Cross-Dehydrogenative Coupling of Tertiary - ACS Publications

Aug 22, 2018 - Department of Chemistry, Visva-Bharati (A Central University), Santiniketan 731235, India. ‡. Department of Chemistry, University of ...
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Visible-Light-Promoted C(sp3)−C(sp2) Cross-Dehydrogenative Coupling of Tertiary Amine with Imidazopyridine Golam Kibriya,† Avik Kumar Bagdi,‡ and Alakananda Hajra*,† †

Department of Chemistry, Visva-Bharati (A Central University), Santiniketan 731235, India Department of Chemistry, University of Kalyani, Kalyani, Nadia 741235, India

‡

J. Org. Chem. 2018.83:10619-10626. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 09/07/18. For personal use only.

S Supporting Information *

ABSTRACT: A metal-free visible-light-promoted C(sp3)−C(sp2) cross-dehydrogenative coupling between tetrahydroisoquinoline and imidazo[1,2-a]pyridine has been developed to afford 3-substituted imidazopyridines using a catalytic amount of rose bengal as photosensitizer under aerobic conditions. The present methodology is also applicable to imidazo[1,2-a]pyrimidine, indolizine, indole, and pyrrole as well as N,N-dimethyl aniline. Wide substrates scope, use of organo photocatalyst, metal-free, and mild reaction conditions are the attractive features of this methodology. irect α-amino C−H functionalization is of great interest in organic synthesis for the generation of pharmaceutically important scaffolds via C−C and C-heteroatom bond formations.1 Transition-metal catalysts (e.g., Pd, Cu, Fe, V salts, etc.) along with terminal oxidants as well as stoichiometric hypervalent iodines are generally used for this purpose.2 Recently, synthetic chemists are very much involved in the visible-light-promoted direct C−H functionalization.3 The pioneering work of Stephenson revealed the efficiency of photoredox catalysis in direct sp3 C−H functionalization adjacent to nitrogen via imine or iminium ion intermediate.4 Subsequently, different expensive transition metals like Ru, Ir, Co complexes are employed as photoredox catalysts for the cross-dehydrogenative coupling of tertiary amine with various nucleophiles such as nitroalkanes, dialkyl malonates, dialkyl phophonates, and ketones, etc.5 However, use of these expensive metal catalysts limits their practical applicability. Therefore, inexpensive organophotocatalysts like rose bengal (RB), eosin Y, methylene blue, etc., have gained much attention and emerged as an alternative to the transitionmetal photoredox catalysts.6 Imidazo[1,2-a]pyridine, a N-containing fused heterocycle, exhibits a wide range of biological activities such as antibacterial, antiviral, antitumor, antipyretic, antifungal, antiinflammatory, anxioselective, and analgesic activities.7 There are several marketed drugs with imidazo[1,2-a]pyridine moiety such as alpidem, zolpidem, olprinone, necopidem, saripidem, and zolimidine. These are also important in material science

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© 2018 American Chemical Society

because of their capabilities to exhibit excited-state intramolecular proton transfer.8 As a consequence, functionalization of imidazoheterocycles has drawn considerable attention.9,10 On the other hand, tetrahydroisoquinoline moiety is also important in the field of natural products and pharmaceuticals.11 Because of the importance of these two skeletons, we became interested about the direct oxidative coupling between these two moieties. To the best of our knowledge, there is no such method for the coupling between tetrahydroisoquinoline and imidazo[1,2-a]pyridine. Herein, we report a metal-free cross-dehydrogenative coupling between imidazo[1,2-a]pyridine and N-phenyltetrahydroisoquinoline/N,N-dimethyl aniline using RB as photosensitizer under aerobic conditions (Scheme 1). We commenced our study by using 2-phenylimidazo[1,2a]pyridine (1a) and N-phenyl tetrahydroisoquinoline (2a) as model substrates. Initially the reaction was carried out employing RB as photocatalyst in CH3CN under 34 W blue LED at room temperature. To our delight, the crossdehydrogenative coupling product (3aa) was obtained with 53% yield after 24 h under aerobic conditions (Table 1, entry 1). After that, we carried out the reaction under different conditions to further improvement of the yield, and the results are summarized in Table 1. During the solvent screening it was observed that toluene was the best solvent to increase the yield Received: June 7, 2018 Published: August 22, 2018 10619

DOI: 10.1021/acs.joc.8b01433 J. Org. Chem. 2018, 83, 10619−10626

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The Journal of Organic Chemistry Scheme 2. Substrate Scope of Imidazopyridinesa

Scheme 1. Visible-Light-Promoted Cross-Dehydrogenative Coupling

Table 1. Optimization of Reaction Conditionsa

entry

photocatalyst

solvent

yield (%)

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

RB RB RB RB RB RB RB RB RB eosin Y eosin B Ru(bpy)3Cl2·6H2O Ir(ppy)3 − RB RB

CH3CN THF DCM 1,2-DCE toluene DMF DMSO 1,4-dioxane H2O toluene toluene toluene toluene toluene toluene toluene

53 55 18 42 83 15 trace 61 trace 75 55 62 68 nrb nrc nrd

a

a Reaction conditions: 0.2 mmol of 1, 0.2 mmol of 2, RB (2 mol %), in 3 mL toluene irradiated with 34 W blue LED for 24 h. bSix mmol scale. cReaction complete in 16 h. dReaction continued for 28 h.

up to 83% among solvents like THF, DCM, 1,2-DCE, toluene, DMF, DMSO, 1,4-dioxane, and H2O (Table 1, entries 2−9). Then the effects of other photocatalysts such as eosin Y, eosin B, Ru(bpy)3Cl2·6H2O, and Ir(ppy)3 were also studied, but none of them was as effective as RB (Table 1, entries 10−13). No formation of product was observed in the absence of any photocatalyst (Table 1, entry 14). In addition, the formation of product did not take place in the dark as well as under argon atmosphere (Table 1, entries 15 and 16). Moreover, the yield of the reaction did not improve upon addition of acid or base as additive (see SI, Table S1, entry 1−4). Thus, the optimized yield was obtained using RB as photocatalyst in toluene under room temperature in the presence of 34 W blue LED (Table 1, entry 5). With the optimized conditions in hand, we investigated the scope of this coupling reaction to show the generality of this methodology (Scheme 2). Initially we examined the effect of substituents in C-2 position of imidazo[1,2-a]pyridines. Imidazopyridine moiety with electron-donating substituents like −CH3 and −OCH3 on the phenyl ring afforded the

corresponding cross-coupling products with excellent yields (3ba and 3ca). Halogens were also well tolerated under the present reaction conditions (3da−3fa). Strong electronwithdrawing groups like −CN and −CF3 in a phenyl ring also successfully afforded the desired products without any difficulties (3ga and 3ha). Hydroxy-substituted imidazo[1,2a]pyridine also furnished the coupling product with excellent yield (3ia). Interestingly, coupling of the anti-ulcer drug, zolimidine was also worked well (3ja). To our delight, naphthyl- and thiophene-substituted imidazo[1,2-a]pyridines afforded the products with excellent yields (3ka and 3la). In addition, cyclopropyl imidazopyridine was found to be very effective for this reaction (3ma). Unsubstituted imidazo[1,2a]pyridine also produced the desired product regioselectively (3na). Imidazo[1,2-a]pyridines bearing methyl and halogen substituents on pyridine ring at different positions efficiently reacted with N-phenyl tetrahydroisoquinoline to afford the desired products with good yields (3oa-3ta). The structure of 1-(6-fluoro-2-phenylimidazo[1,2-a]pyridin-3-yl)-2-phenyl1,2,3,4-tetrahydroisoquinoline (3qa) was confirmed by single crystal X-ray crystallography analysis.12 In addition, 2phenylimidazo[1,2-a]pyrimidine, indolizine, indolizine, indole,

Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), photocatalyst (2 mol %), solvent (3 mL), 34 W blue LED. bNo reaction. cIn dark. d Under argon atmosphere.

10620

DOI: 10.1021/acs.joc.8b01433 J. Org. Chem. 2018, 83, 10619−10626

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The Journal of Organic Chemistry and pyrrole derivatives were also suitable substrates for this coupling reaction with very good yields (3ua−3ya). However, 1-phenylnaphtho[2,1-b]furan, benzofuran, and electron-rich arenes such as anisole and mesitylene did not participate in this coupling reaction. The gram-scale reaction of the present methodology was also performed in the usual laboratory setup by taking 2-phenylimidazo[1,2-a]pyridine (1a) and N-phenyltetrahydrisoquinoline (2a) on 6 mmol scale. The desired product (3aa) was obtained without significant decrease in yield which implies the practical applicability of this methodology. To extend the scope of the present methodology, we carried out the reaction with substituted N-aryl tetrahydroisoquinolines (Scheme 3). To our delight, N-aryl tetrahydroisoquino-

Scheme 5. Control Experiment

5, eq A (ii)). However, in both cases, the reactions were slightly inhibited which suggests that the key bond-formation step is not radical in nature and the single electron transfer (SET) was quite facile and fast. When the reaction was carried out in the presence of a singlet oxygen quencher like 1,4diazabicyclo[2.2.2]octane (DABCO)13b (Scheme 5, eq B), the yield of the reaction dropped significantly. This result suggests that the singlet oxygen may be involved in this cross-coupling reaction. On the basis of control experiments and literature reports,5,13a a plausible mechanistic pathway has been outlined in Scheme 6. From the redox potential values, it is expected

Scheme 3. Substrate Scope of Tetrahydroisoquinolinesa

Scheme 6. Proposed Mechanism

a

Reaction conditions: 0.2 mmol of 1a, 0.2 mmol of 2, RB (2 mol %) in 3 mL toluene irradiated with 34 W blue LED for 24 h.

lines having electron-donating, halogen, and electron-withdrawing substituents on the phenyl ring successfully furnished the desired products (3ab-3ae). Substituted tetrahydroisoquinolines were also able to afford the corresponding coupling products with good yields (3af and 3ag). The present protocol is also applicable to N,N-dimethyl aniline derivatives (Scheme 4). N,N-Dimethyl anilines efficiently reacted with imidazo[1,2-a]pyridine to provide the coupling products in high yields (5aa−5oa). Few control experiments were performed to understand the mechanistic pathway of this reaction (Scheme 5). The reaction was carried out in the presence of radical scavengers such as 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) (Scheme 5, eq A, (i)) and 2,6-di-tert-butyl-4-methylphenol (BHT) (Scheme

that RB in excited state [Et (RB*/RB•−) = 0.81 V vs SCE]13c can not oxidize N-phenyltetrahydroisoquinoline (Eox = 0.88 V vs SCE).5f Therefore, we believe that energy-transfer process instead of photoredox catalysis is possibly involved in the reaction. The ground state of RB is converted to its excited state RB* upon absorption of photon. RB* transfers its energy to the ground-state oxygen (3O2), forming the singlet oxygen (1O2), and tertiary amine is oxidized by singlet oxygen.13d A SET from 2a to 1O2 results the formation of amine radical cation (A) and superoxide radical anion (O2•−). The intermediate A gives up a hydrogen atom, presumably to the superoxide radical anion to form iminium ion B and HO2−. Consequently, electrophilic addition of iminium ion B to 2phenylimidazo[1,2-a]pyridine (1a) affords imidazolenium ion C. Finally a proton abstraction by HO2− from intermediate C affords the cross-coupling product 3aa along with H2O2 which is detected by starch-iodine test.6e In summary, we have developed an aerobic visible-lightpromoted C(sp3)−C(sp2) cross-dehydrogenative coupling

Scheme 4. Substrate Scope of Other Tertiary Aminesa

a

Reaction conditions: 0.2 mmol of 1, 0.2 mmol of 4, RB (2 mol %) in 3 mL toluene irradiated with 34 W blue LED for 24 h. 10621

DOI: 10.1021/acs.joc.8b01433 J. Org. Chem. 2018, 83, 10619−10626

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The Journal of Organic Chemistry

86%); 1H NMR (CDCl3, 400 MHz): δ 8.17−8.15 (m, 1H), 7.53 (d, J = 9.2 Hz, 1H), 7.38−7.34 (m, 2H), 7.26 (d, J = 6.8 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.11−7.06 (m, 1H), 7.04−6.96 (m, 3H), 6.92−6.88 (m, 4H), 6.70−6.68 (m, 2H), 6.60−6.56 (m, 1H), 5.94 (s, 1H), 3.84 (s, 3H), 3.56−3.40 (m, 3H), 3.02−2.99 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 159.5, 151.4, 146.6, 145.0, 135.5, 135.0, 132.1, 130.1, 129.0, 128.7, 127.1, 126.8, 126.6, 126.1, 124.5, 124.4, 123.6, 119.3, 117.1, 113.9, 111.5, 59.0, 55.4, 52.8, 30.6. Anal. calcd for C29H25N3O: C, 80.72; H, 5.84; N, 9.74%; found C, 80.49, H, 5.89; N, 9.87%. 1-(2-(4-Fluorophenyl)imidazo[1,2-a]pyridin-3-yl)-2-phenyl1,2,3,4-tetrahydroisoquinoline (3da). Brown solid (72 mg, 86%), mp: 120−122 °C; 1H NMR (CDCl3, 400 MHz): δ 8.17−8.15 (m, 1H), 7.55−7.52 (m, 1H), 7.37−7.32 (m, 2H), 7.26 (d, J = 6.4 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.13−7.09 (m, 1H), 7.07−6.98 (m, 5H), 6.95−6.91 (m, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.68−6.66 (m, 2H), 6.63−6.59 (m, 1H), 5.88 (s, 1H), 3.55−3.41 (m, 3H), 3.05− 3.00 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 162.7 (d, JC−F = 245 Hz), 151.4, 145.9, 145.0, 135.5, 134.7, 130.7, 130.6 (d, JC−F = 11 Hz), 130.5, 129.1, 128.7, 127.2, 126.8, 126.4, 126.1, 124.7 (d, JC−F = 4 Hz), 123.6, 119.7, 117.2, 115.3 (d, JC−F = 21 Hz), 111.7, 59.3, 52.3, 30.4. Anal. calcd for C28H22FN3: C, 80.17; H, 5.29; N, 10.02%; found C, 80.45; H, 5.23; N, 10.11%. 1-(2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl)-2-phenyl1,2,3,4-tetrahydroisoquinoline (3ea). Brown gummy mass (73 mg, 84%); 1H NMR (CDCl3, 400 MHz): δ 8.17 (d, J = 6.8 Hz, 1H), 7.70 (d, J = 9.2 Hz, 1H), 7.35−7.30 (m, 4H), 7.26 (d, J = 7.6 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.15−7.10 (m, 1H), 7.04−6.98 (m, 3H), 6.95−6.91 (m, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.68−6.66 (m, 2H), 6.64−6.60 (m, 1H), 5.88 (s, 1H), 3.55−3.44 (m, 3H), 3.03−3.00 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 151.4, 145.5, 145.1, 135.5, 134.6, 134.0, 133.0, 130.1, 129.1, 128.7, 128.5, 127.2, 126.8, 126.4, 126.2, 124.9, 124.8, 123.6, 120.0, 117.2, 111.9, 59.3, 52.4, 30.4. Anal. calcd for C28H22ClN3: C, 77.14; H, 5.09; N, 9.64%; found C, 77.01; H, 5.13; N, 9.53%. 1-(2-(3-Bromophenyl)imidazo[1,2-a]pyridin-3-yl)-2-phenyl1,2,3,4-tetrahydroisoquinoline (3fa). Yellow gummy mass (80 mg, 83%); 1H NMR (CDCl3, 400 MHz): δ 8.16 (d, J = 6.8 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.39 (s, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.25 (d, J = 7.2 Hz, 1H), 7.20 (t, J = 8.0 Hz, 2H), 7.14 (t, J = 8.4 Hz, 1H), 7.06−6.95 (m, 4H), 6.78 (d, J = 80 Hz, 1H), 6.69 (d, J = 7.6 Hz, 2H), 6.63 (t, J = 7.2 Hz, 1H), 5.85 (s, 1H), 3.55−3.41 (m, 3H), 3.05−2.99 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 151.4, 145.4, 145.1, 136.7, 135.5, 134.6, 131.9, 130.9, 129.7, 129.1, 128.9, 127.4, 127.2, 126.8, 126.5, 126.2, 125.0, 124.9, 123.7, 122.4, 120.3, 117.4, 111.9, 59.7, 51.9, 30.4. Anal. calcd for C28H22BrN3: C, 70.00; H, 4.62; N, 8.75%; found C, 69.81; H, 4.58; N, 8.83%. 4-(3-(2-Phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)imidazo[1,2a]pyridin-2-yl)benzonitrile (3ga). Brown solid (70 mg, 82%), mp: 135−137 °C; 1H NMR (CDCl3, 400 MHz): δ 8.16 (d, J = 7.2 Hz, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 9.2 Hz, 1H), 7.49−7.46 (m, 2H), 7.27 (d, J = 9.2 Hz, 1H), 7.22−7.14 (m, 2H), 7.03−6.93 (m, 4H), 6.79 (d, J = 7.6 Hz, 1H), 6.67−6.64 (m, 3H), 5.87 (s, 1H), 3.54−3.42 (m, 3H), 3.04−3.01 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 151.3, 145.4, 144.7, 139.3, 135.5, 134.3, 132.1, 129.3, 129.2, 128.8, 127.4, 126.9, 126.38, 126.34, 125.3, 125.0, 123.6, 120.9, 119.0, 117.5, 112.2, 111.3, 59.7, 52.0, 30.2. Anal. calcd for C29H22N4: C, 81.66; H, 5.20; N, 13.14%; found C, 81.87; H, 5.15; N, 12.98%. 2-Phenyl-1-(2-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin3-yl)-1,2,3,4-tetrahydroisoquinoline (3ha). Brown gummy mass (79 mg, 84%); 1H NMR (CDCl3, 400 MHz): δ 8.20−8.18 (m, 1H), 7.60−7.55 (m, 3H), 7.47 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 7.2 Hz, 1H), 7.18−7.13 (m, 1H), 7.03−6.92 (m, 4H), 6.81 (d, J = 8.0 Hz, 1H), 6.69−6.63 (m, 3H), 5.89 (s, 1H), 3.55−3.44 (m, 3H), 3.03−2.99 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 151.4, 145.34, 145.30, 138.2, 135.5, 134.5, 130.0, 129.7, 128.8, 127.7 (q, JC−F = 278 Hz), 127.3, 126.9, 125.7, 125.5 (q, JC−F = 7 Hz), 125.1, 124.9, 123.6, 120.6, 117.4, 112.7, 112.0, 59.6, 52.1, 30.3. Anal. calcd for C29H22F3N3: C, 74.19; H, 4.72; N, 8.95%; found C, 74.36; H, 4.66; N, 8.84%.

reaction between imidazo[1,2-a]pyridines and N-aryl tetrahydroisoquinolines/N,N-dimethyl anilines. Present methodology is also suitable for imidazo[1,2-a]pyrimidine, indolizine, indole, and pyrrole moieties. A wide variety of functionalities are tolerant under the present reaction conditions. The experimental results suggest that the RB acts as a photosensitizer in this reaction. To the best of our knowledge, this is the first report of cross-dehydrogenative coupling between imidazoheterocycles and N-aryl tetrahydroisoquinolines. Metal-free, aerobic reaction conditions, atom economy, and amenable to gram-scale synthesis make this method a practical one.

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EXPERIMENTAL SECTION

General Information. All reagents were purchased from commercial sources and used without further purification. 1H NMR spectra were determined on 400 MHz spectrometer as solutions in CDCl3. Chemical shifts are expressed in parts per million (δ), and the signals were reported as s (singlet), d (doublet), t (triplet), m (multiplet), and coupling constants (J) were given in Hz. 13C{1H} NMR spectra were recorded at 100 MHz in CDCl3 solution. Chemical shifts are referenced to CDCl3 (δ = 7.26 for 1H and δ = 77.16 for 13C{1H} NMR) as internal standard. TLC was done on silica gel-coated glass slides. All solvents were dried and distilled before use. Commercially available solvents were freshly distilled before the reaction. All reactions involving moisture-sensitive reactants were executed using oven-dried glassware. X-ray single crystal data were collected using MoKα (λ = 0.71073 Å) adiation with CCD area detector. Melting points were determined on a glass disk with an electrical bath and are uncorrected. All the imidazopyridines were prepared by our reported method.9d General Experimental Procedure for the Cross-Dehydrogenative-Coupling Reaction (3). Imidazo[1,2-a]pyridine (1, 0.2 mmol), N-aryltetrahydroisoquinoline (2, 0.2 mmol), RB (2.0 mol %, 4 mg), and toluene (3 mL) were added to an oven-dried reaction vessel equipped with a magnetic stir bar, and the reaction vessel was irradiated using a 34 W blue LED at room temperature under open atmosphere for 24 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (15 mL). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get the crude residue which was purified by column chromatography on silica gel (60−120 mesh) using petroleum ether/ethyl acetate as an eluent to afford the pure products. 2-Phenyl-1-(2-phenylimidazo[1,2-a]pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline (3aa). Brown solid (66.5 mg, 83%), mp: 118−120 °C; 1H NMR (CDCl3, 400 MHz): δ 8.18 (d, J = 6.8 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.43−7.34 (m, 5H), 7.26 (d, J = 6.4 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.12−7.08 (m, 1H), 7.05−6.96 (m, 3H), 6.92−6.89 (m, 2H), 6.69−6.67 (m, 2H), 6.62−6.58 (m, 1H), 5.97 (s, 1H), 3.56−3.41 (m, 3H), 3.04−2.96 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 151.4, 146.8, 145.0, 135.5, 134.9, 134.5, 129.0, 128.9, 128.7, 128.4, 127.9, 127.1, 126.8, 126.6, 126.2, 124.62, 124.60, 123.6, 119.7, 117.2, 111.6, 59.0, 52.7, 30.6; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C28H24N3: 402.1965; found: 402.1940. 2-Phenyl-1-(2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline (3ba). Brown solid (70.5 mg, 85%), mp: 105−107 °C; 1H NMR (CDCl3, 400 MHz): δ 8.20−8.18 (m, 1H),7.60−7.57 (m, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 7.2 Hz, 1H), 7.19 (d, J = 8.0 Hz, 3H), 7.12−7.08 (m, 1H), 7.04−6.97 (m, 3H), 6.93−6.89 (m, 2H), 6.71−6.69 (m, 2H), 6.61−6.58 (m, 1H), 5.97 (s, 1H), 3.57−3.53 (m, 1H), 3.49−3.42 (m, 2H), 3.05−2.96 (m, 1H), 2.39 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 151.4, 146.7, 144.9, 137.7, 135.5, 135.0, 131.5, 129.1, 129.0, 128.7, 128.6, 127.1, 126.8, 126.6, 126.2, 124.57, 124.54, 123.6, 119.5, 117.1, 111.6, 58.9, 52.8, 30.6, 21.4. Anal. calcd for C29H25N3: C, 83.82; H, 6.06; N, 10.11%; found C, 83.61; H, 6.13; N, 10.26%. 1-(2-(4-Methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)-2-phenyl1,2,3,4-tetrahydroisoquinoline (3ca). Yellow gummy mass (74 mg, 10622

DOI: 10.1021/acs.joc.8b01433 J. Org. Chem. 2018, 83, 10619−10626

Note

The Journal of Organic Chemistry

1-(8-Methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)-2-phenyl1,2,3,4-tetrahydroisoquinoline (3oa). Yellow solid (69 mg, 83%), mp: 119−121 °C; 1H NMR (CDCl3, 400 MHz): δ 8.06 (d, J = 6.8 Hz, 1H), 7.42−7.32 (m, 5H), 7.24 (d, J = 8.4 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.03−6.97 (m, 3H), 6.94−6.87 (m, 3H), 6.70−6.67 (m, 2H), 6.52 (t, J = 6.8 Hz, 1H), 5.91 (s, 1H), 3.56−3.40 (m, 3H), 3.01−2.98 (m, 1H), 2.58 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 151.5, 146.4, 145.4, 135.5, 135.2, 134.9, 129.1, 129.0, 128.9, 128.7, 128.3, 127.8, 127.0, 126.77, 126.74, 124.4, 124.0, 123.6, 123.4, 120.0, 111.6, 59.0, 52.6, 30.6, 17.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C29H26N3: 416.2121; found: 416.2129. 1-(7-Methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)-2-phenyl1,2,3,4-tetrahydroisoquinoline (3pa). Brown solid (67 mg, 81%), mp: 136−138 °C; 1H NMR (CDCl3, 400 MHz): δ 8.06 (d, J = 7.2 Hz, 1H) 7.43−7.40 (m, 2H), 7.38−7.32 (m, 4H), 7.26 (d, J = 7.6 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.05−6.96 (m, 3H), 6.93−6.90 (m, 2H), 6.70−6.68 (m, 2H), 6.45−6.42 (m, 1H), 5.93 (s, 1H), 3.56− 3.51 (m, 1H), 3.48−3.40 (m, 2H), 3.04−2.96 (m, 1H), 2.32 (s, 3H); 13 C{1H} NMR (CDCl3, 100 MHz): δ 151.4, 146.4, 145.4, 135.55, 135.51, 135.1, 134.6, 129.0, 128.8, 128.6, 128.3, 127.8, 127.1, 126.7, 126.6, 125.3, 124.5, 123.6, 119.1, 115.6, 114.3, 59.0, 52.7, 30.6, 21.4. Anal. calcd for C29H25N3: C, 83.82; H, 6.06; N, 10.11%; found: C, 83.69; H, 6.11; N, 10.20%. 1-(6-Fluoro-2-phenylimidazo[1,2-a]pyridin-3-yl)-2-phenyl1,2,3,4-tetrahydroisoquinoline (3qa). White solid (70 mg, 84%), mp: 152−154 °C; 1H NMR (CDCl3, 400 MHz): δ 8.17−8.15 (m, 1H), 7.52−7.48 (m, 1H), 7.45−7.43 (m, 2H), 7.42−7.36 (m, 3H), 7.28 (d, J = 7.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.07−6.96 (m, 4H), 6.94−6.89 (m, 2H), 6.72−6.69 (m, 2H), 5.98 (s, 1H), 3.57−3.37 (m, 3H), 3.05−2.99 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 152.3 (q, JC−F = 234 Hz), 151.2, 148.0, 142.7, 135.5, 134.3, 129.2, 128.7, 128.5, 128.1, 127.4, 126.9, 126.8, 126.5, 124.7, 123.6, 121.2, 117.5 (q, JC−F = 9 Hz), 116.4 (q, JC−F = 25 Hz), 113.1, 112.7, 58.7, 53.0, 30.5. Anal. calcd for C28H22FN3: C, 80.17; H, 5.29; N, 10.02%; found: C, 80.45; H, 5.35; N, 9.91%. 1-(6-Chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)-2-phenyl1,2,3,4-tetrahydroisoquinoline (3ra). Brown solid (69 mg,79%), mp: 153−155 °C; 1H NMR (CDCl3, 400 MHz): δ 8.28 (d, J = 1.6 Hz, 1H) 7.48−7.41 (m, 3H), 7.40−7.36 (m, 3H), 7.29 (d, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.07−7.04 (m, 2H), 7.02−6.98 (m, 2H), 6.94−6.88 (m, 2H), 6.72−6.70 (m, 2H), 5.98 (s, 1H), 3.57− 3.38 (m, 3H), 3.05−2.99 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 151.2, 147.7, 143.4, 135.5, 134.3, 134.1, 129.2, 128.7, 128.5, 128.2, 127.4, 126.9, 126.5, 125.8, 124.8, 124.1, 123.6, 120.5, 119.5, 118.7, 117.6, 58.7, 52.9, 30.5; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C28H23ClN3: 436.1575; found: 436.1549. 1-(6-Bromo-2-phenylimidazo[1,2-a]pyridin-3-yl)-2-phenyl1,2,3,4-tetrahydroisoquinoline (3sa). Brown gummy mass (79 mg, 82%); 1H NMR (CDCl3, 400 MHz): δ 8.16 (d, J = 6.8 Hz, 1H), 7.55 (d, J = 9.2 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.40−7.39 (m, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.26−7.24 (m, 1H), 7.20 (t, J = 7.6 Hz, 2H), 7.16−7.12 (m, 1H), 7.06−6.95 (m, 4H), 6.78 (d, J = 8.0 Hz, 1H), 6.71−6.69 (m, 2H), 6.65−6.63 (m, 1H), 5.85 (s, 1H), 3.55−3.43 (m, 3H), 3.03−2.99 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 151.4, 145.4, 145.1, 136.7, 135.4, 131.8, 130.9, 129.7, 128.9, 127.4, 127.2, 126.8, 126.5, 126.2, 124.9, 123.7, 122.4, 120.3, 117.4, 111.9, 59.7, 51.9, 30.3. Anal. calcd for C28H22BrN3: C, 70.00; H, 4.62; N, 8.75%; found: C, 70.17; H, 4.57; N, 8.62%. 1-(8-Bromo-2-phenylimidazo[1,2-a]pyridin-3-yl)-2-phenyl1,2,3,4-tetrahydroisoquinoline (3ta). Yellow gummy mass (81 mg, 84%); 1H NMR (CDCl3, 400 MHz): δ 8.23−8.21 (m, 1H), 7.45− 7.42 (m, 2H), 7.38−7.35 (m, 4H), 7.26 (d, J = 7.2 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.05−6.98 (m, 3H), 6.95−6.92 (m, 1H), 6.86 (d, J = 7.6 Hz, 1H), 6.70−6.68 (m, 2H), 6.48 (t, J = 7.2 Hz, 1H), 5.94 (s, 1H), 3.55−3.38 (m, 3H), 3.04−2.95 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 151.3, 147.5, 142.9, 135.4, 134.6, 134.1, 129.2, 129.1, 128.8, 128.3, 128.1, 127.2, 127.0, 126.8, 126.6, 125.6, 124.8, 123.6, 121.7, 111.6, 111.2, 59.0, 52.9, 30.5. Anal. calcd for C28H22BrN3: C, 70.00; H, 4.62; N, 8.75%; found C, 69.78; H, 4.67; N, 8.89%.

2-(3-(2-Phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)imidazo[1,2a]pyridin-2-yl)phenol (3ia). White solid (73 mg, 88%), mp: 180−182 °C; 1H NMR (CDCl3, 400 MHz): δ 11.75 (brs, 1H), 8.31 (d, J = 6.8 Hz, 1H), 7.48−7.46 (m, 3H), 7.29 (d, J = 7.6 Hz, 1H), 7.27−7.20 (m, 2H), 7.16−7.12 (m, 1H), 7.08−7.01 (m, 2H), 6.98−6.91 (m, 3H), 6.89−6.82 (m, 2H), 6.77−6.75 (m, 2H), 6.66−6.63 (m, 1H), 6.29 (s, 1H), 3.61−3.45 (m, 3H), 3.09−3.04 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 157.3, 150.9, 144.0, 143.6, 135.5, 134.4, 129.9, 129.1, 128.7, 127.3, 127.1, 126.9, 126.5, 125.3, 124.6, 123.1, 119.7, 119.0, 117.8, 117.67, 117.60, 116.5, 112.1, 58.6, 53.4, 30.6. Anal. calcd for C28H23N3O: C, 80.55; H, 5.55; N, 10.06%; found C, 80.36; H, 5.51; N, 10.19%. 1-(2-(4-(Methylsulfonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)-2phenyl-1,2,3,4-tetrahydroisoquinoline (3ja). Yellow gummy mass (79 mg, 82%); 1H NMR (CDCl3, 400 MHz): δ 8.19 (d, J = 7.2 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.20−7.15 (m, 2H), 7.03−6.93 (m, 4H), 6.75 (d, J = 7.6 Hz, 1H), 6.68−6.65 (m, 3H), 5.86 (s, 1H), 3.54−3.44 (m, 3H), 3.08−3.01 (m, 4H); 13C{1H} NMR (CDCl3, 100 MHz): δ 151.3, 144.6, 140.3, 139.4, 135.5, 134.3, 129.6, 129.2, 128.9, 128.5, 128.0, 127.3, 126.8, 126.4, 126.3, 125.3, 125.1, 123.6, 121.0, 117.5, 112.2, 59.9, 51.8, 44.7, 30.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C29H26N3O2S: 480.1740; found: 480.1730. 1-(2-(Naphthalen-2-yl)imidazo[1,2-a]pyridin-3-yl)-2-phenyl1,2,3,4-tetrahydroisoquinoline (3ka). Brown gummy mass (82 mg, 91%); 1H NMR (CDCl3, 400 MHz): δ 8.23−8.21 (m, 1H), 7.87− 7.84 (m, 2H), 7.78−7.76 (m, 1H), 7.73 (s, 1H), 7.64−7.59 (m, 2H), 7.49−7.47 (m, 2H), 7.26 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.16−7.11 (m, 1H), 7.05−6.99 (m, 3H), 6.97−6.91 (m, 2H), 6.73− 6.71 (m, 2H), 6.65−6.61 (m, 1H), 6.03 (s, 1H), 3.57−3.43 (m, 3H), 3.05−2.97 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 151.5, 146.8, 145.2, 135.5, 134.9, 133.3, 133.0, 132.0, 129.1, 129.0, 128.8, 128.4, 128.0, 127.8, 127.17, 127.11, 127.0, 126.8, 126.7, 126.2, 126.1, 124.76, 124.72, 123.7, 120.2, 117.3, 111.7, 59.5, 52.4, 30.5. Anal. calcd for C32H25N3: C, 85.11; H, 5.58; N, 9.31%; found C, 85.28; H, 5.53; N, 9.19%. 2-Phenyl-1-(2-(thiophen-2-yl)imidazo[1,2-a]pyridin-3-yl)-1,2,3,4tetrahydroisoquinoline (3la). Brown gummy mass (72 mg, 89%); 1H NMR (CDCl3, 400 MHz): δ 8.26 (d, J = 6.8 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.38−7.36 (m, 1H), 7.30−7.25 (m, 2H), 7.19 (t, J = 8.0 Hz, 1H), 7.10−6.99 (m, 5H), 6.91−6.84 (m, 4H), 6.59−6.56 (m, 1H), 6.26 (s, 1H), 3.64−3.60 (m, 1H), 3.56−3.44 (m, 2H), 3.04−2.98 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 151.1, 145.0, 140.4, 137.1, 135.3, 134.5, 129.0, 128.8, 127.5, 127.1, 126.8, 126.7, 126.25, 126.21, 125.4, 124.8, 124.4, 123.1, 119.7, 117.0, 111.7, 58.4, 53.2, 30.6. Anal. calcd for C26H21N3S: C, 76.63; H, 5.19; N, 10.31%; found: C, 76.86; H, 5.25; N, 10.18%. 1-(2-Cyclopropylimidazo[1,2-a]pyridin-3-yl)-2-phenyl-1,2,3,4tetrahydroisoquinoline (3ma). White solid (62 mg, 85%), mp: 95− 97 °C; 1H NMR (CDCl3, 400 MHz): δ 7.95 (d, J = 6.8 Hz, 1H), 7.44−7.41 (m, 1H), 7.20−7.14 (m, 4H), 7.09−7.06 (m, 1H),7.05− 6.99 (m, 3H), 6.97−6.92 (m, 2H), 6.57−6.54 (m, 1H), 6.01 (s, 1H), 3.65−3.57 (m, 2H), 3.24−3.17 (m, 1H), 3.03−2.96 (m, 1H), 1.52− 1.46 (m, 1H), 1.11−1.05 (m, 1H), 0.83−0.75 (m, 2H), 0.71−0.64 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 150.9, 147.8, 144.5, 135.6, 134.6, 129.04, 129.01, 127.4, 127.1, 126.6, 124.9, 123.7, 123.0, 121.6, 119.8, 116.4, 111.2, 57.1, 50.0, 28.7, 8.1, 7.9, 7.5. Anal. calcd for C25H23N3: C, 82.16; H, 6.34; N, 11.50%; found: C, 81.95; H, 6.41; N, 11.64%. 1-(Imidazo[1,2-a]pyridin-3-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline (3na). Brown solid (51 mg, 78%), mp: 80−82 °C; 1H NMR (CDCl3, 400 MHz): δ 8.04 (d, J = 6.8 Hz, 1H), 7.62 (d, J = 9.2 Hz, 1H), 7.28−7.18 (m, 6H), 7.15 (t, J = 7.2 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.95 (s, 1H), 6.91 (t, J = 7.6 Hz, 1H), 6.76−6.72 (m, 1H), 6.05 (s, 1H), 3.68−3.63 (m, 1H), 3.48−3.40 (m, 1H), 3.04−2.91 (m, 1H), 2.67−2.61 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 149.5, 146.4, 135.9, 134.7, 133.3, 129.5, 128.3, 127.6, 126.2, 125.6, 125.3, 124.5, 120.8, 118.5, 117.7, 112.5, 112.3, 54.8, 44.2, 25.1. Anal. calcd for C22H19N3: C, 81.20; H, 5.89; N, 12.91%; found: C, 81.41; H, 5.83; N, 12.76%. 10623

DOI: 10.1021/acs.joc.8b01433 J. Org. Chem. 2018, 83, 10619−10626

Note

The Journal of Organic Chemistry 2-Phenyl-1-(2-phenylimidazo[1,2-a]pyrimidin-3-yl)-1,2,3,4-tetrahydroisoquinoline (3ua). Brown gummy mass (63 mg, 78%); 1H NMR (CDCl3, 400 MHz): δ 8.51−8.48 (m, 1H), 8.45−8.44 (m, 1H), 7.58−7.56 (m, 2H), 7.41−7.40 (m, 3H), 7.28 (d, J = 7.2 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H), 6.99−6.89 (m, 4H), 6.69−6.64 (m, 3H), 6.06 (s, 1H), 3.56−3.37 (m, 3H), 3.04−3.00 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 151.0, 149.7, 148.1, 148.0, 135.3, 134.3, 133.9, 133.8, 129.2, 128.9, 128.8, 128.5, 128.4, 127.5, 126.9, 126.6, 124.9, 123.5, 118.5, 108.0, 58.4, 53.3, 30.6. Anal. calcd for C27H22N4: C, 80.57; H, 5.51; N, 13.92%; found C, 80.38; H, 5.58; N, 14.04%. 3-(2-Phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)indolizine-1-carbonitrile (3va). Yellow solid (56 mg, 80%), mp: 168−170 °C; 1H NMR (CDCl3, 400 MHz): δ 8.00 (d, J = 6.8 Hz, 1H), 7.64 (d, J = 9.2 Hz, 1H), 7.28−7.21 (m, 4H), 7.15 (t, J = 7.6 Hz, 2H), 7.10−7.05 (m, 3H), 6.93 (t, J = 7.2 Hz, 1H), 6.73−6.69 (m, 1H), 6.35 (s, 1H), 5.97 (s, 1H), 3.68−3.63 (m, 1H), 3.42−3.35 (m, 1H), 2.96−2.88 (m, 1H), 2.64−2.59 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 149.3, 138.9, 135.9, 133.2, 129.66, 129.62, 128.4, 127.7, 127.0, 126.3, 125.6, 122.4, 121.0, 118.9, 118.7, 117.9, 117.1, 112.8, 80.6, 55.6, 44.5, 24.9. Anal. calcd for C24H19N3: C, 82.49; H, 5.48; N, 12.03%; found: C, 82.71; H, 5.41; N, 11.88%. Methyl 3-(2-Phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)indolizine-1-carboxylate (3wa). Brown solid (59 mg, 77%), mp: 166−168 °C; 1H NMR (CDCl3, 400 MHz): δ 8.23−8.21 (m, 1H), 7.98 (d, J = 7.2 Hz, 1H), 7.28−7.19 (m, 5H), 7.13 (d, J = 7.2 Hz, 1H), 7.11−7.06 (m, 3H), 6.95−6.88 (m, 1H), 6.70−6.66 (m, 1H), 6.60 (s, 1H), 6.00 (s, 1H), 3.82 (s, 3H), 3.68−3.63 (m, 1H), 3.48− 3.41 (m, 1H), 2.97−2.88 (m, 1H), 2.62−2.57 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 165.5, 149.4, 136.9, 135.9, 133.8, 129.5, 128.6, 127.4, 126.4, 126.2, 125.1, 122.5, 120.5, 119.8, 118.4, 118.3, 114.9, 112.5, 102.4, 55.5, 50.9, 44.1, 24.9. Anal. calcd for C25H22N2O2: C, 78.51; H, 5.80; N, 7.32%; found: C, 78.60; H, 5.78; N, 7.43%. 1-(1-Methyl-1H-indol-3-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline (3xa).5d White solid (58 mg, 86%), mp: 119−121 °C; 1H NMR (CDCl3, 400 MHz): δ 7.45 (d, J = 8.0 Hz, 1H), 7.21−7.18 (m, 1H), 7.15−7.12 (m, 3H), 7.11−7.03 (m, 4H), 6.94−6.91 (m, 3H), 6.69− 6.65 (m, 1H), 6.40 (s, 1H), 6.08 (s, 1H), 3.56−3.51 (m, 5H), 3.01− 2.93 (m, 1H), 2.74−2.68 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 149.9, 137.7, 137.4, 135.6, 129.3, 128.93, 128.90, 128.1, 127.0, 126.7, 125.8, 121.7, 120.2, 119.2, 118.1, 117.7, 115.7, 109.2, 56.7, 42.3, 32.8, 26.7. Anal. calcd for C24H22N2: C, 85.17; H, 6.55; N, 8.28%; found C, 84.98; H, 6.60; N, 8.42%. 1-(1-Methyl-1H-pyrrol-2-yl)-2-phenyl-1,2,3,4-tetrahydroquinoline (3ya). Brown solid (43 mg, 74%), mp: 105−107 °C; 1H NMR (CDCl3, 400 MHz): δ 7.48−7.21 (m, 2H), 7.20−7.13 (m, 3H), 7.09 (d, J = 7.2 Hz, 1H), 7.02 (d, J = 8.0 Hz, 2H), 6.83 (t, J = 7.2 Hz, 1H), 6.61 (t, J = 2.4 Hz, 1H), 5.96 (t, J = 3.6 Hz, 1H), 5.78 (s, 1H), 5.45− 5.44 (m, 1H), 3.69−3.58 (m, 2H), 3.57 (s, 3H), 3.01−2.89 (m, 1H), 2.63−2.57 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 149.7, 135.7, 135.5, 134.1, 129.3, 129.2, 128.7, 126.8, 125.6, 122.9, 119.6, 117.7, 111.2, 106.0, 55.7, 42.9, 34.3, 25.2. Anal. calcd for C20H20N2: C, 83.30; H, 6.99; N, 9.71%; found C, 83.51; H, 6.93; N, 9.56%. 1-(2-Phenylimidazo[1,2-a]pyridin-3-yl)-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline (3ab). Brown gummy mass (71 mg, 85%); 1H NMR (CDCl3, 400 MHz): δ 8.21−8.19 (m, 1H),7.54 (d, J = 8.8 Hz, 1H), 7.45−7.42 (m, 2H), 7.40−7.34 (m, 3H), 7.25 (d, J = 7.6 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H),7.12−7.07 (m, 1H), 7.02 (t, J = 8.0 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 8.0 Hz, 2H), 6.61−6.56 (m, 3H), 5.92 (s, 1H), 3.51−3.38 (m, 3H), 3.02−2.96 (m, 1H), 2.16 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 149.0, 146.8, 145.0, 135.5, 135.1, 134.6, 134.2, 129.3, 129.0, 128.9, 128.3, 127.9, 127.1, 126.7, 126.6, 126.3, 124.5, 123.5, 119.8, 117.2, 111.5, 59.3, 53.0, 30.6, 20.8. Anal. calcd for C29H25N3: C, 83.82; H, 6.06; N, 10.11%; found C, 83.65; H, 6.12; N, 10.23%. 1-(2-Phenylimidazo[1,2-a]pyridin-3-yl)-2-(o-tolyl)-1,2,3,4-tetrahydroisoquinoline (3ac). Yellow gummy mass (67 mg, 81%); 1H NMR (CDCl3, 400 MHz): δ 8.10 (d, J = 6.8 Hz, 1H), 7.64 (d, J = 6.8 Hz, 2H), 7.49−7.42 (m, 4H), 7.31 (d, J = 7.6 Hz, 1H), 7.27−7.23 (m,

1H), 7.12−7.09 (m, 2H), 7.06−7.02 (m, 1H), 6.90 (d, J = 7.2 Hz, 1H), 6.80−6.76 (m, 1H), 6.67−6.62 (m, 1H), 6.54−6.50 (m, 2H), 6.25 (s, 1H), 3.59−3.50 (m, 1H), 3.30−3.26 (m, 1H), 3.12−3.06 (m, 1H), 3.00−2.96 (m, 1H), 2.06 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 149.0, 147.0, 145.1, 135.6, 135.4, 134.9, 134.4, 130.8, 129.3, 128.9, 128.5, 128.1, 127.2, 126.8, 126.53, 126.50, 125.9, 124.5, 124.4, 122.4, 119.3, 117.2, 111.1, 57.0, 30.6, 17.4. Anal. calcd for C29H25N3: C, 83.82; H, 6.06; N, 10.11%; found C, 84.01; H, 6.01; N, 9.98%. 2-(4-Bromophenyl)-1-(2-phenylimidazo[1,2-a]pyridin-3-yl)1,2,3,4-tetrahydroisoquinoline (3ad). Brown solid (83 mg, 86%), mp: 130−132 °C; 1H NMR (CDCl3, 400 MHz): δ 8.07 (d, J = 7.2 Hz, 1H),7.55 (d, J = 8.8 Hz, 1H), 7.52−7.49 (m, 2H), 7.44−7.37 (m, 3H), 7.27 (d, J = 7.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.13−7.02 (m, 4H), 6.96 (d, J = 7.6 Hz, 1H), 6.61−6.57 (m, 1H), 6.53−6.49 (m, 2H), 5.98 (s, 1H), 3.52−3.38 (m, 3H), 3.02−2.98 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 150.3, 147.0, 145.2, 135.3, 134.5, 134.4, 131.6, 129.1, 128.8, 128.5, 128.1, 127.3, 126.9, 126.5, 126.0, 125.0, 124.7, 119.2, 117.4, 117.3, 111.8, 58.3, 52.9, 30.5. Anal. calcd for C28H22BrN3: C, 70.00; H, 4.62; N, 8.75%; found C, 70.23; H, 4.57; N, 8.62%. 1-(2-Phenylimidazo[1,2-a]pyridin-3-yl)-2-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (3ae). Brown gummy mass (77 mg, 82%); 1H NMR (CDCl3, 400 MHz): δ 8.08 (d, J = 6.8 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.48−7.46 (m, 2H), 7.42−7.37 (m, 3H), 7.29 (d, J = 7.2 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H),7.14−6.95 (m, 6H), 6.71 (d, J = 8.0 Hz, 1H), 6.64−6.60 (m, 1H), 6.06 (s, 1H), 3.59−3.43 (m, 3H), 3.08−3.01 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 151.6, 146.9, 145.2, 135.3, 134.3, 134.0, 131.2, 130.9, 129.1, 128.7, 128.5, 128.23, 128.20 (q, JC−F = 248 Hz), 127.0, 126.5, 125.9, 124.8, 122.5, 120.9 (q, JC−F = 8 Hz), 119.8 (q, JC−F = 7 Hz), 118.9, 117.4, 112.0, 58.2, 52.6, 30.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C29H23F3N3: 470.1839; found: 470.1810. 6,7-Dimethoxy-2-phenyl-1-(2-phenylimidazo[1,2-a]pyridin-3-yl)1,2,3,4-tetrahydroisoquinoline (3af). Yellow solid (74 mg, 80%), mp: 121−123 °C; 1H NMR (CDCl3, 400 MHz): δ 8.26−8.24 (m, 1H), 7.54 (d, J = 9.2 Hz, 1H), 7.39−7.33 (m, 5H), 7.14−7.10 (m, 1H), 7.02−6.98 (m, 2H), 6.94−6.90 (m, 1H), 6.73−6.70 (m, 3H), 6.64−6.61 (m, 1H), 6.30 (s, 1H), 5.88 (s, 1H), 3.87 (s, 3H), 3.56− 3.52 (m, 1H), 3.50 (s, 3H), 3.46−3.32 (m, 2H), 2.91−2.87 (m, 1H); 13 C{1H} NMR (CDCl3, 100 MHz): δ 151.5, 148.2, 147.9, 146.7, 145.1, 134.7, 128.8, 128.7, 128.3, 127.9, 127.6, 126.6, 126.4, 124.6, 124.4, 123.4, 119.9, 117.2, 111.6, 111.5, 109.3, 58.8, 56.0, 55.9, 52.3, 29.9. Anal. Calcd for C30H27N3O2: C, 78.07; H, 5.90; N, 9.10%; Found C, 78.26; H, 5.84; N, 9.23%. 6,7-Dimethoxy-1-(2-phenylimidazo[1,2-a]pyridin-3-yl)-2-(ptolyl)-1,2,3,4-tetrahydroisoquinoline (3ag). Brown solid (74 mg, 78%), mp: 135−137 °C; 1H NMR (CDCl3, 400 MHz): δ 8.27 (d, J = 6.8 Hz, 1H), 7.54 (d, J = 9.2 Hz, 1H), 7.41−7.33 (m, 5H), 7.14−7.10 (m, 1H), 6.79 (d, J = 8.4 Hz, 2H), 6.70 (s, 1H), 6.64−6.59 (m, 3H), 6.29 (s, 1H), 5.83 (s, 1H), 3.87 (s, 3H), 3.49 (s, 3H), 3.48−3.36 (m, 3H), 2.92−2.86 (m, 1H), 2.16 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 149.1, 148.1, 147.9, 146.6, 145.1, 134.7, 134.2, 129.3, 128.8, 128.3, 127.8, 127.6, 126.8, 126.5, 124.5, 123.4, 120.0, 117.2, 111.6, 111.5, 109.3, 59.1, 56.0, 55.9, 52.7, 30.0, 20.8. Anal. calcd for C31H29N3O2: C, 78.29; H, 6.15; N, 8.84%; found C, 78.04; H, 6.11; N, 8.98%. N-Methyl-N-((2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)aniline (5aa). Yellow solid (53 mg, 85%), mp: 120−122 °C; 1H NMR (CDCl3, 400 MHz): δ 8.06 (d, J = 6.8 Hz, 1H), 7.80−7.78 (m, 2H), 7.68 (d, J = 8.8 Hz, 1H), 7.48−7.44 (m, 2H), 7.40−7.36 (m, 1H), 7.33−7.29 (m, 2H), 7.25−7.20 (m, 1H), 6.99 (d, J = 8.0 Hz, 2H), 6.87 (t, J = 7.6 Hz, 1H), 6.79−6.76 (m, 1H), 4.83 (s, 2H), 2.70 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 150.4, 145.7, 145.3, 134.3, 129.4, 128.8, 128.7, 128.0, 124.8, 124.7, 118.7, 117.5, 116.3, 114.7, 112.5, 46.1, 36.2. Anal. calcd for C21H19N3: C, 80.48; H, 6.11; N, 13.41%; found C, 80.31; H, 6.18; N, 13.51%. N-4-Dimethyl-N-((2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)aniline (5ab). Brown solid (54 mg, 82%), mp: 137−139 °C; 1H NMR (CDCl3, 400 MHz): δ 8.11 (d, J = 6.8 Hz, 1H), 7.80−7.78 (m, 2H), 7.67 (d, J = 8.8 Hz, 1H), 7.48−7.43 (m, 2H), 7.39−7.35 (m, 10624

DOI: 10.1021/acs.joc.8b01433 J. Org. Chem. 2018, 83, 10619−10626

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The Journal of Organic Chemistry 1H), 7.24−7.20 (m, 1H), 7.12 (d, J = 8.4 Hz, 2H), 6.93−6.89 (m, 2H), 6.79−6.75 (m, 1H), 4.77 (s, 2H), 2.67 (s, 3H), 2.30 (s, 3H); 13 C{1H} NMR (CDCl3, 100 MHz): δ 148.5, 145.6, 145.3, 134.4, 129.6, 128.9, 128.6, 128.0, 126.1, 124.8, 124.7, 117.5, 116.5, 115.3, 112.4, 46.7, 36.9, 20.4. Anal. calcd for C22H21N3: C, 80.70; H, 6.46; N, 12.83%; found C, 80.41; H, 6.54; N, 13.05%. N-Methyl-N-((8-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)aniline (5oa). Brown solid (56 mg, 86%), mp: 140−142 °C; 1 H NMR (CDCl3, 400 MHz): δ 7.93 (d, J = 6.8 Hz, 1H), 7.80−7.78 (m, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.39 (d, J = 7.2 Hz, 1H), 7.32 (t, J = 8.0 Hz, 2H), 7.02 (d, J = 6.8 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.86 (t, J = 7.2 Hz, 1H), 6.70 (t, J = 6.8 Hz, 1H), 4.80 (s, 2H), 2.70 (s, 6H); 13C{1H} NMR (CDCl3, 100 MHz): δ 150.5, 145.7, 145.3, 134.6, 129.4, 129.0, 128.6, 127.9, 127.5, 123.6, 122.4, 118.5, 116.6, 114.5, 112.5, 46.0, 36.1, 17.2. Anal. calcd for C22H21N3: C, 80.70; H, 6.46; N, 12.83%; found C, 80.86; H, 6.41; N, 12.73%.

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in Organic Synthesis. Chem. Rev. 2013, 113, 5322−5363. (b) Narayanam, J. M. R.; Stephenson, C. R. J. Visible Light Photoredox Catalysis: Applications in Organic Synthesis. Chem. Soc. Rev. 2011, 40, 102−113. (c) Shaw, M. H.; Twilton, J.; MacMillan, D W. C. Photoredox Catalysis in Organic Chemistry. J. Org. Chem. 2016, 81, 6898−6926. (d) Xiao, W.-J.; Zhou, Q.-Q.; Zou, Y.-Q.; Lu, L.-Q. Visible-Light-Induced Organic Photochemical Reactions via Energy Transfer Pathways. Angew. Chem., Int. Ed. 2018, DOI: 10.1002/ anie.201803102. (4) Condie, A. G.; González-Gómez, J. C.; Stephenson, C. R. J. Visible-Light Photoredox Catalysis: Aza-Henry Reactions via C−H Functionalization. J. Am. Chem. Soc. 2010, 132, 1464−1465. (5) (a) Beatty, J. W.; Stephenson, C. R. J. Amine Functionalization via Oxidative Photoredox Catalysis: Methodology Development and Complex Molecule Synthesis. Acc. Chem. Res. 2015, 48, 1474−1484. (b) Shi, L.; Xia, W. Photoredox Functionalization of C−H Bonds Adjacent to a Nitrogen Atom. Chem. Soc. Rev. 2012, 41, 7687−7697. (c) Wu, C.-J.; Zhong, J.-J.; Meng, Q.-Y.; Lei, T.; Gao, X.-W.; Tung, C.-H.; Wu, L.-Z. Cobalt-Catalyzed Cross-Dehydrogenative Coupling Reaction in Water by Visible Light. Org. Lett. 2015, 17, 884−887. (d) Zhong, J.-J.; Meng, Q.-Y.; Liu, B.; Li, X.-B.; Gao, X.-W.; Lei, T.; Wu, C.-J.; Li, Z.-J.; Tung, C.-H.; Wu, L.-Z. Cross-Coupling Hydrogen Evolution Reaction in Homogeneous Solution without Noble Metals. Org. Lett. 2014, 16, 1988−1991. (e) Zhou, W.-J.; Cao, G.-M.; Shen, G.; Zhu, X.-Y.; Gui, Y.-Y.; Ye, J.-H.; Sun, L.; Liao, L.-L.; Li, J.; Yu, D.G. Visible-Light-Driven Palladium-Catalyzed Radical Alkylation of CH Bonds with Unactivated Alkyl Bromides. Angew. Chem., Int. Ed. 2017, 56, 15683−15687. (f) Yang, Q.; Zhang, L.; Ye, C.; Luo, S.; Wu, L.-Z.; Tung, C.-H. Visible-Light-Promoted Asymmetric CrossDehydrogenative Coupling of Tertiary Amines to Ketones by Synergistic Multiple Catalysis. Angew. Chem., Int. Ed. 2017, 56, 3694−3698. (g) Rueping, M.; Zoller, J.; Fabry, D.; Poscharny, K.; Koenigs, M.; Mayer, E. W. Light-Mediated Heterogeneous Cross Dehydrogenative Coupling Reactions: Metal Oxides as Efficient, Recyclable, Photoredox Catalysts in C−C Bond-Forming Reactions. Chem. - Eur. J. 2012, 18, 3478−3481. (h) Ren, L.; Cong, H. VisibleLight-Driven Decarboxylative Alkylation of C−H Bond Catalyzed by Dye-Sensitized Semiconductor. Org. Lett. 2018, 20, 3225−3228. (6) (a) Pan, Y.; Kee, C. W.; Chen, L.; Tan, C.-H. Dehydrogenative Coupling Reactions Catalysed by Rose Bengal using Visible Light Irradiation. Green Chem. 2011, 13, 2682−2685. (b) Ravelli, D.; Fagnoni, M. Dyes as Visible Light Photoredox Organocatalysts. ChemCatChem 2012, 4, 169−171. (c) Fukuzumi, S.; Ohkubo, K. Selective Photocatalytic Reactions with Organic Photocatalysts. Chem. Sci. 2013, 4, 561−574. (d) Hari, D. P.; König, B. Synthetic Applications of Eosin Y in Photoredox Catalysis. Chem. Commun. 2014, 50, 6688−6699. (e) Hari, D. P.; König, B. Eosin Y Catalyzed Visible Light Oxidative C−C and C−P bond Formation. Org. Lett. 2011, 13, 3852−3855. (f) Majek, M.; von Wangelin, A. J. Mechanistic Perspectives on Organic Photoredox Catalysis for Aromatic Substitutions. Acc. Chem. Res. 2016, 49, 2316−2327. (g) Romero, N. A.; Nicewicz, D. A. Organic Photoredox Catalysis. Chem. Rev. 2016, 116, 10075−10166. (7) Enguehard-Gueiffier, C.; Gueiffier, A. Recent Progress in the Pharmacology of Imidazo[1,2-a]Pyridines. Mini-Rev. Med. Chem. 2007, 7, 888−899. (8) Stasyuk, A. J.; Banasiewicz, M.; Cyrański, M. K.; Gryko, D. T. Imidazo[1,2-a]pyridines Susceptible to Excited State Intramolecular Proton Transfer: One-Pot Synthesis via an Ortoleva−King Reaction. J. Org. Chem. 2012, 77, 5552−5558. (9) (a) Bagdi, A. K.; Santra, S.; Monir, K.; Hajra, A. Synthesis of Imidazo[1,2-a]Pyridines: a Decade Update. Chem. Commun. 2015, 51, 1555−1575. (b) Pericherla, K.; Kaswan, P.; Pandey, K.; Kumar, A. Recent Developments in the Synthesis of Imidazo[1,2-a]pyridines. Synthesis 2015, 47, 887−912. (c) Koubachi, J.; El Kazzouli, S. E.; Bousmina, M.; Guillaumet, G. Functionalization of Imidazo[1,2a]pyridines by Means of Metal-Catalyzed Cross-Coupling Reactions. Eur. J. Org. Chem. 2014, 2014, 5119−5138. (d) Bagdi, A. K.; Rahman, M.; Santra, S.; Majee, A.; Hajra, A. Copper-Catalyzed Synthesis of

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01433. Scanned copies of 1H and 13C{1H} NMR spectra of the synthesized compounds (PDF) X-ray crystallographic data for compound 3qa (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Alakananda Hajra: 0000-0001-6141-0343 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS A.H. acknowledges the financial support from CSIR, New Delhi (grant no. 02(0307)/17/EMR-II). REFERENCES

(1) (a) Mitchell, E. A.; Peschiulli, A.; Lefevre, N.; Meerpoel, L.; Maes, B. U. W. Direct α-Functionalization of Saturated Cyclic Amines. Chem. - Eur. J. 2012, 18, 10092−10142. (b) Girard, S. A.; Knauber, T.; Li, C.-J. The Cross-Dehydrogenative Coupling of Csp3-H Bonds: A Versatile Strategy for C−C Bond Formations. Angew. Chem., Int. Ed. 2014, 53, 74−100. (c) Huo, C.; Yuan, Y.; Wu, M.; Jia, X.; Wang, X.; Chen, F.; Tang, J. Auto-Oxidative Coupling of Glycine Derivatives. Angew. Chem., Int. Ed. 2014, 53, 13544−13547. (d) Zhang, L.; Liu, Z.-Q. Molecular Oxygen-Mediated Minisci-Type Radical Alkylation of Heteroarenes with Boronic Acids. Org. Lett. 2017, 19, 6594−6597. (2) (a) Ratnikov, M. O.; Xu, X.; Doyle, M. P. Simple and Sustainable Iron-Catalyzed Aerobic C−H Functionalization of N,N-Dialkylanilines. J. Am. Chem. Soc. 2013, 135, 9475−9479. (b) Ghobrial, M.; Harhammer, K.; Mihovilovic, M. D.; Schnürch, M. Facile, Solvent and Ligand Free Iron Catalyzed Direct Functionalization of N-Protected Tetrahydroisoquinolines and Isochroman. Chem. Commun. 2009, 46, 8836−8838. (c) Sud, A.; Sureshkumar, D.; Klussmann, M. Oxidative Coupling of Amines and Ketones by Combined Vanadium- and Organocatalysis. Chem. Commun. 2009, 0, 3169−3171. (d) Dutta, B.; Sharma, V.; Sassu, N.; Dang, Y.; Weerakkody, C.; Macharia, J.; Miao, R.; Howell, A.; Suib, S. L. Cross Dehydrogenative Coupling of NAryltetrahydroisoquinolines (Sp3 C−H) with Indoles (Sp2 C−H) Using a Heterogeneous Mesoporous Manganese Oxide Catalyst. Green Chem. 2017, 19, 5350−5355. (3) (a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications 10625

DOI: 10.1021/acs.joc.8b01433 J. Org. Chem. 2018, 83, 10619−10626

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The Journal of Organic Chemistry Imidazo[1,2-a]pyridines through Tandem Imine Formation-Oxidative Cyclization under Ambient Air: One-Step Synthesis of Zolimidine on a Gram-Scale. Adv. Synth. Catal. 2013, 355, 1741−1747. (e) Lei, S.; Mai, Y.; Yan, C.; Mao, J.; Cao, H. A Carbonylation Approach Toward Activation of Csp2-H and Csp3-H Bonds: Cu-Catalyzed Regioselective Cross Coupling of Imidazo[1,2-a]pyridines with Methyl Hetarenes. Org. Lett. 2016, 18, 3582−3585. (f) Huang, H.; Ji, X.; Tang, X.; Zhang, M.; Li, X.; Jiang, H. Conversion of Pyridine to Imidazo[1,2a]pyridines by Copper-Catalyzed Aerobic Dehydrogenative Cyclization with Oxime Esters. Org. Lett. 2013, 15, 6254−6257. (g) Sun, P.; Yang, D.; Wei, W.; Jiang, M.; Wang, Z.; Zhang, L.; Zhang, H.; Zhang, Z.; Wang, Y.; Wang, H. Visible Light-Induced C−H Sulfenylation using Sulfinic Acids. Green Chem. 2017, 19, 4785−4791. (h) Chang, Q.; Liu, Z.; Liu, P.; Yu, L.; Sun, P. Visible-Light-Induced Regioselective Cyanomethylation of Imidazopyridines and Its Application in Drug Synthesis. J. Org. Chem. 2017, 82, 5391−5397. (i) Ravi, C.; Mohan, D. C.; Adimurthy, S. N-ChlorosuccinimidePromoted Regioselective Sulfenylation of Imidazoheterocycles at Room Temperature. Org. Lett. 2014, 16, 2978−2981. (10) (a) Kibriya, G.; Bagdi, A. K.; Hajra, A. Visible Light Induced Tetramethylethylenediamine Assisted Formylation of Imidazopyridines. Org. Biomol. Chem. 2018, 16, 3473−3478. (b) Kibriya, G.; Samanta, S.; Jana, S.; Mondal, S.; Hajra, A. Visible Light Organic Photoredox-Catalyzed C−H Alkoxylation of Imidazopyridine with Alcohol. J. Org. Chem. 2017, 82, 13722−13727. (c) Mitra, S.; Ghosh, M.; Mishra, S.; Hajra, A. Metal-Free Thiocyanation of Imidazoheterocycles through Visible Light Photoredox Catalysis. J. Org. Chem. 2015, 80, 8275−8281. (11) (a) Shamma, M.; The isoquinoline alkaloids: Chemistry and pharmacology; Academic Press: New York, 1972, Vol. 25. (b) Kobayashi, H.; Fukuhara, K.; Tada-Oikawa, S.; Yada, Y.; Hiraku, Y.; Murata, M.; Oikawa, S. The Mechanisms of Oxidative DNA Damage and Apoptosis Induced by Norsalsolinol, an Endogenous Tetrahydroisoquinoline Derivative Associated with Parkinson’s Disease. J. Neurochem. 2009, 108, 397−407. (c) Sun, H.; He, X.; Liu, C.; Li, L.; Zhou, R.; Jin, T.; Yue, S.; Feng, D.; Gong, J.; Sun, J.; Ji, J.; Xiang, L. Effect of Oleracein E, a Neuroprotective Tetrahydroisoquinoline, on Rotenone-Induced Parkinson’s Disease Cell and Animal Models. ACS Chem. Neurosci. 2017, 8, 155−164. (12) Further information can be found in the CIF file. This crystal was deposited in the Cambridge Crystallographic Data Centre and assigned as CCDC 1847123. (13) (a) Ding, X.; Dong, C.-L.; Guan, Z.; He, Y.-H. Visible-LightPromoted Alkylation of Indoles with Tertiary Amines by the Oxidation of a sp3 C-H Bond. Adv. Synth. Catal. 2018, 360, 762− 767. (b) Keshari, T.; Yadav, V. K.; Srivastava, V. P.; Yadav, L. D. S. Visible Light Organophotoredox Catalysis: a General Approach to βKeto Sulfoxidation of Alkenes. Green Chem. 2014, 16, 3986−3992. (c) Fidaly, K.; Ceballos, C.; Falguières, A.; Veitia, M. S.-I.; Guy, A.; Ferroud, C. Visible Light Photoredox Organocatalysis: a Fully Transition Metal-Free Direct Asymmetric α-Alkylation of Aldehydes. Green Chem. 2012, 14, 1293−1297. (d) Ferroud, C.; Rool, P.; Santamaria, J. Singlet Oxygen Mediated Alkaloid Tertiary Amines Oxidation by Single Electron Transfer. Tetrahedron Lett. 1998, 39, 9423−9426.

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DOI: 10.1021/acs.joc.8b01433 J. Org. Chem. 2018, 83, 10619−10626