Tropylium-Promoted Oxidative Functionalization of

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Tropylium-Promoted Oxidative Functionalization of Tetrahydroisoquinolines Giulia Oss, Sander D. de Vos, Kevin N. H. Luc, Jason Brian Harper, and Thanh Vinh Nguyen J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02584 • Publication Date (Web): 12 Dec 2017 Downloaded from http://pubs.acs.org on December 15, 2017

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The Journal of Organic Chemistry

Tropylium-Promoted Oxidative Functionalization of Tetrahydroisoquinolines Giulia Oss, Sander D. de Vos, Kevin N. H. Luc, Jason B. Harper, and Thanh V. Nguyen* School of Chemistry, University of New South Wales, Sydney, Australia.. Supporting Information Placeholder

ABSTRACT: Structural modification of tetrahydroisoquinoline (THIQ) framework is of significant interest to organic chemists due to its central role in heterocyclic and medicinal chemistry. Here we demonstrate an efficient metal-free method for the oxidative functionalization of THIQs at the C1-position, which is amenable to a diverse range of C-C coupling reactions. These reactions proceed through a hydride abstraction involving the tropylium ion followed by quenching the generated iminium intermediates with nucleophiles to afford THIQ derivatives with excellent efficiencies and interesting selectivities.

Tetrahydroisoquinolines possess a structural motif commonly found in naturally occurring alkaloids1 as well as biologically valuable synthetic substances.2 Since the success of trabectedin,3 an antitumour drug containing three THIQ rings in its structure,4 there has been an increasing interest in drug development based on THIQ derivatives as many of them have been known for neurotoxicity in Parkinson’s diseases,5 anticancer and antibiotic activities.6 Functionalization of THIQs therefore has been an ongoing challenge in synthetic organic chemistry.7 Most efforts have been directed towards C-C coupling reactions at the C1-position,8 which generally lead to building blocks and synthetic intermediates for further construction of potentially bioactive scaffolds.9 Prior to this study, there have been numerous synthetic approaches to C1-functionalization of THIQs, including the highly utilized transition metal-catalyzed,10 metal-free oxidative,11 electrochemical12 and photocatalytic7,13 cross dehydrogenative coupling (CDC) reactions.14 Herein we demonstrate a mild, efficient and environmentally benign method to use tropylium salts for the selective oxidative functionalization of THIQs, which is amenable to a diverse range of alkylation and arylation reactions at the C1position. The non-benzenoid aromatic tropylium ion possesses a planar conjugated seven-membered carbocycle with six electrons and a positive charge delocalised over the system.15 It has a unique combination of stablility and reactivity that normal benzenoid and other charged polyene structures do not have.16 Based on our previous reports on tropylium ion as electrophiles and Lewis acid,17 we envision that tropylium salts might also serve as effective and universal oxidizing agents in organic synthesis.18 The tropylium ion is also known to be a hydride acceptor with a similar electrophilicity parameter to the commonly used oxidant DDQ.19 This role of tropylium was recently examined by Lambert and co-

workers in an elegant study on the cyanation of tertiary amine.20,.21 We report here our development of a new versatile method to use tropylium salts for the C1-functionalization of Nsubstituted THIQs (Scheme 1). These reactions involve a simple and mild hydride abstraction with tropylium salt22 followed by quenching the generated iminium intermediates with different types of nucleophiles to afford a broad library of alkylated and arylated THIQ products with excellent efficiencies and notable selectivities. Our initial investigation used the readily available tropylium tetrafluoroborate23 to oxidize N-substituted THIQs (1) and examined their conversion to the corresponding iminium salts (3) using NMR spectroscopy (Table 1). Interestingly, N-aryl, N-Cbz as well

Scheme 1. Oxidative α-functionalization of THIQs.

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Table 1. Optimization of the iminium formation reaction with tropylium salta

X N

R

(2) N

MeCN, reflux, 3 h

3

H

1 a

H H

R 4

X

X

conversionb (%)

Ph

BF4

Me>Ph>Cbz N-substituted THIQs (Table 1). When the alkyl group was isopropyl or n-nonyl (entries 5 and 6, Table 1), the results were anomalous as the consumptions of starting materials 1 were higher than the conversions to iminium intermediates 3 (also see page S4 in the ESI). A closer analysis of the reaction mixtures for these substrates revealed the formations of unidentifiable products, which we did not investigated further. Unlike THIQs, isochroman (entry 18) did not react with tropylium to form the corresponding oxonium product. A study on the oxidizing ability of tropylium in comparison to tritylium and nitrosonium tetrafluoroborate, often considered to be better hydride acceptors than tropylium,22,28 towards N-benzyl

Scheme 2. Notable selectivities of tropylium salt oxidant.

Trop+BF4-

X

N Ph ubiquitous in traditional CDC reaction because Ph stabilized iminium [see Todd et al. ref 27]

N Ph no reaction (entry 1 - Table 1)

Trop+BF4N

selective to THIQ-C1 but not N-Me [see Ofial et al. ref 32]

Ph

H H 100% selectivity to THIQ-C1 out of three possible sites


N CH3

H N

(see Scheme 3)

H

Nuc Ph

H ~ quant. conversion (entry 8 - Table 1)

CH3

Nuc

90% conversion (entry 4 - Table 1)

Trop+BF4-

H N

Nuc N

CH3

N Nuc H

Ph

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Scheme 3. Substrate scope of the α-alkylation of tetrahydroisoquinolines.

the silyl enol ethers 5a and 5b at ambient temperature gave quick access to a family of THIQ derivatives (6, Scheme 3). Most of the considered tetrahydroisoquinoline substrates afforded products in good to high yields, except the N-cyclohexylmethyl (CH2Cy) THIQ. The significant difference in reaction outcomes in the NCH2Cy (6ga-6gb) and N-CH2Ph (6aa-6ab) series once again suggested the importance of an aromatic ring in the substituent. Among the N-phenylalkyl series, product yields generally decreased with the increasing length of alkyl spacer (6aa-6ab, 6ca6cb, 6da-6db), indicating that the aromatic ring on N-Bn group is probably at the optimal proximity for the hydride abstraction reaction. The structures of ester derivatives 6aa - 6ab and nitro derivative 6ac were elucidated by HMBC NMR studies, which again confirmed the regioselectivities of these reactions.25 Alkylation of selected substrates with nitromethane (5c), a frequently used CDC alkylating reagent,7 using a similar procedure also gave the products 6ac and 6fc in good yields (Scheme 3). These nitroalkylation reactions were facilitated by pre-treating nitromethane with an organic base,25 suggesting that the coupling reaction proceeds through a nitrocarbanion intermediate. However, the corresponding alkylation reactions using organolithium reagents33 (either nBuLi or MeLi, see Scheme 4) failed to generate products at satisfactory level.25 We believe that the butyl and methyl carbanions are too hard as nucleophiles for direct coupling reactions with iminium intermediates.34 As such, ‘softer’ organometallic reagents were considered for this type of chemical transformation. It should be noted here that iminium ions like 3 tend to be deprotonated in contact with basic compounds (in these cases being organolithium reagents) to form enamines; however we did not observe any formation of 2,3-dihydroisoquinolines. Given the aforementioned results involving organolithium reagents (6ad and 6ae, Scheme 4), we decided to further investigate the tropylium-promoted oxidative functionalization reactions of THIQs with organozinc and Grignard reagents as nucleophiles (Scheme 4). It is noteworthy that these are underexplored11e,35 coupling partners for traditional CDC reactions with THIQs.7,36 Gratifyingly, these reactions generally proceed to give either the alkylated or the arylated THIQ derivatives in moderate to high yields (6af-6jf, Scheme 4, top). These coupling reactions demonstrated the versatility of our newly developed tropylium-promoted

oxidative functionalization method and also broadened the general scope of THIQ functionalization chemistry. The unusual reactivity difference observed in Table 1 can be exploited to carry out selective functionalization of N-benzyl THIQ (1a) in a mixture with N-phenyl THIQ (1l) and isochroman

Scheme 4. α-Alkylation/arylation of THIQs with organometallic nucleophiles.



(1q). Thus, reactions between 1.1 equiv of tropylium tetrafluoroborate and a 1 : 1 : 1 mixture of heterocycles 1a, 1l and 1q followed by subsequent quenching with either silyl enol ether 5a or Grignard reagent 5g afforded the selective conversion of 1a to the products while leaving the other two substrates unaffected (Scheme 4, bottom). These results again highlighted the interesting difference between tropylium salt and other traditionally used oxidants, especially DDQ27 – a hydride acceptor with a similar electrophilicity parameter to the tropylium ion,19 for this type of reaction. Further computational and mechanistic investigations are currently ongoing to interpret these unusual reaction profiles. In conclusion, we have developed a new mild and efficient method using tropylium salts for the ‘metal-free’ oxidative C1functionalization of THIQs, which can be applied to a diverse range of C-C coupling reactions. Our protocol offers an operationally simple, selective and mild alternative to the currently predominant transition metal catalyzed functionalization of THIQs. Further applications of this new method in asymmetric synthesis of biologically valuable substances are currently under development in our group and will be reported in due course.

EXPERIMENTAL DATA General Methods: Reactions, unless otherwise stated, were conducted under a positive pressure of dry nitrogen in oven-dried glassware. Toluene, hexane, CH2Cl2, tetrahydrofuran (THF), and diethyl ether were dried with an SPS apparatus. Commercially available reagents were used as purchased unless otherwise noted. Analytical thin layer chromatography was performed using silica gel plates pre-coated with silica gel 60 F254 (0.2 mm). Flash chromatography employed 230-400 mesh silica-gel. Solvents used for chromatography are quoted as volume/volume ratios. NMR spectroscopy was performed at 298 K using either a Bruker Avance III 300 (300.13 MHz, 1H; 75.5 MHz, 13C; BBFO probe), a Avance I 300 (300.13 MHz, 1H; 75.5 MHz, 13C; BBFO probe), a Avance III 400 (400.13 MHz, 1H; 100.6 MHz, 13C; BBFO probe or Prodigy cryoprobe), a Varian Mercury 300 (300.13 MHz, 1H), a Varian Inova 400 (400.13 MHz, 1H; 100.6 MHz, 13C), or a Varian Inova 600 (600.13 MHz, 1H; 150.0 MHz, 13 C). Data is expressed in parts per million (ppm) downfield shift from tetramethylsilane with residual solvent as an internal reference (δ 7.26 ppm for chloroform, 5.27 ppm for dichloromethane, 1.94 ppm for acetonitrile, and 2.09 ppm for the toluene methyl group) and is reported as position (δ in ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant (J in Hz) and integration (number of protons). 13C NMR spectra were recorded at 298 K with complete proton decoupling. Data is expressed in parts per million (ppm) downfield shift relative to the internal reference (δ 77.2 ppm for the central peak of deuterated chloroform). Infrared spectra were obtained on a ThermoNicolet Avatar 370 FT-IR spectrometer and are reported in wavenumbers (cm-1). HRMS were performed at the Bioanalytical Mass Spectrometry Facility within the Mark Wainwright Analytical Centre at the University of New South Wales on an Orbitrap LTQ XL (Thermo Fisher Scientific, San Jose, CA, USA) ion trap mass spectrometer. General Procedure and Synthesis of the N-Substituted Tetrahydroisoquinolines: To a solution of 20 mmol (2.0 equiv) potassium carbonate and 15 mL MeCN, 10 mmol (1.0 equiv) 1,2,3,4-tetrahydroisoquinoline 1m was added. The resulting mixture was stirred for 30 min then 10 mmol (1.0 equiv) alkyl bromide was added and and the reaction mixture was heated to reflux overnight. Subsequently the reaction mixture was filtered, concentrated under reduced pressure and the resulting crude product was purified by flash chromatography (silica-gel, n-hexane/ethyl acetate).

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2-Benzyl-1,2,3,4-tetrahydroisoquinoline37 (1a): Compound 1a was prepared according to the general procedure from 1,2,3,4tetrahydroisoquinoline and benzyl bromide to yield the title compound as a yellow oil (2.05 g, 9.2 mmol, 92% yield). The crude product was purified by flash chromatography (silica-gel, nhexane/ethyl acetate, 70:30). 1H NMR (400 MHz, CDCl3) δ 7.54 – 7.48 (m, 2H), 7.46 – 7.41 (m, 2H), 7.38 (m, 1H), 7.27 – 7.15 (m, 3H), 7.11 – 7.04 (m, 1H), 3.79 (s, 2H), 3.74 (s, 2H), 3.00 (t, J = 6.0 Hz, 2H), 2.85 (t, J = 5.9 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 138.4, 135.0, 134.5, 129.2, 128.8, 128.4, 127.2, 126.7, 126.2, 125.7, 62.8, 56.2, 50.7, 29.2 ppm. 2-Methyl-1,2,3,4-tetrahydroisoquinoline37 (1b): Compound 1b was prepared by heating a solution of 1.5 mL (20 mmol, 2.0 equiv) formaldehyde, 0.5 mL (10 mmol, 1.0 equiv) formic acid and 1.3 mL (10 mmol, 1.0 equiv) 1,2,3,4-tetrahydroisoquinoline in 12 mL of dry toluene to reflux for 5 h under an argon atmosphere. The reaction mixture was adjusted to basic conditions with 20 mL of a saturated aqueous solution of potassium carbonate; the layers were separated and the organic layer was washed with saturated aqueous solution of potassium carbonate (2 x 20 mL). The organic phase was then dried over magnesium sulphate, filtered, concentrated under reduced pressure and purified by flash chromatography (methanol/dichloromethane 5:95) to yield the title compound as a yellow oil (0.79 g, 5.3 mmol, 53% yield). 1H NMR (300 MHz, CDCl3) δ 7.21 – 6.85 (m, 4H), 3.61 (s, 2H), 3.08 – 2.87 (t, 2H), 2.71 (t, J = 6.0 Hz, H), 2.48 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 134.8, 133.8, 128.6, 126.4, 126.1, 125.6, 58.0, 53.0, 46.2, 29.3 ppm. 2-Phenethyl-1,2,3,4-tetrahydroisoquinoline (1c): Compound 1c was prepared according to the general procedure from 1,2,3,4tetrahydroisoquinoline and the 2-(1-phenyl) ethyl bromide to yield the title compound as a yellow oil (2.11 g, 8.9 mmol, 89% yield). The crude product was purified by flash chromatography (silicagel, n-hexane/ethyl acetate, 70:30). 1H NMR (400 MHz, CDCl3) δ 7.52 – 7.33 (m, 5H), 7.32 – 7.23 (m, 3H), 7.21 – 7.13 (m, 1H), 3.86 (s, 2H), 3.12 – 3.03 (m, 4H), 2.98 – 2.87 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3) δ 140.5, 134.9, 134.4, 129.2, 129.1, 128.9, 128.8, 128.7, 128.6, 126.8, 126.3, 126.3, 125.8, 60.5, 56.3, 51.1, 34.1, 29.3 ppm. IR (ATR) 3331, 2923, 2794, 1683, 1364 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C17H20N 238.1596; Found 238.1591. 2-(3-Phenylpropyl)-1,2,3,4-tetrahydroisoquinoline37 (1d): Compound 1d was prepared according to the general procedure from 1,2,3,4-tetrahydroisoquinoline and the 3-(1-phenyl) propyl bromide to yield the title compound as a yellow oil (2.26 g, 9.0 mmol, 90% yield). The crude product was purified by flash chromatography (silica-gel, n-hexane/ethyl acetate, 70:30). 1H NMR (400 MHz, CDCl3) δ 7.38 – 7.31 (m, 2H), 7.31 – 7.10 (m, 6H), 7.10 – 7.00 (m, 1H), 3.70 – 3.65 (m, 2H), 2.96 (t, J = 5.9 Hz, 2H), 2.81 – 2.70 (m, 4H), 2.64 – 2.52 (m, 2H), 2.05 – 1.92 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 142.3, 134.9, 134.4, 128.7, 128.5, 128.4 (2C), 126.6, 126.1, 125.8, 125.6, 57.8, 56.2, 51.0, 33.7, 29.2, 28.9 ppm. 2-Benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline37 (1e): Compound 1e was prepared according to the general procedure from 1,2,3,4-tetrahydroisoquinoline and benzyl bromide to yield the title compound as a white solid (1.86 g, 0.8 mmol, 16% yield). The crude product was purified by flash chromatography (silica-gel, methanol/dichloromethane, 1:20). 1H NMR (300 MHz, CDCl3) δ 7.63 – 7.10 (m, 5H), 6.63 (s, 1H), 6.51 (s, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 3.74 (s, 2H), 3.61 (s, 2H), 2.96 – 2.71 (m, 4H) ppm; 13C NMR (75 MHz, CDCl3) δ 147.6, 147.3, 137.8, 129.3, 128.4, 127.3, 126.1 (2C), 111.5, 109.5, 62.48, 55.9 (2C), 55.4, 50.7, 28.4 ppm. 2-Benzhydryl-1,2,3,4-tetrahydroisoquinoline (1f): Compound 1f was prepared according to the general procedure from


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1,2,3,4-tetrahydroisoquinoline and diphenylmethyl bromide to yield the title compound as a white solid (2.45 g, 8.2 mmol, 82% yield). The crude product was purified by flash chromatography (silica-gel, n-hexane/ethyl acetate, 70:30). 1H NMR (300 MHz, CDCl3) δ 7.71 – 7.62 (m, 4H), 7.51 – 7.41 (m, 4H), 7.39 – 7.32 (m, 2H), 7.31 – 7.17 (m, 3H), 7.04 (dt, J = 7.1, 1.1 Hz, 1H), 4.59 (s, 1H), 3.76 (d, J = 1.2 Hz, 2H), 3.06 (t, J = 5.8 Hz, 2H), 2.90 (t, J = 5.8 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 143.1, 135.4, 134.9, 128.8, 128.7, 128.0, 127.2, 127.0, 126.2, 125.7, 76.1, 55.3, 49.4, 29.5 ppm. IR (ATR) 3020, 2917, 2793, 1656, 1597, 1490, 1386, 1255 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C22H22N 300.1752; Found 300.1746. 2-(Cyclohexylmethyl)-1,2,3,4-tetrahydroisoquinoline (1g): Compound 1g was prepared according to the general procedure from 1,2,3,4-tetrahydroisoquinoline and the cyclohexylmethyl bromide to yield the title compound as a yellow oil (1.82 g, 7.9 mmol, 79% yield). The crude product was purified by flash chromatography (silica-gel, n-hexane/ethyl acetate, 90:10). 1H NMR (400 MHz, CDCl3) δ δ 7.28 – 6.64 (m, 4H), 3.63 (s, 2H), 2.94 (t, J = 5.9 Hz, 2H), 2.73 (t, J = 5.9 Hz, 2H), 2.35 (d, J = 7.1 Hz, 2H), 1.92 – 1.83 (m, 2H), 1.81 – 1.70 (m, 3H), 1.65 (ddp, J = 10.9, 7.3, 3.7 Hz, 1H), 1.40 – 1.14 (m, 3H), 1.02 – 0.89 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 135.3, 134.6, 128.7, 126.6, 126.0, 125.5, 65.6, 56.9, 51.3, 35.4, 32.0 (2C), 29.2, 26.9, 26.2 (2C). IR (ATR) 2916, 2846, 1650, 1447 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C16H24N 230.1909; Found 230.1901. 2-(4-Methoxybenzyl)-1,2,3,4-tetrahydroisoquinoline37 (1h): Compound 1h was prepared according to the general procedure from 1,2,3,4-tetrahydroisoquinoline and the 4-methoxybenzyl bromide to yield the title compound as an orange oil (1.44 g, 5.6 mmol, 56% yield). The crude product was purified by flash chromatography (silica-gel, n-hexane/ethyl acetate, 90:10). 1H NMR (300 MHz, CDCl3) δ 7.57 – 6.57 (m, 8H), 3.85 (s, 3H), 3.66 (s, 4H), 2.93 (t, J = 5.9 Hz, 2H), 2.77 (t, J = 5.9 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 158.8, 135.0, 134.5, 130.4, 130.3 (2C), 128.7, 126.6, 126.1, 125.6, 113.7 (2C), 62.2, 56.1, 55.3, 50.5, 29.2 ppm. 2-(4-Bromobenzyl)-1,2,3,4-tetrahydroisoquinoline (1i): Compound 1i was prepared according to the general procedure from 1,2,3,4-tetrahydroisoquinoline and 4-bromobenzyl bromide to yield the title compound as a white solid (1.86 g, 6.2 mmol, 62% yield). The crude product was purified by flash chromatography (silica-gel, n-hexane/ethyl acetate, 90:10). 1H NMR (400 MHz, CDCl3) δ 7.99 – 6.74 (m, 8H), 3.67 (s, 4H), 2.94 (t, J = 6.0 Hz, 2H), 2.77 (t, J = 5.9 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 137.5, 134.7, 134.3, 131.4 (2C), 130.7 (2C), 128.7, 126.6, 126.2, 125.7, 120.9, 62.0, 56.1, 50.7, 29.1 ppm. IR (ATR) 2783, 2749, 1481 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C16H17BrN 302.0544; Found 302.0535. 2-(4-Nitrobenzyl)-1,2,3,4-tetrahydroisoquinoline (1j): Compound 1j was prepared according to the general procedure from 1,2,3,4-tetrahydroisoquinoline and 4-nitrobenzyl bromide to yield the title compound as an orange solid (2.45 g, 9.1 mmol, 91% yield). The crude product was purified by flash chromatography (silica-gel, n-hexane/ethyl acetate, 70:30).1H NMR (400 MHz, CDCl3) δ 8.43 – 5.72 (m, 8H), 3.81 (s, 2H), 3.68 (s, 2H), 2.96 (t, J = 5.9 Hz, 2H), 2.80 (t, J = 5.9 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 147.2, 146.5, 134.4, 134.1, 129.4 (2C), 128.8, 126.5, 126.4, 125.8, 123.6 (2C), 61.9, 56.1, 50.9, 29.1 ppm. IR (ATR) 2913, 2755, 1598, 1511, 1460, 1339 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C16H17N2O2 269.1290; Found 269.1281. 2-(Naphthalen-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (1k): Compound 1k was prepared according to the general procedure from 1,2,3,4-tetrahydroisoquinoline and (1-naphthyl)methyl bromide to yield the title compound as a white solid (2.41 g, 8.8 mmol, 88% yield). The crude product was purified by flash chromatography (silica-gel, n-hexane/ethyl acetate, 70:30). 1H NMR

(400 MHz, CDCl3) δ 7.93 (dt, J = 6.7, 4.1 Hz, 4H), 7.68 (dd, J = 8.5, 1.5 Hz, 1H), 7.62 – 7.51 (m, 2H), 7.26 – 7.14 (m, 2H), 7.09 – 7.03 (d, J = 1.7 Hz, 1H), 3.93 (s, 2H), 3.78 (s, 2H), 3.02 (t, J = 5.9 Hz, 2H), 2.89 (t, J = 5.9 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 136.2, 135.0, 134.5, 133.5, 132.9, 128.8, 128.1, 127.8, 127.8, 127.6, 127.5, 126.7, 126.2, 126.1, 125.7 (2C), 63.1, 56.4, 50.9, 29.2 ppm. IR (ATR) 2794, 1688, 1273 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C20H20N 274.1596; Found 274.1591. 2-Phenyl-1,2,3,4-tetrahydroisoquinoline37 (1l): Compound 1l was prepared by treating a slurry of 0.77 mL (14 mmol, 2.1 equiv) ethylene glycol, 0.131 g (0.7 mmol, 0.1 equiv) copper iodide and 2.97 g (14 mmol, 2.1 equiv) potassium phosphate in 15 mL isopropanol with 1.50 mL (10 mmol, 1.5 equiv) 1,2,3,4tetrahydroisoquinoline and 0.80 mL (0.67 mmol, 1 equiv) iodobenzene under an argon atmosphere. The reaction mixture was heated to reflux at 90 °C for 24 h, cooled to room temperature then 20 mL water and 20 mL Et2O were added. Subsequently, the layers were separated and the aqueous layer was washed with more Et2O (2 x 20 mL). The organic layers were combined, dried over magnesium sulphate, filtered, concentrated under reduced pressure and purified by flash chromatography (n-hexane/ethyl acetate 20:1) to yield the title compound as a yellow oil (1.05 g, 5.1 mmol, 76% yield). 1H NMR (400 MHz, CDCl3) δ 7.38 – 7.27 (m, 2H), 7.28 – 7.15 (m, 4H), 7.07 – 6.97 (m, 2H), 6.87 (tt, J = 7.3, 1.1 Hz, 1H), 4.46 (s, 2H), 3.61 (t, J = 5.9 Hz, 2H), 3.03 (t, J = 5.8 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 150.6, 134.9, 134.5, 129.2, 128.5, 126.6, 126.3, 126.0, 118.7, 115.2, 50.8, 46.6, 29.1 ppm. 2-Carboxybenzyl-1,2,3,4-tetrahydroisoquinoline37 (1n): 1,2,3,4-tetrahydroisoquinoline was dissolved in 10 mL of acetonitrile, triethylamine was added drop-wise and the reaction mixture was cooled down to 0 °C for 10 min before benzyl chloroformate was added dropwise to the flask and the temperature was kept at 0 °C for 10 min. The reaction mixture was left stirring for two hours until completion was confirmed by TLC. The reaction mixture was washed with water (3 x 20 mL) and dried with anhydrous sodium sulfate. The organic solution was concentrated under reduced pressure and purified with flash chromatography (EtOAc/hexanes 3:7) to give the title compound as a yellow oil (1.17 g, 4.4 mmol, 88% yield). 1H NMR (400 MHz, CDCl3) δ 7.42 – 7.37 (m, 4H), 7.28 – 7.17 (m, 4H), 5.22 (s, 2H), 4.69 (s, 2H), 3.76 (s, 2H), 2.89 (s, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 163.8, 154.5, 139.6, 135.5, 133.2, 129.8, 128.63, 128.1 (2C), 127.4 (2C), 127.3, 126.7, 126.5, 68.8, 44.8, 28.3 ppm. 2-Isopropyl-1,2,3,4-tetrahydroisoquinoline37 (1o): Compound 1o was prepared according to the general procedure from 1,2,3,4-tetrahydroisoquinoline and isopropyl bromide to yield the title compound as a yellow liquid (1.4 g, 8.0 mmol, 80% yield). The crude product was purified by flash chromatography (silicagel, methanol/dichloromethane, 10:90). 1H NMR (400 MHz, CDCl3) δ 7.24 – 6.78 (m, 4H), 3.76 (s, 2H), 2.93 (ddd, J = 10.3, 6.5, 3.9 Hz, 3H), 2.81 (t, J = 5.9 Hz, 2H), 1.17 (d, J = 6.6 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 135.4, 134.6, 128.7, 126.8, 125.9, 125.5, 54.1, 51.7, 46.3, 29.8, 18.5 (2C) ppm. 2-Nonyl-1,2,3,4-tetrahydroisoquinoline (1p): Compound 1p was prepared according to the general procedure from 1,2,3,4tetrahydroisoquinoline and nonyl bromide to yield the title compound as a yellow solid (1.99 g, 7.7 mmol, 77% yield). The crude product was purified by flash chromatography (silica-gel, methanol/dichloromethane 1:20). 1H NMR (400 MHz, CD3CN) δ 7.23 (dd, J = 85.6, 3.0 Hz, 4H), 4.21 (s, 2H), 3.59 – 2.66 (m, 6H), 1.45 – 1.15 (m, 12H), 0.99 – 0.63 (m, 3H) ppm; 13C NMR (100 MHz, CD3CN) δ 132.0, 129.2, 128.6, 127.6, 126.7 (2C), 56.3, 52.9, 49.7, 31.6, 29.5 – 27.9 (m), 26.5, 25.6, 24.2, 22.4, 13.4 ppm. IR (ATR) 2917, 2850, 2673, 2575, 1434 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C18H30N 260.2378; Found 260.2369.



General Procedure for the Tropylium-Promoted C1Functionalization of Tetrahydroisoquinolines: 0.5 mmol (1.0 equiv) N-substituted tetrahydroisoquinoline and 0.5 mmol (1.0 equiv) tropylium tetrafluoroborate were dissolved in 5 mL dry MeCN and the resulting mixture was heated to reflux for 3 h under an argon atmosphere. Subsequently the reaction was cooled to room temperature (or −78 °C for organolithium or 0 °C for other organometallic reagents) and 1.5 mmol (3.0 equiv) nucleophile was added. The reaction mixture was stirred for 2 h then concentrated under reduced pressure. The resulting crude product mixture was purified by flash chromatography (silica-gel, nhexane/ethyl acetate). Methyl 2-(2-benzyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-2methylpropanoate (6aa): Compound 6aa was prepared according to the general procedure from tetrahydroisoquinoline 1a and the corresponding nucleophile to yield the title compound as a yellow oil (0.147 g, 0.46 mmol, 91% yield). The structure of this compound was confirmed by HMBC NMR (see page S40 in the SI). The crude product was purified by flash chromatography (silica-gel, n-hexane/ethyl acetate, 70:30). 1H NMR (400 MHz, CDCl3) δ 7.42 – 7.31 (m, 4H), 7.35 – 7.21 (m, 2H), 7.26 – 7.12 (m, 2H), 7.10 (dd, J = 7.5, 1.6 Hz, 1H), 4.19 (s, 1H), 4.01 (d, J = 13.6 Hz, 1H), 3.71 (s, 3H), 3.67 (s, 1H) 3.26 (ddd, J = 12.0, 6.5, 5.3 Hz, 1H), 2.84 – 2.66 (m, 2H), 2.45 (ddd, J = 12.6, 7.7, 5.3 Hz, 1H), 1.21 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 178.0, 139.9, 137.4, 134.5, 128.9, 128.4 (2C), 128.2, 126.9, 126.7, 125.4, 69.0, 62.4, 51.7, 50.7, 46.2, 26.5, 24.4, 22.2 ppm. IR (ATR) 2945, 2803, 1719, 1451 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C21H26NO2 324.1964; Found 324.1957. Methyl 2-(2-benzyl-1,2,3,4-tetrahydroisoquinolin-1yl)acetate (6ab): Compound 6ab was prepared according to the general procedure from tetrahydroisoquinoline 1a and the corresponding nucleophile to yield the title compound as a yellow oil (0.136 g, 0.46 mmol, 91% yield). The structure of this compound was confirmed by HMBC NMR (see page S41 in the SI). The crude product was purified by flash chromatography (silica-gel, nhexane/ethyl acetate, 70:30). 1H NMR (300 MHz, CDCl3) δ 7.50 – 7.26 (m, 5H), 7.31 – 7.05 (m, 4H), 4.32 (dd, J = 9.4, 5.2 Hz, 1H), 3.83 (d, J = 13.4 Hz, 1H), 3.76 (d, J = 9.5 Hz, 1H), 3.71 (s, 3H), 3.22 (ddd, J = 13.2, 11.0, 4.7 Hz, 1H), 3.12 – 2.72 (m, 3H), 2.74 – 2.50 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 172.3, 139.3, 137.1, 134.4, 129.3, 128.9, 128.2, 127.6, 127.0, 126.5, 126.1, 58.6, 57.7, 51.6, 42.0, 42.0, 23.8 ppm. IR (ATR) 3022, 2945, 2832, 1732, 1600 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C19H22NO2 296.1651; Found 296.1642. 2-Benzyl-1-(nitromethyl)-1,2,3,4-tetrahydroisoquinoline (6ac): Compound 6ac was prepared according to the general procedure from tetrahydroisoquinoline 1a and the corresponding nucleophile to yield the title compound as a yellow oil (0.0931 g, 0.33 mmol, 66% yield). The structure of this compound was confirmed by HMBC NMR (see page S42 in the SI). The crude product was purified by flash chromatography (silica-gel, methanol/dichloromethane, 1:20). 1H NMR (400 MHz, CDCl3) δ 7.40 – 7.26 (m, 6H), 7.26 – 7.17 (m, 2H), 7.13 (dd, J = 7.2, 1.8 Hz, 1H), 4.77 (dd, J = 11.6, 10.2 Hz, 1H), 4.59 (dd, J = 10.1, 4.5 Hz, 1H), 4.51 (dd, J = 11.6, 4.4 Hz, 1H), 3.88 (d, J = 13.3 Hz, 1H), 3.79 (d, J = 13.2 Hz, 1H), 3.25 (ddd, J = 13.8, 11.4, 4.6 Hz, 1H), 3.14 – 2.92 (m, 2H), 2.56 (ddd, J = 16.9, 4.5, 2.0 Hz, 1H) ppm; 13 C NMR (100 MHz, CDCl3) δ 138.3, 135.3, 132.1, 129.7, 128.8, 128.4, 127.7, 127.6, 127.4, 126.6, 79.5, 59.7, 57.6, 41.8, 22.9 ppm. IR (ATR) 3254, 3021, 2920, 2628, 2319, 2105, 1645, 1545 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C17H19N2O2 283.1447; Found 283.1440. 2-Benzyl-1-ethyl-1,2,3,4-tetrahydroisoquinoline (6af): Compound 6af was prepared according to the general procedure from

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tetrahydroisoquinoline 1a and the corresponding nucleophile to yield the title compound as a yellow oil (0.0297 g, 0.11 mmol, 59% yield). The crude product was purified by flash chromatography (silica-gel, n-hexane/ethyl acetate, 70:30). 1H NMR (400 MHz, CDCl3) δ 7.63 – 6.90 (m, 9H), 3.86 (d, J = 13.5 Hz, 1H), 3.72 (d, J = 13.8 Hz, 1H), 3.60 (dd, J = 7.2, 5.2 Hz, 1H), 3.22 (ddd, J = 12.9, 9.1, 5.1 Hz, 1H), 2.93 (ddd, J = 16.7, 8.6, 5.4 Hz, 1H), 2.86 – 2.71 (m, 1H), 2.65 (dt, J = 16.5, 4.8 Hz, 1H), 1.99 – 1.60 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 140.0, 139.0, 134.9, 128.9 (d, J = 5.7 Hz), 128.2, 127.9, 126.8, 125.7 (d, J = 7.2 Hz), 62.4, 58.0, 43.8, 28.9, 25.1, 10.7 ppm. IR (ATR) 2923, 1650, 1491, 1450 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C18H22N 252.1752; Found 252.1742. 2-Benzyl-1-(4-methoxyphenyl)-1,2,3,4tetrahydroisoquinoline (6ag): Compound 6ag was prepared according to the general procedure from tetrahydroisoquinoline 1a and the corresponding nucleophile to yield the title compound as a yellow oil (0.0396 g, 0.12 mmol, 64% yield). The crude product was purified by flash chromatography (silica-gel, methanol/dichloromethane, 1:20). 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.31 (m, 5H), 7.28 (d, J = 7.0 Hz, 1H), 7.16 – 7.13 (m, 2H), 7.09 – 6.95 (m, 2H), 6.91 (d, J = 8.7 Hz, 2H), 6.80 – 6.76 (m, 1H), 4.62 (s, 1H), 3.87 (d, J = 10.8 Hz, 1H), 3.84 (s, 3H), 3.28 (d, J = 13.5 Hz, 1H), 3.18 – 3.05 (m, 2H), 2.89 – 2.74 (m, 1H), 2.56 (ddd, J = 13.2, 10.5, 4.0 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 158.8, 139.7, 138.9, 136.5, 134.8, 131.0, 130.7, 128.9, 128.7, 128.4, 128.2, 127.8, 126.8, 125.8, 125.6, 124.3, 114.2, 113.7, 68.2, 58.8, 55.2, 47.3, 29.2 ppm. IR (ATR) 2805, 1606, 1492, 1451 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C23H24NO 330.1858; Found 330.1855. 2-Benzyl-1-(3-methoxyphenyl)-1,2,3,4tetrahydroisoquinoline (6ah): Compound 6ah was prepared according to the general procedure from tetrahydroisoquinoline 1a and the corresponding nucleophile to yield the title compound as a yellow oil (0.0441 g, 0.13 mmol, 67% yield). The crude product was purified by flash chromatography (silica-gel, methanol/dichloromethane, 1:20). 1H NMR (400 MHz, CDCl3) δ 7.47 – 7.22 (m, 6H), 7.20 – 7.11 (m, 2H), 7.03 (dt, J = 10.1, 1.9 Hz, 3H), 6.89 – 6.72 (m, 2H), 4.62 (s, 1H), 3.88 (d, J = 12.4 Hz, 1H), 3.82 (s, 3H), 3.29 (d, J = 13.6 Hz, 1H), 3.24 – 3.02 (m, 2H), 2.80 (dt, J = 15.8, 4.3 Hz, 1H), 2.55 (ddd, J = 12.8, 10.4, 3.9 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 159.7, 146.0, 139.6, 138.3, 134.7, 129.2, 128.7 (2C), 128.7, 128.5, 128.2 (2C), 126.8, 125.9, 125.6, 122.2, 115.2, 112.5, 68.9, 58.9, 55.2, 47.4, 29.2 ppm. IR (ATR) 2791, 1596, 1485, 1450 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C23H24NO 330.1858; Found 330.1850. Methyl 2-(1,2,3,4-tetrahydroisoquinolin-1-yl)-2methylpropanoate (6ba): Compound 6ba was prepared according to the general procedure from tetrahydroisoquinoline 1b and the corresponding nucleophile to yield the title compound as a yellow oil (0.090 g, 0.37 mmol, 73% yield). The crude product was purified by flash chromatography (silica-gel, methanol/dichloromethane, 1:20). 1H NMR (400 MHz, CDCl3) δ 7.23 – 6.94 (m, 4H), 3.95 (s, 1H), 3.71 (s, 3H), 3.27 (dt, J = 11.2, 4.9 Hz, 1H), 2.86 (ddd, J = 15.9, 10.0, 4.6 Hz, 1H), 2.66 (dt, J = 15.9, 4.6 Hz, 1H), 2.51 (s, 3H), 2.48 – 2.40 (m, 1H), 1.11 (d, J = 26.8 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 178.1, 137.6, 134.6, 128.7, 127.9, 126.5, 125.3, 70.0, 51.5 (2C), 50.8, 46.9, 28.3, 22.7, 22.3 ppm. IR (ATR) 2942, 2790, 1718 cm−1; ESIMS m/z: [M+H]+ Calcd. for C15H22NO2 248.1651; Found 248.1642. Methyl 2-(1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (6bb): Compound 6bb was prepared according to the general procedure from tetrahydroisoquinoline 1b and the corresponding nucleophile to yield the title compound as a yellow oil (0.0745 g, 0.34 mmol, 68% yield). The crude product was purified by flash chromatog-


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raphy (silica-gel, methanol/dichloromethane, 1:20). 1H NMR (400 MHz, CDCl3) δ 7.22 – 7.05 (m, 4H), 4.18 (dd, J = 7.9, 5.3 Hz, 1H), 3.73 (s, 3H), 3.21 – 3.09 (m, 1H), 3.07 – 2.95 (m, 1H), 2.91 – 2.78 (m, 2H), 2.74 – 2.58 (m, 2H), 0.98 – 0.86 (m, 2H), 0.13 (d, J = 7.6 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 172.6, 137.1, 134.0, 131.5, 129.0, 127.3, 126.4, 126.0, 59.9, 51.7, 46.2, 42.2, 40.7, 25.7, 24.9 ppm. IR (ATR) 2943, 2798, 1729 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C13H18NO2 220.1338; Found 220.1330. 1-(3-Methoxyphenyl)-2-methyl-1,2,3,4tetrahydroisoquinoline (6bh): Compound 6bh was prepared according to the general procedure from tetrahydroisoquinoline 1b and the corresponding nucleophile to yield the title compound as a yellow oil (0.0683 g, 0.27 mmol, 54% yield). The crude product was purified by flash chromatography (silica-gel, methanol/dichloromethane, 1:20). 1H NMR (400 MHz, CDCl3) δ 7.31 – 7.21 (m, 1H), 7.17 – 7.05 (m, 2H), 7.01 (ddd, J = 8.4, 7.1, 2.1 Hz, 1H), 6.90 (dt, J = 7.5, 1.3 Hz, 1H), 6.87 – 6.80 (m, 2H), 6.76 – 6.64 (m, 1H), 4.25 (s, 1H), 3.79 (s, 3H), 3.41 – 3.21 (m, 1H), 3.16 (ddd, J = 8.3, 5.5, 2.8 Hz, 1H), 2.85 (dt, J = 16.2, 3.4 Hz, 1H), 2.66 (td, J = 11.3, 3.9 Hz, 1H), 2.28 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 159.6, 145.444 138.3, 134.2, 129.2, 128.4, 128.3, 126.0, 125.7, 122.2, 115.1, 112.7, 71.6, 55.2, 52.4, 44.4, 29.5 ppm. IR (ATR) 2958, 2782, 1597, 1450 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C17H20NO 254.1545; Found 254.1538. Methyl 2-methyl-2-(2-phenethyl-1,2,3,4tetrahydroisoquinolin-1-yl)propanoate (6ca): Compound 6ca was prepared according to the general procedure from tetrahydroisoquinoline 1c and the corresponding nucleophile to yield the title compound as a yellow oil (0.103 g, 0.31 mmol, 61% yield). The crude product was purified by flash chromatography (silicagel, n-hexane/ethyl acetate, 70:30). 1H NMR (400 MHz, CDCl3) δ 7.35 – 7.25 (m, 2H), 7.25 – 7.10 (m, 6H), 7.07 – 7.00 (m, 1H), 4.09 (s, 1H), 3.69 (s, 3H), 3.54 – 3.44 (m, 1H), 2.98 – 2.59 (m, 7H), 1.15 (d, J = 3.5 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 178.0, 140.5, 137.2, 134.7, 129.1, 128.9, 128.7, 128.6, 128.3, 128.2, 126.6, 125.9, 125.3, 68.7, 60.2, 51.6, 50.6, 46.9, 34.8, 26.7, 23.9, 22.5 ppm. IR (ATR) 2926, 1718, 1667 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C22H28NO2 338.2120; Found 338.2113. Methyl 2-(2-phenethyl-1,2,3,4-tetrahydroisoquinolin-1yl)acetate (6cb): Compound 6cb was prepared according to the general procedure from tetrahydroisoquinoline 1c and the corresponding nucleophile to yield the title compound as a yellow oil (0.113 g, 0.37 mmol, 72% yield). The crude product was purified by flash chromatography (silica-gel, n-hexane/ethyl acetate, 70:30). 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.08 (m, 9H), 4.42 (dd, J = 9.2, 5.1 Hz, 1H), 3.73 (s, 3H), 3.33 – 3.20 (m, 1H), 3.09 – 2.94 (m, 2H), 2.97 – 2.78 (m, 5H), 2.71 – 2.53 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 172.5, 140.5, 137.1, 134.4, 129.2, 128.8, 128.3, 127.7, 126.5, 126.1, 125.9, 57.9, 55.4, 51.7, 43.6, 41.6, 34.8, 24.0 ppm. IR (ATR) 3022, 2944, 2835, 1731 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C20H24NO2 310.1807; Found 310.1802. 1-Ethyl-2-phenylethyl-1,2,3,4-tetrahydroisoquinoline (6cf): Compound 6cf was prepared according to the general procedure from tetrahydroisoquinoline 1c and the corresponding nucleophile to yield the title compound as a yellow oil (0.0637 g, 0.24 mmol, 48% yield). The crude product was purified by flash chromatography (silica-gel, n-hexane/ethyl acetate, 70:30). 1H NMR (400 MHz, CDCl3) δ 7.29 (dt, J = 7.2, 2.6 Hz, 3H), 7.25 – 7.21 (m, 2H), 7.17 – 7.13 (m, 2H), 7.09 (dd, J = 6.8, 2.5 Hz, 2H), 3.64 (t, J = 6.1 Hz, 1H), 3.42 (t, J = 6.6 Hz, 1H), 3.33 – 3.17 (m, 1H), 3.08 – 2.91 (m, 2H), 2.87 (s, 5H), 2.75 – 2.57 (m, 1H), 1.92 – 1.64 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 128.9, 128.8, 128.8, 128.5, 128.4, 128.3, 128.1, 127.8, 125.9, 125.8, 125.6, 62.7, 55.9, 44.5, 34.8, 28.7, 25.2, 11.0 ppm. IR

(ATR) 2927, 1599, 1514 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C19H24N 266.1909; Found 266.1901. Methyl 2-methyl-2-(2-(3-phenylpropyl)-1,2,3,4tetrahydroisoquinolin-1-yl)propanoate (6da): Compound 6da was prepared according to the general procedure from tetrahydroisoquinoline 6d and the corresponding nucleophile to yield the title compound as a yellow oil (0.130 g, 0.37 mmol, 74% yield). The crude product was purified by flash chromatography (silicagel, n-hexane/ethyl acetate, 70:30). 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.25 (m, 2H), 7.19 (ddd, J = 13.1, 7.0, 1.2 Hz, 4H), 7.15 – 7.08 (m, 2H), 7.02 (dd, J = 7.6, 1.6 Hz, 1H), 3.99 (s, 1H), 3.67 (s, 3H), 3.42 (dt, J = 12.3, 6.2 Hz, 1H), 2.90 – 2.36 (m, 7H), 1.83 (ddt, J = 15.5, 8.6, 6.3 Hz, 2H), 1.13 (d, J = 12.4 Hz, 6H) ppm; 13 C NMR (760 MHz, CDCl3) δ 137.0, 128.7, 128.3 (d, J = 4.4 Hz), 126.6, 125.7, 125.303 68.7, 57.5, 53.9 – 46.2 (m), 33.5, 26.2, 24.2, 22.5 ppm. IR (ATR) 2924, 2340, 1720, 1640 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C23H30NO2 352.2277; Found 352.2268. Methyl 2-(2-(3-phenylpropyl)-1,2,3,4-tetrahydroisoquinolin1-yl)acetate (6db): Compound 6db was prepared according to the general procedure from tetrahydroisoquinoline 1d and the corresponding nucleophile to yield the title compound as a yellow oil (0.039 g, 0.12 mmol, 60% yield). The crude product was purified by flash chromatography (silica-gel, n-hexane/ethyl acetate, 70:30). 1H NMR (300 MHz, CDCl3) δ 7.38 – 7.19 (m, 4H), 7.24 – 7.18 (m, 1H), 7.22 – 7.12 (m, 2H), 7.11 (ddd, J = 6.5, 3.7, 1.9 Hz, 2H), 4.31 (dd, J = 9.4, 5.1 Hz, 1H), 3.73 (s, 3H), 3.29 –3.17 (m, 1H), 3.04 – 2.88 (m, 2H), 2.85 (dd, J = 14.7, 9.4 Hz, 1H), 2.71 – 2.47 (m, 6H), 1.94 – 1.78 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 172.6, 142.5, 137.2, 134.5, 129.2, 128.5, 128.3, 127.7, 126.4, 126.0, 125.6, 58.0, 52.5, 51.6, 43.1, 41.5, 33.4, 29.6, 23.8 ppm. IR (ATR) 3021, 2940, 1732, 1601 cm−1; ESI-MS m/z: [M+H]+ Calcd. forC21H26NO2: m/z = 324.1963; found 324.1954. 1-Ethyl-2-(3-phenylpropyl)-1,2,3,4-tetrahydroisoquinoline (6df): Compound 6df was prepared according to the general procedure from tetrahydroisoquinoline 1d and the corresponding nucleophile to yield the title compound as a yellow oil (0.0683 g, 0.25 mmol, 49% yield). The crude product was purified by flash chromatography (silica-gel, n-hexane/ethyl acetate, 70:30). 1H NMR (400 MHz, CDCl3) δ 7.35 – 7.26 (m, 2H), 7.23 (dt, J = 8.1, 2.1 Hz, 3H), 7.18 – 7.12 (m, 2H), 7.11 – 7.05 (m, 2H), 3.54 (dd, J = 7.4, 5.3 Hz, 1H), 3.25 (ddd, J = 12.9, 8.7, 5.0 Hz, 1H), 3.02 – 2.77 (m, 2H), 2.78 – 2.43 (m, 5H), 2.00 – 1.82 (m, 2H), 1.80 – 1.62 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 142.6, 134.8, 128.8, 128.4 (2C), 128.3 (2C), 127.9, 125.7 (2C), 125.6, 125.5, 62.5, 53.0, 44.1, 33.6, 29.8, 28.9, 24.8, 11.2 ppm. IR (ATR) 2927, 1719, 1650 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C20H26N 280.2065; Found 280.2059. Methyl-2-(2benzyl-6,7-dimethoxy-1,2,3,4tetrahydroisoquinolin-1-yl)-2-methylpropanoate (6ea): Compound 6ea was prepared according to the general procedure from tetrahydroisoquinoline 1e and the corresponding nucleophile to yield the title compound as a yellow oil (0.0048 g, 0.01 mmol, 4% yield). The crude product was purified by flash chromatography (silica-gel, methanol/dichloromethane, 1:20). 1H NMR (400 MHz, CDCl3) δ 7.42 – 7.22 (m, 5H), 6.62 (d, J = 11.6 Hz, 2H), 4.10 (s, 1H), 3.95 (d, J = 13.6 Hz, 1H), 3.88 (d, J = 7.6 Hz, 6H), 3.69 (s, 3H), 3.64 (s, 0H), 3.35 – 3.13 (m, 1H), 2.64 (td, J = 6.0, 2.9 Hz, 2H), 2.45 (dt, J = 12.3, 6.1 Hz, 1H), 1.20 (d, J = 2.3 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 164.6, 157.8, 148.9, 132.3, 131.1, 130.0, 129.8, 129.5, 129.3, 128.8, 117.1, 115.7, 110.7, 63.6, 61.0, 60.4, 56.7, 56.4, 55.9, 50.2, 47.1, 25.3, 14.2 ppm. IR (ATR) 2933, 1719, 1511 cm−1; ESI-MS m/z: [M+H]+ Calcd. For C23H30NO4 284.2175; Found 284.2164. Methyl 2-(2-benzhydryl-1,2,3,4-tetrahydroisoquinolin-1-yl)2-methylpropanoate (6fa): Compound 6fa was prepared according to the general procedure from tetrahydroisoquinoline 1f and the corresponding nucleophile to yield the title compound as a



yellow oil (0.158 g, 0.40 mmol, 79% yield). The crude product was purified by flash chromatography (silica-gel, n-hexane/ethyl acetate, 70:30). 1H NMR (400 MHz, CDCl3) δ 7.47 – 6.90 (m, 13H), 6.78 (dd, J = 7.6, 1.3 Hz, 1H), 4.67 (s, 1H), 3.96 (d, J = 1.3 Hz, 1H), 3.75 (s, 3H), 3.46 (ddd, J = 14.1, 10.3, 6.5 Hz, 1H), 2.98 – 2.87 (m, 1H), 2.83 (ddd, J = 17.7, 10.3, 7.4 Hz, 1H), 2.52 (ddd, J = 17.5, 6.7, 2.1 Hz, 1H), 1.21 (s, 3H), 1.12 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 177.7, 142.9, 142.7, 135.7, 133.7, 128.9, 128.8, 128.6, 128.4, 128.2, 128.2, 127.0 (2C), 126.8, 125.3, 70.8, 64.9, 51.6, 49.2, 40.4, 26.4, 23.7, 22.7 ppm. IR (ATR) 2970, 1725, 1597 cm−1; ESI- m/z: [M+H]+ Calcd. for C27H30NO2 400.2277; Found 400.2270. Methyl 2-(2-benzhydryl-1,2,3,4-tetrahydroisoquinolin-1yl)acetate (6fb): Compound 6fb was prepared according to the general procedure from tetrahydroisoquinoline 1f and the corresponding nucleophile to yield the title compound as a yellow oil (0.1506 g, 0.41 mmol, 81% yield). The crude product was purified by flash chromatography (silica-gel, n-hexane/ethyl acetate, 70:30). 1H NMR (400 MHz, CDCl3) δ 7.54 – 7.44 (m, 2H), 7.39 – 7.10 (m, 11H), 6.96 – 6.89 (m, 1H), 4.74 (s, 1H), 4.30 (dd, J = 9.3, 5.6 Hz, 1H), 3.77 (s, 3H), 3.32 (ddd, J = 14.1, 12.1, 5.1 Hz, 1H), 3.13 – 2.88 (m, 3H), 2.61 (dd, J = 14.0, 5.5 Hz, 1H), 2.44 (dd, J = 17.1, 5.0 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 171.9, 143.0, 142.8, 136.8, 134.3, 129.3, 128.5, 128.4, 128.0, 127.9, 127.8, 127.2, 127.1, 126.6, 126.0, 69.6, 55.6, 51.5, 42.2, 39.5, 25.7, 22.9 ppm. IR (ATR) 3022, 2947, 2839, 1734, 1597 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C25H25NO2 372.1964; Found 372.1995. 2-Benzhydryl-1-(nitromethyl)-1,2,3,4tetrahydroisoquinoline (6fc): Compound 6fc was prepared according to the general procedure from tetrahydroisoquinoline 1f and the corresponding nucleophile to yield the title compound as a white solid (0.1038 g, 0.29 mmol, 58% yield). The crude product was purified by flash chromatography (silica-gel, methanol/dichloromethane, 1:20). 1H NMR (400 MHz, CDCl3) δ 7.58 – 7.45 (m, 2H), 7.39 – 7.20 (m, 11H), 7.20 (s, 1H), 6.98 – 6.89 (m, 1H), 4.85 (t, J = 9.6, 1H), 4.78 (s, 1H), 4.57 (dd, J = 10.7, 4.6 Hz, 1H), 4.43 (dd, J = 11.2, 4.6 Hz, 1H), 3.35 (ddd, J = 14.8, 12.6, 4.9 Hz, 1H), 3.20 (ddt, J = 14.7, 6.3, 1.3 Hz, 1H), 3.04 (ddd, J = 18.5, 12.5, 6.3 Hz, 1H), 2.44 (dd, J = 17.4, 4.7 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 142.3, 142.0, 135.2, 131.7, 129.8, 128.7, 128.0, 128.0, 127.7, 127.7, 127.6, 127.3, 126.6, 79.3, 69.1, 56.7, 39.4, 21.9 ppm. IR (ATR) 2841, 1597, 1549, 1490, 1435 cm−1; ESI-MS m/z: [M+H]+ Calcd. For C23H23N2O2 359.1760; Found 359.1755. 2-Benzhydryl-1-ethyl-1,2,3,4-tetrahydroisoquinoline (6ff): Compound 6ff was prepared according to the general procedure from tetrahydroisoquinoline 1f and the corresponding nucleophile to yield the title compound as a yellow oil (0.1243 g, 0.38 mmol, 76% yield). The crude product was purified by flash chromatography (silica-gel, n-hexane/ethyl acetate, 70:30). 1H NMR (400 MHz, CDCl3) δ 7.79 – 6.61 (m, 14H), 4.81 (s, 1H), 3.81 – 3.56 (m, 1H), 3.29 (ddd, J = 15.6, 12.4, 5.2 Hz, 1H), 3.10 – 2.72 (m, 3H), 2.62 – 2.33 (m, 1H), 1.90 (ddt, J = 14.6, 9.2, 7.3 Hz, 1H), 1.68 (ddd, J = 14.1, 7.2, 5.3 Hz, 1H), 1.12 (t, J = 7.3 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 144.0, 143.2, 139.1, 134.4, 129.0, 128.6, 128.4 (d, J = 4.1 Hz), 128.3, 128.1 (d, J = 3.5 Hz), 127.9, 126.9, 126.8, 125.9, 125.6, 69.5, 59.4, 39.3, 29.9, 23.2, 11.7 ppm. IR (ATR) 2958, 1488, 1449 cm−1; ESI-MS m/z: [M+H]+ Calcd. For C24H26N 328.2065; Found 328.2058. 2-Benzhydryl-1-(4-methoxyphenyl)-1,2,3,4tetrahydroisoquinoline (6fg): Compound 6fg was prepared according to the general procedure from tetrahydroisoquinoline 1f and the corresponding nucleophile to yield the title compound as a yellow oil (0.1782 g, 0.44 mmol, 88% yield). The crude product was purified by flash chromatography (silica-gel, methanol/dichloromethane, 1:20). 1H NMR (400 MHz, CDCl3) δ 7.50

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(dt, J = 8.2, 1.1 Hz, 2H), 7.44 – 7.37 (m, 3H), 7.35 – 7.24 (m, 6H), 7.17 (dd, J = 6.5, 1.4 Hz, 2H), 7.10 – 7.00 (m, 2H), 6.90 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 7.7 Hz, 1H), 4.91 (s, 1H), 4.86 (s, 1H), 3.83 (s, 3H), 3.19 (ddd, J = 12.3, 6.9, 5.1 Hz, 1H), 3.00 – 2.88 (m, 2H), 2.73 – 2.61 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 158.6, 143.2, 139.8, 137.9, 136.4, 135.0, 130.4 (2C), 129.5 (2C), 129.3, 128.7, 128.2 (2C), 128.0 (2C), 127.2, 126.7, 125.9, 125.6, 113.6 (3C), 67.9, 63.1, 55.2, 41.7, 27.6 ppm. IR (ATR) 3022, 2903, 2831, 2244, 1602, 1489, 1449, 1245 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C29H28NO 406.2171; Found 406.2166. 2-Benzhydryl-1-(3-methoxyphenyl)-1,2,3,4tetrahydroisoquinoline (6fh): Compound 6fh was prepared according to the general procedure from tetrahydroisoquinoline 1f and the corresponding nucleophile to yield the title compound as a yellow oil (0.1763 g, 0.44 mmol, 87% yield). The crude product was purified by flash chromatography (silica-gel, methanol/dichloromethane, 1:20). 1H NMR (400 MHz, CDCl3) δ 7.52 (ddd, J = 8.2, 1.4, 0.8 Hz, 2H), 7.45 – 7.39 (m, 3H), 7.36 – 7.25 (m, 5H), 7.19 – 7.16 (m, 2H), 7.01 (dt, J = 4.4, 1.9 Hz, 2H), 6.84 (dq, J = 8.3, 1.2 Hz, 2H), 4.95 (s, 1H), 4.88 (s, 1H), 3.82 (s, 3H), 3.22 (ddd, J = 12.1, 6.7, 5.1 Hz, 1H), 3.07 – 2.85 (m, 3H), 2.72 – 2.58 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 159.6, 146.1, 143.1, 139.6, 137.3, 135.0, 129.6, 129.2, 129.1, 128.8, 128.6, 128.3 (2C), 128.2, 128.1 (2C), 127.9, 127.2, 126.8, 126.0, 125.6, 121.9, 115.1, 112.2, 68.0, 63.8, 55.2, 41.9, 27.6 ppm. IR (ATR) 3022, 2909, 2830, 2244, 1595, 1485, 1449, 1252 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C29H28NO 406.2171; Found 406.2166. Methyl 2-(2-(cyclohexylmethyl)-1,2,3,4tetrahydroisoquinolin-1-yl)-2-methylpropanoate (6ga): Compound 6ga was prepared according to the general procedure from tetrahydroisoquinoline 1g and the corresponding nucleophile to yield the title compound as a yellow oil (0.0523g, 0.16 mmol, 32% yield). The crude product was purified by flash chromatography (silica-gel, n-hexane/ethyl acetate, 90:10). 1H NMR (400 MHz, CDCl3) δ 7.24 – 6.91 (m, 4H), 3.90 (s, 1H), 3.70 (s, 3H), 3.39 (ddd, J = 13.1, 7.9, 5.5 Hz, 1H), 2.78 (ddd, J = 16.6, 7.9, 5.7 Hz, 1H), 2.72 – 2.60 (m, 1H), 2.51 (dd, J = 12.5, 6.2 Hz, 1H), 2.38 (qd, J = 12.3, 7.3 Hz, 2H), 1.96 – 1.82 (m, 1H), 1.78 – 1.58 (m, 3H), 1.50 (dqq, J = 11.3, 5.8, 3.0 Hz, 1H), 1.42 – 1.19 (m, 4H), 1.13 (s, 3H), 0.91 – 0.74 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 177.8, 136.9, 134.8, 128.8, 128.4, 126.5, 125.1, 69.3, 64.5, 51.5, 50.3, 45.6, 36.2, 32.1, 31.2, 27.0, 26.3 (d, J = 7.1 Hz, 2C), 25.3, 24.8, 22.8 ppm. IR (ATR) 2917, 2846, 1722, 1447, 1248 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C21H32NO2 330.2433; Found 330.2423. Methyl 2-(2-(cyclohexylmethyl)-1,2,3,4tetrahydroisoquinolin-1-yl)acetate (6gb): Compound 6gb was prepared according to the general procedure from tetrahydroisoquinoline 1g and the corresponding nucleophile to yield the title compound as a yellow oil (0.0768 g, 0.26 mmol, 51% yield). The crude product was purified by flash chromatography (silica-gel, nhexane/ethyl acetate, 90:10). 1H NMR (400 MHz, CDCl3) δ 7.19 – 7.05 (m, 4H), 4.19 (dd, J = 9.7, 5.1 Hz, 1H), 3.72 (s, 3H), 3.21 (td, J = 12.3, 4.5 Hz, 1H), 3.08 – 2.71 (m, 3H), 2.67 – 2.25 (m, 4H), 1.94 – 1.41 (m, 7H), 1.39 – 1.13 (m, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 172.5, 129.2, 127.6, 126.3, 125.8, 60.4, 59.0, 51.5, 43.2, 41.9, 35.9, 31.7, 31.5, 26.9, 26.1, 23.5 ppm. IR (ATR) 2920, 2848, 1731, 1637 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C19H28NO2 302.2120; Found 302.2118. 2-(Cyclohexylmethyl)-1-ethyl-1,2,3,4tetrahydroisoquinoline (6gf): Compound 6gf was prepared according to the general procedure from tetrahydroisoquinoline 1g and the corresponding nucleophile to yield the title compound as a yellow oil (0.0604 g, 0.24 mmol, 47% yield). The crude product was purified by flash chromatography (silica-gel, n-hexane/ethyl acetate, 90:10). 1H NMR (400 MHz, CDCl3) δ 7.17 – 7.11 (m, 2H), 7.11 – 7.04 (m, 2H), 3.46 (t, J = 6.2 Hz, 1H), 3.20 (ddd, J =


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12.8, 9.2, 4.8 Hz, 1H), 2.89 (ddd, J = 16.1, 9.2, 5.2 Hz, 1H), 2.70 (dt, J = 12.8, 4.7 Hz, 1H), 2.58 (dt, J = 16.2, 4.6 Hz, 1H), 2.36 (dd, J = 7.1, 1.7 Hz, 2H), 1.94 – 1.79 (m, 2H), 1.78 – 1.66 (m, 5H), 1.53 (dtq, J = 14.8, 7.5, 3.6 Hz, 2H), 1.38 – 1.14 (m, 4H), 0.95 (t, J = 7.3 Hz, 3H), 0.90 – 0.77 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 135.3, 128.7, 127.8, 125.5, 125.444 (2C), 63.4, 61.0, 44.5, 36.3, 32.0, 31.8, 29.0, 27.0, 26.3, 26.2, 25.1, 10.9 ppm. IR (ATR) 2918, 2846, 1446 cm−1; ESI- m/z: [M+H]+ Calcd. for C18H28N 258.2222; Found 258.2215. 2-(Cyclohexylmethyl)-1-(4-methoxyphenyl)-1,2,3,4tetrahydroisoquinoline (6gg): Compound 6gg was prepared according to the general procedure from tetrahydroisoquinoline 1g and the corresponding nucleophile to yield the title compound as a yellow oil (0.0637 g, 0.19 mmol, 38% yield). The crude product was purified by flash chromatography (silica-gel, methanol/dichloromethane, 1:20). 1H NMR (400 MHz, CDCl3) δ 7.25 – 7.16 (m, 2H), 7.16 – 7.08 (m, 2H), 7.04 – 6.95 (m, 1H), 6.92 – 6.80 (m, 2H), 6.78 – 6.60 (m, 1H), 4.42 (s, 1H), 3.83 (s, 3H), 3.29 – 3.16 (m, 1H), 3.10 (ddd, J = 15.3, 9.5, 5.1 Hz, 1H), 2.84 (dt, J = 16.1, 4.1 Hz, 1H), 2.50 (ddd, J = 11.6, 9.6, 4.0 Hz, 1H), 2.28 (dd, J = 12.4, 9.5 Hz, 1H), 2.09 (dd, J = 12.4, 4.6 Hz, 1H), 1.88 (ddd, J = 15.3, 3.8, 1.9 Hz, 1H), 1.76 – 1.47 (m, 5H), 1.35 – 1.00 (m, 3H), 0.89 – 0.73 (m, 1H), 0.68 – 0.50 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 158.5, 136.9, 135.0, 130.7 (2C), 128.9, 128.3, 125.6, 125.4, 113.3 (2C), 68.9, 61.2, 55.2, 47.7, 35.5, 31.9, 31.4, 29.2, 26.8, 26.3, 26.1 ppm. IR (ATR) 2918, 2846, 2788, 1607, 1507, 1448 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C23H30NO 336.2327; Found 336.2321. 2-(Cyclohexylmethyl)-1-(3-methoxyphenyl)-1,2,3,4tetrahydroisoquinoline (6gh): Compound 6gh was prepared according to the general procedure from tetrahydroisoquinoline 1g and the corresponding nucleophile to yield the title compound as a yellow oil (0.0654 g, 0.20 mmol, 39% yield). The crude product was purified by flash chromatography (silica-gel, methanol/dichloromethane, 1:20). 1H NMR (400 MHz, CDCl3) δ 7.30 – 7.18 (m, 1H), 7.18 – 7.08 (m, 2H), 7.01 (ddd, J = 8.2, 6.9, 2.0 Hz, 1H), 6.95 – 6.85 (m, 2H), 6.86 – 6.72 (m, 2H), 4.43 (s, 1H), 3.79 (s, 3H), 3.24 (ddd, J = 11.6, 5.2, 4.0 Hz, 1H), 3.19 – 3.04 (m, 1H), 2.84 (dt, J = 16.1, 4.0 Hz, 1H), 2.49 (ddd, J = 11.6, 9.9, 3.8 Hz, 1H), 2.29 (dd, J = 12.4, 9.6 Hz, 1H), 2.11 (dd, J = 12.4, 4.5 Hz, 1H), 1.97 – 1.83 (m, 1H), 1.73 – 1.53 (m, 5H), 1.37 – 1.00 (m, 3H), 0.88 – 0.72 (m, 1H), 0.71 – 0.51 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 159.4, 146.5, 138.7, 134.9, 128.8, 128.4, 125.7, 125.5, 122.4, 115.1 (2C), 112.5, 69.7, 61.4, 55.1, 47.7, 35.5, 31.8, 31.4, 29.2, 26.8, 26.3, 26.0 ppm. IR (ATR) 2918, 1596, 1484, 1449 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C23H30NO 336.2327; Found 336.2320. Methyl 2-(2-(4-methoxybenzyl)-1,2,3,4tetrahydroisoquinolin-1-yl)-2-methylpropanoate (6ha): Compound 6ha was prepared according to the general procedure from tetrahydroisoquinoline 1h and the corresponding nucleophile to yield the title compound as a yellow oil (0.0865 g, 0.25 mmol, 49% yield). The crude product was purified by flash chromatography (silica-gel, n-hexane/ethyl acetate, 90:10). 1H NMR (400 MHz, CDCl3) δ 7.45 – 6.72 (m, 8H), 4.14 (s, 1H), 3.90 (d, J = 13.3 Hz, 1H), 3.83 (s, 3H), 3.70 (s, 3H), 3.59 (d, J = 13.3 Hz, 1H), 3.22 (ddd, J = 12.2, 6.5, 5.5 Hz, 1H), 2.80 – 2.61 (m, 2H), 2.42 (ddd, J = 12.6, 7.2, 5.6 Hz, 1H), 1.18 (d, J = 2.8 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 178.0, 158.5, 137.4, 134.5, 131.9, 129.6 (2C), 128.9, 128.3, 126.6, 125.29, 113.6 (2C), 68.8, 61.5, 55.3, 51.6, 50.6, 45.9, 26.4, 24.4, 22.2 ppm. IR (ATR) 2945, 2832, 1721, 1609, 1508 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C22H28NO3 354.2069; Found 354.2058 Methyl 2-(2-(4-methoxybenzyl)-1,2,3,4tetrahydroisoquinolin-1-yl)acetate (6hb): Compound 6hb was prepared according to the general procedure from tetrahydroisoquinoline 1h and the corresponding nucleophile to yield the title

compound as a yellow oil (0.1008 g, 0.31 mmol, 62% yield). The crude product was purified by flash chromatography (silica-gel, nhexane/ethyl acetate, 90:10). 1H NMR (400 MHz, CDCl3) δ 7.36 – 6.39 (m, 8H), 4.29 (dd, J = 9.4, 5.2 Hz, 1H), 3.83 (s, 3H), 3.79 – 3.58 (m, 5H), 3.18 (ddd, J = 13.3, 11.2, 4.8 Hz, 1H), 3.00 (ddd, J = 17.0, 11.2, 6.0 Hz, 1H), 2.93 – 2.78 (m, 2H), 2.64 (dd, J = 14.6, 5.2 Hz, 1H), 2.58 – 2.47 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 172.3, 158.7, 134.4, 129.9 (2C), 129.3, 127.6, 126.5, 126.0, 113.5 (3C), 58.3, 57.0, 55.3, 51.6, 41.8 (2C), 23.7, ppm. IR (ATR) 2945, 2831, 1731, 1609, 1509 cm−1; ESI-MS m/z: [M+Na]+ Calcd. for C20H23NO3Na 348.1576; Found 348.1570. 1-Ethyl-2-(4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinoline (6hf): Compound 6hf was prepared according to the general procedure from tetrahydroisoquinoline 1h and the corresponding nucleophile to yield the title compound as a yellow oil (0.0661 g, 0.24 mmol, 47% yield). The crude product was purified by flash chromatography (silica-gel, n-hexane/ethyl acetate, 90:10). 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.26 (m, 2H), 7.23 – 7.02 (m, 4H), 7.01 – 6.79 (m, 2H), 3.84 (s, 3H), 3.77 (d, J = 13.3 Hz, 1H), 3.64 (d, J = 13.3 Hz, 1H), 3.60 – 3.51 (m, 1H), 3.20 (ddd, J = 12.8, 9.1, 5.1 Hz, 1H), 2.91 (ddd, J = 16.2, 9.1, 5.3 Hz, 1H), 2.81 – 2.69 (m, 1H), 2.62 (dt, J = 16.3, 4.7 Hz, 1H), 1.91 – 1.71 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 158.6, 139.0, 134.9, 132.0, 129.9 (2C), 128.8, 127.884, 125.6 (d, J = 5.1 Hz, 2C), 113.5 (2C), 62.1, 57.3, 55.3, 43.6, 28.9, 25.0, 10.8 ppm. IR (ATR) 2928, 2830, 1609, 1508 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C19H24NO 282.1858; Found 282.1851. Methyl 2-(2-(4-bromobenzyl)-1,2,3,4-tetrahydroisoquinolin1-yl)-2-methylpropanoate (6ia): Compound 6ia was prepared according to the general procedure from tetrahydroisoquinoline 1i and the corresponding nucleophile to yield the title compound as a yellow oil (0.1183 g, 0.30 mmol, 59% yield). The crude product was purified by flash chromatography (silica-gel, n-hexane/ethyl acetate, 90:10). 1H NMR (400 MHz, CDCl3) δ 7.62 – 6.85 (m, 8H), 4.14 (s, 1H), 3.91 (d, J = 13.8 Hz, 1H), 3.67 (s, 3H), 3.62 (d, J = 13.9 Hz, 1H), 3.22 (ddd, J = 12.0, 6.6, 5.3 Hz, 1H), 2.87 – 2.57 (m, 2H), 2.40 (ddd, J = 12.6, 7.8, 5.2 Hz, 1H), 1.17 (d, J = 8.5 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 177.9, 138.9, 137.2, 134.2, 131.3 (2C), 130.1 (2C), 128.9, 128.3, 126.8, 125.4, 120.5, 69.0, 61.7, 51.7, 50.5, 46.3, 26.5, 24.5, 21.9 ppm. IR (ATR) 2944, 2819, 1719, 1587, 1483 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C21H25BrNO2 402.1069; Found 402.1057 Methyl 2-(2-(4-bromobenzyl)-1,2,3,4-tetrahydroisoquinolin1-yl)acetate (6ib): Compound 6ib was prepared according to the general procedure from tetrahydroisoquinoline 1i and the corresponding nucleophile to yield the title compound as a yellow oil (0.1082 g, 0.29 mmol, 58% yield). The crude product was purified by flash chromatography (silica-gel, n-hexane/ethyl acetate, 90:10). 1H NMR (300 MHz, CDCl3) δ 7.46 (d, J = 8.3 Hz, 1H), 7.36 – 6.91 (m, 7H), 4.27 (dd, J = 9.4, 5.1 Hz, 1H), 3.88 – 3.51 (m, 1H), 3.70 (s, 4H), 3.21 (ddd, J = 13.5, 11.3, 4.8 Hz, 1H), 3.00 (ddd, J = 17.1, 11.2, 6.1 Hz, 1H), 3.02 – 2.74 (m, 2H), 2.76 – 2.46 (m, 2H) ppm; 13C NMR (101 MHz, CDCl3) δ 172.2, 138.3, 136.9, 134.2, 131.3, 130.8, 130.5, 129.3, 127.6, 126.6, 126.1, 120.8, 58.5, 57.0, 51.6, 42.0 (2C), 23.6 ppm. IR (ATR) 2944, 2830, 1731, 1484 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C19H21BrNO2 374.0756; Found 374.0750. Methyl 2-(2-(4-nitrobenzyl)-1,2,3,4-tetrahydroisoquinolin-1yl)-2-methylpropanoate (6ja): Compound 6ja was prepared according to the general procedure from tetrahydroisoquinoline 1j and the corresponding nucleophile to yield the title compound as a yellow oil (0.0865 g, 0.24 mmol, 47% yield). The crude product was purified by flash chromatography (silica-gel, n-hexane/ethyl acetate, 90:10). 1H NMR (400 MHz, CDCl3) δ 8.40 – 6.69 (m, 8H), 4.17 (s, 1H), 4.06 (d, J = 14.8 Hz, 1H), 3.80 (d, J = 14.9 Hz, 1H), 3.66 (s, 3H), 3.23 (ddd, J = 11.8, 6.3, 5.2 Hz, 1H), 2.93 – 2.57 (m, 2H), 2.41 (ddd, J = 12.0, 8.2, 5.0 Hz, 1H), 1.17 (d, J =



10.9 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 177.8, 147.9, 147.0, 137.0, 133.9, 129.0 (2C), 128.8, 128.4, 126.9, 125.5, 123.6 (2C), 69.236, 61.9, 51.7, 50.6, 46.9, 26.7, 24.6, 21.6 ppm. IR (ATR) 2945, 2836, 1719, 1599, 1515, 1340 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C21H25N2O4 369.1814; Found 369.1801. Methyl 2-(2-(4-nitrobenzyl)-1,2,3,4-tetrahydroisoquinolin-1yl)acetate (6jb): Compound 6jb was prepared according to the general procedure from tetrahydroisoquinoline 1j and the corresponding nucleophile to yield the title compound as a yellow oil (0.1156 g, 0.34 mmol, 68% yield). The crude product was purified by flash chromatography (silica-gel, n-hexane/ethyl acetate, 90:10). 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.7 Hz, 2H), 7.60 – 6.81 (m, 6H), 4.26 (dd, J = 9.6, 4.9 Hz, 1H), 4.01 – 3.78 (m, 2H), 3.71 (s, 3H), 3.26 (ddd, J = 13.7, 11.4, 4.9 Hz, 1H), 3.17 – 2.74 (m, 3H), 2.74 – 2.53 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 172.1, 147.2, 136.5, 134.0, 129.3, 129.3 (2C), 127.5, 126.8, 126.3, 123.6, 123.5 (2C), 58.7, 57.1, 51.7, 42.4, 41.9, 23.5 ppm. IR (ATR) 2945, 2836, 1731, 1599, 1515, 1341 cm−1; ESIMS m/z: [M+H]+ Calcd. for C19H21N2O4 341.1501; Found 341.1492. 1-Ethyl-2-(4-nitrobenzyl)-1,2,3,4-tetrahydroisoquinoline (6jf): Compound 6jf was prepared according to the general procedure from tetrahydroisoquinoline 1j and the corresponding nucleophile to yield the title compound as a yellow oil (0.0740 g, 0.25 mmol, 50% yield). The crude product was purified by flash chromatography (silica-gel, n-hexane/ethyl acetate, 90:10). 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.32 – 6.93 (m, 4H), 3.85 (q, J = 14.6 Hz, 2H), 3.62 – 3.40 (m, 1H), 3.22 (ddd, J = 13.2, 9.1, 5.0 Hz, 1H), 3.05 – 2.47 (m, 3H), 1.79 (tdt, J = 12.2, 7.1, 6.1 Hz, 2H), 0.97 (t, J = 7.3 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 148.1, 147.1, 138.3, 134.4, 129.2 (2C), 128.9, 127.8, 126.0, 125.9, 123.5 (2C), 62.6, 57.4, 43.9, 29.0, 24.9, 10.8 ppm. IR (ATR) 2925, 2794, 1599, 1513, 1340 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C18H21N2O2 297.1603; Found 297.1594. Methyl 2-methyl-2-(2-(naphthalen-2-ylmethyl)-1,2,3,4tetrahydroisoquinolin-1-yl)propanoate (6ka): Compound 6ka was prepared according to the general procedure from tetrahydroisoquinoline 1k and the corresponding nucleophile to yield the title compound as a yellow oil (0.1250 g, 0.34 mmol, 67% yield). The crude product was purified by flash chromatography (silicagel, n-hexane/ethyl acetate, 90:10). 1H NMR (400 MHz, CDCl3) δ 7.89 – 7.77 (m, 3H), 7.72 (s, 1H), 7.57 (dd, J = 8.5, 1.7 Hz, 1H), 7.51 – 7.44 (m, 2H), 7.30 – 7.07 (m, 5H), 4.22 (s, 1H), 4.13 (d, J = 13.5 Hz, 1H), 3.83 (d, J = 13.7 Hz, 1H), 3.70 (s, 3H), 3.33 – 3.22 (m, 1H), 2.75 (s, 1H), 2.80 – 2.67 (m, 1H), 2.49 (ddd, J = 12.5, 7.2, 5.6 Hz, 1H), 1.22 (d, J = 2.4 Hz, 6H) ppm; 13C NMR (75 MHz, CDCl3) δ 178.0, 137.5, 137.3, 134.4, 133.4, 132.8, 128.9, 128.4, 127.9, 127.7, 126.9, 126.8, 126.7, 125.9, 125.4, 125.3, 77.2, 69.0, 62.4, 51.7, 50.6, 46.2, 26.4, 24.6, 22.1 ppm. IR (ATR) 2922, 1719, 1457 cm−1; ESI-MS m/z: [M+H]+ Calcd. for C25H28NO2 374.2120; Found 374.2110. Methyl-(2-(naphthalen-2-ylmethyl)-1,2,3,4tetrahydroisoquinolin-1-yl)acetate (6kb): Compound 6kb was prepared according to the general procedure from tetrahydroisoquinoline 1k and the corresponding nucleophile to yield the title compound as a yellow oil (0.1259 g, 0.37 mmol, 73% yield). The crude product was purified by flash chromatography (silica-gel, nhexane/ethyl acetate, 90:10). 1H NMR (300 MHz, CDCl3) δ 8.28 – 7.63 (m, 4H), 7.68 – 7.37 (m, 3H), 7.36 – 6.81 (m, 4H), 4.38 (dd, J = 9.4, 5.1 Hz, 1H), 4.08 – 3.78 (m, 2H), 3.69 (s, 3H), 3.26 (ddd, J = 13.2, 11.1, 4.7 Hz, 1H), 3.17 – 2.98 (m, 1H), 3.04 – 2.81 (m, 2H), 2.69 (dd, J = 14.6, 5.1 Hz, 1H), 2.58 (ddd, J = 16.5, 4.8, 2.0 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 172.3, 137.1, 136.9, 134.4, 133.3, 132.9, 129.3, 127.8, 127.7 – 127.4 (m), 127.2 (d, J = 2.5 Hz), 126.6, 126.1, 125.9, 125.5, 58.6, 57.8, 51.6, 42.0 (d, J = 6.7 Hz), 25.7, 23.8 ppm. IR (ATR) 2943, 2827, 1732

Page 10 of 11

cm−1; ESI-MS m/z: [M+H]+ Calcd. for C23H23NO2 346.1807; Found 346.1805.

ASSOCIATED CONTENT Supporting Information NMR spectra and NMR studies data are available free of charge on the ACS Publications website.

AUTHOR INFORMATION Corresponding Author * Dr. Thanh Vinh Nguyen: [email protected]

ACKNOWLEDGMENT The project was supported by the Australian Research Council (grant DE150100517). The authors thank Hon. Assoc. Prof. Roger Read (UNSW), Prof. Rene Koenigs (RWTH Aachen) and Dr Armin Ofial (LMU Munich) for helpful discussions. Mr Domenic Pace (UNSW) is acknowledged for carrying out some preliminary experiments.

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