

1,4-

ND

dioxane

a

12c

CH

AgSbF6

NaOAc

DCE

56/0

13d

CH

AgSbF6

NaOAc

DCE

37/0

All reactions were carried out in 0.1 mmol scale. bYields refer 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.


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A wide variety of anilines containing functional groups such as methoxy (3q, 3v, 3v’), OTBDMS (3u), trifluoromethoxy (3t), methyl (3f, 3l, 3p, 3q), tert-butyl (3s), trifluoromethyl (3h, 3n, 3o), aryl (3m) etc. were compatible under these mild reaction conditions. Notably, the annulation reaction took place regioselectively at the ortho position of -NHPy group while NHPiv (3e) remains inert suggesting a strong, electron-rich directing group is necessary for electrophilic ortho metalation. Other weakly coordinating groups such as -CO2Me (3d), -NO2 (3j), -CH2CO2Me (3k), -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, 3g) and chloro (3c, 3o, 3p) are compatible under the reaction conditions. Interestingly, electron-deficient p-nitro aniline also produced the desired product with good yield (3j). Electron-rich m-methoxy aniline furnished a mixture of two regio-isomeric products through ortho metallation 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 lower yield (3w). Interestingly, no double allylation followed by singular cyclization to provide 7-allyl,2methylindole was observed (Table 2). Table 2. Substrate Scope of Indolesa,b




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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 m-methoxy aniline. 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 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 through C-H activation is unknown. Being encouraged by this exciting result we started further optimization to get indoline product exclusively. As expected indoline formation was favoured 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 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). Table 3. Optimization of the Reaction Conditionsa

entry X

Ag(I)

additive solvent yieldb

salts

5c/5c’

1

CH2 AgSbF6

NaOAc

DCE

36/17

2

CH2 AgSbF6

NaOAc

TFE

54/8

3

N

AgSbF6

NaOAc

DCE

43/26

4

N

AgSbF6

NaOAc

TFE

82/trace

5

N

AgSbF6

-

TFE

82/trace



a

All reactions were carried out in 0.1 mmol scale. bYields refer to here are overall isolated yields

and the product distribution was measured from NMR . Although, sterically less hindered fluorine substitution at the ortho position of aniline yielded indole as predominant product (3g), other larger halogens such as ortho chloro (5a) and bromo (5b) substituted anilines provided exclusive indoline products in high yields. Besides halogen, methyl (5c, 5d, 5e), methoxy (5f), isopropyl (5g) substituted aniline at ortho position produces the corresponding indoline products in good yield. Presumably, syn β-hydrogen may not be accessible for elimination instead protoderuthenation occurs in 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 C-H allylation product which do not undergo further cyclization due to steric hindrance. Table 4. Substrate Scope of Indolinesa,b


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H N

R N

[Ru(p-cymene)Cl 2]2 (5 mol %) OAc AgSbF6 (20 mol %) TFE, 16 h 120 oC 2 equiv 2

H + N

4

Me

Me

N Cl

N

Br

N

5a: 82%

R

N

N

5a-5i

Me

N

N

Me N

N N

Me

5b: 78%

N

N

5c: 82%

CCDC:1817992

Me Me

Me

N

Cl Me

N

N

Me

5d: 80% Me Pr

N

N

OMe N

N

N N

5f: 70%

Et

N

N

5g: 63%

Me N

5h: 35% a

N

Me

N

5e: 56%

N n

Me

N

i

Pr

N

5i: 65%

NH N

t

Bu

N

6a: 65%

NH N

Ph

N

N

6b: 35%

All reactions were carried out in 0.2 mmol scale. bYields refer to the average of isolated yields

of at least two experiments. When deuterated 1a-d5 was subjected under standard reaction condition in the absence of olefin 70% ortho D-H exchange was observed (Scheme 2, a). Whereas, in the absence of metal catalyst no D-H exchange was observed, suggesting the involvement of a reversible directed ortho metalation step. A similar experiment in the presence of allyl acetate provided desired product in 80% yield with a 83% D-H exchange at the C-7 position (Scheme 2, b). 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 by taking an equimolecular mixture of 1a and 1a-d5 kH/kD = 1.2 was determined from 1H NMR (Scheme 2, c). 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 2, d) 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 reaction condition to form the annulation product in 84% yield (Scheme 2, e). 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 sequences may be involved for the indole formation (Scheme 2, e). 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 2, f) suggesting a protodemetalation step is involved for the indoline formation.


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Scheme 2. Control Experiments From the control experiments and previous reports,12 the active catalyst is generated from [Ru(pcymene)Cl2]2 in presence of AgSbF6 and NaOAc through the removal of silver chloride which undergoes directed ortho metalation to the substrate in reversible manner to generate the intermediate B. Migratory insertion of the intermediate B to alkene generates an alkyl ruthenium intermediate C which undergoes rapid β-acetoxy elimination to generate a 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 intramolecular C-N bond formation. In case of ortho unsubstituted anilines the intermediate F undergoes a rapid β-hydride elimination and double bond isomerization to produce the desired indole product. But in 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 presumably by the formation of hydrogen gas reacting with AcOH generated in the reaction medium (Scheme 3).13

Scheme 3. Plausible Catalytic Cycle


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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 CONCLUSION In conclusion, we have developed an unprecedented sterically controlled synthesis of 2methylindoles and indolines. Mechanistically, the 2-methylindole nucleus is obtained through CH allylation/carboamination/β-hydride elimination/double bond isomerization cascade whereas for ortho substituted sterically hindered anilines, the indolines are obtained through C-H allylation/carboamination/protodemetalation cascade in protic solvent. This mild intermolecular annulation cascade proceeds smoothly by 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 C-H activation cascade will be a valuable tool in organic and medicinal chemistry. EXPERIMENTAL SECTION 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-aryl pyridines,14,15 N-aryl pyrimidines3g and deuterated N-phenyl pyridine (1a-d5)

15

were prepared using 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 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) frequency and

13

C NMR spectra were recorded at 75 MHz (Bruker-DPX)

and 150 MHz

(Bruker-Avance) frequency in CDCl3 solvent using TMS as the internal standard.

19

F 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, br. = broad. Coupling constants, J were reported in Hertz unit (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 Fourier Transform Infrared Spectroscopy (Bruker Tensor 27), only intense peaks were reported. General Experimental Procedure for Ruthenium-Catalyzed 2-Methylindole Synthesis from the Corresponding N-aryl pyridines and Allyl acetates. A mixture of N-aryl pyridine (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 oC 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 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 1.0 mmole scale and the desired product 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); 13

C 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) calcd. for C14H13N2 [M+H]+ : 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


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(neat): υmax 2921, 1585, 1466, 1179, 780 cm-1; HRMS (ESI, m/z) calcd. for C14H12N2F [M+H]+ : 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);

13

C 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) calcd. for C14H12N2Cl [M+H]+ : 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 ºC. 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) calcd. for C16H14N2O2 [M]+ : 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 ºC. 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);

13

C 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) calcd. for C19H21N3O [M]+ : 307.1685; found: 307.1684.



Page 16 of 28

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) calcd. for C15H14N2 [M]+ : 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);

13

C 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) calcd. for C14H11N2F [M]+ : 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%). 1H 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);

13

C 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) calcd. for C15H12F3N2 [M+H]+ : 277.0953; found: 277.0951. 2-Methyl-1-(pyridin-2-yl)-1H-indol-5-yl acetate, 3i, Table 2


Page 17 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Column chromatography (SiO2, eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a white solid, (46 mg, 87%), mp 74-76 ºC. 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);

13

C 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) calcd. for C16H14N2O2 [M]+ : 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 ºC. 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), 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) calcd. for C14H11N3O2 [M]+ : 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) calcd. for C17H16N2O2 [M]+ : 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



Page 18 of 28

(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) calcd. for C15H14N2 [M]+ : 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 ºC. 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), 7.447.48 (m, 4H), 7.39-7.40 (m, 1H), 7.31-7.36 (m, 2H), 6.49 (s, 1H), 2.51 (s, 3H);

13

C 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) calcd. for C20H16N2 [M]+ : 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%). 1H 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) calcd. for C15H11N2F3 [M]+ : 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 ºC. 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) calcd. for C15H10ClF3N2 [M]+ : 310.0485; found: 310.0486.


Page 19 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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);

13

C 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, 754 cm-1; HRMS (EI, m/z) calcd. for C15H13ClN2 [M]+ : 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 ºC. 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), 7.317.33 (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) calcd. for C16H16N2O [M]+ : 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);

13

C 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) calcd. for C16H14N2ONa [M+Na]+ : 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);

13

Page 20 of 28

C 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) calcd. for C18H20N2Na [M+Na]+ : 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);

13

C 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;

19

F NMR (376 MHz, CDCl3): δ -58.0 (s, 3F); IR (neat): υmax

2924, 1585, 1466, 1262, 1163, 782 cm-1; HRMS (EI, m/z) calcd. for C15H11F3N2O [M]+ : 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) calcd. for C20H26N2OSi [M]+ : 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) calcd. for C15H14N2O [M]+ : 238.1106; found: 238.1104.


Page 21 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


6-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, (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) calcd. for C15H14N2O [M]+ : 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);

13

C 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) calcd. for C15H14N2 [M]+ : 222.1157; found: 222.1157. General Experimental Procedure for Ruthenium-Catalyzed 2-Methylindoline 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 oC 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 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 ºC. 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);

13

C 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; υmax 2976, 1568, 1458, 1050, 770 cm-1; HRMS (EI, m/z) calcd. for C13H12N3Cl [M]+ : 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 ºC. 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);

13

C 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; υmax 2972, 1564, 1415, 1215, 1049, 769 cm-1; HRMS (EI, m/z) calcd. for C13H12BrN3 [M]+ : 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 ºC. 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) calcd. for C14H15N3 [M]+ : 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 ºC. 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), 4.945.03 (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; υmax 2967, 1572, 1448, 1176, 788 cm-1; HRMS (EI, m/z) calcd. for C14H14N3Cl [M]+ : 259.0876; found: 259.0871.


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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 ºC. 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 (, 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; υmax 2951, 1579, 1426, 1191, 793 cm-1; HRMS (ESI, m/z) calcd. for C15H18N3 [M+H]+ : 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 ºC. 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; υmax 2941, 1561, 1430, 1271, 1078, 768 cm-1; HRMS (EI, m/z) calcd. for C14H15N3O [M]+ : 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) calcd. for C15H18N3 [M+H]+ : 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 =



Page 24 of 28

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);

13

C 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) calcd. for C16H20N3 [M+H]+ : 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; υmax 2966, 1580, 1435, 1186, 787 cm-1; HRMS (EI, m/z) calcd. for C16H19N3 [M]+ : 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);

13

C 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) calcd. for C17H22N3 [M+H]+ : 268.1814; found: 268. 1807. 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), 5.035.11(m, 2H), 3.40-3.43 (m, 2H);

13

C 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) calcd. for C19H18N3 [M+H]+ : 288.1501; found: 288. 1496.


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Deprotection of the directing group of Iodole 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). 2M aq. NaOH solution (2.0 mL) was added to it and stirring was continued at 60 oC 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, 7a16 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); 13

C NMR (150 MHz, CDCl3): δ 135.9, 135.1, 128.9, 120.8, 119.5, 110.2, 100.2, 13.5.

ASSOCIATED CONTENT Supporting Information Mechanistic study, spectral data of 3a’, crystallographic data of 3m, 5c, 1H and

13

C NMR

spectra for all synthesized compounds. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] ACKNOWLEDGMENT This work was supported by DST, SERB, Govt. of India, Ramanujan fellowship; award no. SR/S2/RJN-97/2012 and extra mural research grant no. EMR/2014/000469. MKM and GB thank UGC for their fellowships. REFERENCES



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Sterically Controlled Ru(II)-Catalyzed Divergent Synthesis of 2

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