Combined Di-tert-butyl Peroxide and Inorganic Base Promoted α

Publication Date (Web): May 4, 2017 ... characterized by capturing in situ generated vinylogous imine intermediates for the C(sp3)–H bond alkylation...
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Combined Di-tert-butyl Peroxide and Inorganic Base Promoted α‑Alkylation of Ethers with Arenesulfonylindoles Zheng Gu, Yao Tang, and Guo-Fang Jiang* State Key Lab of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China S Supporting Information *

ABSTRACT: The di-tert-butyl peroxide (DTBP) induced coupling of arenesulfonylindoles with ethers such as 1,4-dioxane, tetrahydropyran, tetrahydrofuran, and 1,2-dimethoxyethane was studied. The distinguishing feature of this strategy was characterized by capturing in situ generated vinylogous imine intermediates for the C(sp3)−H bond alkylation of ethers. This general procedure presents the major advantages of its wide substrate scope and good functional group compatibility

D

irect functionalization of C−H bonds has drawn great attention during the past decade owing to its step and atom economy with environmental sustainability to construct C−C and C−heteroatom bonds.1 Unlike the C(sp2)−H bonds,2 direct functionalization of inactive C(sp3)−H bonds in a predictable and efficient manner has become a central challenge in modern organic chemistry for their relatively strong bond dissociation energy and low polarity.3 To the best of our knowledge, ethers are ubiquitous structural motifs that frequently appear in numerous biologically active molecules, medicines, and natural products (selected examples are shown in Figure 1).4 Thus, the strategy based on the functionalization5−8 of C(sp3)−H bonds adjacent to the oxygen of ethers represents one of many interesting topics in synthetic chemistry. Especially, enormous effort has been dedicated to direct alkylation of ethers, and significant progress has been made. Following the initial report by Elad,6a several elegant methods for the alkylation of ethers with alkenes have been developed (Scheme 1, eq 1).6b−e Furthermore, Vishwakarma and Ghosh discovered novel cross-coupling of organometallic species with

cyclic ethers by iron-catalyzed C(sp3)−H bond functionalization (Scheme 1, eq 2).7 Later, transition-metal-catalyzed or metal-free oxidative couplings of carbonyl compounds with ethers have also been witnessed for the C(sp3)−H bond alkylation of cyclic or acyclic ethers (Scheme 1, eq 3).8 However, despite the success of inactive C(sp3)−H alkylation methods that have been developed, the coupling counterparts are mainly limited to alkenes,6 organometallic species,7 and carbonyl compounds.8 Therefore, developing an efficient and expeditious procedure for α-alkylation of ethers involving other counterparts is highly demanded. The indole ring is included in a plethora of biologically active compounds, and this feature fully justifies the deep interest addressed to all synthetic processes concerning this heterocyclic system.9 Meanwhile, the use of sulfones as an auxiliary group is an important synthetic strategy in organic synthesis; this functional group can modify the polarity of the molecule by acting as an electron-withdrawing group to stabilize carbanions or as a leaving group. Due to this dual chemical behavior, numerous organic compounds containing sulfones have been designed and applied in organic synthesis.10 It is worthy of note that the sulfonyl moiety at the benzylic position of 3-substituted indoles acts as a good leaving group, which enables the generation of vinylogous imine intermediates under basic conditions. The generated vinylogous imine intermediates are equal to α,β-unsaturated imines, which are able to react with

Figure 1. Selected biologically active ether compounds.

Received: February 27, 2017 Published: May 4, 2017

© 2017 American Chemical Society

5441

DOI: 10.1021/acs.joc.7b00463 J. Org. Chem. 2017, 82, 5441−5448

Note

The Journal of Organic Chemistry

DTBP as the oxidant. Running the reaction at 120 °C gave a 63:37 mixture of corresponding products anti-(±)-3a and syn(±)-3a, in a total yield of 59% (Table 1, entry 1). Decreasing the temperature to 100 °C indicated a deterioration of activity (Table 1, entry 2). When the reaction was conducted at 60 and 80 °C, the desired product was not detected by TLC (Table 1, entries 3−4). It demonstrated that temperature had a great influence on the yield of the desired products. With other inorganic bases that were examined, the yield decreased slightly (Table 1, entries 5−6). It is worthy of note that when the organic base NEt3 was used, only a trace of the mixture was detected (Table 1, entry 7). Surprisingly, dropping the base load to 1.0 equiv improved the yield (Table 1, entry 8). Tests revealed that the use of a suitable amount of DTBP was vital to the alkylation of 1,4-dioxane, with insufficiency or excess leading to worse results (Table 1, entries 9−10). In addition, no product was obtained in the absence of K2CO3 or DTBP, indicating that both K2CO3 and DTBP were crucial for this transformation (Table 1, entries 11−12). Careful analysis of the results revealed that 1.0 equiv of K2CO3, 0.1 mL of DTBP, and 120 °C would be the best reaction conditions for further studies. With the optimal conditions in hand, we then explored the substrate scope (Table 2). As shown in Table 2, dr values of all products were distributed between 1.2:1 and 2:1. All of the tested arenesulfonylindoles (1) acted as excellent substrates to react with 1,4-dioxane (2a), in the presence of K2CO3 and DTBP, furnishing the corresponding products in moderate to good yields (Table 2, entries 1−5). Substituents at the 2- and 5position of arenesulfonylindoles made almost no difference on the activity and diastereoselectivity (Table 2, entries 1−4). While, the R3 substituent of arenesulfonylindole bore unfavorably on the yield (Table 2, entries 5). Notably, alkylation of tetrahydropyran with arenesulfonylindoles (1) also exhibited good activity (Table 2, entries 6−12). Similarly, the 2-methyl substituted sulfonyl indoles was suitable reaction partner under the optimal conditions, providing the desired

Scheme 1. α-Alkylation of Ethers

numerous nucleophiles.11 Inspired by these elegant studies, we envisioned that these vinylogous imine intermediates in situ generated under basic conditions would be captured by DTBP promoted free-radical activation of ethers, resulting in the αalkylation of ethers involving arenesulfonylindoles as coupling counterparts. By this strategy, a rapid entry to biologically active indole derivatives would be supplied. Our initial attempts focused on identifying suitable conditions for the coupling of arenesulfonylindoles with ethers (Table 1). We commenced our investigation by screening the coupling of 2-methyl substituted arenesulfonylindole (1a) with 1,4-dioxane (2a) in the presence of K2CO3 as the base and Table 1. Optimization of the Reaction Conditionsa

a b

entry

base (equiv)

DTBP (mL)

T (°C)

yieldb (%)

drc

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

K2CO3 (3.0) K2CO3 (3.0) K2CO3 (3.0) K2CO3 (3.0) Cs2CO3 (3.0) NaOH (3.0) NEt3 (3.0) K2CO3 (1.0) K2CO3 (1.0) K2CO3 (1.0) − K2CO3 (1.0)

0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.05 0.15 0.1 −

120 100 80 60 120 120 120 120 120 120 120 120

59 trace ndd ndd 57 46 trace 67 52 60 ndd ndd

63:37 − − − 66:34 64:36 − 66:34 60:40 66:34 − −

Reaction conditions: 1a (0.2 mmol, 1.0 equiv), K2CO3 (0.2 mmol, 1.0 equiv), DTBP (0.1 mL), 1,4-dioxane (2.0 mL), 12 h in a sealed tube. Isolated yields. cDetermined by 1H NMR of the mixture of anti-(±)-3a and syn-(±)-3a. dnd = no product was detected. 5442

DOI: 10.1021/acs.joc.7b00463 J. Org. Chem. 2017, 82, 5441−5448

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The Journal of Organic Chemistry Table 2. Scope for the Reaction of α-Alkylation of Ethers with Arenesulfonylindolesa

a b

entry

1

2

3

yield (%)b

drc

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

1a 1b 1c 1d 1e 1a 1b 1c 1d 1e 1f 1g 1a 1b 1e 1h

2a 2a 2a 2a 2a 2b 2b 2b 2b 2b 2b 2b 2c 2c 2c 2c

3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o 3p

67 71 64 69 62 61 80 65 59 70 61 45 64 63 48 60

66:34 60:40 66:34 64:36 67:33 57:43 63:37 63:37 60:40 63:37 57:43 55:45 67:33 62:38 67:33 57:43

Reaction conditions: 1 (0.2 mmol, 1equiv), K2CO3 (0.2 mmol, equiv), DTBP (0.1 mL), cyclic ethers 2 (2 mL), 120 °C, 12 h in a sealed tube. Isolated yields. cDetermined by 1H NMR of the mixture of anti-(±)-3 and syn-(±)-3.

Scheme 2. Reaction of (±)-1a with Acyclic Ether 2d

Scheme 3. Control Experiment

product in moderate yield regardless of the electronic property of the R1 and R3 substituents (Table 2, entries 6, 8−11). When R2 and R3 were phenyl, up to 80% yield was obtained (Table 2, entry 7). Moveover, 2-position unsubstituted sulfonyl indoles

proceed smoothly for this transformation, along with a 45% yield (Table 2, entry 12). Finally, the coupling component of ether was changed to tetrahydrofuran. As demonstrated, various substituted arenesulfonylindoles reacted smoothly, affording 5443

DOI: 10.1021/acs.joc.7b00463 J. Org. Chem. 2017, 82, 5441−5448

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The Journal of Organic Chemistry Scheme 4. Proposed Mechanism

substrate scope and good functional group tolerance. This discovery could be of great significance in other inactive C(sp3)−H bond functionalizations.

the targets in moderate yields (Table 2, entries 13−16). Pleasingly, the 2-ester carbonyl substituted arenesulfonylindoles successfully underwent the alkylation (Table 2, entry 16). Finally, the relative configuration of anti-(±)-3i was confirmed by single-crystal X-ray diffraction anaysis (see the Supporting Information, Figure S1). To further expand the scope of this alkylation reaction, we turned our attention to acyclic ether substrates. Fortunately, acyclic ether 2d was suitable for the C(sp3)−H functionalized reaction, not only providing the internal methylene functionalized products (anti-(±)-3q and syn-(±)-3q) but also affording the isomer (±)-3q′ which was generated by C(sp3)−H activation at the terminal methyl group (Scheme 2). To understand the mechanism of this reaction, a control experiment was performed. When the radical inhibitor, 2,2,6,6tetramethyl-1-piperidinyloxy (TEMPO), was added to the present reaction system, only a trace amount of the desired product 3a was observed by TLC (Scheme 3). On the basis of the above results and previous publications,6e,12 a plausible catalytic mechanism was presented (Scheme 4). First, high temperature results in the homolysis of DTBP, which is decomposed to the tert-butoxyl radical. Then, the tert-butoxyl radical can abstract hydrogen from the ether to generate the corresponding alkoxy radical intermediate (A). Meanwhile, the vinylogous imine intermediate (B) can be generated from arenesulfonylindole (1) under the mild basic conditions.11 Subsequently, the alkoxy radical (A) reacted with the vinylogous imine intermediate (B) affording the corresponding radical intermediate (C). Finally, the corresponding radical intermediate (C) abstracts a hydrogen atom to generate the corresponding product 3. In summary, an efficient and practical di-tert-butyl peroxide (DTBP) and inorganic base promoted C(sp3)−H bond alkylation method was developed, which enables the αalkylation of ethers with arenesulfonylindoles under standard conditions. The distinguishing feature of this strategy was highlighted by capturing in situ generated vinylogous imine intermediates for the C(sp3)−H bond alkylation of ethers. This general procedure presents the major advantages of a broad

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EXPERIMENTAL SECTION

General Information. Products were purified by flash chromatography on silica gel (200−300 mesh) using petroleum ether/ethyl acetate (5/1) and were characterized by 1H, 13C NMR, and all subject products were further characterized by IR and HRMS. 1H NMR spectra were recorded on 400 MHz in CDCl3, and 13C NMR spectra were recorded on 100 MHz in CDCl3 using TMS as internal standard. Chemical shifts (δ) are reported in ppm, and coupling constants (J) are in hertz (Hz). The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. HRMS data were obtained on a Thermo Scientific LTQ Orbitrap Discovery spectrometer (Bremen, Germany). Unless otherwise noted, all reagents and solvent were obtained commercially and used without further purification. Arylsulfonylindoles 1 were prepared according to the known methods.13 Preparation of Compounds. To a 35 mL oven-dried sealing tube were added substrate (±)-1 (0.2 mmol, 1.0 equiv), K2CO3 (0.2 mmol, 1.0 equiv), DTBP (0.1 mL), and ether 2 (2.0 mL). The resulting mixture was stirred at 120 °C for 12 h, then diluted by EtOAc, and washed with saturated salt water. The organic phase was separated, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel to give the desired products. 3-((1,4-Dioxan-2-yl)(phenyl)methyl)-2-methyl-1H-indole. 41.0 mg, 67% yield. anti-(±)-3a: yellow solid; mp = 127−128 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.80 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 7.2 Hz, 2H), 7.27−7.20 (m, 3H), 7.13 (t, J = 7.2 Hz, 1H), 7.09−7.00 (m, 2H), 4.66 (td, J = 10.0, 2.4 Hz, 1H), 4.22 (d, J = 10.4 Hz, 1H), 3.84−3.82 (m, 2H), 3.71 (d, J = 11.2 Hz, 1H), 3.65− 3.60 (m, 1H), 3.56 (dd, J = 11.6, 2.4 Hz, 1H), 3.31 (dd, J = 11.6, 9.6 Hz, 1H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 142.1, 135.4, 131.6, 128.4, 128.3, 127.6, 126.2, 121.2, 119.7, 119.3, 111.0, 110.5, 76.0, 70.8, 66.9, 66.5, 44.7, 12.4; IR (film) ν (cm−1) = 3322, 3059, 3025, 2971, 2950, 2910, 2858, 1496, 1461, 1308, 1281, 1247, 1222, 1115, 1079, 1055, 902, 882, 742, 699, 669, 645, 622; HRMS (ESI) calcd for C20H22NO2 [M + H]+ 308.1645; found 308.1651. syn-(±)-3a: yellow solid; mp = 189−191 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.77 (s, 1H), 7.74−7.72 (m, 1H), 7.34 (d, J = 7.6 Hz, 2H), 7.24−7.21 (m, 3H), 7.16−7.06 (m, 3H), 4.63 (td, J = 5444

DOI: 10.1021/acs.joc.7b00463 J. Org. Chem. 2017, 82, 5441−5448

Note

The Journal of Organic Chemistry 9.2, 2.0 Hz, 1H), 4.18 (d, J = 9.2 Hz, 1H), 3.80−3.78 (m, 2H), 3.68 (dd, J = 11.2, 2.0 Hz, 2H), 3.61−3.55 (m, 1H), 3.39 (dd, J = 11.6, 9.6 Hz, 1H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 141.9, 135.4, 132.2, 128.6, 128.4, 128.2, 126.5, 120.8, 119.52, 119.48, 111.5, 110.5, 76.5, 71.0, 67.1, 66.5, 45.8, 12.7; IR (film) ν (cm−1) = 3293, 3059, 3032, 2971, 2918, 2859, 1619, 1498, 1461, 1309, 1281, 1248, 1222, 1119, 1079, 912, 884, 737, 700, 671; HRMS (ESI) calcd for C20H22NO2 [M + H]+ 308.1645; found 308.1644. 3-((1,4-Dioxan-2-yl)(phenyl)methyl)-2-phenyl-1H-indole. 52.5 mg, 71% yield. anti-(±)-3b: white solid; mp = 229−230 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 8.11 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.47−7.40 (m, 7H), 7.31 (d, J = 8.0 Hz, 1H), 7.25 (t, J = 7.6 Hz, 2H), 7.16 (t, J = 6.8 Hz, 2H), 7.08 (t, J = 7.6 Hz, 1H), 4.63 (t, J = 9.6 Hz, 1H), 4.34 (d, J = 10.4 Hz, 1H), 3.75 (d, J = 6.4 Hz, 2H), 3.62 (d, J = 11.6 Hz, 1H), 3.53−3.46 (m, 2H), 3.13 (t, J = 10.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 142.4, 136.3, 136.2, 132.8, 129.1, 129.0, 128.7, 128.4, 128.3, 127.5, 126.3, 122.4, 121.0, 120.2, 111.6, 111.2, 76.5, 70.6, 66.9, 66.3, 44.8; IR (film) ν (cm−1) = 3396, 3056, 3035, 2965, 2850, 1560, 1541, 1508, 1495, 1456, 1282, 1119, 884, 771, 752, 699, 636; HRMS (ESI) calcd for C25H24NO2 [M + H]+ 370.1802; found 370.1813. syn-(±)-3b: white solid; mp = 214−215 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 8.10 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.45−7.37 (m, 5H), 7.35 (d, J = 7.6 Hz, 2H), 7.30 (d, J = 8.0 Hz, 1H), 7.24−7.11 (m, 5H), 4.56 (t, J = 9.2 Hz, 1H), 4.34 (d, J = 8.8 Hz, 1H), 3.68 (d, J = 11.2 Hz, 1H), 3.63−3.58 (m, 3H), 3.48 (td, J = 11.6, 2.4 Hz, 1H), 3.28 (t, J = 10.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 141.9, 136.5, 136.2, 133.4, 129.3, 128.7, 128.6, 128.5, 128.21, 128.18, 126.6, 122.0, 121.5, 119.9, 112.6, 111.2, 76.6, 70.9, 67.0, 66.5, 45.8; IR (film) ν (cm−1) = 3281, 3053, 3026, 2966, 2898, 2858, 1559, 1541, 1508, 1457, 1122, 1101, 913, 880, 745, 699, 669; HRMS (ESI) calcd for C25H24NO2 [M + H]+ 370.1802; found 370.1811. 3-((1,4-Dioxan-2-yl)(phenyl)methyl)-2,5-dimethyl-1H-indole. 41.2 mg, 64% yield. anti-(±)-3c: yellow solid; mp = 187−188 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.70 (s, 1H), 7.41 (d, J = 7.6 Hz, 2H), 7.32 (s, 1H), 7.24 (t, J = 7.6 Hz, 2H), 7.13 (t, J = 7.2 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 4.64 (t, J = 8.8 Hz, 1H), 4.19 (d, J = 10.0 Hz, 1H), 3.83 (d, J = 6.4 Hz, 2H), 3.71 (d, J = 11.2 Hz, 1H), 3.66−3.60 (m, 1H), 3.56 (d, J = 12.4 Hz, 1H), 3.29 (t, J = 10.4 Hz, 1H), 2.40 (s, 3H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 142.2, 133.7, 131.8, 128.7, 128.4, 128.2, 127.8, 126.1, 122.7, 119.0, 110.4, 110.1, 75.9, 70.8, 66.9, 66.5, 44.7, 21.8, 12.4; IR (film) ν (cm−1) = 3323, 3022, 2982, 2947, 2910, 2859, 2841, 1557, 1541, 1508, 1456, 1287, 1118, 1094, 976, 919, 907, 884, 798, 723, 697, 671; HRMS (ESI) calcd for C21H24NO2 [M + H]+ 322.1802; found 322.1806. syn-(±)-3c: yellow solid; mp = 214−215 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.67 (s, 1H), 7.50 (s, 1H), 7.33 (d, J = 7.6 Hz, 2H), 7.23 (t, J = 7.2 Hz, 2H), 7.16−7.10 (m, 2H), 6.91 (d, J = 8.4 Hz, 1H), 4.62 (td, J = 9.2, 2.0 Hz, 1H), 4.18 (d, J = 8.8 Hz, 1H), 3.79 (dd, J = 6.8, 1.6 Hz, 2H), 3.68 (dt, J = 11.6, 2.0 Hz, 2H), 3.61−3.55 (m, 1H), 3.39 (dd, J = 11.2, 9.2 Hz, 1H), 2.45 (s, 3H), 2.33 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ (ppm) = 142.0, 133.7, 132.3, 128.7, 128.6, 128.5, 128.3, 126.5, 122.4, 119.2, 111.0, 110.1, 76.5, 71.1, 67.0, 66.5, 45.7, 21.9, 12.8; IR (film) ν (cm−1) = 3317, 3029, 2968, 2908, 2862, 1581, 1481, 1449, 1314, 1280, 1223, 1124, 1085, 913, 881, 794, 719, 702, 669, 592; HRMS (ESI) calcd for C21H24NO2 [M + H]+ 322.1802; found 322.1802. 3-((1,4-Dioxan-2-yl)(phenyl)methyl)-5-chloro-2-methyl-1Hindole. 47.2 mg, 69% yield. (±)-3d (anti-(±)-3d and syn-(±)-3d were inseparable): yellow solid; 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.84−7.81 (m, 2.76H), 7.67 (s, 1H, syn-(±)-3d), 7.48 (s, 1.77H, anti(±)-3d), 7.38 (d, J = 7.6 Hz, 3.59 H, anti-(±)-3d), 7.31−7.23 (m, 9.61H), 7.17−7.10 (m, 5.64 H), 7.03−7.01 (m, 2.79 H), 4.61−4.53 (m, 2.77 H), 4.18 (d, J = 10.4 Hz, 1.76H, anti-(±)-3d), 4.14 (d, J = 8.8 Hz, 0.97H, syn-(±)-3d), 3.84 (d, J = 6.4 Hz, 3.54H, anti-(±)-3d), 3.80 (d, J = 6.0 Hz, 2.05H, syn-(±)-3d), 3.73−3.55 (m, 6.80H), 3.51 (d, J = 11.6 Hz, 1.79H, anti-(±)-3d), 3.37 (t, J = 10.0 Hz, 1.09H, syn-(±)-3d), 3.29 (t, J = 10.4 Hz, 1.78H, anti-(±)-3d), 2.37 (s, 4.99H, anti-(±)-3d), 2.35 (s, 2.91H, syn-(±)-3d); 13C NMR (100 MHz, CDCl3) δ (ppm) = 141.53 (anti-(±)-3d), 141.47 (syn-(±)-3d), 133.83, 133.80, 133.73, 133.26, 129.52, 128.75, 128.65, 128.40, 128.36, 128.19, 126.73 (syn-

(±)-3d), 126.35 (anti-(±)-3d), 125.39 (anti-(±)-3d), 125.25 (syn(±)-3d), 121.59 (anti-(±)-3d), 121.14 (syn-(±)-3d), 119.09 (syn(±)-3d), 118.70 (anti-(±)-3d), 111.49, 111.43, 111.33, 111.05, 76.37 (syn-(±)-3d), 75.65 (anti-(±)-3d), 70.96 (syn-(±)-3d), 70.69 (anti(±)-3d), 67.07 (syn-(±)-3d), 66.90 (anti-(±)-3d), 66.53 (2 peaks overlap), 45.59 (syn-(±)-3d), 44.45 (anti-(±)-3d), 12.83 (syn-(±)-3d), 12.54 (anti-(±)-3d); IR (film) ν (cm−1) = 3422, 3295, 3060, 3026, 2964, 2907, 2851, 1541, 1471, 1456, 1309, 1277, 1120, 1081, 1068, 912, 881, 798, 746, 700, 653, 640, 593; HRMS (ESI) calcd for C20H21ClNO2 [M + H]+ 342.1255; found 342.1257. 3-((1,4-Dioxan-2-yl)(p-tolyl)methyl)-2-methyl-1H-indole. 39.9 mg, 62% yield. anti-(±)-3e: yellow solid; mp = 162−164 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.78 (s, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 7.6 Hz, 1H), 7.08−6.99 (m, 4H), 4.64 (td, J = 10.0, 2.4 Hz, 1H), 4.17 (d, J = 10.4 Hz, 1H), 3.83−3.80 (m, 2H), 3.70 (d, J = 11.6 Hz, 1H), 3.64−3.59 (m, 1H), 3.55 (dd, J = 11.6, 2.4 Hz, 1H), 3.29 (dd, J = 11.6, 9.6 Hz, 1H), 2.34 (s, 3H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 139.1, 135.5, 135.4, 131.6, 129.0, 128.2, 127.5, 121.1, 119.6, 119.3, 111.0, 110.5, 76.0, 70.8, 66.9, 66.5, 44.4, 21.1, 12.4; IR (film) ν (cm−1) = 3303, 3049, 3017, 2950, 2917, 2849, 1511, 1457, 1285, 1121, 1094, 1062, 905, 881, 819, 741, 667, 638, 611; HRMS (ESI) calcd for C21H24NO2 [M + H]+ 322.1802; found 322.1807. syn-(±)-3e: yellow solid; mp = 176−177 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.77 (s, 1H), 7.72−7.70 (m, 1H), 7.23−7.19 (m, 3H), 7.09−7.02 (m, 4H), 4.60 (t, J = 8.8 Hz, 1H), 4.15 (d, J = 9.2 Hz, 1H), 3.77 (d, J = 6.0 Hz, 2H), 3.69 (t, J = 10.8 Hz, 2H), 3.61−3.53 (m, 1H), 3.38 (t, J = 10.0 Hz, 1H), 2.32 (s, 3H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 138.8, 136.0, 135.4, 132.1, 129.3, 128.4, 128.1, 120.8, 119.5, 119.4, 111.6, 110.5, 76.5, 71.1, 67.1, 66.5, 45.4, 21.1, 12.7; IR (film) ν (cm−1) = 3289, 3046, 3020, 2953, 2908, 2852, 1684, 1653, 1559, 1544, 1507, 1457, 1121, 912, 886, 738, 672; HRMS (ESI) calcd for C21H24NO2 [M + H]+ 322.1802; found 322.1804. 2-Methyl-3-(phenyl(tetrahydro-2H-pyran-2-yl)methyl)-1Hindole. 37.4 mg, 61% yield. anti-(±)-3f: yellow solid; mp = 145−148 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.75 (s, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.24−7.19 (m, 3H), 7.11−6.98 (m, 3H), 4.36 (t, J = 10.0 Hz, 1H), 4.19 (d, J = 10.0 Hz, 1H), 4.03 (dd, J = 10.8, 2.4 Hz, 1H), 3.53 (t, J = 11.6 Hz, 1H), 2.38 (s, 3H), 1.75− 1.72 (m, 1H), 1.64−1.43 (m, 4H), 1.22−1.18 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 143.2, 135.4, 131.7, 128.5, 128.1, 127.8, 125.8, 120.9, 119.5, 119.3, 112.9, 110.4, 78.6, 68.8, 48.6, 30.6, 26.2, 23.9, 12.5; IR (film) ν (cm−1) = 3392, 3056, 3023, 2953, 2921, 2853, 1700, 1683, 1648, 1620, 1557, 1539, 1510, 1492, 1458, 1360, 1308, 1291, 1205, 1170, 1084, 1046, 1017, 896, 738, 701, 607, 595; HRMS (ESI) calcd for C21H24NO [M + H]+ 306.1852; found 306.1868. syn(±)-3f: yellow solid; mp = 152−153 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.73−7.71 (m, 2H), 7.34 (d, J = 7.6 Hz, 2H), 7.22−7.19(m, 3H), 7.13−7.03 (m, 3H), 4.29 (t, J = 8.8 Hz, 1H), 4.15 (d, J = 8.4 Hz, 1H), 3.97 (d, J = 10.8 Hz, 1H), 3.50 (t, J = 11.2 Hz, 1H), 2.30 (s, 3H), 1.81−1.78 (m, 1H), 1.56−1.45 (m, 4H), 1.37−1.31 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 143.5, 135.4, 132.1, 128.8, 128.6, 128.3, 126.0, 120.6, 119.8, 119.2, 112.6, 110.3, 79.3, 68.9, 50.0, 31.1, 26.1, 23.9, 12.8; IR (film) ν (cm−1) = 3282, 3056, 3026, 2923, 2853, 1690, 1619, 1494, 1461, 1356, 1308, 1269, 1205, 1085, 1044, 913, 733, 699; HRMS (ESI) calcd for C21H24NO [M + H]+ 306.1852; found 306.1859. 2-Phenyl-3-(phenyl(tetrahydro-2H-pyran-2-yl)methyl)-1Hindole. 58.8 mg, 80% yield. anti-(±)-3g: yellow solid; mp = 210−211 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 8.00 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.49−7.36 (m, 7H), 7.28 (d, J = 8.0 Hz, 1H), 7.21 (t, J = 7.2 Hz, 2H), 7.16−7.04 (m, 3H), 4.35 (d, J = 4.8 Hz, 2H), 3.95 (d, J = 10.0 Hz, 1H), 3.45 (t, J = 10.8 Hz, 1H), 1.67−1.64 (m, 1H), 1.54− 1.33 (m, 4H), 1.17−1.09 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 143.5, 136.3, 136.2, 133.2, 129.2, 128.9, 128.7, 128.2, 128.1, 127.7, 125.9, 122.1, 121.1, 119.8, 113.7, 111.1, 79.3, 68.7, 48.4, 30.7, 26.0, 23.9; IR (film) ν (cm−1) = 3388, 3059, 3024, 2949, 2917, 2849, 1596, 1544, 1490, 1452, 1360, 1337, 1308, 1291, 1262, 1239, 1205, 1176, 1082, 1044, 896, 844, 809, 766, 739, 698, 602, 568, 516; HRMS (ESI) calcd for C26H26NO [M + H]+ 368.2009; found 368.2010. syn5445

DOI: 10.1021/acs.joc.7b00463 J. Org. Chem. 2017, 82, 5441−5448

Note

The Journal of Organic Chemistry (±)-3g: white solid; mp = 203−205 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 8.02 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 6.8 Hz, 2H), 7.39−7.32 (m, 5H), 7.28 (d, J = 7.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 2H), 7.17−7.09 (m, 3H), 4.31 (d, J = 8.8 Hz, 1H), 4.25 (t, J = 9.6 Hz, 1H), 3.88 (d, J = 11.2 Hz, 1H), 3.32 (t, J = 10.8 Hz, 1H), 1.74−1.71 (m, 1H), 1.48−1.37 (m, 4H), 1.23−1.18 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 143.5, 136.3, 136.2, 133.7, 129.3, 128.9, 128.58, 128.55, 128.3, 127.9, 126.1, 122.0, 121.8, 119.6, 113.8, 111.0, 79.4, 68.8, 49.8, 30.9, 26.0, 23.9; IR (film) ν (cm−1) = 3323, 3079, 3062, 3023, 2963, 2938, 2836, 1599, 1490, 1454, 1369, 1314, 1261, 1202, 1173, 1083, 1043, 1027, 905, 814, 742, 696, 605, 566; HRMS (ESI) calcd for C26H26NO [M + H]+ 368.2009; found 368.2012. 2,5-Dimethyl-3-(phenyl(tetrahydro-2H-pyran-2-yl)methyl)1H-indole. 41.5 mg, 65% yield. anti-(±)-3h: yellow solid; mp = 193− 194 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.62 (s, 1H), 7.40 (d, J = 7.6 Hz, 2H), 7.30 (s, 1H), 7.21 (t, J = 6.8 Hz, 2H), 7.11−7.06 (m, 2H), 6.87 (d, J = 8.0 Hz, 1H), 4.33 (t, J = 10.4 Hz, 1H), 4.16 (d, J = 10.4 Hz, 1H), 4.03 (dd, J = 10.8, 2.4 Hz, 1H), 3.54 (t, J = 10.8 Hz, 1H), 2.40 (s, 3H), 2.32 (s, 3H), 1.75−1.72 (m, 1H), 1.61−1.58 (m, 1H), 1.51−1.43 (m, 3H), 1.24−1.17 (m,1H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 143.3, 133.7, 131.8, 128.5, 128.4, 128.1, 128.0, 125.7, 122.4, 119.2, 112.4, 110.0, 78.6, 68.7, 48.5, 30.7, 26.2, 23.9, 21.8, 12.5; IR (film) ν (cm−1) = 3305, 3026, 2957, 2941, 2917, 2856, 1561, 1544, 1483, 1457, 1312, 1291, 1205, 1176, 1085, 1043, 940, 911, 871, 796, 723, 698, 655; HRMS (ESI) calcd for C22H26NO [M + H]+ 320.2009; found 320.2008. syn-(±)-3h: yellow solid; mp = 162−164 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.63 (s, 1H), 7.49 (s, 1H), 7.33 (d, J = 7.6 Hz, 2H), 7.21 (t, J = 7.6 Hz, 2H), 7.13−7.07 (m, 2H), 6.88 (d, J = 8.4 Hz, 1H), 4.28 (t, J = 9.2 Hz, 1H), 4.13 (d, J = 8.4 Hz, 1H), 3.97 (d, J = 10.8 Hz, 1H), 3.50 (t, J = 10.8 Hz, 1H), 2.45 (s, 3H), 2.27 (s, 3H), 1.84−1.76 (m, 1H), 1.56−1.45 (m, 4H), 1.37−1.31 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 143.6, 133.7, 132.3, 129.1, 128.6, 128.3, 128.1, 126.0, 122.0, 119.4, 112.1, 110.0, 79.2, 68.8, 49.9, 31.1, 26.1, 23.9, 22.4, 22.0, 12.9; IR (film) ν (cm−1) = 3315, 3025, 2933, 2852, 2837, 1698, 1684, 1558, 1541, 1508, 1489, 1454, 1315, 1207, 1088, 1047, 907, 796, 700, 669, 591; HRMS (ESI) calcd for C22H26NO [M + H]+ 320.2009; found 320.2012. 5-Chloro-2-methyl-3-(phenyl(tetrahydro-2H-pyran-2-yl)methyl)-1H-indole. 39.9 mg, 59% yield. anti-(±)-3i: yellow solid; mp = 205−206 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.78 (s, 1H), 7.47 (s, 1H), 7.37 (d, J = 7.6 Hz, 2H), 7.26−7.22 (m, 2H), 7.14− 7.09 (m, 2H), 7.00 (dd, J = 8.4, 2.0 Hz, 1H), 4.29 (td, J = 10.4, 2.0 Hz, 1H), 4.14 (d, J = 10.0 Hz, 1H), 4.03 (dt, J = 11.2, 1.6 Hz, 1H), 3.54 (td, J = 11.6, 2.4 Hz, 1H), 2.38 (s, 3H), 1.78−1.75 (m, 1H), 1.62−1.40 (m, 4H), 1.28−1.21 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 142.7, 133.8, 133.3, 128.9, 128.5, 128.2, 126.0, 125.1, 121.2, 118.9, 112.9, 111.3, 78.3, 68.7, 48.4, 30.6, 26.1, 23.9, 12.6; IR (film) ν (cm−1) = 3285, 3086, 3063, 3026, 2937, 2916, 2848, 1559, 1542, 1474, 1456, 1315, 1203, 1081, 1042, 898, 793, 740, 700, 645; HRMS (ESI) calcd for C21H23ClNO [M + H]+ 340.1463; found 340.1470. syn-(±)-3i: yellow solid; mp = 191−192 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.75 (s, 1H), 7.68 (s, 1H), 7.30 (d, J = 7.2 Hz, 2H), 7.23 (t, J = 7.2, 2H), 7.14 (t, J = 7.2 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 7.00 (dd, J = 8.4, 1.6 Hz, 1H), 4.23 (t, J = 10.0 Hz, 1H), 4.07 (d, J = 8.8 Hz, 1H), 3.98 (d, J = 11.2 Hz, 1H), 3.51 (t, J = 10.8 Hz, 1H), 2.22 (s, 3H), 1.81−1.79 (m, 1H), 1.56−1.48 (m, 4H), 1.34−1.29 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 143.0, 133.8, 133.7, 129.9, 128.52, 128.47, 126.2, 125.0, 120.8, 119.3, 112.6, 111.2, 79.1, 68.8, 49.9, 31.1, 26.0, 23.8, 12.8; IR (film) ν (cm−1) = 3284, 3080, 3060, 3025, 2939, 2921, 2849, 1568, 1475, 1451, 1314, 1205, 1083, 1052, 908, 874, 854, 797, 754, 700, 566; HRMS (ESI) calcd for C21H23ClNO [M + H]+ 340.1463; found 340.1469. 2-Methyl-3-((tetrahydro-2H-pyran-2-yl)(p-tolyl)methyl)-1Hindole. 44.5 mg, 70% yield. anti-(±)-3j: yellow solid; mp = 179−180 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.71 (s, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 2H), 7.18 (d, J = 8.0 Hz, 1H), 7.06− 6.98 (m, 4H), 4.34 (t, J = 10.0 Hz, 1H), 4.14 (d, J = 10.0 Hz, 1H), 4.02 (dd, J = 11.2, 1.6 Hz, 1H), 3.52 (t, J = 11.2 Hz, 1H), 2.35 (s, 3H), 2.24 (s, 3H), 1.74−1.71 (m, 1H), 1.60−1.57 (m, 1H), 1.50−1.42 (m, 3H), 1.23−1.20 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 140.2,

135.4, 135.1, 131.6, 128.8, 128.3, 127.8, 120.8, 119.5, 119.3, 113.0, 110.4, 78.7, 68.8, 48.3, 30.7, 26.2, 23.9, 21.1, 12.4; IR (film) ν (cm−1) = 3288, 3044, 3019, 2948, 2930, 2859, 1684, 1653, 1559, 1540, 1507, 1456, 1289, 1082, 1043, 895, 817, 735; HRMS (ESI) calcd for C22H26NO [M + H]+ 320.2009; found 320.2009. syn-(±)-3j: yellow solid; mp = 115−116 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.73−7.69 (m, 2H), 7.24−7.21 (m, 2H), 7.19−7.17 (m, 1H), 7.05− 7.00 (m, 4H), 4.27 (t, J = 9.2 Hz, 1H), 4.10 (d, J = 8.8 Hz, 1H), 3.96 (d, J = 10.8 Hz, 1H), 3.49 (t, J = 10.8 Hz, 1H), 2.27 (s, 3H), 2.25 (s, 3H), 1.81−1.78 (m, 1H), 1.58−1.44 (m, 4H), 1.35−1.30 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 140.4, 135.5, 135.4, 132.0, 129.0, 128.8, 128.4, 120.5, 119.8, 119.1, 112.7, 110.3, 79.3, 68.9, 49.6, 31.1, 26.1, 23.9, 21.1, 12.7; IR (film) ν (cm−1) = 3402, 3308, 3054, 3020, 2930, 2853, 1684, 1653, 1559, 1540, 1507, 1457, 1201, 1086, 1045, 907, 819, 738, 669; HRMS (ESI) calcd for C22H26NO [M + H]+ 320.2009; found 320.2014. 3-((2-Fluorophenyl)(tetrahydro-2H-pyran-2-yl)methyl)-2methyl-1H-indole. 39.5 mg, 61% yield. anti-(±)-3k: yellow solid; mp = 135−136 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.73 (s, 1H), 7.68−7.64 (m, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.11−6.97 (m, 4H), 6.90−6.86 (m, 1H), 4.46 (d, J = 10.4 Hz, 1H), 4.40 (t, J = 10.0 Hz, 1H), 4.01 (dd, J = 10.8, 2.0 Hz, 1H), 3.52 (t, J = 11.2 Hz, 1H), 2.43 (s, 3H), 1.77−1.73 (m, 1H), 1.64−1.38 (m, 4H), 1.31−1.22 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 161.6 (d, JC−F = 243.3 Hz), 135.4, 132.3, 129.6 (d, JC−F = 13.9 Hz), 129.1 (d, JC−F = 4.5 Hz), 127.5, 127.2 (d, JC−F = 8.4 Hz), 123.6 (d, JC−F = 3.4 Hz), 120.8, 119.3(d, JC−F = 3.1 Hz), 115.5 (d, JC−F = 22.7 Hz), 111.0, 110.4, 77.3, 68.8, 41.8 (d, JC−F = 2.1 Hz), 30.4, 26.2, 23.8, 12.3 (d, JC−F = 2.6 Hz); 19F NMR (376 MHz, CDCl3) δ (ppm) = −116.9; IR (film) ν (cm−1) = 3391, 3302, 3058, 2939, 2845, 1718, 1698, 1684, 1651, 1558, 1541, 1508, 1489, 1456, 1343, 1229, 1088, 1047, 754, 672; HRMS (ESI) calcd for C21H23FNO [M + H]+ 324.1758; found 324.1754. syn-(±)-3k: yellow solid; mp = 100−101 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.71−7.69 (m, 1H), 7.65 (s, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.11−7.09 (m, 1H), 7.02−6.97 (m, 3H), 6.91−6.86 (m, 2H), 4.50 (d, J = 9.2 Hz, 1H), 4.21 (t, J = 9.6 Hz, 1H), 3.89 (d, J = 11.2 Hz, 1H), 3.41 (t, J = 11.2 Hz, 1H), 2.25 (s, 3H), 1.75−1.73 (m, 1H), 1.52−1.29 (m, 5H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 160.5 (d, JC−F = 242.7 Hz), 135.4, 132.5, 130.5 (d, JC−F = 14.5 Hz), 130.2 (d, JC−F = 4.3 Hz), 128.7, 127.6 (d, JC−F = 8.3 Hz), 124.2 (d, JC−F = 3.4 Hz), 120.6, 119.7, 119.3, 115.2 (d, JC−F = 23.2 Hz), 111.5, 110.4, 79.0, 68.8, 41.8, 30.6, 26.0, 23.8, 12.5; 19F NMR (376 MHz, CDCl3) δ (ppm) = −117.5; IR (film) ν (cm−1) = 3399, 3303, 3061, 2938, 2851, 1584, 1487, 1459, 1306, 1226, 1086, 1040, 1018, 907, 796, 756, 739, 609, 533; HRMS (ESI) calcd for C21H23FNO [M + H]+ 324.1758; found 324.1758. 3-(Phenyl(tetrahydro-2H-pyran-2-yl)methyl)-1H-indole. 26.2 mg, 45% yield. anti-(±)-3l: yellow solid; mp = 65−67 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.99 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 7.6 Hz, 2H), 7.29 (d, J = 8.0 Hz, 1H), 7.25 (t, J = 8.4 Hz, 2H), 7.14 (td, J = 7.6, 2.4 Hz, 2H), 7.07−7.03 (m, 2H), 4.22 (d, J = 7.6 Hz, 1H), 4.06−3.99 (m, 2H), 3.46 (t, J = 11.2 Hz, 1H), 1.79−1.77 (m, 1H), 1.62−1.42 (m, 4H), 1.40−1.30 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 143.0, 136.2, 128.9, 128.1, 127.4, 126.1, 122.2, 122.0, 119.47, 119.46, 118.0, 111.2, 80.5, 68.9, 48.9, 30.7, 26.2, 23.9; IR (film) ν (cm−1) = 3422, 3311, 3080, 3057, 3027, 2926, 2851, 1650, 1558, 1541, 1492, 1456, 1437, 1338, 1262, 1203, 1174, 1087, 1043, 1013, 899, 812, 739, 699, 672, 605; HRMS (ESI) calcd for C20H22NO [M + H]+ 292.1696; found 292.1698. syn-(±)-3l: yellow solid; mp = 124−128 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 8.01 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.30−7.28 (m, 4H), 7.22 (t, J = 7.6 Hz, 2H), 7.16−7.08 (m, 2H), 6.96 (t, J = 7.6 Hz, 1H), 4.24 (d, J = 7.6 Hz, 1H), 4.05−4.02 (m, 1H), 3.94 (td, J = 9.2, 3.2 Hz, 1H), 3.48 (td, J = 11.6, 2.0 Hz, 1H), 1.81−1.79 (m, 1H), 1.63−1.37 (m, 5H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 143.0, 136.3, 128.9, 128.3, 128.0, 126.3, 122.1, 121.8, 119.7, 119.2, 117.0, 111.0, 80.9, 68.9, 49.3, 30.5, 26.2, 23.8; IR (film) ν (cm−1) = 3251, 3081, 3058, 3021, 2960, 2926, 2843, 1646, 1542, 1490, 1457, 1353, 1262, 1226, 1207, 1087, 1049, 797, 739, 700, 645, 606; HRMS (ESI) calcd for C20H22NO [M + H]+ 292.1696; found 292.1696. 5446

DOI: 10.1021/acs.joc.7b00463 J. Org. Chem. 2017, 82, 5441−5448

Note

The Journal of Organic Chemistry

(cm−1) = 3298, 3053, 3020, 2919, 2853, 1719, 1699, 1685, 1619, 1558, 1512, 1458, 1340, 1303, 1246, 1059, 1020, 925, 854, 820, 781, 737, 671, 620; HRMS (ESI) calcd for C21H24NO [M + H]+ 306.1852; found 306.1855. Ethyl 3-(Phenyl(tetrahydrofuran-2-yl)methyl)-1H-indole-2carboxylate. 41.9 mg, 60% yield. anti-(±)-3p: white solid; mp = 177−178 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 8.87 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 1H), 7.27−7.23 (m, 3H), 7.12 (t, J = 7.2 Hz, 1H), 7.04 (t, J = 7.2 Hz, 1H), 5.26 (d, J = 10.0 Hz, 1H), 5.10−5.04 (m, 1H), 4.45 (q, J = 7.2 Hz, 2H), 4.00−3.95 (m, 1H), 3.92−3.86 (m, 1H), 1.93−1.69 (m, 3H), 1.60−1.55 (m, 1H), 1.43 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 162.4, 142.9, 136.2, 128.7, 128.2, 126.9, 126.1, 125.5, 125.0, 123.5, 123.0, 120.4, 112.0, 80.2, 68.6, 61.1, 47.4, 31.1, 25.9, 14.6; IR (film) ν (cm−1) = 3215, 3058, 2984, 2876, 1690, 1528, 1494, 1452, 1441, 1383, 1343, 1324, 1245, 1185, 1090, 1044, 1024, 946, 923, 894, 871, 797, 780, 769, 744, 704, 637, 580, 562; HRMS (ESI) calcd for C22H24NO3 [M + H]+ 350.1751; found 350.1759. syn(±)-3p: white solid; mp = 188−189 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 8.77 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 7.6 Hz, 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.25−7.22 (m, 3H), 7.14 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 5.31 (d, J = 8.4 Hz, 1H), 5.07 (q, J = 7.2 Hz, 1H), 4.41 (q, J = 7.2 Hz, 2H), 3.78−3.69 (m, 2H), 2.05−1.99 (m, 1H), 1.89−1.68 (m, 3H), 1.42 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 162.3, 143.0, 136.3, 128.8, 128.3, 127.2, 126.2, 125.3, 125.2, 124.0, 124.0, 120.4, 111.9, 80.4, 68.4, 60.9, 47.7, 31.3, 25.8, 14.6; IR (film) ν (cm−1) = 3264, 3062, 2979, 2931, 2882, 1702, 1655, 1557, 1542, 1510, 1459, 1436, 1378, 1315, 1253, 1184, 1084, 1059, 1028, 743, 703; HRMS (ESI) calcd for C22H24NO3 [M + H]+ 350.1751; found 350.1757. 3-(2,3-Dimethoxy-1-phenylpropyl)-2-methyl-1H-indole. 27.9 mg, 45% yield. anti-(±)-3q (anti-(±)-3q and (±)-3q′ were inseparable): yellow liquid; 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.83 (s, 2.38H), 7.61 (d, J = 7.6 Hz, 1.02H, anti-(±)-3q), 7.48−7.38 (m, 5.92H), 7.28−7.24 (m, 6.91H), 7.19−7.13 (m, 2.39H), 7.10−6.98 (m, 4.71H), 4.60 (t, J = 7.6 Hz, 1.31H, (±)-3q′), 4.47 (d, J = 10.0 Hz, 1.00H, anti-(±)-3q), 4.40−4.38 (m, 1.00H, anti-(±)-3q), 4.33 (t, J = 9.2 Hz, 1.34H, (±)-3q′), 4.11 (dd, J = 9.2, 6.0 Hz, 1.33H, (±)-3q′), 3.70−3.61 (m, 3.91H, (±)-3q′), 3.54−3.53 (m, 2.36H), 3.41 (s, 3.07H, anti-(±)-3q), 3.35 (s, 3.94H, (±)-3q′), 3.22−3.16 (m, 4.01H, anti-(±)-3q), 2.41 (s, 3.02H, anti-(±)-3q), 2.33 (s, 3.92H, (±)-3q′). 13 C NMR (100 MHz, CDCl3) δ (ppm) = 143.1 anti-(±)-3q, 142.9 (±)-3q′, 135.5 anti-(±)-3q, 135.4 (±)-3q′, 132.00, 131.99, 128.7, 128.3, 128.24 (two peaks), 128.22, 128.1, 126.1 (±)-3q′, 125.9 anti(±)-3q, 120.88 anti-(±)-3q, 120.86 (±)-3q′, 119.6, 119.4, 119.29, 119.27, 112.5, 112.3, 110.5 anti-(±)-3q, 110.4 (±)-3q′, 81.8, 74.3, 72.6 anti-(±)-3q, 72.1, 70.4, 59.3, 59.1, 58.2, 44.7 anti-(±)-3q, 42.4 (±)-3q′, 12.4 (±)-3q′, 12.3 anti-(±)-3q; IR (film) ν (cm−1) = 3416, 3060, 3026, 2980, 2925, 1620, 1460, 1383, 1121, 741, 700; HRMS (ESI) calcd for C20H24NO2 [M + H]+ 310.1802; found 310.1802. syn(±)-3q: yellow solid; mp = 122−124 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.78 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 7.6 Hz, 2H), 7.23 (t, J = 7.6 Hz, 3H), 7.14 (t, J = 7.2 Hz, 1H), 7.09− 7.01 (m, 2H), 4.49 (d, J = 6.8 Hz, 1H), 4.35−4.31 (m, 1H), 3.44−3.30 (m, 8H), 2.31 (s, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm) = 143.2, 135.4, 132.9, 128.8, 128.5, 128.3, 126.0, 120.7, 120.3, 119.2, 111.6, 110.3, 82.1, 72.7, 59.2, 58.3, 44.5, 12.6; IR (film) ν (cm−1) = 3408, 3328, 3060, 3026, 2925, 1618, 1490, 1463, 1383, 1123, 741,702; HRMS (ESI) calcd for C20H24NO2 [M + H]+ 310.1802; found 310.1800.

2-Methyl-3-(phenyl(tetrahydrofuran-2-yl)methyl)-1H-indole. 37.3 mg, 64% yield. anti-(±)-3m: yellow solid; mp = 145−146 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.75 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 7.6 Hz, 2H), 7.25−7.18 (m, 3H), 7.10 (t, J = 7.2 Hz, 1H), 7.06 (t, J = 7.2 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 4.97−4.91 (m, 1H), 4.17 (d, J = 10.0 Hz, 1H), 3.99−3.94 (m, 1H), 3.89−3.83 (m, 1H), 2.34 (s, 3H), 1.88−1.76 (m, 3H), 1.57−1.48 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 143.6, 135.3, 131.5, 128.4, 128.2, 128.0, 125.9, 120.9, 119.5, 119.3, 113.4, 110.4, 80.9, 68.5, 48.3, 31.3, 25.7, 12.5; IR (film) ν (cm−1) = 3317, 3051, 3029, 2972, 2944, 2919, 2867, 2841, 1700, 1683, 1620, 1557, 1539, 1495, 1459, 1361, 1308, 1246, 1057, 1015, 912, 861, 738, 700, 671, 602; HRMS (ESI) calcd for C20H22NO [M + H]+ 292.1696; found 292.1698. syn-(±)-3m: yellow solid; mp = 147−148 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.76 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.25− 7.17 (m, 3H), 7.13 (t, J = 7.6 Hz, 1H), 7.06−6.99 (m, 2H), 4.93−4.88 (m, 1H), 4.21 (d, J = 7.6 Hz, 1H), 3.77 (t, J = 7.2 Hz, 2H), 2.32 (s, 3H), 2.01−1.93 (m, 1H), 1.89−1.72 (m, 2H), 1.70−1.63 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 143.6, 135.4, 132.1, 128.7, 128.5, 128.3, 126.0, 120.7, 119.8, 119.3, 112.5, 110.3, 80.8, 68.4, 48.4, 31.3, 26.0, 12.8; IR (film) ν (cm−1) = 3307, 3057, 3022, 2920, 2880, 1557, 1539, 1489, 1458, 1361, 1309, 1246, 1062, 1017, 936, 844, 738, 703, 631, 602; HRMS (ESI) calcd for C20H22NO [M + H]+ 292.1696; found 292.1693. 2-Phenyl-3-(phenyl(tetrahydrofuran-2-yl)methyl)-1H-indole. 44.4 mg, 63% yield. anti-(±)-3n: yellow solid; mp = 211−212 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 8.06 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.48−7.36 (m, 5H), 7.33 (d, J = 8.0 Hz, 1H), 7.27−7.23 (m, 2H), 7.19−7.13 (m, 2H), 7.06 (t, J = 7.6 Hz, 1H), 4.91−4.86 (m, 1H), 4.32 (d, J = 9.6 Hz, 1H), 3.88−3.82 (m, 1H), 3.80−3.75 (m, 1H), 1.72−1.66 (m, 3H), 1.41−1.30 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 144.0, 136.2, 136.0, 133.2, 129.0, 128.9, 128.7, 128.3, 128.2, 128.0, 126.1, 122.2, 121.2, 119.9, 114.3, 111.1, 81.6, 68.4, 48.4, 31.3, 25.6; IR (film) ν (cm−1) = 3358, 3059, 3023, 2971, 2940, 2895, 2870, 1602, 1488, 1451, 1430, 1367, 1344, 1309, 1263, 1240, 1177, 1054, 1026, 1017, 919, 844, 769, 739, 698, 602; HRMS (ESI) calcd for C25H24NO [M + H]+ 354.1852; found 354.1856. syn-(±)-3n: white solid; mp = 183−184 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 8.03 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 7.6 Hz, 2H), 7.44 (t, J = 7.2 Hz, 2H), 7.40−7.36 (m, 3H), 7.30 (d, J = 8.0 Hz, 1H), 7.24−7.21 (m, 2H), 7.13 (t, J = 7.2 Hz, 2H), 7.05 (t, J = 7.6 Hz, 1H), 4.92 (q, J = 7.2 Hz, 1H), 4.38 (d, J = 8.0 Hz, 1H), 3.76−3.67 (m, 2H), 1.98−1.90 (m, 1H), 1.85−1.66 (m, 2H), 1.63− 1.54 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 143.5, 136.3 (2 peaks), 133.7, 129.3, 128.7, 128.6, 128.3, 128.0 (2 peaks), 126.1, 122.05, 121.98, 119.8, 113.9, 111.0, 81.0, 68.2, 48.3, 31.2, 26.0; IR (film) ν (cm−1) = 3364, 3062, 3018, 2964, 2922, 2859, 1601, 1490, 1450, 1423, 1369, 1348, 1310, 1262, 1242, 1182, 1155, 1070, 1027, 1013, 960, 926, 839, 767, 740, 697, 638, 604; HRMS (ESI) calcd for C25H24NO [M + H]+ 354.1852; found 354.1855. 2-Methyl-3-((tetrahydrofuran-2-yl)(p-tolyl)methyl)-1H-indole. 29.3 mg, 48% yield. anti-(±)-3o: yellow solid; mp = 65−66 °C; 1 H NMR (400 MHz, CDCl3) δ (ppm) = 7.76 (s, 1), 7.54 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 7.6 Hz, 1H), 7.08−6.98 (m, 4H), 4.95−4.89 (m, 1H), 4.14 (d, J = 9.6 Hz, 1H), 3.99−3.94 (m, 1H), 3.87−3.82 (m, 1H), 2.39 (s, 3H), 2.25 (s, 3H), 1.88−1.77 (m, 3H), 1.57−1.49 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 140.6, 135.4, 135.3, 131.4, 129.0, 128.3, 128.1, 120.9, 119.6, 119.4, 113.7, 110.4, 81.1, 68.5, 48.1, 31.3, 25.8, 21.1, 12.6; IR (film) ν (cm−1) = 3404, 3044, 3019, 2972, 2922, 2865, 1718, 1699, 1683, 1651, 1618, 1559, 1541, 1509, 1457, 1343, 1303, 1065, 1017, 920, 812, 772, 734, 666, 579, 545; HRMS (ESI) calcd for C21H24NO [M + H]+ 306.1852; found 306.1857. syn-(±)-3o: yellow solid; mp = 148−150 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.73 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.28 (d, J = 7.6 Hz, 2H), 7.20 (d, J = 7.6 Hz, 1H), 7.06−6.99 (m, 4H), 4.88 (q, J = 7.2 Hz, 1H), 4.18 (d, J = 7.6 Hz, 1H), 3.77 (t, J = 6.4 Hz, 2H), 2.37 (s, 3H), 2.27 (s, 3H), 2.01−1.94 (m, 1H), 1.89−1.72 (m, 2H), 1.69−1.60 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 140.6, 135.4 (two peaks), 132.0, 129.0, 128.7, 128.4, 120.7, 119.9, 119.3, 112.8, 110.3, 80.9, 68.4, 48.1, 31.3, 26.0, 21.1, 12.8; IR (film) ν

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b00463. Spectral data for all compounds (PDF) 5447

DOI: 10.1021/acs.joc.7b00463 J. Org. Chem. 2017, 82, 5441−5448

Note

The Journal of Organic Chemistry

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Zheng Gu: 0000-0001-9183-6388 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for the financial support from the National Natural Science Foundation of China (21578244) and the Natural Science Foundation of Hunan Province (2015JJ4018).

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REFERENCES

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DOI: 10.1021/acs.joc.7b00463 J. Org. Chem. 2017, 82, 5441−5448