Metal-free regioselective C-3 acetoxylation of N-substituted indoles: crucial impact of nitrogen-substituent

Abstract

A metal-free method for the regioselective C-3 acetoxylation of the N-substituted indoles with PhI(OAc)₂ is described under mild reaction conditions. This method tolerates a broad range of functional groups with moderate to good yields. The π-electron-deficient aryl-substituents on the N-atom of indoles and the acidic reaction medium remarkably favor C-3 acetoxylation.

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Introduction

Direct functionalization of a C–H bond to form a C–O bond is amongst the most demanding chemical reactions in synthetic organic chemistry.¹ The C–O bond formation in arenes to obtain hydroxylated-,² alkoxylated-³ or acetoxylated-arenes⁴ have been extensively explored, and regioselectivity has been successfully achieved by the installation of a Lewis-base directing group. In contrast to many reports on the acetoxylation of arenes, the synthesis of the regioselectively acetoxylated heteroarenes is relatively scarce.⁵ Among the heteroarenes, the indole derivatives are very important building blocks, found in many pharmaceuticals as well as in the biologically active compounds. In particular, 3-acetoxyindoles are potential materials, applied for the detection of acetylcholinesterase in tissue slices⁶ and they could also be used as starting precursors for the synthesis of potential 5-hydroxytryptamine₆ (5-HT₆) receptor ligand scaffolds.⁷ Hence, the efficient synthesis of 3-acetoxyindoles through the regioselective C-3 acetoxylation of indole derivatives is highly desirable. The groups of Lei,⁸ Kwong⁷ and Suna⁹ have independently reported the C-3 acetoxylation of N-substituted indoles using Pd(OAc)₂ catalyst, and PhI(OAc)₂ as external oxidant (Scheme 1a). This palladium-catalyzed regioselective acetoxylation process is applicable to the various indole substrates containing methyl, benzyl, aryl or arenesulfonyl groups as the nitrogen-substituents. However, the employment of the precious metal catalysts for the functionalization of probable pharmacological indole derivatives, limit the advancement of these metal-catalyzed acetoxylation processes.

Scheme 1 Regioselective C-3 acetoxylation of substituted-indoles: (a) palladium-catalyzed acetoxylation of N-methyl, N-benzyl- or N-aryl indoles, (b) this work demonstrates: metal-free acetoxylation of N-(hetero)aryl indoles.

In recent years, numerous reports have been described for the C–H bond functionalization under the transition-metal-free conditions.¹⁰ A transition-metal-free C-3 acetoxylation of the free NH-indole has been described under the strong basic condition by Huang and co-workers.¹¹ However, this method is not applicable to the N-substituted indole substrates and has limited scope. The C-3 acetoxylation of N-Boc-protected indole has been observed by Lei et al. during their studies directed toward the synthesis of diacetoxylated indolines.¹² To our knowledge, a comprehensive approach for the metal-free C-3 acetoxylation of the N-substituted indoles with high regioselectivity is not known. Herein, we present the regioselective C-3 acetoxylation of the N-substituted indoles with PhI(OAc)₂ as an oxidant under the metal-free and mild reaction conditions. Moreover, we have demonstrated the effect of the N-substituents on reactivity and selectivity of the indole acetoxylations.

Results and discussion

During the investigation of a less expensive first-row transition metal catalyst for the acetoxylation of the N-substituted indoles employing PhI(OAc)₂ in acetic acid solvent, we observed that the C-3 acetoxylation of indole occurred in the absence of metal catalysts, when a suitable substituent on the nitrogen atom of indole was installed. For example, the reaction of 1-pyrimidinyl indole (1a) with PhI(OAc)₂ in AcOH/Ac₂O solvent at 60 °C, exclusively produced 1-(pyrimidin-2-yl)-1H-indol-3-yl acetate (2a) in 93% isolated yield (Table 1, entry 1). The 1-arylindoles, like 1-phenylindole (3a) reacted with PhI(OAc)₂ under the metal-free condition to afford the corresponding C-3 acetoxylated indole 4a in 50% yield; whereas the reaction of 1-(4-methoxyphenyl)indole (3b) with PhI(OAc)₂ under the same condition produced only 37% of the acetoxylated compound 4b. Surprisingly, the free NH-indole or indoles having electron-rich substituents at the nitrogen-center, such as 1-methylindole, were decomposed to the unknown compounds at room temperature. However, the indoles bearing strong electron-withdrawing substituents at the nitrogen-atom, such as 1-(acetyl)indole and 1-(tosyl)indole produced the diacetoxylated indolines in 91% and 28% yields, respectively (Table 1, entries 6 and 7).¹² These studies on the effect of N-substituents towards the acetoxylation of indoles suggested that a π-electron-deficient (hetero)arene-substituent on the nitrogen atom of indole greatly enhances the selective C-3 acetoxylation reaction.

Table 1 Effect of nitrogen-substituents on C-3 acetoxylation of indoles^a

Entry	R	% Yield (2 or 4)	5	Recovered (1 or 3)
a Reaction conditions: compound 1 or 3 (0.30 mmol), PhI(OAc)2 (0.106 g, 0.33 mmol), AcOH/Ac2O (1.0 mL), yields of isolated compounds.b Starting compound was not recovered.c Decomposed into intractable products at room temperature.
1	2-Pym	93 (2a)	—	—
2	Ph	50 (4a)	—	35 (3a)
3	4-MeO-C6H4	37 (4b)	—	—^b
4	H	—	—	—^c
5	CH3	—	—	—^c
6	C(O)CH3	—	91	5
7	Tosyl	—	28	70

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After optimizing the effect of N-substituent's on the metal-free acetoxylation of indoles, we have tested the impact of various solvents and oxidants on the acetoxylation reaction (Table 2). The use of glacial acetic acid as solvent instead of AcOH/Ac₂O, produced the desired acetoxylated product 2a in 76% isolated yield (entry 2). However, the complete decomposition of 1a was observed in TFA/TFAA under the reaction conditions (entry 3). The employment of non-acid solvent 2,2,2-trifluoroethanol (TFE) gave only 20% of product 2a, whereas the reactions in CH₃CN or 1,2-dichloroethane (DCE) did not produce any acetoxylated products (entry 4 and 5). The presence of strong oxidant PhI(TFA)₂ resulted in the decomposition of 1a; however, other organic oxidants, such as m-CPBA, tert-BuOOH or inorganic oxidants like K₂S₂O₈ and oxone were ineffective, and most of the starting material was recovered (entry 6–8).

Table 2 Optimization of reaction parameters for C-3 acetoxylation of 1a^a

Entry	Variation from “standard condition”	Yield^b (%)
a Reaction conditions: 1a (0.059 g, 0.30 mmol), PhI(OAc)2 (0.106 g, 0.33 mmol), AcOH/Ac2O (1.0 mL). TFE (2,2,2-trifluoroethanol), TFA (trifluoroacetic acid), TFAA (trifluoroacetic anhydride), NR = no reaction.b Yields of isolated compounds.c Decomposed into intractable compounds.
1	—	93
2	AcOH instead of AcOH/Ac2O	76
3	TFA/TFAA instead of AcOH/Ac2O	—^c
4	TFE instead of AcOH/Ac2O	20
5	CH3CN, DCE instead of AcOH/Ac2O	NR
6	PhI(TFA)2 instead of PhI(OAc)2	—^c
7	m-CPBA instead of PhI(OAc)2	Trace
8	K2S2O8, oxone or t-BuOOH instead of PhI(OAc)2	NR
9	25 °C instead of 60 °C	15

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Having the optimized reaction conditions in hand, we probed the scope of the metal-free C-3 acetoxylation of the N-heteroaryl-substituted indoles 1 employing PhI(OAc)₂ as the oxidant in AcOH/Ac₂O solvent (Scheme 2). Notably, the N-pyrimidinyl indoles containing electronically different functional groups reacted smoothly to produce the desired acetoxylated products (2a–2e) in good yields. The tolerability of the functional groups such as –F, –Br is significant, as they can be further functionalized into important compounds. It is noteworthy that the direct acetoxylation of indoles 1 occurred with excellent regioselectivity to predominantly produce C-3 acetoxylated indoles. Particularly, by employing 2-pyrimidinyl as the N-substituent on indoles, neither the starting compounds nor the acetoxylated products were decomposed. More hindered 2-substituted indole 1f reacted with low efficacy to produced 2f in 26% yield. In addition to the N-pyrimidinyl indoles, the indoles containing 2-pyridinyl and 2-pyrazinyl as nitrogen-substituents reacted efficiently to give the desired acetoxylated products in good yields. The pyridinyl-substituted indoles, 1h and 1i reacted moderately to yield the corresponding acetoxylated compounds 2h and 2i, respectively. Evidently, the π-electron-rich 2-thiophenyl substituted indole 1m produced the acetoxylated compound 2m in low yield.

Scheme 2 Scope of C-3 acetoxylation of N-heteroaryl substituted indoles.

We further extended the metal-free acetoxylation method for the selective acetoxylation of the N-aryl substituted indoles. Hence, the different substituted N-aryl indoles 3 undergo acetoxylations at C-3 position to give the desired products in moderate yields (Scheme 3). Interestingly, a number of important functional groups like –F, –CF₃, –C(O)Me, –C(O)OMe, –CN and –NO₂ are well tolerated under the reaction conditions. To our surprise, the 2,4-dinitrophenyl substituted indoles 3i and 3j produced the acetoxylated products in good yields. The indoles containing N-aryl substituents with electron-withdrawing groups on the aryl backbone were found to produce improved yields of the C-3 acetoxylation, than the N-aryl substituents bearing electron-donating groups. Unlike free-NH-indole or indoles bearing electron-rich N-protecting groups, the N-aryl substituted indoles does not impart decomposition; however they produced 1-aryl-indolin-3-one and 2-oxo-1-aryl-indolin-3-yl acetate as the side products in different scale, which accounts for the low yields of the C-3 acetoxylated products.¹³ Most likely, these side products are formed from the hydrolysis of C-3 acetoxylated and diacetoxylated indoles.

Scheme 3 Scope of C-3 acetoxylation of N-aryl substituted indoles.

In order to obtain the mechanistic insight, the intermolecular competition experiments between the indoles 1a and 3a as well as between 1a and 1m, were conducted (Scheme 4a and b); which highlighted that the indoles bearing π-electron-rich arene substituents were acetoxylated predominantly, though the yields were unsatisfactory. Further, an additional experiment between the different substituted N-pyrimidinyl-indoles 1a and 1c (Scheme 4c) clearly demonstrated that the electron-rich indole was preferentially acetoxylated, which revealed the nucleophilicity parameter¹⁴ of indoles for the acetoxylation process.

Scheme 4 Intermolecular competition experiments.

Further, to isolate the probable intermediate species, an experiment of 1a with PhI(OAc)₂ was carried out at room temperature, which produced the diacetoxylated indoline 5a in 53% yield after 1 h (Scheme 5a). The formation of 5a might follow the pathway proposed for the similar compounds.¹² Compound 5a led to the complete conversion into the acetoxylated product 2a upon heating in AcOH/Ac₂O solvent for 3 h (Scheme 5b). This clearly demonstrated that the formation of 2a from 1a occurred via the intermediacy of 5a. The dehydroacetoxylation of 5a to 2a also occurred under non-acidic condition, however with low efficacy. Similar to the indoline 5a, the intermediate species for the indole 1m could not be observed; instead the direct formation of 2m was accomplished, including the intractable decomposed products.

Scheme 5 Synthesis and reactivity of intermediate species.

To understand the dehydroacetoxylation process of the different N-substituted diacetoxyindolines, the compound 5a and 1-acetylindoline-2,3-diyl diacetate were heated in a single pot at 60 °C (Scheme 6). The compound 5a was completely converted into the C-3 acetoxylated product 2a in 2 h, whereas a trace amount of the C-3 acetoxylated product was formed from the 1-acetylindoline-2,3-diyl diacetate; suggesting that the dehydroacetoxylation of diacetoxylated indoline is significant in the presence of 2-pyrimidinyl as the N-substituent. Further, looking into the excellent reactivities of the indoles containing 2-Py, 2-Pym, 2-pyrazinyl or 2-nitroarene as the N-substituents (1a–1g, 1i–1l, 3i and 3j); we assume that the N-atom or N-group at the ortho-position of the substituents might have some additional influence on the dehydroacetoxylation reaction, in addition to the electronics of the substituents.

Scheme 6 Dehydroacetoxylation of diacetoxylated compounds.

Conclusions

In summary, we have reported an efficient and regioselective method for the C-3 acetoxylation of the N-substituted indoles in the absence of metal-catalysts, wherein a broad range of functional groups are tolerated. The indoles containing π-electron-deficient arene substituents on the N-atom are acetoxylated efficiently than the one bearing strong sigma electron-donating or sigma electron-withdrawing substituents. The diacetoxylated indoline is proposed to be the active intermediate for the acetoxylation of the N-substituted indoles, where the dehydroacetoxylation is facilitated in the presence of a π-deficient arene substituents on the N-atom of indoles.

Experimental section

General information

All manipulations were conducted in an argon atmosphere using standard Schlenk techniques in pre-dried glassware. Liquid reagents were flushed with argon prior to use. The starting compounds, N-acyl-1H-indole,¹² N-tosyl-1H-indole,¹² N-benzyl-1H-indole,⁷ N-aryl-1H-indoles,¹⁵ N-pyridinyl-1H-indole,¹⁶ N-pyrimidinyl-1H-indole^15a,17 and 1-acetylindoline-2,3-diyl diacetate¹² were synthesized according to the previously described procedures. All other chemicals were obtained from commercial sources and were used without further purification. Representative starting compounds 1 and 3 as well as PhI(OAc)₂ were analyzed by ICP-AES, which showed only trace amount of transition metals (<0.1 ppm Fe, Co, Ni, Cu, Pd, Rh and Ru). The yields refer to isolated compounds, estimated to be >95% pure as determined by ¹H NMR. The ¹H and ¹³C NMR spectra are referenced to the residual solvent signals (CDCl₃: δ H = 7.26 ppm, δ C = 77.2 ppm).

Representative procedures for the preparation of N-substituted indoles

Representative procedure A. To a stirred solution of 1H-indole (0.120 g, 1.00 mmol) in DMF (15 mL) at 0 °C was added NaH (0.027 g, 1.10 mmol). After stirring the reaction mixture at 0 °C for 30 min, (hetero)aryl halide (1.20 mmol) was added and the reaction mixture was heated at 130 °C for 24 h. Then the reaction mixture was cooled to ambient temperature, poured into H₂O (20 mL) and extracted with EtOAc (15 mL × 3). The combined organic phase was washed with H₂O (15 mL × 3) and dried over Na₂SO₄. After filtration and evaporation of the solvents in vacuo, the crude product was purified by column chromatography on silica gel.

Representative procedure B. A mixture of 1H-indole (0.328 g, 2.80 mmol), (hetero)aryl halide (2.00 mmol), CuI (0.076 g, 0.40 mmol) and Cs₂CO₃ (1.30 g, 4.00 mmol) were taken in a flask and DMF (15 mL) was added into it. The reaction mixture was vigorously stirred at 120 °C under argon atmosphere for 40 h. Then the reaction mixture was cooled to ambient temperature, poured into H₂O (20 mL) and extracted with EtOAc (15 mL × 3). The combined organic phase was washed with H₂O (15 mL × 3) and dried over Na₂SO₄. After filtration and evaporation of the solvents in vacuo, the crude product was purified by column chromatography on silica gel.

2-Methyl-1-(pyrimidin-2-yl)-1H-indole (1f)¹⁸. The representative procedure A was followed using, 2-methyl-1H-indole (0.40 g, 3.05 mmol), 2-chloropyrimidine (0.489 g, 4.27 mmol), and NaH (0.095 g, 3.96 mmol). Purification by column chromatography on silica gel (hexane/EtOAc/Et₃N: 20/1/0.5) yielded 1f (0.153 g, 24%) as a brown solid. M. p. = 48–50 °C. ¹H-NMR (500 MHz, CDCl₃): δ = 8.79 (d, J = 4.9 Hz, 2H), 8.37 (d, J = 8.2 Hz, 1H), 7.59 (d, J = 7.3 Hz, 1H), 7.31–7.24 (m, 2H), 7.11 (t, J = 4.9 Hz, 1H), 6.50 (s, 1H), 2.78 (s, 3H). ¹³C{¹H}-NMR (125 MHz, CDCl₃): δ = 158.5, 158.1, 137.9, 137.0, 129.6, 122.5, 121.9, 119.6, 117.0, 114.1, 106.8, 16.7. IR (neat): ν_max/cm⁻¹ 3032, 2962, 2853, 1562, 1417, 1305, 1205, 785, 733. HRMS (ESI) m/z calcd for C₁₃H₁₁N₃ + H⁺ [M + H]⁺ 210.1026; found 210.1024.

1-(Pyrazin-2-yl)-1H-indole (1j)¹⁹. The representative procedure A was followed, using 1H-indole (0.120 g, 1.00 mmol), NaH (0.027 g, 1.10 mmol) and 2-iodopyrazine (0.246 g, 1.20 mmol). Purification by column chromatography on silica gel (hexane/EtOAc: 2/1) yielded 1j (0.186 g, 95%) as a brown solid. M. p. = 77–79 °C. ¹H-NMR (500 MHz, CDCl₃): δ = 8.85 (s, 1H), 8.44 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 2.1 Hz, 1H), 8.26 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 3.4 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.31 (dd, J = 7.9, 7.3 Hz, 1H), 7.23 (dd, J = 7.9, 7.0 Hz, 1H), 6.74 (d, J = 3.4 Hz, 1H). ¹³C{¹H}-NMR (125 MHz, CDCl₃): δ = 149.2, 142.8, 140.0, 136.4, 135.2, 130.7, 125.0, 123.9, 122.2, 121.4, 113.5, 107.3. IR (neat): ν_max/cm⁻¹ 3108, 3053, 1450, 1360, 839, 739. HRMS (ESI) m/z calcd for C₁₂H₉N₃ + H⁺ [M + H]⁺ 196.0869; found 196.0869.

5-Fluoro-1-(pyrazin-2-yl)-1H-indole (1k). The representative procedure A was followed, using 5-fluoro-1H-indole (0.23 g, 1.70 mmol), NaH (0.045 g, 1.87 mmol) and 2-iodopyrazine (0.420 g, 2.04 mmol). Purification by column chromatography on silica gel (hexane/EtOAc: 2/1) yielded 1k (0.33 g, 91%) as a brown solid. M. p. = 112–114 °C. ¹H-NMR (400 MHz, CDCl₃): δ = 8.84 (d, J = 1.2 Hz, 1H), 8.47–8.46 (m, 1H), 8.41 (d, J = 2.7 Hz, 1H), 8.30 (dd, J = 9.1, 4.6 Hz, 1H), 7.72 (d, J = 3.7 Hz, 1H), 7.29 (dd, J = 9.1, 2.7 Hz, 1H), 7.06 (td, J = 9.1, 2.5 Hz, 1H), 6.71 (d, J = 3.4 Hz, 1H). ¹³C{¹H}-NMR (100 MHz, CDCl₃): δ = 159.0 (d, J_C–F = 239.0 Hz), 149.1, 142.6, 140.2, 136.0, 131.8, 131.4 (d, J_C–F = 10.0 Hz), 126.3, 114.9 (d, J_C–F = 9.3 Hz), 111.9 (d, J_C–F = 25.4 Hz), 107.2 (d, J_C–F = 3.8 Hz), 106.5 (d, J_C–F = 23.9 Hz). ¹⁹F-NMR (377 MHz, CDCl₃): δ = −121.6 (s). IR (neat): ν_max/cm⁻¹ 2921, 1469, 1443, 1353, 809, 753, 714, 616. HRMS (ESI) m/z calcd for C₁₂H₈FN₃ + H⁺ [M + H]⁺ 214.0775; found 214.0775.

5-Bromo-1-(pyrazin-2-yl)-1H-indole (1l). The representative procedure A was followed, using 5-bromo-1H-indole (0.330 g, 1.70 mmol), NaH (0.045 g, 1.87 mmol) and 2-iodopyrazine (0.420 g, 2.04 mmol). Purification by column chromatography on silica gel (hexane/EtOAc: 2/1) yielded 1l (0.44 g, 95%) as off-white solid. M. p. = 98–100 °C. ¹H-NMR (400 MHz, CDCl₃): δ = 8.84 (d, J = 1.2 Hz, 1H), 8.49–8.48 (m, 1H), 8.43 (d, J = 2.7 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 3.4 Hz, 1H), 7.40 (dd, J = 8.8, 2.0 Hz, 1H), 6.69 (d, J = 3.2 Hz, 1H). ¹³C{¹H}-NMR (100 MHz, CDCl₃): δ = 149.0, 142.8, 140.5, 136.2, 134.0, 132.3, 126.7, 126.0, 123.9, 115.4, 115.3, 106.7. IR (neat): ν_max/cm⁻¹ 2921, 1519, 1482, 1416, 1198, 1136, 1054, 1004, 957, 752, 709. HRMS (ESI) m/z calcd for C₁₂H₈BrN₃ + H⁺ [M + H]⁺ 273.9974, 275.9954; found 273.9974, 275.9953.

1-(Thiophen-2-yl)-1H-indole (1m)^15c. The representative procedure B was followed, using 1H-indole (0.328 g, 2.80 mmol), 2-bromothiophene (0.326 g, 2.00 mmol), CuI (0.076 g, 0.40 mmol) and Cs₂CO₃ (1.30 g, 4.00 mmol). Purification by column chromatography on silica gel (hexane/EtOAc: 100/1) yielded 1m (0.286 g, 72%) as a green liquid. ¹H-NMR (400 MHz, CDCl₃): δ = 7.64 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.27–7.22 (m, 2H), 7.17 (dd, J = 7.1, 6.9 Hz, 1H), 7.12 (dd, J = 5.6, 1.5 Hz, 1H), 7.03 (dd, J = 3.7, 1.5 Hz, 1H), 7.01–6.99 (m, 1H), 6.63 (d, J = 3.2 Hz, 1H). ¹³C{¹H}-NMR (100 MHz, CDCl₃): δ = 141.8, 137.2, 129.5, 129.2, 126.2, 123.0, 121.8, 121.2, 121.0, 120.6, 110.8, 104.3. IR (neat): ν_max/cm⁻¹ 3108, 3009, 1611, 1550, 1459, 1312, 1226, 1201, 1013, 903, 842. HRMS (ESI) m/z calcd for C₁₂H₉NS + H⁺ [M + H]⁺ 200.0528; found 200.0526.

1-(4-(Trifluoromethyl)phenyl)-1H-indole (3d)²⁰. The representative procedure B was followed, using 1H-indole (0.302 g, 2.58 mmol), 1-iodo-4-(trifluoromethyl)benzene (0.50 g, 1.84 mmol), CuI (0.070 g, 0.368 mmol) and Cs₂CO₃ (1.20 g, 3.68 mmol). Purification by column chromatography on silica gel (hexane/EtOAc: 20/1) yielded 3d (0.408 g, 85%) as a brown solid. M. p. = 50–52 °C. ¹H-NMR (400 MHz, CDCl₃): δ = 7.75 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 7.6 Hz, 1H), 7.60–7.56 (m, 3H), 7.31 (d, J = 3.4 Hz, 1H), 7.24–7.17 (m, 2H), 6.70 (d, J = 3.2 Hz, 1H). ¹³C{¹H}-NMR (100 MHz, CDCl₃): δ = 143.0, 135.7, 129.9, 128.3 (q, J_C–F = 32.4 Hz), 127.6, 127.1 (q, J_C–F = 3.8 Hz), 124.2 (q, J_C–F = 171.8 Hz), 124.1, 123.1, 121.6, 121.2, 110.5, 105.1. ¹⁹F-NMR (377 MHz, CDCl₃): δ = −62.2 (s). IR (neat): ν_max/cm⁻¹ 3058, 2962, 1607, 1521, 1455, 1318, 1158, 1061, 1013, 840. HRMS (ESI) m/z calcd for C₁₅H₁₀F₃N + H⁺ [M + H]⁺ 262.0838; found 262.0837.

Methyl-4-(1H-indol-1-yl)benzoate (3f)^15c. The representative procedure B was followed, using 1H-indole (0.328 g, 2.80 mmol), methyl 4-iodobenzoate (0.524 g, 2.00 mmol), CuI (0.076 g, 0.40 mmol) and K₂CO₃ (0.553 g, 4.00 mmol). Purification by column chromatography on silica gel (hexane/EtOAc: 10/1) yielded 3f (0.231 g, 46%) as a grey solid. M. p. = 55–57 °C. ¹H-NMR (500 MHz, CDCl₃): δ = 8.18 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 3.4 Hz, 1H), 7.25 (t, J = 7.3 Hz, 1H), 7.19 (t, J = 7.3 Hz, 1H), 6.71 (d, J = 3.4 Hz, 1H), 3.95 (s, 3H). ¹³C{¹H}-NMR (125 MHz, CDCl₃): δ = 166.6, 143.9, 135.6, 131.4, 130.0, 127.8, 127.6, 123.4, 123.0, 121.5, 121.1, 110.7, 105.1, 52.4. IR (neat): ν_max/cm⁻¹ 3106, 3049, 2947, 1707, 1602, 1509, 1455, 1433, 1281, 1117, 1097, 720. HRMS (ESI) m/z calcd for C₁₆H₁₃NO₂ + H⁺ [M + H]⁺ 252.1019; found 252.1012.

1-(4-Nitrophenyl)-1H-indole (3h)^19,20. The representative procedure B was followed, using 1H-indole (0.328 g, 2.80 mmol), 1-iodo-4-nitrobenzene (0.50 g, 2.00 mmol), CuI (0.076 g, 0.40 mmol) and K₂CO₃ (0.553 g, 4.00 mmol). Purification by column chromatography on silica gel (hexane/EtOAc: 20/1) yielded 3h (0.224 g, 47%) as a yellow solid. M. p. = 132–134 °C. ¹H-NMR (500 MHz, CDCl₃): δ = 8.33 (d, J = 8.9 Hz, 2H), 7.68 (d, J = 7.6 Hz, 1H), 7.62–7.60 (m, 3H), 7.33 (d, J = 3.1 Hz, 1H), 7.27 (dd, J = 7.6, 7.3 Hz, 1H), 7.21 (dd, J = 7.6, 7.3 Hz, 1H), 6.75 (d, J = 3.0 Hz, 1H). ¹³C{¹H}-NMR (125 MHz, CDCl₃): δ = 145.3, 145.1, 135.4, 130.2, 127.2, 125.6, 123.5, 123.4, 121.8, 121.7, 110.6, 106.3. IR (neat): ν_max/cm⁻¹ 3109, 1592, 1503, 1455, 1317, 1100, 882, 852, 690. HRMS (ESI) m/z calcd for C₁₄H₁₀N₂O₂ + H⁺ [M + H]⁺ 239.0815; found 239.0811.

1-(2,4-Dinitrophenyl)-1H-indole (3i)²¹. The representative procedure B was followed, using 1H-indole (0.351 g, 3.00 mmol), 1-chloro-2,4-dinitrobenzene (0.73 g, 3.60 mmol), CuI (0.114 g, 0.60 mmol), K₂CO₃ (0.830 g, 6.00 mmol). Purification by column chromatography on silica gel (hexane/EtOAc: 5/1) yielded 3i (0.424 g, 50%) as an orange solid. M. p. = 96–98 °C. ¹H-NMR (400 MHz, CDCl₃): δ = 8.89 (d, J = 2.5 Hz, 1H), 8.54 (dd, J = 8.8, 2.5 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 6.6 Hz, 1H), 7.30–7.21 (m, 3H), 7.15 (d, J = 3.4 Hz, 1H), 6.83 (d, J = 3.2 Hz, 1H). ¹³C{¹H}-NMR (100 MHz, CDCl₃): δ = 145.4, 144.6, 138.0, 135.8, 129.7, 129.6, 128.1, 127.2, 123.9, 122.2, 121.9, 121.8, 109.4, 107.5. IR (neat): ν_max/cm⁻¹ 3103, 1601, 1539, 1493, 1453, 1339, 1231, 1200, 844, 769, 752. HRMS (ESI) m/z calcd for C₁₄H₉N₃O₄ + H⁺ [M + H]⁺ 284.0666; found 284.0668.

1-(2,4-Dinitrophenyl)-5-fluoro-1H-indole (3j)²². The representative procedure B was followed, using 5-fluoro-1H-indole (0.203 g, 1.50 mmol), 1-chloro-2,4-dinitrobenzene (0.365 g, 1.80 mmol), CuI (0.057 g, 0.30 mmol), K₂CO₃ (0.415 g, 3.00 mmol). Purification by column chromatography on silica gel (hexane/EtOAc: 2/1) yielded 3j (0.138 g, 31%) as a yellow solid. M. p. = 151–153 °C. ¹H-NMR (400 MHz, CDCl₃): δ = 8.90 (d, J = 2.2 Hz, 1H), 8.60 (dd, J = 8.8, 2.2 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.34 (dd, J = 9.1, 2.2 Hz, 1H), 7.17 (d, J = 3.4 Hz, 1H), 7.13–7.10 (m, 1H), 7.00 (td, J = 8.8, 2.2 Hz, 1H), 6.77 (d, J = 2.9 Hz, 1H). ¹³C{¹H}-NMR (100 MHz, CDCl₃): δ = 159.1 (d, J_C–F = 238.1 Hz), 145.8, 145.0, 138.0, 132.6, 130.5 (d, J_C–F = 10.0 Hz), 129.9, 128.9, 128.4, 122.0, 112.3 (d, J_C–F = 27.0 Hz), 110.3 (d, J_C–F = 9.2 Hz), 107.5 (d, J_C–F = 4.6 Hz), 107.3 (d, J_C–F = 23.9 Hz). ¹⁹F-NMR (377 MHz, CDCl₃): δ = −121.5 (s). IR (neat): ν_max/cm⁻¹ 3147, 3117, 3100, 1601, 1524, 1339, 1135, 908, 729. MS (EI) m/z: 301 [M]⁺, 281, 256, 226, 208, 181, 135.

1-(3,5-Bis(trifluoromethyl)phenyl)-1H-indole (3k)²². The representative procedure B was followed, using 1H-indole (0.328 g, 2.80 mmol), 1-bromo-3,5-bis(trifluoromethyl)benzene (0.586 g, 2.00 mmol), CuI (0.076 g, 0.40 mmol) and Cs₂CO₃ (1.30 g, 4.00 mmol). Purification by column chromatography on silica gel (hexane/EtOAc: 10/1) yielded 3k (0.222 g, 34%) as a light yellow liquid. ¹H-NMR (400 MHz, CDCl₃): δ = 7.97 (s, 2H), 7.84 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 3.4 Hz, 1H), 7.29 (dd, J = 8.0, 7.3 Hz, 1H), 7.22 (dd, J = 7.6, 7.3 Hz, 1H), 6.75 (d, J = 3.2 Hz, 1H). ¹³C{¹H}-NMR (100 MHz, CDCl₃): δ = 141.5, 135.6, 133.6 (q, J_C–F = 34.0 Hz), 130.0, 127.3, 124.0 (q, J_C–F = 3.0 Hz), 123.7, 123.1 (q, J_C–F = 272.6 Hz), 121.9, 121.7, 119.8 (q, J_C–F = 3.8 Hz), 109.9, 106.1. ¹⁹F-NMR (377 MHz, CDCl₃): δ = −63.0 (s). IR (neat): ν_max/cm⁻¹ 3284, 3062, 2963, 1477, 1402, 1275, 1115, 1103, 890, 847, 702. MS (EI) m/z: 329 [M]⁺, 310, 233, 213, 116.

Representative procedure for C-3 acetoxylation of N-substituted indoles

Synthesis of 1-(pyrimidin-2-yl)-1H-indol-3-yl acetate (2a). To a flame-dried Schlenk tube equipped with magnetic stir bar was introduced PhI(OAc)₂ (0.106 g, 0.33 mmol) and 1-(pyrimidin-2-yl)-1H-indole (1a) (0.059 g, 0.30 mmol) under argon. The Schlenk tube with the mixture was evacuated and refilled with argon. To the above mixture was added acetic acid and acetic anhydride (7 : 3) solvent mixture (1.0 mL). The resultant reaction mixture was then degassed, refilled with argon and stirred at 60 °C in a pre-heated oil bath for 5 h. At ambient temperature, H₂O (5 mL) and saturated NaHCO₃ solution (15 mL) were added and the reaction mixture was extracted with ethyl acetate (15 mL × 3). The combined organic layers were dried over Na₂SO₄ and the solvent was evaporated in vacuo. The resultant residue was purified by column chromatography on silica gel (hexane/EtOAc: 5/1) to yielded acetoxylated compound 2a (0.071 g, 93%) as off-white solid. M. p. = 117–119 °C. ¹H-NMR (500 MHz, CDCl₃): δ = 8.81 (d, J = 8.6 Hz, 1H), 8.66 (d, J = 4.7 Hz, 2H), 8.43 (s, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.25 (dd, J = 7.6, 7.3 Hz, 1H), 7.01 (t, J = 4.7 Hz, 1H), 2.40 (s, 3H). ¹³C{¹H}-NMR (125 MHz, CDCl₃): δ = 168.3, 158.3, 157.9, 133.7, 133.0, 124.8, 124.2, 122.3, 117.6, 116.6, 116.2, 114.7, 21.2. IR (neat): ν_max/cm⁻¹ 3195, 2926, 1744, 1455, 1430, 1368, 1208, 809, 787. HRMS (ESI) m/z calcd for C₁₄H₁₁N₃O₂ + Na⁺ [M + Na]⁺ 276.0743; found 276.0738.

5-Methyl-1-(pyrimidin-2-yl)-1H-indol-3-yl acetate (2b). The representative procedure was followed, using 5-methyl-1-(pyrimidin-2-yl)-1H-indole (1b) (0.063 g, 0.30 mmol) and PhI(OAc)₂ (0.106 g, 0.33 mmol). Purification by column chromatography on silica gel (hexane/EtOAc: 5/1) yielded 2b (0.061 g, 76%) as a brown solid. M. p. = 161–163 °C. ¹H-NMR (500 MHz, CDCl₃): δ = 8.66 (d, J = 8.6 Hz, 1H), 8.62 (d, J = 4.9 Hz, 2H), 8.37 (s, 1H), 7.34 (s, 1H), 7.19 (d, J = 8.6, 1H), 6.95 (t, J = 4.7 Hz, 1H), 2.48 (s, 3H), 2.40 (s, 3H). ¹³C{¹H}-NMR (125 MHz, CDCl₃): δ = 168.3, 158.1, 157.8, 133.4, 131.8, 131.3, 126.2, 124.3, 117.3, 116.3, 115.9, 114.7, 21.5, 21.1. IR (neat): ν_max/cm⁻¹ 3202, 2917, 2851, 1747, 1579, 1451, 1430, 1206, 908, 785, 711. HRMS (ESI) m/z calcd for C₁₅H₁₃N₃O₂ + Na⁺ [M + Na]⁺ 290.0900; found 290.0894.

5-Methoxy-1-(pyrimidin-2-yl)-1H-indol-3-yl acetate (2c). The representative procedure was followed, using 5-methoxy-1-(pyrimidin-2-yl)-1H-indole (1c) (0.068 g, 0.30 mmol) and PhI(OAc)₂ (0.106 g, 0.33 mmol). Purification by column chromatography on silica gel (hexane/EtOAc: 2/1) yielded 2c (0.064 g, 75%) as a light brown crystalline solid. M. p. = 166–168 °C. ¹H-NMR (500 MHz, CDCl₃): δ = 8.69 (d, J = 9.5 Hz, 1H), 8.61 (d, J = 4.7 Hz, 2H), 8.39 (s, 1H), 6.99–6.95 (m, 3H), 3.89 (s, 3H), 2.40 (s, 3H). ¹³C{¹H}-NMR (125 MHz, CDCl₃): δ = 168.2, 158.2, 157.7, 155.7, 133.5, 127.9, 124.8, 117.7, 116.0, 115.2, 114.1, 99.5, 55.8, 21.2. IR (neat): ν_max/cm⁻¹ 3209, 2923, 1745, 1435, 1222, 1204, 911, 821, 776. HRMS (ESI) m/z calcd for C₁₅H₁₃N₃O₃ + Na⁺ [M + Na]⁺ 306.0849; found 306.0844.

5-Fluoro-1-(pyrimidin-2-yl)-1H-indol-3-yl acetate (2d). The representative procedure was followed, using 5-fluoro-1-(pyrimidin-2-yl)-1H-indole (1d) (0.064 g, 0.30 mmol) and PhI(OAc)₂ (0.106 g, 0.33 mmol). Purification by column chromatography on silica gel (hexane/EtOAc: 3/1) yielded 2d (0.070 g, 86%) as an off-white solid. M. p. = 173–175 °C. ¹H-NMR (500 MHz, CDCl₃): δ = 8.77 (dd, J = 9.2, 4.6 Hz, 1H), 8.66 (d, J = 4.9 Hz, 2H), 8.46 (s, 1H), 7.20 (dd, J = 6.7, 1.8 Hz, 1H), 7.09 (td, J = 9.2, 1.8 Hz, 1H), 7.03 (t, J = 4.9 Hz, 1H), 2.39 (s, 3H). ¹³C{¹H}-NMR (125 MHz, CDCl₃): δ = 168.2, 159.1 (d, J_C–F = 239.4 Hz), 158.3, 157.7, 133.4, 129.4, 124.9 (d, J_C–F = 9.5 Hz), 117.9 (d, J_C–F = 9.5 Hz), 116.4, 116.3, 112.7 (d, J_C–F = 24.8 Hz), 103.2 (d, J_C–F = 24.8 Hz), 21.1. ¹⁹F-NMR (377 MHz, CDCl₃): δ = −121.0 (s). IR (neat): ν_max/cm⁻¹ 3208, 2921, 2852, 1745, 1449, 1197, 792, 786, 588. HRMS (ESI) m/z calcd for C₁₄H₁₀FN₃O₂ + Na⁺ [M + Na]⁺ 294.0649; found 294.0647.

5-Bromo-1-(pyrimidin-2-yl)-1H-indol-3-yl acetate (2e). The representative procedure was followed, using 5-bromo-1-(pyrimidin-2-yl)-1H-indole (1e) (0.082 g, 0.30 mmol) and PhI(OAc)₂ (0.106 g, 0.33 mmol). Purification by column chromatography on silica gel (hexane/EtOAc: 3/1) yielded 2e (0.073 g, 73%) as a light brown solid. M. p. = 178–179 °C. ¹H-NMR (500 MHz, CDCl₃): δ = 8.68–8.65 (m, 3H), 8.42 (s, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.43 (dd, J = 9.2, 2.0 Hz, 1H), 7.04 (t, J = 4.9 Hz, 1H), 2.39 (s, 3H). ¹³C{¹H}-NMR (125 MHz, CDCl₃): δ = 168.1, 158.3, 157.6, 132.6, 131.6, 127.6, 125.8, 120.3, 118.2, 116.5, 115.9, 115.7, 21.1. IR (neat): ν_max/cm⁻¹ 3205, 2923, 1758, 1456, 1433, 1204, 956, 867, 784. HRMS (ESI) m/z calcd for C₁₄H₁₀BrN₃O₂ + Na⁺ [M + Na]⁺ 353.9849, 355.9828; found 353.9848, 355.9824.

2-Methyl-1-(pyrimidin-2-yl)-1H-indol-3-yl acetate (2f). The representative procedure was followed, using 2-methyl-1-(pyrimidin-2-yl)-1H-indole (1f) (0.075 g, 0.358 mmol) and PhI(OAc)₂ (0.127 g, 0.394 mmol). Purification by column chromatography on silica gel (hexane/EtOAc: 2/1) yielded 2f (0.025 g, 26%) as a yellow solid. M. p. = 54–56 °C. ¹H-NMR (500 MHz, CDCl₃): δ = 8.75 (d, J = 4.9 Hz, 2H), 8.42 (d, J = 8.2 Hz, 1H), 7.34 (d, J = 7.6, 1H), 7.27–7.19 (m, 2H), 7.11 (t, J = 4.9 Hz, 1H), 2.59 (s, 3H), 2.42 (s, 3H). ¹³C{¹H}-NMR (125 MHz, CDCl₃): δ = 169.2, 158.5, 158.2, 134.1, 131.4, 127.0, 123.5, 123.1, 122.2, 117.1, 116.6, 114.8, 20.8, 12.8. IR (neat): ν_max/cm⁻¹ 2923, 2852, 1756, 1575, 1559, 1421, 1366, 1205, 733. HRMS (ESI) m/z calcd for C₁₅H₁₃N₃O₂ + Na⁺ [M + Na⁺] 290.0900; found 290.0896.

1-(Pyridin-2-yl)-1H-indol-3-yl acetate (2g). The representative procedure was followed, using 1-(pyridin-2-yl)-1H-indole (1g) (0.058 g, 0.30 mmol) and PhI(OAc)₂ (0.106 g, 0.33 mmol). Purification by preparative TLC (hexane/EtOAc: 5/1) and extraction in CH₂Cl₂ (15 mL × 3) yielded 2g (0.061 g, 81%) as a yellow liquid. ¹H-NMR (500 MHz, CDCl₃): δ = 8.54 (dd, J = 4.9, 1.2 Hz, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.95 (s, 1H), 7.79 (dd, J = 8.3, 7.3 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.44 (dd, J = 8.3, 0.5 Hz, 1H), 7.33 (ddd, J = 8.3, 7.1, 1.2 Hz, 1H), 7.24 (ddd, J = 8.1, 7.1, 1.0 Hz, 1H), 7.14 (dd, J = 7.3, 4.9 Hz, 1H), 2.40 (s, 3H). ¹³C{¹H}-NMR (125 MHz, CDCl₃): δ = 168.4, 152.6, 149.0, 138.6, 133.0, 132.5, 124.3, 122.8, 121.5, 120.1, 117.8, 114.8, 114.4, 113.7, 21.2. IR (neat): ν_max/cm⁻¹ 3178, 2962, 1752, 1449, 1435, 1357, 1207, 1009, 990, 799, 782. HR-MS (ESI) m/z calcd for C₁₅H₁₂N₂O₂ + H⁺ [M + H]⁺ 253.0972; found 253.0969.

1-(Pyridin-3-yl)-1H-indol-3-yl acetate (2h). The representative procedure was followed, using 1-(pyridin-3-yl)-1H-indole (1h) (0.058 g, 0.30 mmol) and PhI(OAc)₂ (0.106 g, 0.33 mmol). Purification by preparative TLC (hexane/EtOAc: 5/1) and extraction in CH₂Cl₂ (15 mL × 3) yielded 2h (0.042 g, 56%) as a yellow liquid. ¹H-NMR (500 MHz, CDCl₃): δ = 8.84 (d, J = 1.8 Hz, 1H), 8.60 (d, J = 4.6 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.59 (s, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.47 (dd, J = 7.9, 4.6 Hz, 1H), 7.28 (dd, J = 7.9, 7.3 Hz, 1H), 7.22 (dd, J = 7.6, 7.3 Hz, 1H), 2.40 (s, 3H). ¹³C{¹H}-NMR (125 MHz, CDCl₃): δ = 168.5, 147.5, 145.7, 136.3, 133.0, 132.5, 131.7, 124.4, 124.0, 121.8, 121.2, 118.3, 116.6, 110.2, 21.2. IR (neat): ν_max/cm⁻¹ 3019, 3011, 1745, 1214, 746, 667. HRMS (ESI) m/z calcd for C₁₅H₁₂N₂O₂ + H⁺ [M + H]⁺ 253.0972; found 253.0969.

1-(Pyridin-4-yl)-1H-indol-3-yl acetate (2i). The representative procedure was followed, using 1-(pyridin-4-yl)-1H-indole (1i) (0.058 g, 0.30 mmol) and PhI(OAc)₂ (0.106 g, 0.33 mmol). Purification by preparative TLC (hexane/EtOAc: 5/1) and extraction in CH₂Cl₂ (15 mL × 3) yielded 2i (0.042 g, 56%) as a yellow liquid. ¹H-NMR (400 MHz, CDCl₃): δ = 8.73 (d, J = 4.7 Hz, 2H), 7.75–7.66 (m, 3H), 7.49 (d, J = 4.9 Hz, 2H), 7.35 (dd, J = 7.8, 7.3 Hz, 1H), 7.29 (d, J = 7.3 Hz, 1H), 2.43 (s, 3H). ¹³C{¹H}-NMR (100 MHz, CDCl₃): δ = 168.3, 151.4, 146.7, 133.4, 132.2, 124.5, 122.7, 121.7, 118.5, 117.4, 115.6, 111.0, 21.2. IR (neat): ν_max/cm⁻¹ 2928, 2855, 1730, 1586, 1512, 1456, 1367, 1161, 993, 943, 807, 659. HRMS (ESI) m/z calcd for C₁₅H₁₂N₂O₂ + H⁺ [M + H]⁺ 253.0972; found 253.0971.

1-(Pyrazin-2-yl)-1H-indol-3-yl acetate (2j). The representative procedure was followed, using 1-(pyrazin-2-yl)-1H-indole (1j) (0.059 g, 0.30 mmol) and PhI(OAc)₂ (0.106 g, 0.33 mmol). Purification by preparative TLC (hexane/EtOAc: 5/1) and extraction in CH₂Cl₂ (15 mL × 3) yielded 2j (0.071 g, 93%) as a brown solid. M. p. = 145–147 °C. ¹H-NMR (500 MHz, CDCl₃): δ = 8.86 (d, J = 1.0 Hz, 1H), 8.48 (dd, J = 2.5, 1.7 Hz, 1H), 8.40 (d, J = 2.5 Hz, 1H), 8.34 (d, J = 8.6 Hz, 1H), 8.01 (s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.37 (dt, J = 8.1, 1.0 Hz, 1H), 7.28 (dd, J = 8.3, 7.8 Hz, 1H), 2.41 (s, 3H). ¹³C{¹H}-NMR (125 MHz, CDCl₃): δ = 168.3, 149.3, 142.7, 140.0, 136.3, 134.1, 132.6, 125.0, 123.2, 122.3, 118.1, 114.0, 113.7, 21.2. IR (neat): ν_max/cm⁻¹ 3021, 2961, 1737, 1449, 1425, 1365, 1210, 1123, 1013, 839, 729. HRMS (ESI) m/z calcd for C₁₄H₁₁N₃O₂ + Na⁺ [M + Na]⁺ 276.0743; found 276.0741.

5-Fluoro-1-(pyrazin-2-yl)-1H-indol-3-yl acetate (2k). The representative procedure was followed, using 5-fluoro-1-(pyrazin-2-yl)-1H-indole (1k) (0.064 g, 0.30 mmol) and PhI(OAc)₂ (0.106 g, 0.33 mmol). Purification by column chromatography on silica gel (CH₂Cl₂/EtOAc: 15/1) yielded 2k (0.050 g, 61%) as an off-white solid. M. p. = 166–168 °C. ¹H-NMR (500 MHz, CDCl₃): δ = 8.81 (s, 1H), 8.47 (s, 1H), 8.41 (s, 1H), 8.37 (dd, J = 9.2, 4.3 Hz, 1H), 8.03 (s, 1H), 7.27–7.25 (m, 1H), 7.10 (td, J = 9.2, 2.4 Hz, 1H), 2.40 (s, 3H). ¹³C{¹H}-NMR (125 MHz, CDCl₃): δ = 168.1, 159.0 (d, J_C–F = 240.3 Hz), 149.1, 142.6, 140.1, 135.8, 133.9, 129.1, 123.9 (d, J_C–F = 9.5 Hz), 115.7 (d, J_C–F = 9.5 Hz), 115.0, 113.2 (d, J_C–F = 24.8 Hz), 103.5 (d, J_C–F = 24.8 Hz), 21.2. ¹⁹F-NMR (377 MHz, CDCl₃): δ = −121.6 (s). IR (neat): ν_max/cm⁻¹ 2924, 1748, 1480, 1446, 1201, 1007, 911, 839, 764. HRMS (ESI) m/z calcd for C₁₄H₁₀FN₃O₂ + H⁺ [M + H]⁺ 272.0830; found 272.0828.

5-Bromo-1-(pyrazin-2-yl)-1H-indol-3-yl acetate (2l). The representative procedure was followed, using 5-bromo-1-(pyrazin-2-yl)-1H-indole (1l) (0.082 g, 0.30 mmol) and PhI(OAc)₂ (0.106 g, 0.33 mmol). Purification by column chromatography on silica gel (CH₂Cl₂/EtOAc: 20/1) yielded 2l (0.069 g, 70%) as a light brown solid. M. p. = 162–164 °C. ¹H-NMR (400 MHz, CDCl₃): δ = 8.81 (s, 1H), 8.48 (s, 1H), 8.42 (d, J = 2.5 Hz, 1H), 8.27 (d, J = 9.1 Hz, 1H), 8.00 (s, 1H), 7.75 (d, J = 1.7 Hz, 1H), 7.44 (dd, J = 8.8, 1.7 Hz, 1H), 2.40 (s, 3H). ¹³C{¹H}-NMR (100 MHz, CDCl₃): δ = 168.1, 149.0, 142.6, 140.4, 136.0, 133.2, 131.2, 127.9, 124.8, 120.8, 115.9, 115.6, 114.6, 21.2. IR (neat): ν_max/cm⁻¹ 3170, 2923, 1759, 1446, 1422, 1243, 1061, 1006, 835, 735. HRMS (ESI) m/z calcd for C₁₄H₁₀BrN₃O₂ + H⁺ [M + H]⁺ 332.0029, 334.0009; found 332.0030, 334.0008.

1-(Thiophen-2-yl)-1H-indol-3-yl acetate (2m). The representative procedure was followed, using 1-(thiophen-2-yl)-1H-indole (1m) (0.043 g, 0.22 mmol) and PhI(OAc)₂ (0.077 g, 0.24 mmol). Purification by preparative TLC (hexane/EtOAc: 5/1) and extraction in CH₂Cl₂ (15 mL × 3) yielded 2m (0.020 g, 35%) as a liquid. ¹H-NMR (400 MHz, CDCl₃): δ = 7.60–7.54 (m, 3H), 7.29–7.25 (m, 1H), 7.22–7.16 (m, 2H), 7.08–7.02 (m, 2H), 2.38 (s, 3H). ¹³C{¹H}-NMR (100 MHz, CDCl₃): δ = 168.4, 141.4, 134.4, 131.9, 126.2, 124.0, 122.0, 121.4, 121.1, 120.9, 118.5, 118.0, 110.9, 21.2. IR (neat): ν_max/cm⁻¹ 3010, 2962, 2854, 1747, 1613, 1547, 1460, 1366, 1225, 1010, 692. HRMS (ESI) m/z calcd for C₁₄H₁₁NO₂S + Na⁺ [M + Na]⁺ 280.0403; found 280.0398.

1-Phenyl-1H-indol-3-yl acetate (4a)⁷. The representative procedure was followed, using 1-phenyl-1H-indole (3a) (0.058 g, 0.30 mmol) and PhI(OAc)₂ (0.106 g, 0.33 mmol). Purification by column chromatography on silica gel (hexane/EtOAc: 5/1) yielded 4a (0.038 g, 50%) as a liquid. ¹H-NMR (500 MHz, CDCl₃): δ = 7.61 (d, J = 7.6 Hz, 1H), 7.57 (s, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.51–7.48 (m, 4H), 7.35–7.31 (m, 1H), 7.23 (dd, J = 7.6, 7.3 Hz, 1H), 7.18 (dd, J = 7.6, 7.3 Hz, 1H), 2.38 (s, 3H). ¹³C{¹H}-NMR (125 MHz, CDCl₃): δ = 168.6, 139.6, 133.0, 131.7, 129.8, 126.6, 124.6, 123.4, 121.4, 120.6, 118.0, 117.2, 110.8, 21.2. IR (neat): ν_max/cm⁻¹ 3007, 2978, 2873, 1745, 1712, 1501, 1457, 1367, 1223, 1110, 696. HRMS (ESI) m/z calcd for C₁₆H₁₃NO₂ + Na⁺ [M + Na]⁺ 274.0838; found 274.0833.

1-(4-Methoxyphenyl)-1H-indol-3-yl acetate (4b)⁷. The representative procedure was followed, using 1-(4-methoxyphenyl)-1H-indole (3b) (0.067 g, 0.30 mmol) and PhI(OAc)₂ (0.106 g, 0.33 mmol). Purification by column chromatography on silica gel (hexane/EtOAc: 4/1) yielded 4b (0.031 g, 37%) as a liquid. ¹H-NMR (400 MHz, CDCl₃): δ = 7.60 (d, J = 7.6 Hz, 1H), 7.49 (s, 1H), 7.43–7.37 (m, 3H), 7.24–7.14 (m, 2H), 7.01 (d, J = 8.6 Hz, 2H), 3.86 (s, 3H), 2.38 (s, 3H). ¹³C{¹H}-NMR (100 MHz, CDCl₃): δ = 168.7, 158.5, 133.5, 132.5, 131.2, 126.2, 123.2, 120.9, 120.3, 117.9, 117.6, 114.9, 110.6, 55.8, 21.2. IR (neat): ν_max/cm⁻¹ 3176, 2966, 2840, 1747, 1548, 1510, 1370, 1207, 1029, 739, 588. HRMS (ESI) m/z calcd for C₁₇H₁₅NO₃ + Na⁺ [M + Na]⁺ 304.0944; found 304.0935.

1-(4-Fluorophenyl)-1H-indol-3-yl acetate (4c). The representative procedure was followed, using 1-(4-fluorophenyl)-1H-indole (3c) (0.076 g, 0.36 mmol) and PhI(OAc)₂ (0.127 g, 0.39 mmol). Purification by column chromatography on silica gel (hexane/EtOAc: 15/1) yielded 4c (0.039 g, 40%) as a yellow liquid. ¹H-NMR (400 MHz, CDCl₃): δ = 7.67 (d, J = 7.6 Hz, 1H), 7.56 (s, 1H), 7.49–7.46 (m, 3H), 7.30–7.21 (m, 4H), 2.43 (s, 3H). ¹³C{¹H}-NMR (125 MHz, CDCl₃): δ = 168.6, 161.2 (d, J_C–F = 246.6 Hz), 135.6 (d, J_C–F = 2.3 Hz), 133.3, 131.7, 126.4 (d, J_C–F = 8.5 Hz), 123.5, 121.3, 120.6, 118.0, 117.2, 116.6 (d, J_C–F = 23.1 Hz), 110.4, 21.2. ¹⁹F-NMR (377 MHz, CDCl₃): δ = −115.1 (s). IR (neat): ν_max/cm⁻¹ 3160, 2927, 2854, 1745, 1509, 1366, 1202, 1128, 819, 738, 558. HRMS (ESI) m/z calcd for C₁₆H₁₂FNO₂ + Na⁺ [M + Na]⁺ 292.0744; found 292.0739.

1-(4-(Trifluoromethyl)phenyl)-1H-indol-3-yl acetate (4d). The representative procedure was followed, using 1-(4-(trifluoromethyl)phenyl)-1H-indole (3d) (0.078 g, 0.30 mmol) and PhI(OAc)₂ (0.106 g, 0.33 mmol). Purification by column chromatography on silica gel (hexane/EtOAc: 10/1) yielded 4d (0.043 g, 45%) as a brown solid. M. p. = 99–101 °C. ¹H-NMR (400 MHz, CDCl₃): δ = 7.79–7.76 (m, 2H), 7.66–7.61 (m, 4H), 7.58 (dd, J = 8.3, 4.9 Hz, 1H), 7.30–7.20 (m, 2H), 2.40 (s, 3H). ¹³C{¹H}-NMR (100 MHz, CDCl₃): δ = 168.5, 142.7, 132.8, 132.6, 128.4 (q, J_C–F = 33.1 Hz), 127.1 (q, J_C–F = 3.1 Hz), 124.2 (q, J_C–F = 272.0 Hz), 124.1, 124.0, 122.0, 121.2, 118.3, 116.6, 110.6, 21.2. ¹⁹F-NMR (377 MHz, CDCl₃): δ = −62.3 (s). IR (neat): ν_max/cm⁻¹ 3163, 2926, 1746, 1369, 1333, 1106, 1065, 841, 763, 736. HRMS (ESI) m/z calcd for C₁₇H₁₂F₃NO₂ + Na⁺ [M + Na]⁺ 342.0712; found 342.0706.

1-(4-Acetylphenyl)-1H-indol-3-yl acetate (4e). The representative procedure was followed, using 1-(4-(1H-indol-1-yl)phenyl)ethan-1-one (3e) (0.071 g, 0.30 mmol) and PhI(OAc)₂ (0.106 g, 0.33 mmol). Purification by column chromatography on silica gel (hexane/EtOAc: 3/1) yielded 4e (0.031 g, 35%) as a light yellow liquid. ¹H-NMR (500 MHz, CDCl₃): δ = 8.10 (d, J = 8.5 Hz, 2H), 7.64–7.58 (m, 5H), 7.28 (dd, J = 8.2, 7.0 Hz, 1H), 7.22 (dd, J = 7.6, 7.3 Hz, 1H), 2.64 (s, 3H), 2.40 (s, 3H). ¹³C{¹H}-NMR (125 MHz, CDCl₃): δ = 197.0, 168.5, 143.6, 134.7, 132.7, 132.6, 130.2, 124.0, 123.5, 122.1, 121.3, 118.3, 116.5, 110.8, 26.8, 21.2. IR (neat): ν_max/cm⁻¹ 2962, 2931, 2861, 1717, 1265, 1128, 1074, 736. HRMS (ESI) m/z calcd for C₁₈H₁₅NO₃ + Na⁺ [M + Na]⁺ 316.0944; found 316.0938.

Methyl 4-(3-acetoxy-1H-indol-1-yl)benzoate (4f). The representative procedure was followed, using methyl 4-(1H-indol-1-yl)benzoate (3f) (0.075 g, 0.30 mmol) and PhI(OAc)₂ (0.106 g, 0.33 mmol). Purification by column chromatography on silica gel (hexane/EtOAc: 5/1) yielded 4f (0.038 g, 41%) as a liquid. ¹H-NMR (500 MHz, CDCl₃): δ = 8.18 (d, J = 8.5 Hz, 2H), 7.64–7.60 (m, 3H), 7.57 (d, J = 8.5 Hz, 2H), 7.28 (dd, J = 8.2, 7.3 Hz, 1H), 7.22 (dd, J = 7.6, 7.3 Hz, 1H), 3.96 (s, 3H), 2.40 (s, 3H). ¹³C{¹H}-NMR (125 MHz, CDCl₃): δ = 168.5, 166.5, 143.5, 132.7, 132.6, 131.4, 127.7, 124.0, 123.4, 122.0, 121.2, 118.2, 116.5, 110.8, 52.4, 21.2. IR (neat): ν_max/cm⁻¹ 3028, 3012, 2954, 1717, 1605, 1515, 1457, 1437, 1365, 1280, 1206, 738, 664. HRMS (ESI) m/z calcd for C₁₈H₁₅NO₄ + Na⁺ [M + Na]⁺ 332.0893; found 332.0887.

1-(4-Cynophenyl)-1H-indol-3-yl acetate (4g). The representative procedure was followed, using 4-(1H-indol-1-yl)benzonitrile (3g) (0.066 g, 0.30 mmol) and PhI(OAc)₂ (0.106 g, 0.33 mmol). Purification by column chromatography on silica gel (hexane/EtOAc: 5/1) yielded 4g (0.046 g, 56%) as a light brown solid. M. p. = 110–112 °C. ¹H-NMR (500 MHz, CDCl₃): δ = 7.81 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 7.6 Hz, 1H), 7.66 (s, 1H), 7.63–7.60 (m, 3H), 7.33 (dd, J = 8.2, 7.3 Hz, 1H), 7.27 (dd, J = 8.2, 7.0 Hz, 1H), 2.43 (s, 3H). ¹³C{¹H}-NMR (125 MHz, CDCl₃): δ = 168.4, 143.4, 133.9, 133.1, 132.4, 124.3, 124.0, 122.3, 121.6, 118.5, 118.4, 116.1, 110.6, 109.4, 21.2. IR (neat): ν_max/cm⁻¹ 2921, 2851, 2225, 1776, 1562, 1509, 1366, 1211, 1126, 1012, 845, 743. HRMS (ESI) m/z calcd for C₁₇H₁₂N₂O₂ + Na⁺ [M + Na]⁺ 299.0791; found 299.0787.

1-(4-Nitrophenyl)-1H-indol-3-yl acetate (4h). The representative procedure was followed, using 1-(4-nitrophenyl)-1H-indole (3h) (0.071 g, 0.30 mmol) and PhI(OAc)₂ (0.106 g, 0.33 mmol). Purification by column chromatography on silica gel (hexane/EtOAc: 5/1) yielded 4h (0.047 g, 53%) as a yellow solid. M. p. = 142–144 °C. ¹H-NMR (500 MHz, CDCl₃): δ = 8.38 (d, J = 8.9 Hz, 2H), 7.68–7.62 (m, 5H), 7.33 (dd, J = 8.2, 7.3 Hz, 1H), 7.24 (dd, J = 7.6, 7.3 Hz, 1H), 2.41 (s, 3H). ¹³C{¹H}-NMR (125 MHz, CDCl₃): δ = 168.4, 145.2, 145.1, 133.5, 132.5, 125.7, 124.6, 123.5, 122.5, 121.8, 118.6, 116.2, 110.7, 21.2. IR (neat): ν_max/cm⁻¹ 2923, 2852, 1746, 1592, 1524, 1222, 1129, 865, 748, 695, 528. HRMS (ESI) m/z calcd for C₁₆H₁₂N₂O₄ + Na⁺ [M + Na]⁺ 319.0689; found 319.0688.

1-(2,4-Dinitrophenyl)-1H-indol-3-yl acetate (4i). The representative procedure was followed, using 1-(2,4-dinitrophenyl)-1H-indole (3i) (0.085 g, 0.30 mmol) and PhI(OAc)₂ (0.106 g, 0.33 mmol). Purification by column chromatography on silica gel (hexane/EtOAc: 4 : 1) yielded 4i (0.078 g, 76%) as an orange solid. M. p. = 147–148 °C. ¹H-NMR (500 MHz, CDCl₃): δ = 8.92 (d, J = 2.4 Hz, 1H), 8.57 (dd, J = 8.9, 2.4 Hz, 1H), 7.84 (d, J = 8.9 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.53 (s, 1H), 7.33–7.27 (m, 2H), 7.16 (d, J = 8.2 Hz, 1H), 2.42 (s, 3H). ¹³C{¹H}-NMR (125 MHz, CDCl₃): δ = 168.0, 145.5, 144.7, 138.0, 134.3, 133.1, 130.0, 128.3, 125.0, 122.3, 122.2, 122.1, 118.8, 116.2, 109.5, 21.2. IR (neat): ν_max/cm⁻¹ 3158, 3084, 2852, 1751, 1601, 1527, 1366, 1224, 1128, 748, 702, 569. HRMS (ESI) m/z calcd for C₁₆H₁₁N₃O₆ + Na⁺ [M + Na]⁺ 364.0540; found 364.0533.

1-(2,4-Dinitrophenyl)-5-fluoro-1H-indol-3-yl acetate (4j). The representative procedure was followed, using 1-(2,4-dinitrophenyl)-5-fluoro-1H-indole (3j) (0.09 g, 0.30 mmol) and PhI(OAc)₂ (0.106 g, 0.33 mmol). Purification by column chromatography on silica gel (hexane/EtOAc: 4 : 1) yielded 4j (0.066 g, 61%) as an orange solid. M. p. = 120–122 °C. ¹H-NMR (400 MHz, CDCl₃): δ = 8.90 (d, J = 2.4 Hz, 1H), 8.57 (dd, J = 8.8, 2.4 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.55 (s, 1H), 7.30 (dd, J = 8.6, 2.2 Hz, 1H), 7.08–6.99 (m, 2H), 2.39 (s, 3H). ¹³C{¹H}-NMR (100 MHz, CDCl₃): δ = 167.9, 159.0 (d, J_C–F = 239.7 Hz), 145.8, 144.9, 137.7, 134.0 (d, J_C–F = 4.6 Hz), 130.1, 129.6, 128.4, 122.9 (d, J_C–F = 10.8 Hz), 122.1, 117.9, 113.5 (d, J_C–F = 26.2 Hz), 110.7 (d, J_C–F = 9.3 Hz), 104.4 (d, J_C–F = 25.4 Hz), 21.1. ¹⁹F-NMR (377 MHz, CDCl₃): δ = −120.4 (s). IR (neat): ν_max/cm⁻¹ 2922, 2852, 1754, 1452, 1338, 1202, 1188, 769, 729, 521. HRMS (ESI) m/z calcd for C₁₆H₁₀FN₃O₆ + Na⁺ [M + Na]⁺ 382.0446; found 382.0445.

1-(3,5-Bis(trifluoromethyl)phenyl)-1H-indol-3-yl acetate (4k). The representative procedure was followed, using 1-(3,5-bis(trifluoromethyl)phenyl)-1H-indole (3k) (0.099 g, 0.30 mmol) and PhI(OAc)₂ (0.106 g, 0.33 mmol). Purification by column chromatography on silica gel (hexane/EtOAc: 20/1) yielded 4k (0.063 g, 54%) as a light brown solid. M. p. = 68–70 °C. ¹H-NMR (400 MHz, CDCl₃): δ = 7.96 (s, 2H), 7.83 (s, 1H), 7.66–7.64 (m, 2H), 7.50 (d, J = 8.3 Hz, 1H), 7.32 (dd, J = 7.3, 7.1 Hz, 1H), 7.24 (dd, J = 7.6, 7.3 Hz, 1H), 2.40 (s, 3H). ¹³C{¹H}-NMR (100 MHz, CDCl₃): δ = 168.4, 141.1, 133.5 (q, J = 33.3 Hz), 133.2, 132.7, 124.6, 124.0 (q, J = 2.9 Hz), 123.1 (q, J = 272.8 Hz), 122.2, 121.7, 119.7, 118.6, 116.2, 110.0, 21.1. ¹⁹F-NMR (377 MHz, CDCl₃): δ = −63.0 (s). IR (neat): ν_max/cm⁻¹ 3185, 3066, 2927, 1750, 1279, 1216, 1202, 1168, 1085, 888, 737, 682. HRMS (ESI) m/z calcd for C₁₈H₁₁F₆NO₂ + H⁺ [M + H]⁺ 388.0767; found 388.0762.

Synthesis of 1-(pyrimidin-2-yl)indoline-2,3-diyl diacetate (5a). To a flame-dried Schlenk tube equipped with magnetic stir bar was introduced phenyl-λ³-iodanediyl diacetate, PhI(OAc)₂ (0.354 g, 1.1 mmol) and 1-(pyrimidin-2-yl)-1H-indole (1a) (0.195 g, 1.0 mmol) under argon. The Schlenk tube with reaction mixture was evacuated and refilled with argon. To the above mixture was added acetic acid and acetic anhydride (7 : 3) solvent mixture (1.0 mL). The resultant reaction mixture was then degassed, refilled with argon and stirred at room temperature for 1 h. Then the reaction mixture was quenched with H₂O (5 mL) and saturated NaHCO₃ solution (15 mL) and the reaction mixture was extracted with ethyl acetate (15 mL × 3). The combined organic layers were dried over Na₂SO₄ and the solvent was evaporated in vacuo. The crude residue was purified by column chromatography on silica gel (hexane/EtOAc: 2/1) to yielded diacyloxylated compound 5a (0.165 g, 53%) as an off-white solid. M. p. = 143–145 °C. ¹H-NMR (500 MHz, CDCl₃): δ = 8.54 (d, J = 4.6 Hz, 2H), 8.45 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.43 (dd, J = 8.2, 7.3 Hz, 1H), 7.22 (s, 1H), 7.06 (dd, J = 7.6, 7.3 Hz, 1H), 6.85 (t, J = 4.6 Hz, 1H), 6.01 (s, 1H), 2.07 (s, 3H), 2.05 (s, 3H). ¹³C{¹H}-NMR (125 MHz, CDCl₃): δ = 170.2, 170.1, 158.4, 158.0, 144.4, 131.0, 127.6, 127.4, 122.9, 116.2, 114.0, 87.9, 75.6, 21.1. IR (neat): ν_max/cm⁻¹ 3735, 3015, 1734, 1730, 1585, 1488, 1444, 1227, 1014, 761, 617. HRMS (ESI) m/z calcd for C₁₆H₁₅N₃O₄ + Na⁺ [M + Na]⁺ 336.0955; found 336.0952.

Representative procedure for the competition experiments

To a flame-dried Schlenk tube equipped with magnetic stir bar was introduced compound 1a (0.117 g, 0.6 mmol), compound 3a (0.116 g, 0.6 mmol) and PhI(OAc)₂ (0.097 g, 0.30 mmol) under argon. The Schlenk tube with the mixture was evacuated and refilled with argon. To the above mixture was added acetic acid and acetic anhydride (7 : 3) solvent mixture (2.0 mL). The resultant reaction mixture was then degassed, refilled with argon and stirred at 60 °C in a pre-heated oil bath for 5 h. At ambient temperature, H₂O (5 mL) and saturated NaHCO₃ solution (15 mL) were added and the reaction mixture was extracted with ethyl acetate (15 mL × 3). The combined organic layers were dried over Na₂SO₄ and the solvent was evaporated in vacuo. To the resultant residue, acetone (5 mL) and p-xylene (0.3 mmol) were added and injected into Gas Chromatograph. The GC yield was calculated with respect to internal standard p-xylene.

Procedure for the dehydroacetoxylation reaction

To a flame-dried Schlenk tube equipped with magnetic stir bar was introduced compound 5a (0.031 g, 0.1 mmol) and 1-acetylindoline-2,3-diyl diacetate (0.028 g, 0.1 mmol). To the above mixture was added acetic acid and acetic anhydride (7 : 3) solvent mixture (1.0 mL). The resultant reaction mixture was then degassed, refilled with argon and stirred at 60 °C in a pre-heated oil bath for 2 h. At ambient temperature, H₂O (3 mL) and saturated NaHCO₃ solution (10 mL) were added and the reaction mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over Na₂SO₄ and the solvent was evaporated in vacuo. To the resultant residue, acetone (5 mL) and p-xylene (0.2 mmol) were added and injected into Gas Chromatograph. The GC yield was calculated with respect to internal standard p-xylene.

Acknowledgements

This work was financially supported by CSIR-NCL (start-up grant, MLP025926), SERB, New Delhi (SR/S1/IC-42/2012) and CSIR, New Delhi as part of XII Five Year plan programme under title ORIGIN (CSC-0108). V.S. and U.N.P. thank CSIR, New Delhi for research fellowship. We thank Dr P. R. Rajmohanan for NMR facility, Dr (Mrs) Shanthakumari for HRMS and Dr C. V. V. Satyanarayana for ICP-AES analyses.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra10428a

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