Oxidative Difluoromethylation of Tetrahydroisoquinolines Using

Article Cite This: J. Org. Chem. 2018, 83, 765−782

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Oxidative Difluoromethylation of Tetrahydroisoquinolines Using TMSCF2SPh: Synthesis of Fluorinated Pyrrolo[2,1‑a]isoquinolines and Benzo[a]quinolizidines Teerachai Punirun, Darunee Soorukram, Chutima Kuhakarn, Vichai Reutrakul, and Manat Pohmakotr* Center of Excellence for Innovation in Chemistry (PERCH−CIC) and Department of Chemistry, Faculty of Science, Mahidol University, Rama VI Road, Bangkok 10400, Thailand S Supporting Information *

ABSTRACT: An efficient C1-difluoromethylation of tetrahydroisoquinolenes was achieved using TMSCF2SPh as a difluoromethylating agent and 2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (TEMPO+BF4−) as an oxidant. The process provides an access to a variety of C1-difluoro(phenylsulfanyl)methylated tetrahydroisoquinoline adducts in good yields. These adducts were employed as key precursors for preparing fluorinated pyrrolo[2,1-a]isoquinoline and benzo[a]quinolizidines.

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existed. Qing and co-workers first reported CuBr catalyzed oxidative C1-difluoromethylation of tetrahydroisoquinolines through the addition of α,α-difluorosilyl enol ether to the iminium ions generated in situ from tetrahydroisoquinolines (Scheme 1, eq 1).8 Later, Zhu and co-workers disclosed Ru(bpy)3Cl2-induced C1-difluoromethylation of tetrahydroisoquinolines with in situ generated difluoroenolates derived from pentafluoro-β-diketone hydrate (Scheme 1, eq 2).9 Most recently, Wang and co-workers reported C1-difluoromethylation of tetrahydroisoquinolines with difluoroenolates derived from α,α-difluoroacetamides, -phosphonates and -acetates employing DDQ as an oxidant (Scheme 1, eq 3).10 To the best of our knowledge, only the stabilized difluoroenolates were employed in these difluoromethylations. Herein, we report our results on the oxidative phenylsulfanyldifluoromethylation of tetrahydroisoquinolines 211 using 1 as a difluoromethylene building block (Scheme 1, eq 4). These mild and transition metal-free reaction conditions offer convenient and practical advantages for difluoromethylation of tetrahydroisoquinolines. Additionally, subsequent synthetic manipulation by reductive cleavage of the phenylsulfanyl group of 3 followed by an intramolecular cyclization of the resulting difluoromethyl

INTRODUCTION Interest in the utilization of organofluorine compounds in agrochemicals, pharmaceuticals, and materials science has accumulated over the past decades due to the unique characteristics of fluorine atom, which can alter properties of those organofluorines.1 The presence of fluorine atom(s) in small organic molecules was found to have profound effects to their physical, chemical and biological properties in comparison to those of nonfluorinated parent compounds.2 Since most of the organofluorines were obtained from chemical synthesis, as a result, tremendous efforts have been devoted to the development of efficient and practical methods to introduce fluorine atom(s) or fluorine-containing motif to organic frameworks using a variety of fluorinating agents, such as Selectfluor,3 NFSI,4 and TMSCF3.5 Our research group has long been interested in developing fluorination methods focusing on the use of TMSCF2SPh (1) as a versatile difluoromethylene (CF2) building block for the synthesis of difluoromethylene containing compounds.6 Although fluoride-induced addition of 1 to electrophilic Csp2 of carbonyl derivatives was thoroughly investigated, direct addition of 1 to Csp3 via in situ oxidative coupling reaction has not been explored. Among approaches toward Csp3−CF 2 bond formation,7 a few precedent examples described for the coupling between Csp3 and CF2 for C1-difluoromethylation of tetrahydroisoquinolines © 2017 American Chemical Society

Received: November 3, 2017 Published: December 22, 2017 765

DOI: 10.1021/acs.joc.7b02783 J. Org. Chem. 2018, 83, 765−782

Article

The Journal of Organic Chemistry Scheme 1. Oxidative Difluoromethylation of Tetrahydroisoquinolines

Table 1. Optimization of Oxidative Phenylsulfanyldifluoromethylation of 2a Using 1

entry

1 (equiv)

oxidant (equiv)

solvent

fluoride source (equiv)

additive

yield of 3a (%)

1 2 3 4 5 6 7 8c 9c 10c 11d

1.2 2.0 2.0 2.0 1.5 2.0 3.0 3.0 2.0 3.0 3.0

DIB (1.1) CuI (0.1)/O2 CuI (0.1)/DDQ (1.3) CuCl2 (0.1)/O2 DDQ (1.0) DDQ (1.0) DDQ (1.0) DDQ (1.0) TEMPO+BF4− (1.5) TEMPO+BF4− (1.5) TEMPO+BF4− (1.5)

THF THF DMF DMF THF THF THF THF CH3CN CH3CN CH3CN

TBAT (1.2) TBAT (2.0) TBAT (2.0) KF (2.0) CsF (1.5) CsF (2.0) CsF (3.0) CsF (3.0) CsF (3.0) CsF (3.0) CsF (3.0)

− 4 Å MS − − − − − − − − AcOH (1.0)

−a −a −b −b 20 42 44 57 61 72 86

a

2a was recovered. b2a was consumed but 3a was not observed. c2a, CsF and an oxidant were premixed and the mixture was stirred for 15 min prior to the addition of 1. d2a, CsF, TEMPO+BF4− and glacial AcOH were premixed and the mixture was stirred for 15 min prior to the addition of 1.

radical will lead to the synthesis of fluorinated analogs of pyrrolo[2,1-a]isoquinoline and benzo[a]quinolizidine alkaloids.

difluorotriphenylsilicate (TBAT) in dry THF at room temperature for overnight (16 h), the desired adduct 3a was not obtained and 2a (91% yield) was recovered together with HCF2SPh (Table 1, entry 1). Next, various combinations of oxidizing reagents were screened12 including CuI/O2,12h CuI/ DDQ12c,f and CuCl2/O212d but none of those led to 3a (Table 1, entries 2−4). Gratifyingly, 3a was first obtained in low yield (20% yield) when DDQ was employed as an oxidant and CsF as a fluoride source in dry THF (Table 1, entry 5).10,13 The yields of 3a was significantly improved upon increasing the

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RESULTS AND DISSUSSION We began our study by screening the optimal reaction conditions for the oxidative phenylsulfanyldifluoromethylation of 2a with 1. Reaction parameters including oxidants, fluoride sources, solvents, and additives were screened (Table 1). Initially, when a mixture of 2a and 1 was treated with diacetoxyiodobenzene (DIB)11b,g,k and tetrabutylammonium 766

DOI: 10.1021/acs.joc.7b02783 J. Org. Chem. 2018, 83, 765−782

Article

The Journal of Organic Chemistry Scheme 2. Oxidative Phenylsulfanyldifluoromethylation of Tetrahydroisoquinolines 2a

a Conditions: 2a (1 equiv), CsF (3 equiv), TEMPO+BF4− (1.5 equiv), glacial AcOH (1 equiv), 1 (3 equiv), CH3CN, rt. bRatio was determined by 1H NMR.

Table 2. Reaction of 1 with Tetrahydroisoquinolines 2s−2u

entry

substrate 2

product 4 (% yield)

1 2 3

2s; R = H 2t; R = TMS 2u; R = TBS

4a (64%) 4a (64%), 4b (0%) 4a (64%), 4c (22%)

rate (TEMPO+BF4−)14 and CsF in dry CH3CN gave comparable results affording 3a in 61% yield (Table 1, entry 9). Increasing the amount of 1 enhanced the yield of 3a from 61% to 72% yields (Table 1, entry 9 vs entry 10). To our delight, 3a was afforded in high yield (86% yield) when glacial

stoichiometry of 1 and CsF (Table 1, entries 6 and 7). Interestingly, the yield of 3a (57% yield) was enhanced when 2a, CsF and DDQ were premixed in dry THF for 15 min prior to the addition of 1 (Table 1, entry 8). A combination of 2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluorobo767

DOI: 10.1021/acs.joc.7b02783 J. Org. Chem. 2018, 83, 765−782

Article

The Journal of Organic Chemistry Table 3. Alternative Synthesis of Compound 4 from 3a

a

Conditions: Step I. HCl (1 equiv), 10% Pd/C, H2, MeOH, rt. Step II. 3-(trimethylsilyl)propargyl bromide (2.5 equiv), anh. K2CO3 (2.0 equiv), acetone, reflux.

AcOH was used as an additive (Table 1, entry 11).14b After extensive screening, the optimum conditions for oxidative phenylsulfanyldifluoromethylation of 2a with 1 were identified as follows: 2a (1 equiv), 1 (3 equiv), TEMPO+BF4− (1.5 equiv), CsF (3 equiv), and AcOH (1 equiv) in CH3CN at room temperature for overnight (16 h) (Table 1, entry 11). Having the optimized reaction conditions in hand (Table 1, entry 11), we next examined the scope of the reaction with a variety of substituted tetrahydroisoquinoline derivatives 2 and the results are summarized in Scheme 2. In general, different substituents at the nitrogen atom including N-aryl,15 Nbenzyl,16 N-allyl16 and N-homoallyl16 tetrahydroisoquinolines were suitable substrates leading to their corresponding products 3b−3r in moderate to good yields (51−89% yields). Under the reaction conditions, alkene geometry of N-homoallylated tetrahydroisoquinolines 2o−2r (E isomer) underwent isomerization to yield 3o−3r each as an inseparable mixture of E:Z

isomers in good yields, presumably as a result from acidic reaction conditions. Under standard reaction conditions, N-propargyl tetrahydroisoquinoline derivative 2s gave 4a in 64% yield (Table 2, entry 1). Unfortunately, tetrahydroisoquinoline derivative 2t bearing a 3-(TMS)propargyl side-chain did not provide the corresponding product 4b but yielded the desilylated product 4a in 64% yield (Table 2, entry 2). Tetrahydroisoquinoline 2u with a more robust 3-(TBS)propargyl side-chain led to the corresponding product 4c in 22% yield and the desilylated product 4a in 51% yield (Table 2, entry 3). It is worth noting that 4a and 4b could be readily prepared from 3c upon removal of a benzyl group (H2, Pd/C, MeOH, HCl)17 yielding 5a in 85% yield. Alkynylation of 5a with propargyl bromide and 3(trimethylsilyl)propargyl bromide gave 4a (86% yield) and 4b (95% yield), respectively (Table 3, entries 1 and 2). By exploiting similar synthetic sequences, compounds 4d−4g were 768

DOI: 10.1021/acs.joc.7b02783 J. Org. Chem. 2018, 83, 765−782

Article

The Journal of Organic Chemistry Scheme 3. Synthesis of Compounds 6 and 7a,b

a

Conditions: Bu3SnH (1.75 equiv), AIBN (0.3 equiv), toluene, reflux. bDiastereomeric ratio was determined by 19F NMR.

allyl substituted adducts 3i−3l in high yields (85−94% yields) with moderate to high diastereoselectivity (Scheme 3). Under similar reaction conditions, N-homoallyl substituted adducts 3m−3r afforded gem-difluoromethylenated benzo[a]quinolizidines 6f−6k in good yields (70−83% yields) with moderate diastereoselectivity (Scheme 3). At this stage, the stereochemical outcome of 6a−6k can be rationalized. On the basis of our previous reports,6a−e a chairlike transition state was proposed as shown in Scheme 4. The intramolecular radical cyclization of radicals derived from 3h−3l was proposed to proceed via 5-exo-trig mode through TS-1, which is energetically more favorable due to the minimized steric repulsion between lone-pair electrons of nitrogen and olefinic moiety (TS-1 vs TS-2), leading to the formation of thermodynamically more stable trans-isomer as a major isomer. On the contrary, the radical intermediates derived from 3k−3r underwent cyclization via 6-endo-trig mode through TS-3 leading to cis-isomer as a major isomer. TS-3 is

prepared in high yields (83−99% yields) from 3d−3g as summarized in Table 3. Having established an efficient access to C1-phenylsulfanyldifluoromethylated tetrahydroisoquinoline derivatives, we further demonstrated the synthetic utility of the present methodology toward the synthesis of gem-difluoromethylenated pyrrolo[2,1a]isoquinoline (6a−6e and 7a−7e) and benzo[a]quinolizidine (6f−6k) alkaloids. Initially, treatment 3h with Bu3SnH (1.75 equiv) in the presence of AIBN (10 mol %) in refluxing toluene for overnight (14 h)6,18 gave 6a in 30% yield as an inseparable mixture of two diastereomers (dr = 1:2.8, 19F NMR analysis). Compound 6a arose from the reductive desulfenylation to generate gem-difluoromethyl radical intermediate, followed by intramolecular cyclization to an unsaturation moiety. Increasing the quantity of AIBN (from 10 mol % to 30 mol %) dramatically increased the yield of 6a (91% yield; dr = 1:3.4). After the optimal reduction conditions were chosen [Bu3SnH (1.75 equiv) and AIBN (30 mol %)], difluoromethylenated pyrrolo[2,1-a]isoquinolines 6a−6e were synthesized from N769

DOI: 10.1021/acs.joc.7b02783 J. Org. Chem. 2018, 83, 765−782

Article

The Journal of Organic Chemistry Scheme 4. Proposed Transition State for Radical Cyclization of Compounds 3h−3r

[2,1-a]isoquinoline (8a) upon standing under air at room temperature. We envisioned that 8a was formed from the oxidative defluoro/desilylation process under air at ambient temperature. This observation encouraged us to investigate a suitable reaction conditions for conversion of 7 to 8 (Table 4). Initially, upon stirring a solution of 7a in CH2Cl2 under air for

more favorable than TS-4 due to a less steric repulsion between a quasiaxial hydrogen and an alkenyl moiety. When 4b and 4d−4g, bearing a trimethylsilylated alkynyl side-chain, were used as substrates, the corresponding cyclized products 7a−7e were readily obtained in good yields (72−92% yields) with moderate isomeric ratios (Scheme 3). Fortunately, two isomers of 7a could be separated by means of chromatographic method to afford 7aA (E isomer, 63% yield) and 7aB (Z isomer, 18% yield). The relative stereoisomers of 7aA and 7aB were assigned on the basis of NOE analysis (see the Supporting Information). Although two isomers of 7b−7e could not be separated, their isomeric ratios could be assigned on the same basis of those of 7a. In all cases, the E-isomer is a major isomer. It should be mentioned that Bu3SnH/AIBN mediated reductive cleavage of the phenylsulfanyl group followed by radical cyclization of 4a under the standard reaction conditions was unsuccessful and the expected cyclized product was not observed. Instead, a mixture of products derived from the addition of “Bu3Sn” radical to alkyne moiety was observed (NMR analysis).19 Unfortunately, due to complex TLC patterns identification of the products was not possible. Compounds 7aA and 7aB proved to be unstable and slowly transformed to an unprecedented 1-fluoro-5,6-dihydropyrrolo-

Table 4. Optimization of Oxidative Defluoro/Desilylation of 7a

a

770

entry

conditions

1 2 3 4 5 6

CH2Cl2, rt, 24 h CH2Cl2, SiO2, rt, 24 h CH2Cl2, TFA, 0 °C to rt, 24 h CH3CN, O2 (balloon), rt, 24 h CH3CN, O2 (balloon), TBAF (5 equiv), rt, 24 h CH3CN, TBAF (5 equiv), rt, 24 h

8a (%) 35 37 41 56 73 60

(56)a (52)a (47)a (14)a (32)a

In parentheses: % recovery of 7a. DOI: 10.1021/acs.joc.7b02783 J. Org. Chem. 2018, 83, 765−782

Article

The Journal of Organic Chemistry

droisoquinolenes employing TMSCF2SPh (1) as a gemdifluoromethylene building block and TEMPO+BF4− as an oxidant. The reaction proceeded through the oxidation at C1 of tetrahydroisoquinolines ring to yield the corresponding iminium ions which were readily trapped by 1 to provide C1difluoro(phenylsulfanyl)methylated tetrahydroisoquinoline adducts in good yields. The resulting adducts were used as useful synthetic precursors for the preparation of gem-difluoromethylenated pyrrolo[2,1-a]isoquinolines and benzo[a]quinolizidines, which are an important class of compounds in organic synthesis and pharmaceutical science. In the present work, the unprecedented formation of a series of 1-fluoro-5,6dihydropyrrolo[2,1-a]isoquinolines was also described.

24 h, 8a was obtained in 35% yield and 7a was recovered (56% yield) (Table 4, entry 1). No appreciable results were observed when SiO2 or TFA was employed as additive (Table 4, entry 2 and entry 3). The yield of 8a was increased to 56% yield when the reaction was carried out under O2 atmosphere (balloon) in CH3CN (Table 4, entry 4). Gratifyingly, when the reaction was performed in CH3CN under O2 atmosphere with the presence of TBAF (5 equiv) for 24 h, 8a was obtained in good yield (73% yield) (Table 4, entry 5). At this point, the optimal conditions for the conversion of 7 to 8 were identified (Table 4, entry 5). In this reaction, the positive pressure of O2 (balloon) is crucial in order to obtain the optimum yields. If the reaction was carried out in an open-flask conditions (TBAF, rt, 24 h), poorer yield was observed; 8a was obtained in 60% yield along with the recovery of 7a in 32% yield (Table 4, entry 6). Under similar reaction conditions, 7b−7e bearing electronically different substituents on aromatic ring provided the corresponding products 8b−8e in low to moderate yields (32−77% yields) as summarized in Scheme 5. It should be noted that the

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EXPERIMENTAL SECTION

General Information. 1H NMR spectra were recorded on 400 and 500 MHz spectrometers and are reported in ppm. Proton decoupled 13 C{H}NMR spectra were recorded on 100 and 125 MHz spectrometers and are reported in ppm. 19F NMR spectra were recorded on 376 MHz spectrometer and are reported in ppm. Reactions were monitored by thin-layer chromatography and visualized by UV light and a solution of KMnO4. Acetonitrile (CH3CN), methanol (MeOH) and toluene were dried over calcium hydride before distillation and stored over activated molecular sieves (4 Å). Acetone was dried over anhydrous K2CO3 before distillation and stored over activated molecular sieves (4 Å). All glasswares and syringes were oven-dried and kept in a desiccator before use. Column chromatography was used silica gel. Other common solvents [dichloromethane (CH2Cl2), hexanes, ethyl acetate (EtOAc), and methanol] were distilled before use. The tetrahydroisoquinolines baring a difference substituent on the aromatic ring were prepared according to the literature method.21 The N-substituted tetrahydroisoquinolines 2a−2b15 and 2c−2t16 were prepared according to the literature methods. Synthesis of Compounds 3, 4a and 4c. General Procedure A. To a reaction flask containing anhydrous cesium fluoride (0.46 g, 3.0 mmol) was added a solution of 2 (0.5 mmol) in dry acetonitrile (1.5 mL) at room temperature. The suspension was treated with a solution of TEMPO+BF4− in dry acetonitrile (1 M solution, 0.75 mL) as dropwise at room temperature for 10 min. Acetic acid (29 μL, 0.5 mmol) was then added. After stirring for 15 min, a solution of TMSCF2SPh (0.35 g, 1.5 mmol) in dry acetonitrile (1.0 mL) was added at room temperature. The reaction was stirred at room temperature for overnight. The reaction was diluted with water (20 mL) followed by extraction with EtOAc (3 × 20 mL). The combined organic phase was washed successively with saturated NaHCO3 (15 mL), brine (15 mL) and dried over anhydrous Na2SO4. After the removal of solvent, a crude product was purified by column chromatography (SiO2). 1-(Difluoro(phenylthio)methyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline (3a). According to the general procedure A, the reaction of 1 (140 mg, 0.6 mmol), 2a (42 mg, 0.2 mmol), CsF (91 mg, 0.6 mmol), TEMPO+BF4− (1 M solution, 0.3 mL), and AcOH (12 μL) in dry acetonitrile (1.0 mL) gave 3a (63 mg, 86%) as a colorless oil after column chromatography (SiO2, 2.5% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 6.8 Hz, 2H), 7.35−7.23 (m, 4H), 7.23−7.13 (m, 3H), 7.13−7.05 (m, 2H), 6.94 (d, J = 8.2 Hz, 2H), 6.78 (t, J = 7.3 Hz, 1H), 5.13 (dd, J = 10.1, 14.6 Hz, 1H), 3.85−3.73 (m, 1H), 3.68 (ddd, J = 4.8, 4.8, 13.5 Hz, 1H), 2.96 (ddd, J = 5.9, 10.3, 16.3 Hz, 1H), 2.74 (ddd, J = 4.2, 4.2, 16.4 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −69.0 (dd, J = 14.5, 202.9 Hz, 1F), −70.4 (dd, J = 10.0, 202.9 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3) δ 149.4 (C), 136.6 (C), 136.3 (2 × CH), 132.3 (dd, J = 283.0, 289.0 Hz, CF2), 130.0 (C), 129.5 (CH), 129.3 (2 × CH), 129.0 (CH), 128.9 (2 × CH), 128.6 (d, J = 4.0 Hz, CH), 128.1 (CH), 127.6 (C), 126.1 (CH), 119.7 (CH), 116.1 (2 × CH), 64.9 (t, J = 26.0 Hz, CH), 43.1 (CH2), 25.7 (CH2); IR (neat) νmax 1493m, 1128s, 1103s, 1043s cm−1; MS m/z

Scheme 5. Preparation of Compounds 8a

a

Conditions: O2 (balloon), TBAF·3H2O (5 equiv), toluene, rt. bThe reaction was performed for 3 days at rt. cThe reaction was heated to 60 °C for 24 h.

electronic property of the substituents on aromatic ring have a profound effect on the reactivity of the substrates. Extended reaction time or heating were required with the substrates without substituent group or bearing an electronegative atom. On the basis of the observed results, the plausible reaction mechanism for the formation of 8 from 7 is proposed (Scheme 6). First, a benzylic carbon next to gem-difluoromethylene moiety is oxidized by molecular oxygen via a single electron transfer (SET) process leading to an iminium ion intermediate A and hydrogen peroxide anion. The following HF elimination provides intermediate B, which is subsequently epoxidized by hydrogen peroxide anion leading to intermediate C.20 The addition of H2O to iminium ion C provides intermediate D, which further reacts with H2O or fluoride ion to form the corresponding intermediate E. Finally, dehydration followed by tautomerization of E affords the observed product 8.

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CONCLUSION In summary, we have developed a convenient and highly efficient C1- difluoro(phenylsulfanyl)methylation of tetrahy771

DOI: 10.1021/acs.joc.7b02783 J. Org. Chem. 2018, 83, 765−782

Article

The Journal of Organic Chemistry Scheme 6. Plausible Mechanism for the Formation of Compounds 8

(%) relative intensity 368 [(M + 1)+, 100]; HRMS (ESI-TOF) calcd for C22H19F2NSNa [M + Na]+ 390.1104, found 390.1105. 1-(Difluoro(phenylthio)methyl)-2-(3-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (3b). According to the general procedure A, the reaction of 1 (209 mg, 0.9 mmol), 2b (72 mg, 0.3 mmol), CsF (136 mg, 0.9 mmol), TEMPO+BF4− (1 M solution, 0.45 mL), and AcOH (17 μL) in dry acetonitrile (1.5 mL) gave 3b (94 mg, 79%) as a yellow oil after column chromatography (SiO2, 5% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.6 Hz, 2H), 7.35−7.19 (m, 4H), 7.19−7.02 (m, 4H), 6.56 (d, J = 8.3 Hz, 1H), 6.51 (s, 1H), 6.34 (dd, J = 1.7, 8.1 Hz, 1H), 5.13 (dd, J = 10.2, 14.4 Hz, 1H), 3.83−3.60 (m, 5H), 2.96 (ddd, J = 5.9, 10.8, 16.3 Hz, 1H), 2.74 (ddd, J = 4.2, 4.2, 16.3 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −69.0 (dd, J = 14.5, 202.9 Hz, 1F), −70.3 (dd, J = 8.6, 202.9 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3) δ 159.7 (C), 149.7 (C), 135.2 (2 × CH), 131.1 (dd, J = 284.1, 289.5 Hz, CF2), 128.9 (CH), 128.8 (C), 128.4 (CH), 128.0 (CH), 127.9 (2 × CH and C), 127.6 (d, J = 3.6 Hz, CH), 127.1 (CH), 126.4 (C), 125.0 (CH), 107.7 (CH), 103.1 (CH), 101.7 (CH), 64.9 (t, J = 26.5 Hz, CH), 52.4 (CH3), 42.0 (CH2), 24.8 (CH2); IR (neat) νmax 1493m, 1370m, 1103s cm−1; MS m/z (%) relative intensity 398 [(M + 1)+, 100]; HRMS (ESI-TOF) calcd for C23H22F2NOS [M + H]+ 398.1390, found 398.1404. 2-Benzyl-1-(difluoro(phenylthio)methyl)-6,7-dimethoxy-1,2,3,4tetrahydroisoquinoline (3c). According to the general procedure A, the reaction of 1 (696 mg, 3.0 mmol), 2c (283 mg, 1.0 mmol), CsF (456 mg, 3.0 mmol), TEMPO+BF4− (1 M solution, 1.5 mL), and AcOH (57 μL) in dry acetonitrile (5.0 mL) gave 3c (370 mg, 84%) as a pale yellow oil after column chromatography (SiO2, 5% EtOAc in hexanes). 1 H NMR (400 MHz, CDCl3) δ 7.55−7.48 (m, 2H), 7.41 (d, J = 7.1 Hz, 2H), 7.34−7.19 (m, 6H), 6.66 (d, J = 2.3 Hz, 1H), 6.57 (s, 1H), 4.08 (dd, J = 8.7, 15.9 Hz, 1H), 3.80 (s, 2H), 3.79 (s, 3H), 3.71 (s, 3H), 3.41−3.28 (m, 1H), 2.92−2.76 (m, 2H), 2.50−2.40 (m, 1H); 19F NMR (376 MHz, CDCl3) δ −69.4 (dd, J = 7.4, 203.0 Hz, 1F), −70.9 (dd, J = 15.5, 203.0 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3) δ 148.7 (C), 147.3 (C), 138.5 (C), 136.3 (2 × CH), 132.7 (dd, J = 280.0, 288.0 Hz, CF2), 129.2 (CH), 129.1 (2 × CH), 128.7 (2 × CH), 128.5 (C), 128.4 (2 × CH), 128.2 (C), 127.4 (CH), 120.5 (C), 112.0 (d, J = 4.0 Hz, CH), 66.1 (t, J = 25.0 Hz, CH), 58.5 (CH2), 55.9 (CH3), 55.8 (CH3), 43.1 (CH2), 22.5 (CH2); IR (neat) νmax 1606m, 1515m, 1223s, 1102s cm−1; MS m/z (%) relative intensity 442 [(M + 1)+, 24], 282

(100); HRMS (ESI-TOF) calcd for C25H26F2NO2S [M + H]+ 442.1652, found 442.1654. 2-Benzyl-1-(difluoro(phenylthio)methyl)-1,2,3,4-tetrahydroisoquinoline (3d). According to the general procedure A, the reaction of 1 (349 mg, 1.5 mmol), 2d (112 mg, 0.5 mmol), CsF (228 mg, 1.5 mmol), TEMPO+BF4− (1 M solution, 0.75 mL), and AcOH (29 μL) in dry acetonitrile (2.5 mL) gave 3d (155 mg, 81%) as a yellow oil after column chromatography (SiO2, 2.5% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 7.5 Hz, 2H), 7.41 (d, J = 7.4 Hz, 2H), 7.35−7.15 (m, 8H), 7.14−7.04 (m, 2H), 4.18 (dd, J = 9.7, 14.7 Hz, 1H), 3.86 (d, J = 13.3 Hz, 1H), 3.81 (d, J = 13.3 Hz, 1H), 3.44−3.32 (m, 1H), 2.99−2.86 (m, 1H), 2.86−2.75 (m, 1H), 2.67− 2.55 (m, 1H); 19F NMR (376 MHz, CDCl3) δ −69.7 (d, J = 203.9 Hz, 1F), −71.1 (dd, J = 15.2, 203.9 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3) δ 138.5 (C), 136.3 (2 × CH), 136.2 (C), 132.5 (dd, J = 281.4, 286.2 Hz, CF2), 129.7 (d, J = 7.2 Hz, CH), 129.2 (CH), 129.1 (2 × CH and C), 129.0 (CH), 128.7 (2 × CH), 128.4 (2 × CH), 127.8 (CH), 127.4 (CH and C), 126.0 (CH), 66.5 (t, J = 24.9 Hz, CH), 58.8 (CH2), 43.3 (CH2), 23.4 (CH2); IR (neat) νmax 1493m, 1370m, 1153m, 1128m, 1072s cm−1; MS m/z (%) relative intensity 381 (M+, trace), 282 (100); HRMS (ESI-TOF) calcd for C23H22F2NS [M + H]+ 382.1455, found 382.1441. 6-Benzyl-5-(difluoro(phenylthio)methyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline (3e). According to the general procedure A, the reaction of 1 (696 mg, 3.0 mmol), 2e (267 mg, 1.0 mmol), CsF (456 mg, 3.0 mmol), TEMPO+BF4− (1 M solution, 1.5 mL), and AcOH (57 μL) in dry acetonitrile (5.0 mL) gave 3e (332 mg, 78%) as a colorless oil after column chromatography (SiO2, 5% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 6.8 Hz, 2H), 7.39 (d, J = 7.3 Hz, 2H), 7.33−7.18 (m, 6H), 6.63 (s, 1H), 6.54 (s, 1H), 5.81 (d, J = 14.6 Hz, 2H), 4.04 (dd, J = 8.8, 15.7 Hz, 1H), 3.80 (d, J = 13.4 Hz, 1H), 3.76 (d, J = 13.4 Hz, 1H), 3.39−3.21 (m, 1H), 2.90−2.68 (m, 2H), 2.52−2.39 (m, 1H); 19F NMR (376 MHz, CDCl3) δ −69.5 (dd, J = 9.4, 202.4 Hz, 1F), −71.0 (dd, J = 15.4, 202.4 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3) δ 147.4 (C), 145.9 (C), 138.4 (C), 136.2 (2 × CH), 132.5 (dd, J = 281.6, 288.7 Hz, CF2), 129.6 (C), 129.2 (CH), 129.1 (2 × CH), 128.7 (2 × CH), 128.4 (2 × CH and C), 127.4 (CH), 121.6 (C), 109.2 (d, J = 4.2 Hz, CH), 108.7 (CH), 100.9 (CH2), 66.4 (t, J = 25.0 Hz, CH), 58.5 (CH2), 43.2 (CH2), 23.3 (CH2); IR (neat) νmax 1503s, 1479s, 1382m, 1221s, 1034s cm−1; MS m/z (%) relative intensity 426 [(M + 1)+, 22], 266 (100); 772

DOI: 10.1021/acs.joc.7b02783 J. Org. Chem. 2018, 83, 765−782

Article

The Journal of Organic Chemistry

hexanes). 1H NMR (400 MHz, CDCl3) δ 7.57−7.51 (m, 2H), 7.40− 7.24 (m, 7H), 7.23−7.15 (m, 1H), 6.68 (d, J = 1.6 Hz, 1H), 6.57 (s, 1H), 6.47 (d, J = 16.0 Hz, 1H), 6.35 (ddd, J = 6.4, 6.4, 16.0 Hz, 1H), 4.15 (dd, J = 8.6, 17.3 Hz, 1H), 3.80 (s, 3H), 3.72 (s, 3H), 3.54−3.36 (m, 3H), 3.05−2.94 (m, 1H), 2.85 (ddd, J = 5.8, 10.6, 16.4 Hz, 1H), 2.49 (br. d, J = 16.4 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −69.8 (d, J = 203.5 Hz, 1F), −71.6 (dd, J = 15.9, 203.5 Hz, 1F); 13 C{H}NMR (100 MHz, CDCl3) δ 148.7 (C), 147.3 (C), 136.8 (C), 136.3 (2 × CH), 133.1 (dd, J = 284.8, 284.8 Hz, CF2), 129.3 (CH), 128.8 (2 × CH), 128.6 (4 × CH), 128.4 (C), 128.1 (C), 127.7 (CH), 127.2 (C), 126.5 (2 × CH), 112.0 (CH), 111.3 (CH), 64.4 (t, J = 25.5 Hz, CH), 56.7 (CH2), 55.9 (CH3), 55.8 (CH3), 44.7 (CH2), 22.7 (CH2); IR (neat) νmax 1515s, 1225s, 1116s, 1098s, 1024s cm−1; MS m/ z (%) relative intensity 468 [(M + 1)+, trace], 306 (100); HRMS (ESITOF) calcd for C27H28F2NO2S [M + H]+ 468.1809, found 468.1805. 2-Allyl-1-(difluoro(phenylthio)methyl)-1,2,3,4-tetrahydroisoquinoline (3j). According to the general procedure A, the reaction of 1 (696 mg, 3.0 mmol), 2j (173 mg, 1.0 mmol), CsF (456 mg, 3.0 mmol), TEMPO+BF4− (1 M solution, 1.5 mL), and AcOH (57 μL) in dry acetonitrile (5.0 mL) gave 3j (235 mg, 71%) as a pale yellow oil after column chromatography (SiO2, 2.5% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 7.55−7.48 (m, 2H), 7.33−7.22 (m, 3H), 7.22−7.12 (m, 2H), 7.12−7.03 (m, 2H), 6.00−5.88 (m, 1H), 5.15 (s, 1H), 5.13−5.09 (m, 1H), 4.17 (dd, J = 8.9, 16.1 Hz, 1H), 3.49−3.37 (m, 1H), 3.49−3.37 (m, 1H), 3.37−3.20 (m, 2H), 2.96−2.80 (m, 2H), 2.66−2.55 (m, 1H); 19F NMR (376 MHz, CDCl3) δ −70.0 (d, J = 203.5 Hz, 1F), −71.6 (dd, J = 16.0, 203.5 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3) δ 136.2 (2 × CH), 135.6 (C), 132.5 (dd, J = 280.6, 287.2 Hz, CF2), 129.6 (d, J = 3.7 Hz, CH), 129.2 (CH and C), 129.0 (C), 128.9 (CH), 128.7 (2 × CH), 128.4 (C), 127.8 (CH), 125.9 (CH), 118.9 (CH2), 64.8 (t, J = 24.9 Hz, CH), 57.6 (CH2), 44.6 (d, J = 2.7 Hz, CH2), 23.6 (CH2); IR (neat) νmax 1452m, 988s cm−1; MS m/ z (%) relative intensity 331 (M+, 23), 172 (100); HRMS (ESI-TOF) calcd for C19H20F2NS [M + H]+ 332.1285, found 332.1280. 2-Allyl-1-(difluoro(phenylthio)methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (3k). According to the general procedure A, the reaction of 1 (696 mg, 3.0 mmol), 2k (334 mg, 1.0 mmol), CsF (456 mg, 3.0 mmol), TEMPO+BF4− (1 M solution, 1.5 mL), and AcOH (57 μL) in dry acetonitrile (5.0 mL) gave 3k (298 mg, 76%) as a yellow oil after column chromatography (SiO2, 5% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 6.4 Hz, 2H), 7.35−7.23 (m, 3H), 6.68 (s, 1H), 6.56 (s, 1H), 6.07−5.89 (m, 1H), 5.20−5.10 (m, 2H), 4.10 (dd, J = 8.7, 16.3 Hz, 1H), 3.79 (s, 1H), 3.73 (s, 3H), 3.46−3.35 (m, 1H), 3.31 (dd, J = 5.7, 13.6 Hz, 1H), 3.24 (dd, J = 7.0, 13.6 Hz, 1H), 2.93 (dd, J = 4.0, 13.6 Hz, 1H), 2.81 (ddd, J = 5.8, 11.0, 16.6 Hz, 1H), 2.47 (br. d, J = 16.6 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −69.7 (d, J = 203.6 Hz, 1F), −71.5 (dd, J = 15.9, 203.6 Hz, 1F); 13 C{H}NMR (100 MHz, CDCl3) δ 148.7 (C), 147.2 (C), 136.2 (2 × CH), 135.7 (CH), 132.5 (dd, J = 282.5, 288.7 Hz, CF2), 129.2 (CH), 128.7 (2 × CH), 128.5 (C), 128.2 (C), 120.3 (C), 118.2 (CH2), 112.0 (d, J = 4.0 Hz, CH), 111.3 (CH), 64.8 (t, J = 25.1 Hz, CH), 57.3 (CH2), 55.9 (CH3), 55.8 (CH3), 44.5 (CH2), 22.7 (CH2); IR (neat) νmax 1515s, 1226s, 1097s cm−1; MS m/z (%) relative intensity 391 (M+, 39), 232 (100); HRMS (ESI-TOF) calcd for C21H24F2NO2S [M + H]+ 392.1496, found 392.1502. 2-Allyl-7-chloro-1-(difluoro(phenylthio)methyl)-1,2,3,4-tetrahydroisoquinoline (3l). According to the general procedure A, the reaction of 1 (695 mg, 3.0 mmol), 2l (208 mg, 1.0 mmol), CsF (456 mg, 3.0 mmol), TEMPO+BF4− (1 M solution, 1.5 mL), and AcOH (56 μL) in dry acetonitrile (5.0 mL) gave 3l (267 mg, 73%) as a colorless oil after column chromatography (SiO2, 3% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 6.9 Hz, 2H), 7.35−7.22 (m, 3H), 7.22−7.16 (m, 1H), 7.13 (dd, J = 1.9, 8.2 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.00−5.82 (m, 1H), 5.20−5.07 (m, 2H), 4.12 (dd, J = 8.6, 16.6 Hz, 1H), 3.47−3.34 (m, 1H), 3.29 (dd, J = 5.8, 13.6 Hz, 1H), 3.20 (dd, J = 7.0, 13.6 Hz, 1H), 2.98−2.87 (m, 1H), 2.86−2.73 (m, 1H), 2.58−2.47 (m, 1H); 19F NMR (376 MHz, CDCl3) δ −69.8 (d, J = 206.9 Hz, 1F), −71.4 (dd, J = 15.3, 206.9 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3) δ 136.3 (2 × CH), 135.3 (CH), 134.5 (C), 132.2 (dd, J = 282.4, 289.3 Hz, CF2), 131.4 (C), 130.6 (C), 130.2 (CH),

HRMS (ESI-TOF) calcd for C24H22F2NO2S [M + H]+ 426.1339, found 426.1341. 2-Benzyl-1-(difluoro(phenylthio)methyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline (3f). According to the general procedure A, the reaction of 1 (696 mg, 3.0 mmol), 2f (253 mg, 1.0 mmol), CsF (456 mg, 3.0 mmol), TEMPO+BF4− (1 M solution, 1.5 mL), and AcOH (57 μL) in dry acetonitrile (5.0 mL) gave 3f (308 mg, 75%) as a colorless oil after column chromatography (SiO2, 5% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.2 Hz, 2H), 7.39 (d, J = 7.3 Hz, 2H), 7.32−7.16 (m, 6H), 7.08 (d, J = 8.3 Hz, 1H), 6.65 (d, J = 6.6 Hz, 1H), 6.61 (s, 1H), 4.11 (dd, J = 8.9, 15.1 Hz, 1H), 3.83 (d, J = 13.3 Hz, 1H), 3.77 (d, J = 13.3 Hz, 1H), 3.69 (s, 3H), 3.39−3.26 (m, 1H), 2.92−2.81 (m, 1H), 2.80−2.70 (m, 1H), 2.55 (d, J = 16.8 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −69.9 (d, J = 203.6 Hz, 1F), −71.4 (dd, J = 14.9, 203.6 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3) δ 158.0 (C), 137.5 (C), 136.5 (C), 135.1 (2 × CH), 131.5 (dd, J = 280.4, 286.8 Hz, CF2), 129.6 (d, J = 2.6 Hz, CH), 128.1 (CH), 128.0 (2 × CH), 127.6 (2 × CH and C), 127.3 (2 × CH), 126.3 (CH), 120.0 (C), 112.5 (CH), 111.2 (CH), 64.9 (t, J = 25.0 Hz, CH), 57.7 (CH2), 54.1 (CH3), 42.2 (CH2), 22.7 (CH2); IR (neat) νmax 1615m, 1473m, 1272m, 1070s cm−1; MS m/z (%) relative intensity 411 (M +, 10), 313 (100); HRMS (ESI-TOF) calcd for C24H24F2NOS [M + H]+ 412.1547, found 412.1552. 2-Benzyl-5-chloro-1-(difluoro(phenylthio)methyl)-6-methoxy1,2,3,4-tetrahydroisoquinoline (3g). According to the general procedure A, the reaction of 1 (696 mg, 3.0 mmol), 2g (288 mg, 1.0 mmol), CsF (456 mg, 3.0 mmol), TEMPO+BF4− (1 M solution, 1.5 mL), and AcOH (57 μL) in dry acetonitrile (5.0 mL) gave 3g (330 mg, 74%) as a pale yellow oil after column chromatography (SiO2, 2.5% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.2 Hz, 2H), 7.38 (d, J = 7.2 Hz, 2H), 7.32−7.19 (m, 6H), 7.36 (dd, J = 1.8, 8.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 4.09 (dd, J = 9.5, 15.9 Hz, 1H), 3.79 (s, 3H), 3.75 (d, J = 13.3 Hz, 1H), 3.70 (d, J = 13.3 Hz, 1H), 3.44−3.30 (m, 1H), 2.92 (dd, J = 6.1, 14.1 Hz, 1H), 2.86−2.73 (m, 1H), 2.61 (dd, J = 4.7, 17.7 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −69.5 (dd, J = 9.2, 205.7 Hz, 1F), −70.6 (dd, J = 15.3, 205.7 Hz, 1F); 13 C{H}NMR (100 MHz, CDCl3) δ 154.7 (C), 138.1 (C), 136.3 (2 × CH), 135.4 (C), 132.4 (dd, J = 281.1, 287.6 Hz, CF2), 129.3 (CH), 129.1 (2 × CH), 128.8 (2 × CH), 128.5 (2 × CH), 128.4 (CH), 128.3 (C), 127.5 (CH), 122.3 (C), 122.2 (C), 109.6 (CH), 65.6 (t, J = 25.4 Hz, CH), 58.0 (CH2), 56.1 (CH3), 42.4 (CH2), 21.1 (CH2); IR (neat) νmax 1598m, 1485s, 1278s cm−1; MS m/z (%) relative intensity 446 [(M + 1) + , 16], 286 (100); HRMS (ESI-TOF) calcd for C24H23ClF2NOS [M + H]+ 446.1161, found 446.1157. 2-Cinnamyl-1-(difluoro(phenylthio)methyl)-1,2,3,4-tetrahydroisoquinoline (3h). According to the general procedure A, the reaction of 1 (696 mg, 3.0 mmol), 2h (250 mg, 1.0 mmol), CsF (456 mg, 3.0 mmol), TEMPO+BF4− (1 M solution, 1.5 mL), and AcOH (57 μL) in dry acetonitrile (5.0 mL) gave 3h (207 mg, 51%) as a yellow oil after column chromatography (SiO2, 2.5% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 7.57−7.49 (m, 2H), 7.38−7.32 (m, 2H), 7.32− 7.23 (m, 5H), 7.23−7.15 (m, 3H), 7.13−7.04 (m, 2H), 6.46 (d, J = 15.9 Hz, 1H), 6.34 (ddd, J = 6.4, 6.4, 15.9 Hz, 1H), 4.23 (dd, J = 10.5, 14.1 Hz, 1H), 3.58−3.37 (m, 3H), 3.05−2.83 (m, 2H), 2.64 (d, J = 15.6 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −70.0 (d, J = 203.6 Hz, 1F), −71.7 (dd, J = 15.8, 203.6 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3) δ 135.8 (C), 135.2 (2 × CH), 131.9 (CH), 131.3 (dd, J = 281.5, 287.7 Hz, CF2), 128.6 (d, J = 3.8 Hz, CH), 128.1 (CH), 127.9 (CH), 127.7 (2 × CH and C), 127.6 (2 × CH), 127.3 (C), 126.7 (CH), 126.6 (CH and C), 126.1 (CH), 125.4 (2 × CH), 124.9 (CH), 64.8 (t, J = 25.0 Hz, CH), 55.9 (CH2), 43.7 (d, J = 2.1 Hz, CH2), 22.6 (CH2); IR (neat) νmax 1515s, 1225s, 1002s cm−1; MS m/z (%) relative intensity 407 (M +, 42), 248 (100); HRMS (ESI-TOF) calcd for C25H24F2NS [M + H]+ 408.1598, found 408.1603. 2-Cinnamyl-1-(difluoro(phenylthio)methyl)-6,7-dimethoxy1,2,3,4-tetrahydroisoquinoline (3i). According to the general procedure A, the reaction of 1 (348 mg, 1.5 mmol), 2i (155 mg, 0.5 mmol), CsF (228 mg, 1.5 mmol), TEMPO+BF4− (1 M solution, 0.75 mL), and AcOH (28 μL) in dry acetonitrile (2.5 mL) gave 3i (119 mg, 51%) as a yellow oil after column chromatography (SiO2, 5% EtOAc in 773

DOI: 10.1021/acs.joc.7b02783 J. Org. Chem. 2018, 83, 765−782

Article

The Journal of Organic Chemistry 129.4 (2 × CH), 128.8 (2 × CH), 127.0 (CH and C), 118.5 (CH2), 64.4 (t, J = 25.3 Hz, CH), 57.4 (CH2), 44.3 (d, J = 2.4 Hz, CH2), 22.7 (CH2); IR (neat) νmax 1483s, 1033s cm−1; MS m/z (%) relative intensity 366 [(M + 1)+, 65], 206 (100); HRMS (ESI-TOF) calcd for C19H19ClF2NS [M + H]+ 366.0895, found 366.0892. 2-(But-3-en-1-yl)-1-(difluoro(phenylthio)methyl)-1,2,3,4-tetrahydroisoquinoline (3m). According to the general procedure A, the reaction of 1 (696 mg, 3.0 mmol), 2m (188 mg, 1.0 mmol), CsF (456 mg, 3.0 mmol), TEMPO+BF4− (1 M solution, 1.5 mL), and AcOH (56 μL) in dry acetonitrile (5.0 mL) gave 3m (266 mg, 77%) as a pale yellow oil after column chromatography (SiO2, 2.5% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.6 Hz, 2H), 7.29−7.15 (m, 4H), 7.15−7.09 (m, 1H), 7.08−7.00 (m, 2H), 5.90− 5.70 (m, 1H), 5.02 (d, J = 17.2 Hz, 1H), 4.94 (d, J = 10.2 Hz, 1H), 4.12 (dd, J = 8.7, 16.2 Hz, 1H), 3.45−3.30 (m, 1H), 2.90−2.76 (m, 2H), 2.68 (t, J = 7.4 Hz, 2H), 2.60−2.50 (m, 1H), 2.37−2.20 (m, 2H); 19 F NMR (376 MHz, CDCl3) δ −69.6 (d, J = 203.4 Hz, 1F), −71.5 (dd, J = 15.7, 203.4 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3) δ 135.3 (CH), 135.2 (C), 135.1 (2 × CH), 131.5 (dd, J = 280.8, 287.8 Hz, CF2), 128.5 (d, J = 3.8 Hz, CH), 128.1 (CH and C), 127.8 (CH), 127.6 (2 × CH), 127.5 (d, J = 2.1 Hz, C), 126.7 (CH), 124.8 (CH), 114.9 (CH2), 65.1 (t, J = 24.9 Hz, CH), 53.1 (CH2), 43.5 (d, J = 2.2 Hz, CH2), 31.6 (CH2), 22.5 (CH2); IR (neat) νmax 1438m, 1099m cm−1; MS m/z (%) relative intensity 346 [(M + 1)+, 27], 186 (100); HRMS (ESI-TOF) calcd for C20H22F2NS [M + H]+ 346.1441, found 346.1446. 2-(But-3-en-1-yl)-1-(difluoro(phenylthio)methyl)-6,7-dimethoxy1,2,3,4-tetrahydroisoquinoline (3n). According to the general procedure A, the reaction of 1 (696 mg, 3.0 mmol), 2n (248 mg, 1.0 mmol), CsF (456 mg, 3.0 mmol), TEMPO+BF4− (1 M solution, 1.5 mL), and AcOH (56 μL) in dry acetonitrile (5.0 mL) gave 3n (271 mg, 67%) as a yellow oil after column chromatography (SiO2, 5% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 7.57−7.48 (m, 2H), 7.36−7.22 (m, 3H), 6.69 (d, J = 2.4 Hz, 1H), 6.54 (s, 1H), 5.91− 5.87 (m, 1H), 5.04 (dd, J = 1.7, 17.2 Hz, 1H), 4.96 (d, J = 10.2 Hz, 1H), 4.06 (dd, J = 8.6, 16.4 Hz, 1H), 3.78 (s, 3H), 3.73 (s, 3H), 3.44− 3.30 (m, 1H), 2.96−2.75 (m, 2H), 2.69 (t, J = 7.4 Hz, 2H), 2.50−2.40 (m, 1H), 2.38−2.24 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −69.4 (d, J = 201.0 Hz, 1F), −71.6 (dd, J = 16.0, 201.0 Hz, 1F); 13 C{H}NMR (100 MHz, CDCl3) δ 148.6 (C), 147.2 (C), 136.4 (CH), 136.2 (2 × CH and C), 132.7 (dd, J = 279.5, 287.5 Hz, CF2), 129.2 (CH), 128.7 (2 × CH), 128.3 (C), 120.6 (C), 115.9 (CH2), 112.0 (d, J = 4.0 Hz, CH), 111.3 (CH), 65.8 (t, J = 25.0 Hz, CH), 55.8 (CH3), 55.7 (CH3), 53.2 (CH2), 44.5 (CH2), 32.8 (CH2), 22.7 (CH2); IR (neat) νmax 1518s, 1228s, 1000s cm−1; MS m/z (%) relative intensity 406 (M+, 53), 246 (100); HRMS (ESI-TOF) calcd for C22H26F2NO2S [M + H]+ 406.1652, found 406.1649. (E)-1-(Difluoro(phenylthio)methyl)-2-(4-(3,4-dimethoxyphenyl)but-3-en-1-yl)-1,2,3,4-tetrahydroisoquinoline (3o). According to the general procedure A, the reaction of 1 (696 mg, 3.0 mmol), 2o (323 mg, 1.0 mmol), CsF (456 mg, 3.0 mmol), TEMPO+BF4− (1 M solution, 1.5 mL), and AcOH (56 μL) in dry acetonitrile (5.0 mL) gave 3o (380 mg, 79%) as a yellow oil after column chromatography (SiO2, 5% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3, the minor isomer was not assigned due to low intensity) δ 7.65 (d, J = 7.2 Hz, 2H), 7.48−7.33 (m, 4H), 7.32−7.26 (m, 1H), 7.25−7.17 (m, 2H), 7.02 (s, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 6.50 (d, J = 15.9 Hz, 1H), 6.31 (dt, J = 6.7, 15.9 Hz, 1H), 4.33 (dd, J = 8.7, 16.2 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.64−3.51 (m, 1H), 3.10−2.86 (m, 4H), 2.79−2.66 (m, 1H), 2.59 (q, J = 6.9 Hz, 2H); 19F NMR (376 MHz, CDCl3, the minor isomer was not assigned due to low intensity) δ −69.6 (dd, J = 9.1, 202.6 Hz, 1F), −71.6 (dd, J = 15.9, 202.6 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3, the minor isomer was not assigned due to low intensity) δ 149.0 (C), 148.4 (C), 136.3 (C), 136.2 (2 × CH), 132.7 (dd, J = 281.0, 287.5 Hz, CF2), 131.0 (C), 130.8 (CH), 129.6 (d, J = 4.0 Hz, CH), 129.3 (CH), 129.2 (C), 129.0 (CH), 128.8 (2 × CH), 128.6 (C), 127.8 (CH), 126.4 (CH), 126.0 (CH), 119.1 (CH), 111.2 (CH), 108.5 (CH), 66.5 (t, J = 25.0 Hz, CH), 55.9 (CH3), 55.8 (CH3), 54.6 (CH2), 44.4 (CH2), 31.7 (CH2), 23.6 (CH2); IR (neat) νmax 1677m, 1512s, 1262s, 1136s, 1022s cm−1;

MS m/z (%) relative intensity 481 (M+, 1), 303 (100); HRMS (ESITOF) calcd for C28H30F2NO2S [M + H]+ 482.1965, found 482.1961. (E)-1-(Difluoro(phenylthio)methyl)-2-(4-(3,4-dimethoxyphenyl)but-3-en-1-yl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (3p). According to the general procedure A, the reaction of 1 (696 mg, 3.0 mmol), 2p (384 mg, 1.0 mmol), CsF (456 mg, 3.0 mmol), TEMPO+BF4− (1 M solution, 1.5 mL), and AcOH (56 μL) in dry acetonitrile (5.0 mL) gave 3p (438 mg, 81%) as a yellow oil after column chromatography (SiO2, 7.5% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3, the Z-isomer was not assigned due to low intensity) δ 7.62 (d, J = 6.6 Hz, 2H), 7.46−7.33 (m, 3H), 6.96 (d, J = 1.6 Hz, 1H), 6.90 (dd, J = 1.8, 8.2 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 6.79 (d, J = 1.8 Hz, 1H), 6.65 (s, 1H), 6.45 (d, J = 15.8 Hz, 1H), 6.27 (dt, J = 6.9, 15.8 Hz, 1H), 4.20 (dd, J = 8.5, 16.4 Hz, 1H), 3.89 (s, 6H), 3.85 (s, 3H), 3.82 (s, 3H), 3.54−3.42 (m, 1H), 3.09−2.99 (m, 1H), 2.99−2.80 (m, 3H), 2.60−2.50 (m, 3H); 19F NMR (376 MHz, CDCl3, the Z-isomer was marked*) δ −69.3 (dd, J = 9.1, 201.3 Hz, 1F), −69.5 (dd, J = 8.8, 205.7 Hz, 1F*), −71.5 (dd, J = 18.6, 201.3 Hz, 1F), −71.7 (dd, J = 18.6, 205.7 Hz, 1F*); 13C{H}NMR (100 MHz, CDCl3, the Z-isomer was not assigned due to low intensity) δ 149.0 (C), 148.7 (C), 148.3 (C), 147.2 (C), 136.1 (2 × CH), 132.7 (dd, J = 281.1, 288.8 Hz, CF2), 130.9 (C), 130.7 (CH), 129.2 (CH), 128.8 (2 × CH), 128.6 (d, J = 3.2 Hz, C), 128.3 (C), 126.4 (CH), 120.6 (C), 119.0 (CH), 111.9 (d, J = 4.5 Hz, CH), 111.3 (CH), 111.1 (CH), 108.5 (CH), 66.1 (t, J = 24.7 Hz, CH), 55.9 (CH3), 55.8 (CH3), 55.7 (CH3), 55.6 (CH3), 54.2 (CH2), 44.2 (CH2), 31.8 (CH2), 22.7 (CH2); IR (neat) νmax 1513s, 1462m, 1262s, 1023s cm−1; MS m/z (%) relative intensity 541 (M+, 2), 363 (100); HRMS (ESI-TOF) calcd for C30H34F2NO4S [M + H]+ 542.2176, found 542.2176. (E)-1-(Difluoro(phenylthio)methyl)-2-(4-(3,4,5-trimethoxyphenyl)but-3-en-1-yl)-1,2,3,4-tetrahydroisoquinoline (3q). According to the general procedure A, the reaction of 1 (696 mg, 3.0 mmol), 2q (354 mg, 1.0 mmol), CsF (456 mg, 3.0 mmol), TEMPO+BF4− (1 M solution, 1.5 mL), and AcOH (56 μL) in dry acetonitrile (5.0 mL) gave 3q (454 mg, 89%) as a yellow oil after column chromatography (SiO2, 5% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3, the Zisomer was not assigned due to low intensity) δ 7.52−7.45 (m, 2H), 7.31−7.21 (m, 5H), 7.10−7.02 (m, 2H), 6.52 (s, 2H), 6.34 (d, J = 15.9 Hz, 1H), 6.23 (dt, J = 6.7, 15.9 Hz, 1H), 4.17 (dd, J = 8.7, 16.1 Hz, 1H), 3.74 (s, 3H), 3.73 (s, 6H), 3.47−3.35 (m, 1H), 2.98−2.72 (m, 3H), 2.67−2.52 (m, 2H), 2.51−2.40 (m, 2H); 19F NMR (376 MHz, CDCl3, the Z-isomer was marked*) δ −69.5 (dd, J = 9.2, 205.6 Hz, 1F), −69.7 (dd, J = 9.0, 201.5 Hz, 1F*), −71.5 (dd, J = 17.5, 205.6 Hz, 1F), −71.7 (dd, J = 18.4, 201.5 Hz, 1F*); 13C{H}NMR (100 MHz, CDCl3, the Z-isomer was marked*) δ 153.3 (3 × C), 153.0 (3 × C*), 137.3 (C*), 136.3 (C), 136.1 (2 × CH and 2 × CH*), 133.6 (C), 133.3 (C*), 132.6 (dd, J = 281.5, 292.8 Hz, CF2 and CF2*), 131.0 (CH), 130.1 (CH*), 129.6 (CH and CH*), 129.5 (CH and CH*), 129.3 (CH and CH*), 129.1 (C and C*), 128.9 (CH and CH*), 128.8 (2 × CH and 2 × CH*), 128.4 (C and C*), 128.0 (CH and CH*), 127.8 (CH and CH*), 126.0 (CH and CH*), 105.9 (CH*), 103.0 (CH), 66.6 (t, J = 25.1 Hz, CH), 66.0 (d, J = 25.1 Hz, CH*), 60.9 (CH3 and CH3*), 56.1 (2 × CH3*), 56.0 (2 × CH3), 54.5 (CH2*), 54.4 (CH2), 44.8 (CH2*), 44.2 (CH2), 31.6 (CH2), 27.8 (CH2*), 23.5 (CH2 and CH2*); IR (neat) νmax 1579m, 1504m, 1236s, 1122s cm−1; MS m/z (%) relative intensity 304 (100); HRMS (ESITOF) calcd for C29H32F2NO3S [M + H]+ 512.2071, found 512.2079. (E)-1-(Difluoro(phenylthio)methyl)-6,7-dimethoxy-2-(4-(3,4,5trimethoxyphenyl)but-3-en-1-yl)-1,2,3,4-tetrahydroisoquinoline (3r). According to the general procedure A, the reaction of 1 (696 mg, 3.0 mmol), 2r (414 mg, 1.0 mmol), CsF (456 mg, 3.0 mmol), TEMPO+BF4− (1 M solution, 1.5 mL), and AcOH (56 μL) in dry acetonitrile (5.0 mL) gave 3r (411 mg, 72%) as a yellow oil after column chromatography (SiO2, 7.5% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3, the Z-isomer was marked*) δ 7.51 (d, J = 6.4 Hz, 2H and 2H*), 7.34−7.23 (m, 3H and 3H*), 6.71−6.67 (m, 1H and 1H*), 6.55 (s, 1H), 6.54 (s, 1H*), 6.52 (s, 2H), 6.47 (s, 2H*), 6.37 (d, J = 11.4 Hz, 1H*), 6.35 (d, J = 15.8 Hz, 1H), 6.24 (dt, J = 6.6, 15.8 Hz, 1H), 5.68 (dt, J = 6.8, 13.5 Hz, 1H*), 4.15−4.00 (m, 1H and 1H*), 3.80−3.70 (m, 15H and 15H*), 3.45−3.32 (m, 1H and 1H*), 3.00− 774

DOI: 10.1021/acs.joc.7b02783 J. Org. Chem. 2018, 83, 765−782

Article

The Journal of Organic Chemistry 2.70 (m, 4H and 4H*), 2.67−2.58 (m, 2H*), 2.53−2.38 (m, 3H and 1H*); 19F NMR (376 MHz, CDCl3, the Z-isomer was marked*) δ −69.2 (dd, J = 9.2, 201.5 Hz, 1F), −69.4 (dd, J = 9.1, 201.4 Hz, 1F*), −71.4 (dd, J = 18.5, 201.5 Hz, 1F), −71.7 (dd, J = 18.5, 201.4 Hz, 1F*); 13C{H}NMR (100 MHz, CDCl3, the Z-isomer was marked*) δ 153.3 (2 × C), 153.0 (2 × C*), 137.3 (C*), 148.7 (C and C*), 147.2 (C and C*), 137.3 (C and C*), 136.1 (2 × CH and 2 × CH*), 133.6 (C), 133.3 (C*), 132.7 (dd, J = 281.9, 290.5 Hz, CF2 and CF2*), 130.9 (CH), 130.0 (CH*), 129.6 (CH*), 129.3 (CH), 128.8 (3 × CH and 3 × CH*), 128.5 (C and C*), 128.3 (C), 128.2 (CH*), 128.0 (CH and CH*), 120.6 (C), 120.4 (C*), 111.9 (d, J = 4.3 Hz, CH and CH*), 111.3 (CH and CH*), 105.9 (CH*), 103.0 (CH), 66.2 (t, J = 25.3 Hz, CH), 65.6 (d, J = 24.9 Hz, CH*), 60.9 (CH3 and CH3*), 56.1 (2 × CH3*), 56.0 (2 × CH3), 55.8 (CH3 and CH3*), 55.7 (CH3 and CH3*), 54.2 (CH2*), 54.1 (CH2), 44.7 (CH2*), 44.1 (CH2), 31.6 (CH2), 28.0 (CH2*), 22.7 (CH2 and CH2*); IR (neat) νmax 1580m, 1120s, 1099s, 1003s cm−1; MS m/z (%) relative intensity 572 [(M + 1)+, 3], 364 (100); HRMS (ESI-TOF) calcd for C31H36F2NO5S [M + H]+ 572.2282, found 572.2284. 1-(Difluoro(phenylthio)methyl)-6,7-dimethoxy-2-(prop-2-yn-1yl)-1,2,3,4-tetrahydroisoquinoline (4a). According to the general procedure A, the reaction of 1 (696 mg, 3.0 mmol), 2s (231 mg, 1.0 mmol), CsF (456 mg, 3.0 mmol), TEMPO+BF4− (1 M solution, 1.5 mL), and AcOH (56 μL) in dry acetonitrile (5.0 mL) gave 4a (250 mg, 64%) as a colorless oil after column chromatography (SiO2, 5% EtOAc in hexanes). According to the general procedure A, the reaction of 1 (696 mg, 3.0 mmol), 2t (303 mg, 1.0 mmol), CsF (456 mg, 3.0 mmol), TEMPO+BF4− (1 M solution, 1.5 mL), and AcOH (56 μL) in dry acetonitrile (5.0 mL) gave 4a (249 mg, 64%) as a colorless oil after column chromatography (SiO2, 5% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 6.5 Hz, 2H), 7.35−7.20 (m, 3H), 6.71 (s, 1H), 6.57 (s, 1H), 4.35 (dd, J = 7.6, 12.4 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.72 (dd, J = 2.3, 17.1 Hz, 1H), 3.51 (dd, J = 2.3, 17.1 Hz, 1H), 3.27−3.16 (m, 1H), 3.04−2.94 (m, 1H), 2.86−2.75 (m, 1H), 2.75−2.65 (m, 1H), 2.17 (t, J = 2.3 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −70.4 (d, J = 202.2 Hz, 1F), −73.6 (dd, J = 12.7, 202.2 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3) δ 148.6 (C), 147.2 (C), 136.3 (2 × CH), 132.4 (dd, J = 282.1, 287.0 Hz, CF2), 129.3 (CH), 129.0 (C), 128.7 (2 × CH), 127.7 (C), 120.9 (C), 112.3 (CH), 110.9 (CH), 79.6 (C), 73.2 (CH), 65.2 (t, J = 24.8 Hz, CH), 55.9 (CH3), 55.8 (CH3), 46.5 (CH2), 44.8 (CH2), 26.0 (CH2); IR (neat) νmax 1608m, 1515s, 1462s, 1228s, 1123s, 1002s cm−1; MS m/z (%) relative intensity 390 [(M + 1)+, 100]; HRMS (ESI-TOF) calcd for C21H22F2NO2S [M + H]+ 390.1339, found 390.1344. 2-(3-(tert-Butyldimethylsilyl)prop-2-yn-1-yl)-1-(difluoro(phenylthio)methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (4c). According to the general procedure A, the reaction of 1 (696 mg, 3.0 mmol), 2u (346 mg, 1.0 mmol), CsF (456 mg, 3.0 mmol), TEMPO+BF4− (1 M solution, 1.5 mL), and AcOH (56 μL) in dry acetonitrile (5.0 mL) gave 4a (199 mg, 51%) as a colorless oil and 4c (111 mg, 22%) as a pale yellow oil after column chromatography (SiO2, 2.5% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 7.55− 7.47 (m, 2H), 7.38−7.26 (m, 3H), 6.71 (s, 1H), 6.59 (s, 1H), 4.43 (dd, J = 4.7, 13.6 Hz, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.76 (d, J = 17.2 Hz, 1H), 3.54 (d, J = 17.2 Hz, 1H), 3.32−3.21 (m, 1H), 3.05−2.95 (m, 1H), 2.85−2.70 (m, 2H), 0.82 (s, 9H), 0.00 (s, 6H); 19F NMR (376 MHz, CDCl3) δ −70.9 (d, J = 200.9 Hz, 1F), −73.7 (dd, J = 13.0, 200.9 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3) δ 148.6 (C), 147.1 (C), 136.2 (2 × CH), 132.4 (dd, J = 282.0, 286.0 Hz, CF2), 129.2 (CH), 129.1 (C), 128.7 (2 × CH), 127.9 (C), 121.0 (C), 112.3 (CH), 110.9 (CH), 102.6 (C), 82.2 (C), 65.0 (t, J = 25.0 Hz, CH), 55.9 (CH3), 55.8 (CH3), 46.8 (CH2), 46.0 (CH2), 26.0 (3 × CH3), 25.9 (CH2), 16.4 (C), −4.6 (2 × CH3); IR (neat) νmax 2163w, 1609w, 1516s, 1462m, 1228s cm−1; MS m/z (%) relative intensity 504 [(M + 1)+, 3], 344 (100); HRMS (ESI-TOF) calcd for C27H36F2NO2SSi [M + H]+ 504.2204, found 504.2200. Synthesis of Compounds 5. General Procedure B. A solution of compounds 3c−3g (1.0 mmol) in dry MeOH (2.5 mL) was cooled to 0 °C, then 1 M solution of HCl in MeOH (1.0 mL) was added

dropwise. After 30 min, the solvent was removed under high vacuum to dryness followed by dry MeOH (5.0 mL) was then added. The mixture was treated with 10% Pd/C (50 mg) under argon atmosphere. The mixture was stirred at room temperature for 16 h under an H2 (balloon) atmosphere. The mixture was filtered through a Celite pad and washed with CH2Cl2. After the removal of solvents, a crude product was purified by column chromatography (SiO2) to give compounds 5. 1-(Difluoro(phenylthio)methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (5a). According to the general procedure B, the reaction of 3c (331 mg, 0.75 mmol), 1 M solution of HCl in MeOH (0.75 mL) and 10% Pd/C (38 mg) in dry MeOH (4.0 mL) under an H2 (balloon) atmosphere gave 5a (224 mg, 85%) as a yellow viscous oil after column chromatography (SiO2, 25% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 6.4 Hz, 2H), 7.42−7.28 (m, 3H), 6.85 (s, 1H), 6.62 (s, 1H), 4.47 (dd, J = 6.8, 14.4 Hz, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 3.43−3.31 (m, 1H), 3.05 (dt, J = 6.2, 12.3 Hz, 1H), 2.82 (dt, J = 5.3, 16.0 Hz, 1H), 2.76−2.64 (m, 1H), 2.15 (br. s, 1H); 19F NMR (376 MHz, CDCl3) δ −72.0 (dd, J = 6.1, 206.1 Hz, 1F), −73.4 (dd, J = 13.8, 206.1 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3) δ 148.5 (C), 147.1 (C), 136.4 (2 × CH), 132.2 (dd, J = 282.1, 285.6 Hz, CF2), 129.5 (CH), 129.1 (C), 128.9 (2 × CH), 127.2 (C), 121.8 (C), 111.5 (CH), 111.2 (CH), 60.8 (t, J = 23.9 Hz, CH), 55.9 (CH3), 55.7 (CH3), 40.1 (CH2), 28.9 (CH2); IR (neat) νmax 3343br, 1609m, 1504m, 1241s, 1011s cm−1; MS m/z (%) relative intensity 351 (M+, 10), 192 (100); HRMS (ESI-TOF) calcd for C18H20F2NO2S [M + H]+ 352.1183, found 352.1193. 1-(Difluoro(phenylthio)methyl)-1,2,3,4-tetrahydroisoquinoline (5b). According to the general procedure B, the reaction of 3d (286 mg, 0.75 mmol), 1 M solution of HCl in MeOH (0.75 mL) and 10% Pd/C (38 mg) in dry MeOH (4.0 mL) under an H2 (balloon) atmosphere gave 5b (195 mg, 89%) as a colorless viscous oil after column chromatography (SiO2, 20% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 6.8 Hz, 2H), 7.34−7.21 (m, 4H), 7.19−7.04 (m, 3H), 4.46 (dd, J = 6.9, 14.7 Hz, 1H), 3.38−3.25 (m, 1H), 2.98 (dt, J = 5.4, 11.8 Hz, 1H), 2.83 (dt, J = 5.4, 16.2 Hz, 1H), 2.78−2.67 (m, 1H), 2.05 (br. s, 1H); 19F NMR (376 MHz, CDCl3) δ −72.0 (dd, J = 6.6, 206.0 Hz, 1F), −73.6 (dd, J = 14.4, 206.0 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3) δ 136.7 (C), 136.4 (2 × CH), 132.1 (dd, J = 284.1, 287.4 Hz, CF2), 130.2(C), 129.5 (CH), 129.3 (CH), 128.9 (2 × CH), 128.6 (CH), 127.7 (CH), 127.2 (C), 125.9 (CH), 60.8 (t, J = 24.0 Hz, CH), 40.1 (CH2), 29.2 (CH2); IR (neat) νmax 3351br, 1439m, 982s cm−1; MS m/z (%) relative intensity 292 [(M + 1)+, 51], 291 (M+, 93), 132 (100); HRMS (ESI-TOF) calcd for C16H16F2NS [M + H]+ 292.0972, found 292.0971. 5-(Difluoro(phenylthio)methyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline (5c). According to the general procedure B, the reaction of 3e (319 mg, 0.75 mmol), 1 M solution of HCl in MeOH (0.75 mL) and 10% Pd/C (38 mg) in dry MeOH (4.0 mL) under an H2 (balloon) atmosphere gave 5c (218 mg, 87%) as a yellow viscous oil after column chromatography (SiO2, 25% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 6.8 Hz, 2H), 7.35−7.23 (m, 3H), 6.76 (s, 1H), 6.53 (s, 1H), 5.85 (d, J = 2.5 Hz, 2H), 4.36 (dd, J = 6.7, 14.2 Hz, 1H), 3.33−3.23 (m, 1H), 3.01−2.89 (m, 1H), 2.79−2.56 (m, 2H), 2.34−1.39 (br., 1H); 19F NMR (376 MHz, CDCl3) δ −72.1 (d, J = 203.7 Hz, 1F), −73.5 (dd, J = 13.7, 203.7 Hz, 1F); 13 C{H}NMR (100 MHz, CDCl3) δ 147.1 (C), 145.9 (C), 136.4 (2 × CH), 132.1 (dd, J = 283.6, 287.0 Hz, CF2), 130.5 (C), 129.5 (CH), 128.9 (2 × CH), 127.1 (C), 122.8 (C), 108.9 (CH), 108.4 (CH), 100.9 (CH2), 60.9 (t, J = 24.1 Hz, CH), 40.0 (CH2), 29.5 (CH2); IR (neat) νmax 3351br, 1503m, 1482s, 1035s cm−1; MS m/z (%) relative intensity 335 (M+, 21), 176 (100); HRMS (ESI-TOF) calcd for C17H16F2NO2S [M + H]+ 336.0870, found 336.0871. 1-(Difluoro(phenylthio)methyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline (5d). According to the general procedure B, the reaction of 3f (309 mg, 0.75 mmol), 1 M solution of HCl in MeOH (0.75 mL) and 10% Pd/C (38 mg) in dry MeOH (4.0 mL) under an H2 (balloon) atmosphere gave 5d (219 mg, 91%) as a pale yellow viscous oil after column chromatography (SiO2, 20% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.0 Hz, 2H), 7.34−7.16 (m, 4H), 775

DOI: 10.1021/acs.joc.7b02783 J. Org. Chem. 2018, 83, 765−782

Article

The Journal of Organic Chemistry 6.66 (dd, J = 2.4, 8.6 Hz, 1H), 6.59 (s, 1H), 4.42 (dd, J = 6.8, 14.2 Hz, 1H), 3.36−3.23 (m, 1H), 3.00−2.90 (m, 1H), 2.87−2.75 (m, 1H), 2.75−2.62 (m, 1H), 2.07 (br. s, 1H); 19F NMR (376 MHz, CDCl3) δ −72.5 (d, J = 205.8 Hz, 1F), −73.9 (dd, J = 13.8, 205.8 Hz, 1F); 13 C{H}NMR (100 MHz, CDCl3) δ 158.9 (C), 138.2 (C), 136.4 (2 × CH), 132.1 (dd, J = 282.6, 286.1 Hz, CF2), 129.8 (CH), 129.5 (CH), 128.9 (2 × CH), 127.2 (C), 122.3 (C), 113.7 (CH), 112.2 (CH), 60.4 (t, J = 24.0 Hz, CH), 40.0 (CH2), 29.8 (CH2); IR (neat) νmax 3354br, 1514m, 1216m, 1016m cm−1; MS m/z (%) relative intensity 321 (M+, 11), 162 (100); HRMS (ESI-TOF) calcd for C17H18F2NOS [M + H]+ 322.1077, found 322.1087. 5-Chloro-1-(difluoro(phenylthio)methyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline (5e). According to the general procedure B, the reaction of 3g (268 mg, 0.6 mmol), 1 M solution of HCl in MeOH (0.6 mL) and 10% Pd/C (30 mg) in dry MeOH (3.5 mL) under an H2 (balloon) atmosphere gave 5e (199 mg, 93%) as a pale yellow viscous oil after column chromatography (SiO2, 20% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 6.7 Hz, 2H), 7.31−7.18 (m, 3H), 7.14 (d, J = 9.2 Hz, 1H), 6.67 (d, J = 8.7 Hz, 1H), 4.35 (dd, J = 7.3, 14.7 Hz, 1H), 3.77 (s, 3H), 3.32−2.22 (m, 1H), 2.99 (dt, J = 5.2, 12.6 Hz, 1H), 2.78 (dt, J = 5.2, 17.2 Hz, 1H), 2.74−2.63 (m, 1H), 2.36−1.31 (br., 1H); 19F NMR (376 MHz, CDCl3) δ −71.8 (d, J = 205.3 Hz, 1F), −72.8 (dd, J = 14.8, 205.3 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3) δ 154.5 (C), 136.3 (2 × CH), 136.2 (C), 131.9 (dd, J = 285.0, 286.6 Hz, CF2), 129.6 (CH), 128.9 (2 × CH), 127.5 (CH), 127.0 (C), 123.9 (C), 122.3 (C), 109.3 (CH), 60.3 (t, J = 24.1 Hz, CH), 56.1 (CH3), 39.3 (CH2), 27.3 (CH2); IR (neat) νmax 3361br, 1597m, 1485s, 1274s, 1068s cm−1; MS m/z (%) relative intensity 356 [(M + 1) + , 22], 196 (100); HRMS (ESI-TOF) calcd for C17H17ClF2NOS [M + H]+ 356.0687, found 356.0684. Synthesis of Compounds 4a−4b and 4d−4g. General Procedure C. A mixture of compound 5 (1.0 mmol), propargyl bromide (0.30 g, 2.5 mmol) or 3-(trimethylsilyl)propargyl bromide (0.48 g, 2.5 mmol) and anhydrous K2CO3 (0.28 g, 2.0 mmol) in dry acetone (5 mL) was refluxed for 16 h. The solid was filtered off and washed with CH2Cl2. After the removal of solvents, a crude product was purified by column chromatography (SiO2). 1-(Difluoro(phenylthio)methyl)-6,7-dimethoxy-2-(prop-2-yn-1yl)-1,2,3,4-tetrahydroisoquinoline (4a). According to the general procedure C, the reaction of 5a (351 mg, 1.0 mmol), propargyl bromide (0.30 g, 2.5 mmol) and anhydrous K2CO3 (0.28 g, 2.0 mmol) in dry acetone (5 mL) gave 4a (335 mg, 86%) as a colorless oil after column chromatography (SiO2, 5% EtOAc in hexanes). 1-(Difluoro(phenylthio)methyl)-6,7-dimethoxy-2-(3-(trimethylsilyl)prop-2-yn-1-yl)-1,2,3,4-tetrahydroisoquinoline (4b). According to the general procedure C, the reaction of 5a (210 mg, 0.6 mmol), 3(trimethylsilyl)propargyl bromide (211 mg, 1.5 mmol) and anhydrous K2CO3 (166 mg, 1.2 mmol) in dry acetone (3 mL) gave 4b (263 mg, 95%) as a pale yellow oil after column chromatography (SiO2, 5% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 7.48−7.40 (m, 2H), 7.29−7.17 (m, 3H), 6.67 (s, 1H), 6.52 (s, 1H), 4.30 (dd, J = 7.5, 14.0 Hz, 1H), 3.76 (s, 3H), 3.71 (s, 3H), 3.65 (d, J = 17.2 Hz, 1H), 3.45 (d, J = 17.2 Hz, 1H), 3.25−3.15 (m, 1H), 2.98−2.85 (m, 1H), 2.77−2.62 (m, 1H), −0.01 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −70.7 (d, J = 201.0 Hz, 1F), −73.6 (dd, J = 13.7, 201.0 Hz, 1F); 13 C{H}NMR (100 MHz, CDCl3) δ 148.6 (C), 147.2 (C), 136.3 (2 × CH), 132.4 (dd, J = 281.9, 287.0 Hz, CF2), 129.3 (CH), 129.1 (C), 128.8 (2 × CH), 128.0 (C), 121.0 (C), 112.3 (CH), 102.1 (C), 90.0 (C), 65.0 (t, J = 24.9 Hz, CH), 56.0 (CH3), 55.8 (CH3), 46.6 (CH2), 45.9 (CH2), 25.7 (CH2), 0.00 (3 × CH3); IR (neat) νmax 2160m, 1516s, 1249s, 1227s cm−1; MS m/z (%) relative intensity 461 (M+, 6), 302 (100); HRMS (ESI-TOF) calcd for C24H30F2NO2SSi [M + H]+ 462.1735, found 462.1745. 1-(Difluoro(phenylthio)methyl)-2-(3-(trimethylsilyl)prop-2-yn-1yl)-1,2,3,4-tetrahydroisoquinoline (4d). According to the general procedure C, the reaction of 5b (175 mg, 0.6 mmol), 3-(trimethylsilyl)propargyl bromide (287 mg, 1.5 mmol) and anhydrous K2CO3 (166 mg, 1.2 mmol) in dry acetone (3 mL) gave 4d (219 mg, 91%) as a colorless oil after column chromatography (SiO2, 2.5% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 7.0 Hz, 2H),

7.29−7.18 (m, 4H), 7.18−7.12 (m, 1H), 7.12−7.04 (m, 2H), 4.42 (dd, J = 7.7, 13.6 Hz, 1H), 3.74 (d, J = 17.4 Hz, 1H), 3.49 (d, J = 17.4 Hz, 1H), 3.28−3.18 (m, 1H), 2.99−2.71 (m, 1H), −0.03 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −71.0 (dd, J = 6.1, 201.8 Hz, 1F), −74.2 (dd, J = 13.3, 201.8 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3) δ 137.1 (C), 136.4 (2 × CH), 132.3 (dd, J = 282.8, 286.7 Hz, CF2), 129.8 (CH), 129.4 (CH and C), 128.8 (2 × CH), 128.4 (CH), 127.9 (C), 127.8 (CH), 126.1 (CH), 102.0 (C), 91.1 (C), 65.6 (t, J = 24.8 Hz, CH), 47.0 (CH2), 46.3 (CH2), 26.9 (CH2), −0.02 (3 × CH3); IR (neat) νmax 2165m, 1249m cm−1; MS m/z (%) relative intensity 402 [(M + 1) + , 15], 242 (100); HRMS (ESI-TOF) calcd for C22H26F2NSSi [M + H]+ 402.1523, found 402.1519. 5-(Difluoro(phenylthio)methyl)-6-(3-(trimethylsilyl)prop-2-yn-1yl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline (4e). According to the general procedure C, the reaction of 5c (201 mg, 0.6 mmol), 3-(trimethylsilyl)propargyl bromide (211 mg, 1.5 mmol) and anhydrous K2CO3 (166 mg, 1.2 mmol) in dry acetone (3 mL) gave 4e (222 mg, 83%) as a pale yellow oil after column chromatography (SiO2, 5% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 6.8 Hz, 2H), 7.29−7.16 (m, 3H), 6.65 (s, 1H), 6.50 (s, 1H), 5.81 (s, 1H), 5.79 (s, 1H), 4.27 (dd, J = 7.4, 13.7 Hz, 1H), 3.65 (d, J = 17.3 Hz, 1H), 3.43 (d, J = 17.3 Hz, 1H), 3.23−3.11 (m, 1H), 2.93−2.83 (m, 1H), 2.76−2.59 (m, 2H), −0.01 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −71.0 (dd, J = 9.1, 202.0 Hz, 1F), −73.9 (dd, J = 13.6, 202.0 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3) δ 147.3 (C), 146.0 (C), 136.3 (2 × CH), 132.3 (dd, J = 284.3, 288.5 Hz, CF2), 130.7 (C), 129.3 (CH), 128.8 (2 × CH), 127.9 (C), 122.2 (C), 109.6 (CH), 108.4 (CH), 102.0 (C), 101.0 (CH2), 65.5 (t, J = 25.0 Hz, CH), 46.6 (CH2), 46.1 (CH2), 26.6 (CH2), 0.00 (3 × CH3); IR (neat) νmax 2165w, 1483s, 1223s, 1035s cm−1; MS m/z (%) relative intensity 445 (M+, 2), 286 (100); HRMS (ESI-TOF) calcd for C23H26F2NO2SSi [M + H]+ 446.1422, found 446.1420. 1-(Difluoro(phenylthio)methyl)-6-methoxy-2-(3-(trimethylsilyl)prop-2-yn-1-yl)-1,2,3,4-tetrahydroisoquinoline (4f). According to the general procedure C, the reaction of 5d (193 mg, 0.6 mmol), 3(trimethylsilyl)propargyl bromide (211 mg, 1.5 mmol) and anhydrous K2CO3 (166 mg, 1.2 mmol) in dry acetone (3 mL) gave 4f (238 mg, 92%) as a pale yellow oil after column chromatography (SiO2, 2.5% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 7.6 Hz, 2H), 7.30−7.18 (m, 3H), 7.11 (d, J = 8.4 Hz, 1H), 6.65 (dd, J = 2.1, 8.4 Hz, 1H), 6.60 (s, 1H), 4.37 (dd, J = 7.7, 13.1 Hz, 1H), 3.72 (d, J = 17.4 Hz, 1H), 3.70 (s, 3H), 3.48 (d, J = 17.4 Hz, 1H), 3.25−3.13 (m, 1H), 2.97−2.78 (m, 2H), 2.78−2.67 (m, 1H), 0.00 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −71.3 (d, J = 202.6 Hz, 1F), −74.5 (dd, J = 12.7, 202.6 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3) δ 159.1 (C), 138.5 (C), 136.3 (2 × CH), 132.3 (dd, J = 286.3, 286.3 Hz, CF2), 130.8 (CH), 129.3 (CH), 128.8 (2 × CH), 127.9 (C), 121.8 (C), 113.2 (CH), 102.0 (C), 90.1 (C), 65.1 (t, J = 24.9 Hz, CH), 55.3 (CH3), 46.9 (CH2), 46.3 (CH2), 27.3 (CH2), 0.00 (3 × CH3); IR (neat) νmax 2165br, 1609m, 1516s, 1227s cm−1; MS m/z (%) relative intensity 431 (M+, 4), 272 (100); HRMS (ESI-TOF) calcd for C23H28F2NOSSi [M + H]+ 432.1629, found 432.1622. 5-Chloro-1-(difluoro(phenylthio)methyl)-6-methoxy-2-(3(trimethylsilyl)prop-2-yn-1-yl)-1,2,3,4-tetrahydroisoquinoline (4g). According to the general procedure C, the reaction of 5e (214 mg, 0.6 mmol), 3-(trimethylsilyl)propargyl bromide (211 mg, 1.5 mmol) and anhydrous K2CO3 (166 mg, 1.2 mmol) in dry acetone (3 mL) gave 4g (276 mg, 99%) as a yellow oil after column chromatography (SiO2, 2.5% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 6.7 Hz, 2H), 7.31−7.18 (m, 3H), 7.11 (d, J = 8.3 Hz, 1H), 6.71 (d, J = 8.7 Hz, 1H), 4.35 (dd, J = 7.8, 14.8 Hz, 1H), 3.80 (s, 3H), 3.64 (d, J = 17.2 Hz, 1H), 3.44 (d, J = 17.2 Hz, 1H), 3.35−3.22 (m, 1H), 3.01 (dt, J = 5.2, 13.1 Hz, 1H), 2.90 (ddd, J = 5.2, 8.5, 17.2 Hz, 1H), 2.74 (dt, 5.2, 17.2 Hz, 1H), 0.00 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −70.9 (d, J = 201.1 Hz, 1F), −73.4 (dd, J = 14.5, 201.1 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3) δ 154.8 (C), 136.4 (2 × CH), 132.2 (dd, J = 282.9, 288.4 Hz, CF2), 129.4 (CH), 128.9 (2 × CH), 128.6 (CH), 128.0 (C), 123.0 (2 × C), 121.8 (C), 109.6 (CH), 102.0 (C), 90.3 (C), 64.9 (t, J = 25.3 Hz, CH), 56.3 (CH3), 45.9 (CH2), 45.7 (CH2), 23.8 (CH2), −0.01 (3 × CH3); IR (neat) νmax 2166w, 776

DOI: 10.1021/acs.joc.7b02783 J. Org. Chem. 2018, 83, 765−782

Article

The Journal of Organic Chemistry 1484m, 1277s cm−1; MS m/z (%) relative intensity 466 [(M + 1)+, 22], 306 (100); HRMS (ESI-TOF) calcd for C23H27ClF2NOSSi [M + H]+ 466.1239, found 466.1238. Synthesis of Compounds 6 and 7. General Procedure D. An argon gas was bubbled though a solution of compound 3 or 4 (0.5 mmol) and Bu3SnH (0.24 mL, 0.88 mmol) in dry toluene (20 mL) for 15 min. The mixture was heated to reflux and a degassed solution of AIBN (25 mg, 0.15 mmol) in dry toluene (10 mL) was added at reflux over 1.5 h period. The reaction mixture was further refluxed for 14 h. The solution mixture was directly subjected to column chromatography (SiO2, 100% hexanes 300 mL to remove tin−byproducts then 15−25% EtOAc in hexanes) to give an isomeric mixture of product 6 or 7. 2-Benzyl-1,1-difluoro-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline (6a). According to the general procedure D, the reaction of 3h (204 mg, 0.5 mmol), Bu3SnH (0.24 mL, 0.88 mmol), and AIBN (25 mg, 0.15 mmol) in dry toluene (30 mL) under reflux conditions for 16 h gave a mixture of isomers of 6a (136 mg, 91%, dr = 1:3.4) as a brown viscous oil after column chromatography (SiO2, 100% henanes then 15% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3, the minor isomer was marked*) δ 7.34−7.02 (m, 9H and 9H*), 4.03 (dd, J = 7.8, 19.9 Hz, 1H*), 3.69 (dd, J = 12.0, 16.9 Hz, 1H), 3.14−2.88 (m, 4H and 3H*), 2.88−2.47 (m, 4H and 6H*), 2.46−2.37 (m, 1H); 19F NMR (376 MHz, CDCl3, the minor isomer was marked*) δ −96.1 (ddd, J = 20.2, 20.2, 228.8 Hz, 1F), −103.7 (d, J = 225.5 Hz, 1F*), −106.7 (d, J = 228.8 Hz, 1F), −116.1 (ddd, J = 17.3, 17.3, 225.5 Hz, 1F*); 13C{H}NMR (100 MHz, CDCl3, the minor isomer was marked*) δ 139.4 (C*), 139.0 (C), 135.9 (C*), 135.1 (C), 130.7 (d, J = 4.0 Hz, C*), 130.3 (C), 128.9 (CH), 128.8 (3 × CH*), 128.7 (2 × CH), 128.6 (2 × CH), 128.5 (2 × CH*), 128.3 (dd, J = 254.4, 257.6 Hz, CF2 and CF2*), 127.2 (CH), 127.1 (CH*), 126.5 (CH), 126.4 (CH*), 126.3 (CH*), 126.0 (CH*), 125.9 (CH), 125.8 (CH), 68.0 (dd, J = 24.3, 28.2 Hz, CH), 66.6 (t, J = 25.3, CH*), 57.6 (t, J = 3.8 Hz, CH2), 55.0 (d, J = 7.9 Hz, CH2*), 48.5 (CH2), 48.3 (CH2*), 46.6 (dd, J = 20.1, 25.2 Hz, CH), 46.1 (t, J = 21.7 Hz, CH*), 33.9 (d, J = 9.1 Hz, CH2), 32.6 (d, J = 9.1 Hz, CH2*), 28.8 (CH2), 27.1 (CH2*); IR (neat) νmax 1452m, 1177m, 1129m cm−1; MS m/z (%) relative intensity 300 [(M + 1)+, 51], 221 (100); HRMS (ESI-TOF) calcd for C19H20F2N [M + H]+ 300.1564, found 300.1563. 2-Benzyl-1,1-difluoro-8,9-dimethoxy-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline (6b). According to the general procedure D, the reaction of 3i (234 mg, 0.5 mmol), Bu3SnH (0.24 mL, 0.88 mmol), and AIBN (25 mg, 0.15 mmol) in dry toluene (30 mL) under reflux conditions for 16 h gave a mixture of isomers of 6b (153 mg, 85%, dr = 1:3.2) as a brown viscous oil after column chromatography (SiO2, 100% henanes then 25% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3, the minor isomer was marked*) δ 7.39−7.30 (m, 2H and 2H*), 7.29−7.22 (m, 3H and 3H*), 6.87 (s, 1H), 6.86 (s, 1H*), 6.67 (s, 1H and 1H*), 4.01 (dd, J = 8.2, 19.0 Hz, 1H*), 3.90 (s, 3H), 3.89 (s, 3H*), 3.88 (s, 3H*), 3.87 (s, 3H), 3.75 (dd, J = 12.1, 16.8 Hz, 1H), 3.24−2.81 (m, 5H and 5H*), 2.80−2.50 (m, 4H and 4H*); 19F NMR (376 MHz, CDCl3, the minor isomer was marked*) δ −96.1 (ddd, J = 20.0, 20.0, 227.9 Hz, 1F), −103.5 (d, J = 224.2 Hz, 1F*), −106.9 (d, J = 227.9 Hz, 1F), −115.9 (ddd, J = 16.7, 16.7, 224.2 Hz, 1F*); 13 C{H}NMR (100 MHz, CDCl3, the minor isomer was marked*) δ 148.3 (C), 148.2 (C*), 147.4 (C*), 147.3 (C), 139.3 (C*), 138.9 (C), 128.8 (2 × CH*), 128.7 (2 × CH), 128.6 (2 × CH), 128.5 (2 × CH*), 128.4 (dd, J = 254.3, 258.9 Hz, CF2), 128.0 (CH*), 127.4 (CH), 127.3 (t, J = 255.4 Hz, CF2*), 126.5 (CH), 126.4 (CH*), 122.4 (C*), 122.1 (C), 111.5 (CH and CH*), 109.0 (CH*), 108.6 (CH), 67.6 (dd, J = 24.1, 28.0 Hz, CH), 66.2 (t, J = 27.8 Hz, CH*), 57.5 (CH2), 56.0 (CH3 and CH3*), 55.8 (CH3 and CH3*), 55.0 (d, J = 8.0 Hz, CH2*), 48.4 (CH2), 48.2 (CH2*), 46.5 (dd, J = 20.3, 25.1 Hz, CH), 46.0 (t, J = 21.6 Hz, CH*), 33.9 (d, J = 8.1 Hz, CH2), 32.7 (d, J = 9.0 Hz, CH2*), 28.4 (CH2), 26.6 (CH2*); IR (neat) νmax 1494s, 1260s, 1210s, 1020s cm−1; MS m/z (%) relative intensity 360 [(M + 1)+, 53], 359 (M+, 57), 205 (100); HRMS (ESI-TOF) calcd for C21H24F2NO2 [M + H]+ 360.1775, found 360.1786. 1,1-Difluoro-2-methyl-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline (6c). According to the general procedure D, the reaction of

3j (166 mg, 0.5 mmol), Bu3SnH (0.24 mL, 0.88 mmol), and AIBN (25 mg, 0.15 mmol) in dry toluene (30 mL) under reflux conditions for 16 h gave a mixture of isomers of 6c (105 mg, 94%, dr = 1:16) as a pale brown viscous oil after column chromatography (SiO2, 100% henanes then 15% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3, the minor isomer was marked*) δ 7.32−7.24 (m, 1H and 1H*), 7.18−7.02 (m, 3H and 3H*), 4.06 (dd, J = 8.3, 19.8 Hz, 1H*), 3.61 (dd, J = 11.4, 17.4 Hz, 1H), 3.28 (t, J = 8.7 Hz, 1H and 1H*), 3.10−2.81 (m, 2H and 2H*), 2.80−2.43 (m, 3H and 3H*), 1.07 (dd, J = 2.5, 7.1 Hz, 3H and 3H*); 19F NMR (376 MHz, CDCl3, the minor isomer was marked*) δ −97.4 (ddd, J = 20.8, 20.8, 225.5 Hz, 1F), −106.0 (dd, J = 8.31, 224.3 Hz, 1F*), −108.8 (d, J = 225.5 Hz, 1F), −118.3 (ddd, J = 18.4, 18.4, 224.3 Hz, 1F*); 13C{H}NMR (100 MHz, CDCl3, the minor isomer was marked*) δ 135.0 (C*), 134.1 (C), 129.8 (d, J = 4.3 Hz, C*), 129.4 (C), 127.8 (CH), 127.7 (dd, J = 255.3, 255.3 Hz, CF2 and CF2*), 127.6 (CH*), 126.1 (CH), 125.9 (CH*), 125.3 (CH*), 124.9 (CH*), 124.8 (CH), 124.7 (CH), 66.2 (dd, J = 24.5, 28.4 Hz, CH), 65.0 (dd, J = 24.3, 26.6 Hz, CH*), 58.1 (t, J = 4.0 Hz, CH), 55.9 (d, J = 8.4 Hz, CH*), 47.4 (CH2), 47.2 (CH2*), 38.8 (dd, J = 21.5, 25.8 Hz, CH2), 38.1 (t, J = 22.6 Hz, CH2*), 28.7 (CH2*), 27.7 (CH2), 11.4 (dd, J = 2.4, 9.7 Hz, CH3), 9.7 (d, J = 9.8 Hz, CH3*); IR (neat) νmax 1637m, 1145m, 1131m cm−1; MS m/z (%) relative intensity 223 (M+, 3), 118 (100); HRMS (ESI-TOF) calcd for C13H16F2N [M + H]+ 224.1251, found 224.1255. 1,1-Difluoro-8,9-dimethoxy-2-methyl-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline (6d). According to the general procedure D, the reaction of 3k (196 mg, 0.5 mmol), Bu3SnH (0.24 mL, 0.88 mmol), and AIBN (25 mg, 0.15 mmol) in dry toluene (30 mL) under reflux conditions for 16 h gave a mixture of isomers of 6d (126 mg, 89%, dr = 1:14) as a yellow viscous oil after column chromatography (SiO2, 100% henanes then 25% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3, the minor isomer was not assigned due to low intensity) δ 6.74 (s, 1H), 6.55 (s, 1H), 3.78 (s, 3H), 3.75 (s, 3H), 3.54 (dd, J = 11.3, 17.4 Hz, 1H), 3.26 (d, J = 8.7 Hz, 1H), 3.05−2.96 (m, 1H), 2.94−2.82 (m, 1H), 2.68−2.59 (m, 1H), 2.54−2.43 (m, 2H), 2.31 (t, J = 9.2 Hz, 1H), 1.05 (dd, J = 2.3, 7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3, the minor isomer was marked*) δ −97.4 (ddd, J = 20.1, 20.1, 226.7 Hz, 1F), −105.7 (d, J = 223.2 Hz, 1F*), −109.1 (d, J = 226.7 Hz, 1F), −118.1 (ddd, J = 18.2, 18.2, 223.2 Hz, 1F*); 13C{H}NMR (100 MHz, CDCl3, the minor isomer was marked*) δ 147.2 (C), 147.0 (C*), 146.3 (C*), 146.2 (C), 127.7 (dd, J = 254.2, 256.6 Hz, CF2), 127.1 (C*), 126.4 (t, J = 255.1 Hz, CF2*), 126.3 (C), 121.6 (C*), 121.3 (C), 110.4 (CH and CH*), 108.0 (CH*), 107.5 (CH), 65.8 (dd, J = 24.2, 28.3 Hz, CH), 64.7 (t, J = 25.6, CH*), 58.0 (CH2), 55.9 (d, J = 8.4 Hz, CH2*), 54.9 (CH3 and CH3*), 54.8 (CH3 and CH3*), 47.4 (CH2), 47.2 (CH2*), 38.7 (dd, J = 21.5, 25.7 Hz, CH), 38.0 (t, J = 22.7 Hz, CH*), 27.4 (CH2), 25.5 (CH2*), 11.4 (dd, J = 2.2, 9.7 Hz, CH3), 9.8 (d, J = 9.8 Hz, CH3*); IR (neat) νmax 1515m, 1200s, 1102s cm−1; MS m/z (%) relative intensity 283 (M+, 21), 282 (100); HRMS (ESI-TOF) calcd for C15H19F2NO2 [M]+ 283.1384, found 283.1381. 9-Chloro-1,1-difluoro-2-methyl-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline (6e). According to the general procedure D, the reaction of 3l (183 mg, 0.5 mmol), Bu3SnH (0.24 mL, 0.88 mmol), and AIBN (25 mg, 0.15 mmol) in dry toluene (30 mL) under reflux conditions for 16 h gave a mixture of isomers of 6e (113 mg, 88%, dr = 1:12) as a pale yellow viscous oil after column chromatography (SiO2, 100% henanes then 10% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3, the minor isomer was marked*) δ 7.36 (s, 1H and 1H*), 7.20 (d, J = 8.2 Hz, 1H and 1H*), 7.10 (m, 1H and 1H*), 4.10 (dd, J = 8.1, 13.4 Hz, 1H*), 3.65 (dd, J = 11.2, 17.1 Hz, 1H), 3.39 (t, J = 8.7 Hz, 1H and 1H*), 3.20−2.87 (m, 2H and 2H*), 2.84−2.53 (m, 3H and 3H*), 2.40 (t, J = 8.7 Hz, 1H and 1H*), 1.17 (dd, J = 2.3, 7.0 Hz, 3H and 3H*); 19F NMR (376 MHz, CDCl3, the minor isomer was marked*) δ −97.4 (ddd, J = 18.7, 22.4, 228.2 Hz, 1F), −106.0 (d, J = 224.4 Hz, 1F*), −109.1 (d, J = 228.2 Hz, 1F), −118.1 (ddd, J = 18.3, 18.3, 224.4 Hz, 1F*); 13C{H}NMR (100 MHz, CDCl3, the minor isomer was marked*) δ 133.7 (C and C*), 132.2 (C and C*), 131.5 (C and C*), 130.1 (CH), 130.0 (CH*), 128.4 (dd, J = 232.2, 232.2 Hz, CF2 and CF2*), 127.4 (CH), 127.2 (CH*), 125.8 (CH*), 125.7 777

DOI: 10.1021/acs.joc.7b02783 J. Org. Chem. 2018, 83, 765−782

Article

The Journal of Organic Chemistry (CH), 67.0 (dd, J = 24.4, 28.6 Hz, CH), 65.8 (dd, J = 24.3, 27.1 Hz, CH*), 59.0 (t, J = 3.9 Hz, CH2), 56.9 (d, J = 8.2 Hz, CH2*), 48.2 (CH2), 47.9 (CH2*), 39.8 (dd, J = 21.4, 25.6 Hz, CH), 39.1 (t, J = 22.7 Hz, CH*), 28.3 (CH2), 27.8 (CH2*), 12.4 (dd, J = 2.5, 9.7 Hz, CH3), 10.7 (d, J = 9.8 Hz, CH3*); IR (neat) νmax 1629m, 1458s, 1075s cm−1; MS m/z (%) relative intensity 258 [(M + 1)+, 100], 257 (M+, 39), 256 (72); HRMS (ESI-TOF) calcd for C13H15ClF2N [M + H]+ 258.0861, found 258.0862. 1,1-Difluoro-2-methyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline (6f). According to the general procedure D, the reaction of 3m (173 mg, 0.5 mmol), Bu3SnH (0.24 mL, 0.88 mmol), and AIBN (25 mg, 0.15 mmol) in dry toluene (30 mL) under reflux conditions for 16 h gave a mixture of isomers of 6f (91 mg, 81%, dr = 1:2.1) as a pale yellow viscous oil after column chromatography (SiO2, 100% henanes then 15% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3, the minor isomer was marked*) δ 7.52 (d, J = 7.5 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H*), 7.16−7.00 (m, 3H and 3H*), 3.99 (t, J = 12.8 Hz, 1H*), 3.67 (d, J = 24.3 Hz, 1H), 3.20−2.89 (m, 3H and 3H*), 2.77− 2.61 (m, 2H and 2H*), 2.60−2.51 (m, 1H), 2.36−2.18 (m, 1H*), 2.13−1.87 (m, 1H and 1H*), 1.78−1.62 (m, 1H and 1H*), 1.62−1.51 (m, 1H and 1H*), 1.14 (d, J = 7.2 Hz, 3H*), 1.04 (d, J = 6.6 Hz, 3H); 19 F NMR (376 MHz, CDCl3, the minor isomer was marked*) δ −102.6 (d, J = 241.5 Hz, 1F), (−102.7) − (−103.2) (m, 2F*), −124.0 (ddd, J = 25.0, 25.0, 241.5 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3, the minor isomer was marked*) δ 136.1 (C), 136.0 (C*), 130.9 (C), 130.8 (C*), 129.1 (CH*), 129.0 (CH), 128.3 (d, J = 13.0 Hz, CH), 128.0 (t, J = 6.5 Hz, CH*), 127.0 (CH and CH*), 125.7 (CH*), 125.5 (CH), 123.1 (t, J = 250.5 Hz, CF2*), 121.9 (dd, J = 247.5, 257.0 Hz, CF2), 65.2 (t, J = 22.6 Hz, CH), 60.8 (t, J = 23.3 Hz, CH*), 54.8 (CH2 and CH2*), 49.3 (CH2), 48.5 (CH2*), 38.9 (t, J = 23.2 Hz, CH), 35.2 (t, J = 22.9 Hz, CH*), 29.7 (CH2), 29.4 (d, J = 8.5 Hz, CH2), 28.3 (CH2), 27.9 (d, J = 4.9 Hz, CH2*), 13.5 (dd, J = 5.9, 5.9 Hz, CH3*), 12.6 (dd, J = 3.5, 5.1 Hz, CH3); IR (neat) νmax 1629s, 1456s, 1215s, 1183s cm−1; MS m/z (%) relative intensity 237 (M+, 31), 235 (100); HRMS (ESI-TOF) calcd for C14H18F2N [M + H]+ 238.1407, found 238.1399. 1,1-Difluoro-9,10-dimethoxy-2-methyl-1,3,4,6,7,11b-hexahydro2H-pyrido[2,1-a]isoquinoline (6g). According to the general procedure D, the reaction of 3n (203 mg, 0.5 mmol), Bu3SnH (0.24 mL, 0.88 mmol), and AIBN (25 mg, 0.15 mmol) in dry toluene (30 mL) under reflux conditions for 16 h gave a mixture of isomers of 6g (109 mg, 73%, dr = 1:1.7) as a yellow viscous oil after column chromatography (SiO2, 100% henanes then 25% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3, the minor isomer was marked*) δ 7.11 (s, 1H), 7.04 (s, 1H*), 6.57 (s, 1H and 1H*), 3.97 (t, J = 13.3 Hz, 1H*), 3.82 (s, 6H and 6H*), 3.64 (d, J = 23.8 Hz, 1H), 3.23−3.05 (m, 1H and 1H*), 3.04−2.51 (m, 5H and 4H*), 2.41−2.24 (m, 1H*), 2.18−1.90 (m, 1H and 1H*), 1.82−1.46 (m, 2H and 2H*), 1.19 (d, J = 7.1 Hz, 3H*), 1.10 (d, J = 6.6 Hz, 3H); 19F NMR (376 MHz, CDCl3, the minor isomer was marked*) δ −102.6 (d, J = 241.5 Hz, 1F), (−102.6) − (−104.5) (m, 2F*), −124.5 (ddd, J = 24.8, 24.8, 241.2 Hz, 1F); 13 C{H}NMR (100 MHz, CDCl3, the minor isomer was marked*) δ 147.9 (C and C*), 146.8 (C*), 146.6 (C), 128.5 (C), 128.4 (CH*), 123.1 (t, J = 250.5 Hz, CF2*), 122.7 (C), 122.5 (C*), 121.9 (dd, J = 246.3, 256.7 Hz, CF2), 111.4 (CH*), 111.2 (t, J = 7.0 Hz, 2 × CH), 110.9 (t, J = 6.8 Hz, CH*), 64.9 (t, J = 22.5 Hz, CH), 60.4 (t, J = 23.0 Hz, CH*), 55.8 (CH3*), 55.7 (CH3), 54.7 (CH3 and CH3*), 49.6 (CH2 and CH2*), 49.4 (CH2), 48.3 (CH2*), 38.8 (t, J = 23.1 Hz, CH), 35.1 (t, J = 22.8 Hz, CH*), 29.4 (d, J = 8.6 Hz, CH2), 29.2 (CH2), 27.8 (2 × CH2), 13.4 (t, J = 5.6 Hz, CH3*), 12.4 (dd, J = 3.5, 4.9 Hz, CH3); IR (neat) νmax 1609m, 1516s, 1462s, 1263s cm−1; MS m/z (%) relative intensity 298 [(M + 1)+, 28], 297 (M+, 47), 296 (100); HRMS (ESI-TOF) calcd for C16H22F2NO2 [M + H]+ 298.1619, found 298.1617. 2-(3,4-Dimethoxybenzyl)-1,1-difluoro-1,3,4,6,7,11b-hexahydro2H-pyrido[2,1-a]isoquinoline (6h). According to the general procedure D, the reaction of 3o (241 mg, 0.5 mmol, E:Z isomer = 32:1), Bu3SnH (0.24 mL, 0.88 mmol), and AIBN (25 mg, 0.15 mmol) in dry toluene (30 mL) under reflux conditions for 16 h gave a mixture of isomers of 6h (131 mg, 70%, dr = 1:1.4) as a pale yellow viscous oil after column

chromatography (SiO2, 100% henanes then 15% EtOAc in hexanes). 1 H NMR (400 MHz, CDCl3, the minor isomer was marked*) δ 7.55 (d, J = 7.5 Hz, 1H), 7.51 (d, J = 7.5 Hz, 1H*), 7.18−7.03 (m, 3H and 3H*), 6.75 (d, J = 4.8 Hz, 1H*), 6.72 (d, J = 4.7 Hz, 1H), 6.70−6.62 (m, 2H and 2H*), 4.08 (t, J = 12.7 Hz, 1H*), 3.82 (s, 3H), 3.81 (s, 3H*), 3.80 (s, 3H), 3.79 (s, 3H*), 3.73 (d, J = 24.4 Hz, 1H), 3.22− 2.90 (m, 4H and 2H*), 2.90−2.80 (m, 1H*), 2.80−2.63 (m, 1H and 3H*), 2.63−2.52 (m, 2H and 1H*), 2.35 (dd, J = 10.6, 13.6 Hz, 1H and 1H*), 2.16−1.96 (m, 1H), 1.88−1.76 (m, 1H*), 1.75−1.57 (m, 2H), 1.56−1.42 (m, 2H); 19F NMR (376 MHz, CDCl3, the minor isomer was marked*) δ −102.0 (d, J = 243.0 Hz, 1F), (−102.1) − (−103.6) (m, 2F*), −121.2 (ddd, J = 24.1, 24.1, 243.0 Hz, 1F); 13 C{H}NMR (100 MHz, CDCl3, the minor isomer was marked*) δ 149.0 (C*), 148.9 (C), 147.6 (C*), 147.5 (C), 136.0 (C), 135.8 (C*), 131.8 (C), 131.6 (C), 130.5 (C*), 130.4 (C*), 129.2 (CH*), 129.0 (CH), 128.3 (d, J = 13.3 Hz, CH), 127.9 (t, J = 6.3 Hz, CH*), 127.1 (CH and CH*), 125.8 (CH*), 125.5 (CH), 122.8 (t, J = 251.4 Hz, CF2*), 121.7 (dd, J = 247.9, 257.0 Hz, CF2), 121.2 (CH and CH*), 112.4 (CH), 112.1 (CH*), 111.2 (CH and CH*), 65.1 (t, J = 22.9 Hz, CH), 61.6 (t, J = 23.7 Hz, CH*), 55.9 (2 × CH3 and 2 × CH3*), 54.6 (CH2), 49.3 (CH2*), 49.1 (CH2), 48.4 (CH2*), 46.2 (t, J = 23.2 Hz, CH), 42.3 (t, J = 21.8 Hz, CH*), 33.1 (CH2), 32.5 (t, J = 5.4 Hz, CH2), 29.6 (CH2), 28.0 (CH2*), 26.2 (d, J = 7.6 Hz, CH2), 23.8 (CH2*); IR (neat) νmax 1515m, 1263s, 732s cm−1; MS m/z (%) relative intensity 373 (M+, 18), 222 (100); HRMS (ESI-TOF) calcd for C22H26F2NO2 [M + H]+ 374.1931, found 374.1929. 2-(3,4-Dimethoxybenzyl)-1,1-difluoro-9,10-dimethoxy1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline (6i). According to the general procedure D, the reaction of 3p (271 mg, 0.5 mmol, E:Z isomer = 15.6:1), Bu3SnH (0.24 mL, 0.88 mmol), and AIBN (25 mg, 0.15 mmol) in dry toluene (30 mL) under reflux conditions for 16 h gave a mixture of isomers of 6i (180 mg, 83%, dr = 1:1.6) as a pale brown viscous oil after column chromatography (SiO2, 100% henanes then 25% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3, the minor isomer was marked*) δ 7.08 (s, 1H), 7.04 (s, 1H*), 6.75 (d, J = 4.9 Hz, 1H*), 6.73 (d, J = 4.9 Hz, 1H), 6.70−6.61 (m, 2H and 2H*), 6.54 (s, 1H and 1H*), 4.00 (t, J = 12.9 Hz, 1H*), 3.83−3.76 (m, 12H and 12H*), 3.65 (d, J = 24.4 Hz, 1H), 3.22−3.01 (m, 2H and 2H*), 3.00− 2.77 (m, 2H and 2H*), 2.77−2.45 (m, 3H and 3H*), 2.43−2.26 (m, 1H and 1H*), 2.15−1.93 (m, 1H), 1.90−1.76 (m, 1H*), 1.72−1.39 (m, 2H and 2H*); 19F NMR (376 MHz, CDCl3, the minor isomer was marked*) δ −101.9 (d, J = 242.5 Hz, 1F), −102.9 (s, 2F*), −121.6 (ddd, J = 25.0, 25.0, 242.5 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3, the minor isomer was marked*) δ 149.0 (C*), 148.9 (C), 148.1 (C and C*), 147.6 (C), 147.5 (C*), 147.0 (C*), 146.8 (C), 131.9 (C), 131.7 (C*), 128.5 (C), 128.3 (C*), 123.1 (t, J = 251.0 Hz, CF2*), 122.4 (C), 122.2 (C*), 122.0 (dd, J = 247.5, 258.1 Hz, CF2), 121.2 (CH and CH*), 112.3 (CH), 112.1 (CH*), 111.5 (CH*), 111.3 (CH and CH*), 111.2 (2 × CH), 110.8 (t, J = 6.8 Hz, CH*), 64.9 (t, J = 22.1 Hz, CH), 61.3 (t, J = 23.3 Hz, CH*), 55.9 (2 × CH3), 55.8 (2 × CH3 and 2 × CH3*), 55.7 (2 × CH3*), 54.7 (CH2), 49.5 (CH2*), 49.4 (CH2), 48.3 (CH2*), 46.2 (t, J = 22.5 Hz, CH), 42.4 (t, J = 21.5 Hz, CH*), 33.1 (CH2), 32.5 (t, J = 5.3 Hz, CH2*), 29.7 (CH2*), 29.2 (CH2), 26.2 (d, J = 7.9 Hz, CH2), 23.8 (CH2*); IR (neat) νmax 1513s, 1261s, 1137s cm−1; MS m/z (%) relative intensity 434 [(M + 1)+, 29], 433 (M+, 91), 282, (100); HRMS (ESI-TOF) calcd for C24H30F2NO4 [M + H]+ 434.2143, found 434.2147. 1,1-Difluoro-2-(3,4,5-trimethoxybenzyl)-1,3,4,6,7,11b-hexahydro2H-pyrido[2,1-a]isoquinoline (6j). According to the general procedure D, the reaction of 3q (256 mg, 0.5 mmol, E:Z isomer = 6.2:1), Bu3SnH (0.24 mL, 0.88 mmol), and AIBN (25 mg, 0.15 mmol) in dry toluene (30 mL) under reflux conditions for 16 h gave a mixture of isomers of 6j (145 mg, 72%, dr = 1:1.5) as a pale brown viscous oil after column chromatography (SiO2, 100% henanes then 20% EtOAc in hexanes). 1 H NMR (400 MHz, CDCl3, the minor isomer was marked*) δ 7.54 (d, J = 7.4 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H*), 7.17−7.02 (m, 3H and 3H*), 6.33 (s, 2H), 6.32 (s, 2H*), 4.08 (t, J = 12.6 Hz, 1H*), 3.83− 3.68 (m, 10H and 9H*), 3.21−2.87 (m, 3H and 4H*), 2.87−2.48 (m, 4H and 3H*), 2.45−2.25 (m, 1H and 1H*), 2.18−1.96 (m, 1H), 1.91−1.76 (m, 1H*), 1.72−1.41 (m, 2H and 2H*); 19F NMR (376 778

DOI: 10.1021/acs.joc.7b02783 J. Org. Chem. 2018, 83, 765−782

Article

The Journal of Organic Chemistry MHz, CDCl3, the minor isomer was marked*) δ −101.9 (d, J = 241.4 Hz, 1F), (−102.5) − (−103.5) (m, 2F*), −121.1 (ddd, J = 25.0, 25.0, 241.4 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3, the minor isomer was marked*) δ 153.2 (C*), 153.1 (C), 136.5 (C*), 136.4 (C), 136.1 (C), 135.9 (C*), 135.1 (C), 135.0 (C*), 130.6 (d, J = 3.9 Hz, C and C*), 129.2 (CH*), 129.1 (CH), 128.3 (d, J = 12.2 Hz, CH), 127.9 (d, J = 6.1 Hz, CH*), 127.2 (CH), 127.1 (CH*), 125.9 (CH*), 125.6 (CH), 122.9 (t, J = 251.3 Hz, CF2*), 121.7 (dd, J = 248.7, 257.3 Hz, CF2), 106.1 (2 × CH), 106.0 (2 × CH*), 65.1 (t, J = 22.5 Hz, CH), 61.8 (t, J = 23.6 Hz, CH*), 60.9 (CH3 and CH3*), 56.2 (2 × CH3*), 56.1 (2 × CH3), 54.6 (CH2), 49.4 (CH2*), 49.1 (CH2), 48.4 (CH2*), 46.2 (t, J = 21.9 Hz, CH), 42.3 (t, J = 21.9 Hz, CH*), 34.0 (CH2), 33.4 (t, J = 5.3 Hz, CH2*), 29.7 (CH2), 28.0 (CH2*), 26.3 (d, J = 7.7 Hz, CH2), 24.0 (CH2*); IR (neat) νmax 1588s, 1505m, 1421s, 1236s, 1121s cm−1; MS m/z (%) relative intensity 404 [(M + 1)+, 9], 403 (M+, 5), 202 (100); HRMS (ESI-TOF) calcd for C23H28F2NO3 [M + H]+ 404.2037, found 404.2039. 1,1-Difluoro-9,10-dimethoxy-2-(3,4,5-trimethoxybenzyl)1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline (6k). According to the general procedure D, the reaction of 3r (286 mg, 0.5 mmol, E:Z isomer = 5.6:1), Bu3SnH (0.24 mL, 0.88 mmol), and AIBN (25 mg, 0.15 mmol) in dry toluene (30 mL) under reflux conditions for 16 h gave a mixture of isomers of 6k (171 mg, 74%, dr = 1:1.4) as a pale brown viscous oil after column chromatography (SiO2, 100% henanes then 25% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3, the minor isomer was marked*) δ 7.08 (s, 1H), 7.01 (s, 1H*), 6.53 (s, 1H and 1H*), 6.33 (s, 1H and 1H*), 6.32 (s, 1H and 1H*), 3.99 (t, J = 12.1 Hz, 1H*), 3.80−3.77 (m, 12H and 12H*), 3.76 (s, 3H), 3.75 (s, 3H*), 3.65 (d, J = 24.0 Hz, 1H), 3.21−3.02 (m, 2H and 2H*), 3.00− 2.88 (m, 2H and 1H*), 2.87−2.49 (m, 3H and 4H*), 2.43−2.26 (m, 1H and 1H*), 2.18−1.96 (m, 1H), 1.89−1.78 (m, 1H*), 1.71−1.43 (m, 2H and 2H*); 19F NMR (376 MHz, CDCl3, the minor isomer was marked*) δ −101.9 (d, J = 241.2 Hz, 1F), −103.1 (s, 2F*), −121.6 (ddd, J = 25.1, 25.1, 241.2 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3, the minor isomer was marked*) δ 153.2 (2 × C*), 153.1 (2 × C), 148.1 (C and C*), 147.0 (C*), 146.8 (C), 136.5 (C*), 136.4 (C*), 135.1 (C), 135.0 (C), 128.6 (C), 128.4 (C*), 123.0 (t, J = 251.1 Hz, CF2*), 122.4 (C*), 122.2 (C), 121.9 (dd, J = 246.9, 257.6 Hz, CF2), 111.5 (CH), 111.3 (CH), 111.2 (CH*), 110.8 (d, J = 6.9 Hz, CH*), 106.1 (2 × CH), 106.0 (2 × CH*), 65.0 (t, J = 22.5 Hz, CH), 61.5 (t, J = 23.5 Hz, CH*), 60.9 (CH3 and CH3*), 56.2 (CH3 and CH3*), 56.1 (2 × CH3), 56.0 (CH3*), 55.9 (CH3*), 55.7 (CH3 and CH3*), 54.7 (CH2), 49.7 (CH2*), 49.5 (CH2), 48.4 (CH2*), 46.2 (t, J = 22.0 Hz, CH), 42.3 (t, J = 22.0 Hz, CH*), 34.0 (CH2), 33.4 (CH2*), 29.3 (CH2), 27.0 (CH2*), 26.4 (d, J = 7.8 Hz, CH2), 24.1 (CH2*); IR (neat) νmax 1589s, 1508s, 1458s, 1233s, 1124s cm−1; MS m/z (%) relative intensity 464 [(M + 1)+, 13], 463 (M+, 35), 262 (100); HRMS (ESI-TOF) calcd for C25H32F2NO5 [M + H]+ 464.2248, found 464.2266. 1,1-Difluoro-8,9-dimethoxy-2-((trimethylsilyl)methylene)1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline (7a). According to the general procedure D, the reaction of 4a (231 mg, 0.5 mmol), Bu3SnH (0.24 mL, 0.88 mmol), and AIBN (25 mg, 0.15 mmol) in dry toluene (30 mL) under reflux conditions for 16 h gave 7aA (111 mg, 63%) as a yellow viscous oil and 7aB (32 mg, 18%) as a pale yellow viscous oil after column chromatography (SiO2, 100% henanes then 15% EtOAc in hexanes). 7aA: 1H NMR (400 MHz, CDCl3) δ 6.68 (s, 1H), 6.46 (s, 1H), 6.08 (s, 1H), 3.70 (br. s, 3H), 3.68 (s, 3H), 3.64− 3.54 (m, 2H), 3.33−3.24 (br. d, J = 14.6 Hz, 1H), 2.99−2.90 (m, 1H), 2.87−2.75 (m, 1H), 2.63 (dt, J = 4.8, 16.2 Hz, 1H), 2.57−2.48 (m, 1H), 0.00 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −99.3 (dd, J = 17.0, 244.9 Hz, 1F), −103.0 (d, J = 244.9 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3) δ 150.2 (t, J = 21.5 Hz, C), 149.3 (C), 148.3 (C), 128.9 (CH), 128.1 (C), 122.7 (C), 122.4 (dd, J = 247.5, 253.6 Hz, CF2), 112.4 (CH), 109.5 (CH), 67.0 (t, J = 23.9 Hz, CH), 56.9 (CH2 and CH3), 56.8 (CH3), 49.5 (CH2), 29.6 (CH2), 0.0 (3 × CH3); IR (neat) νmax 1671m, 1517s, 1248s, 1220s, 1137s cm−1; MS m/z (%) relative intensity 354 [(M + 1)+, 79], 353 (M+, 79), 352 (100); HRMS (ESITOF) calcd for C18H26F2NO2Si [M + H]+ 354.1701, found 354.1709. 7aB: 1H NMR (400 MHz, CDCl3) δ 6.66 (s, 1H), 6.46 (s, 1H), 5.82

(s, 1H), 3.78−3.62 (m, 7H), 3.50−3.36 (m, 2H), 2.94−2.83 (m, 1H), 2.80−2.70 (m, 1H), 2.70−2.60 (m, 1H), 2.55−2.45 (m, 1H), 0.00 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −96.1 (dd, J = 17.0, 248.9 Hz, 1F), −98.4 (dd, J = 248.9 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3) δ 148.9 (t, J = 21.8 Hz, C), 148.6 (C), 147.5 (C), 132.0 (CH), 127.4 (C), 123.2 (dd, J = 248.8, 254.7 Hz, CF2), 128.8 (C), 111.6 (CH), 108.9 (CH), 67.8 (t, J = 24.3 Hz, CH), 59.9 (CH2), 56.2 (CH3), 56.0 (CH3), 48.3 (CH2), 29.0 (CH2), 0.0 (3 × CH3); IR (neat) νmax 1671m, 1517s, 1248s, 1220s, 1137s cm−1; MS m/z (%) relative intensity 354 [(M + 1)+, 79], 353 (M+, 79), 352 (100); HRMS (ESITOF) calcd for C18H26F2NO2Si [M + H]+ 354.1701, found 354.1709. 1,1-Difluoro-2-((trimethylsilyl)methylene)-1,2,3,5,6,10bhexahydropyrrolo[2,1-a]isoquinoline (7b). According to the general procedure D, the reaction of 4b (201 mg, 0.5 mmol), Bu3SnH (0.24 mL, 0.88 mmol), and AIBN (25 mg, 0.15 mmol) in dry toluene (30 mL) under reflux conditions for 16 h gave a mixture of isomers of 7b (135 mg, 92%, E:Z isomer = 1:4) as a pale brown viscous oil after column chromatography (SiO2, 100% henanes then 15% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3, Z-isomer was marked*) δ 7.26−7.18 (m, 1H and 1H*), 7.07−6.95 (m, 3H and 3H*), 6.10 (br. s, 1H), 6.33 (br. s, 1H*), 3.77 (dd, J = 9.6, 17.1 Hz, 1H*), 3.71−3.56 (m, 2H), 3.44 (s, 2H*), 3.28 (d, J = 14.7 Hz, 1H), 3.03−2.79 (m, 2H and 2H*), 2.78−2.66 (m, 1H and 1H*), 2.60−2.48 (m, 1H and 1H*), 0.00 (s, 9H and 9H*); 19F NMR (376 MHz, CDCl3, Z-isomer was marked*) δ −96.3 (dd, J = 16.5, 250.1 Hz, 1F*), −98.1 (dd, J = 6.4, 250.1 Hz, 1F*), −99.3 (dd, J = 17.0, 245.6 Hz, 1F), −103.0 (d, J = 245.6 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3, Z-isomer was marked*) δ 150.1 (t, J = 21.7 Hz, C), 149.5 (t, J = 21.7 Hz, C*), 135.9 (C and C*), 132.7 (CH*), 130.9 (C), 130.8 (C*), 129.8 (CH and CH*), 128.9 (CH), 128.3 (CH and CH*), 126.9 (CH*), 126.8 (CH and CH*), 126.7 (CH), 123.7 (dd, J = 251.2, 256.2 Hz, CF2*), 122.3 (dd, J = 249.5, 255.3 Hz, CF2), 68.9 (t, J = 24.4 Hz, CH*), 67.4 (t, J = 24.1 Hz, CH), 60.6 (t, J = 5.3 Hz, CH2*), 56.9 (CH2), 49.5 (CH2), 49.1 (CH2*), 30.1 (CH2*), 30.0 (CH2), 0.7 (3 × CH3*), 0.0 (3 × CH3); IR (neat) νmax 1672s, 1603m, 1247s, 1061s cm−1; MS m/z (%) relative intensity 294 [(M + 1)+, 100], 293 (M+, 57); HRMS (ESITOF) calcd for C16H22F2NSi [M + H]+ 294.1489, found 294.1491. 1,1-Difluoro-2-((trimethylsilyl)methylene)-1,2,3,5,6,11b-hexahydro-[1,3]dioxolo[4,5-g]pyrrolo[2,1-a]isoquinoline (7c). According to the general procedure D, the reaction of 4c (223 mg, 0.5 mmol), Bu3SnH (0.24 mL, 0.88 mmol), and AIBN (25 mg, 0.15 mmol) in dry toluene (30 mL) under reflux conditions for 16 h gave a mixture of isomers of 7c (121 mg, 72%, E:Z isomer = 1:3.3) as a brown viscous oil after column chromatography (SiO2, 100% henanes then 25% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3, Z-isomer was marked*) δ 6.86 (s, 1H), 6.85 (m, 1H*), 6.61 (s, 1H and 1H*), 6.27 (br. s, 1H), 6.60 (br. s, 1H*), 5.93 (s, 1H and 1H*), 5.92 (s, 1H and 1H*), 3.85 (dd, J = 9.5, 17.1 Hz, 1H*), 3.80−3.68 (m, 2H), 3.60 (br. s, 2H*), 3.45 (d, J = 14.9 Hz, 1H), 3.15−3.02 (m, 1H and 1H*), 3.01−2.86 (m, 1H and 1H*), 2.85−2.74 (m, 1H and 1H*), 2.72−2.61 (m, 1H and 1H*), 0.17 (s, 9H and 9H*); 19F NMR (376 MHz, CDCl3, Z-isomer was marked*) δ −96.2 (dd, J = 16.4, 249.5 Hz, 1F*), −98.4 (d, J = 249.5 Hz, 1F*), −99.4 (dd, J = 17.1, 244.6 Hz, 1F), −103.3 (d, J = 244.6 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3, Zisomer was marked*) δ 150.0 (t, J = 21.9 Hz, C), 149.4 (t, J = 22.2 Hz, C*), 146.9 (C and C*), 145.9 (C and C*), 128.4 (C and C*), 128.1 (C and C*), 126.3 (t, J = 252.8 Hz, CF2*), 122.6 (C), 122.5 (C*), 121.3 (dd, J = 250.0, 255.3 Hz, CF2), 108.6 (CH and CH*), 105.9 (CH*), 105.8 (CH), 100.8 (CH2 and CH2*), 67.8 (t, J = 24.5 Hz, CH*), 66.3 (t, J = 23.8 Hz, CH), 59.5 (CH2*), 55.8 (CH2), 48.4 (CH2), 48.0 (CH2*), 29.2 (CH2*), 29.1 (CH2), −0.3 (3 × CH3*), −1.0 (3 × CH3); IR (neat) νmax 1671s, 1479s, 1227s, 1034s cm−1; MS m/z (%) relative intensity 338 [(M + 1)+, 51], 337 (M+, 80), 336 (100); HRMS (ESI-TOF) calcd for C17H22F2NO2Si [M + H]+ 338.1388, found 338.1386. 1,1-Difluoro-8-methoxy-2-((trimethylsilyl)methylene)1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline (7d). According to the general procedure D, the reaction of 4d (216 mg, 0.5 mmol), Bu3SnH (0.24 mL, 0.88 mmol), and AIBN (25 mg, 0.15 mmol) in dry toluene (30 mL) under reflux conditions for 16 h gave a mixture of 779

DOI: 10.1021/acs.joc.7b02783 J. Org. Chem. 2018, 83, 765−782

Article

The Journal of Organic Chemistry

1462s, 1370s, 1020s cm−1; MS m/z (%) relative intensity 275 (M+, 100); HRMS (ESI-TOF) calcd for C15H15FNO3 [M + H]+ 276.1036, found 276.1029. 1-Fluoro-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carbaldehyde (8b). According to the general procedure E, the reaction of the isomeric mixture of 7b (29 mg, 0.1 mmol), TBAF·3H2O (158 mg, 0.5 mmol) in acetonitrile (1.0 mL) under O2 atmosphere (balloon) for 24 h gave 8b (15 mg, 70%) as a brown viscous oil after column chromatography (SiO2, 15% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.29−7.21 (m, 1H), 7.17−7.08 (m, 2H), 7.01 (d, J = 3.5 Hz, 1H), 4.03 (t, J = 6.5 Hz, 2H), 3.03 (t, J = 6.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ −162.5 (s, 1F); 13C{H}NMR (100 MHz, CDCl3) δ 183.1 (CH), 147.0 (d, J = 257.0 Hz, CF), 130.0 (C), 128.1 (CH and C), 127.7 (CH), 126.8 (CH and 2 × C), 127.0 (d, J = 7.1 Hz, CH), 121.8 (CH), 45.5 (CH2), 29.2 (CH2); IR (neat) νmax 1657s, 1600s, 1522s, 1451s, 1020m cm−1; MS m/z (%) relative intensity 215 (M+, 100); HRMS (ESI-TOF) calcd for C13H10FNONa [M + Na]+ 238.0644, found 238.0642. 1-Fluoro-5,6-dihydro-[1,3]dioxolo[4,5-g]pyrrolo[2,1-a]isoquinoline-2-carbaldehyde (8c). According to the general procedure E, the reaction of the isomeric mixture of 7c (34 mg, 0.1 mmol), TBAF·3H2O (158 mg, 0.5 mmol) in acetonitrile (1.0 mL) under O2 atm (balloon) for 24 h gave 8c (20 mg, 77%) as a brown viscous oil after column chromatography (SiO2, 25% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 9.71 (s, 1H), 7.13 (s, 1H), 6.97 (d, J = 3.5 Hz, 1H), 6.23 (s, 1H), 5.90 (s, 2H), 3.97 (t, J = 6.4 Hz, 2H), 2.92 (t, J = 6.4 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ −164.2 (s, 1F); 13 C{H}NMR (100 MHz, CDCl3) δ 183.0 (CH), 147.2 (C), 146.5 (C), 145.7 (d, J = 255.3 Hz, CF), 124.0 (C), 121.5 (CH), 120.0 (d, J = 4.8 Hz, C), 115.2 (d, J = 19.1 Hz, C), 114.3 (d, J = 9.5 Hz, C), 108.5 (CH), 104.5 (d, J = 6.7 Hz, CH), 101.2 (CH2), 45.5 (CH2), 29.2 (CH2); IR (neat) νmax 1657s, 1599s, 1450s, 1020m cm−1; MS m/z (%) relative intensity 259 (M+, 100); HRMS (ESI-TOF) calcd for C14H11FNO3 [M + H]+ 260.0723, found 260.0726. 1-Fluoro-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carbaldehyde (8d). According to the general procedure E, the reaction of the isomeric mixture of 7d (33 mg, 0.1 mmol), TBAF·3H2O (158 mg, 0.5 mmol) in acetonitrile (1.0 mL) under O2 atm (balloon) for 24 h gave 8d (17 mg, 69%) as a yellow viscous oil after column chromatography (SiO2, 25% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 9.72 (s, 1H), 7.58 (d, J = 8.6 Hz, 1H), 6.97 (d, J = 3.4 Hz, 1H), 6.81 (dd, J = 2.6, 8.6 Hz, 1H), 6.70 (d, J = 2.6, Hz, 1H), 4.00 (t, J = 6.5 Hz, 2H), 3.76 (s, 3H), 3.00 (t, J = 6.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ −164.6 (s, 1F); 13C{H}NMR (100 MHz, CDCl3) δ 183.1 (CH), 158.1 (C), 145.8 (d, J = 254.7 Hz, CF), 131.8 (C), 125.4 (d, J = 6.8 Hz, CH), 121.4 (CH), 119.4 (d, J = 4.4 Hz, C), 115.1 (d, J = 19.5 Hz, C), 114.4 (d, J = 8.6 Hz, C), 113.8 (CH), 113.1 (CH), 55.4 (CH3), 45.3 (CH2), 29.5 (CH2); IR (neat) νmax 1657s, 1599s, 1522s, 1463s, 1370s, 1020s cm−1; MS m/z (%) relative intensity 246 [(M + 1)+, 26], 245 (M+, 100); HRMS (ESI-TOF) calcd for C14H13FNO2 [M + H]+ 246.0930, found 246.0919. 7-Chloro-1-fluoro-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carbaldehyde (8e). According to the general procedure E, the reaction of the isomeric mixture of 7e (36 mg, 0.1 mmol), TBAF·3H2O (158 mg, 0.5 mmol) in acetonitrile (1.0 mL) under O2 atmosphere (balloon) at 60 °C for 24 h gave 8e (9 mg, 32%) as a yellow viscous oil after column chromatography (SiO2, 25% EtOAc in hexanes). 1H NMR (500 MHz, CDCl3) δ 9.83 (s, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 3.5 Hz, 1H), 6.97 (d, J = 8.7 Hz, 1H), 4.12 (t, J = 6.5 Hz, 2H), 3.96 (s, 3H), 3.28 (t, J = 6.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ −163.3 (s, 1F); 13C{H}NMR (125 MHz, CDCl3) δ 182.9 (CH), 153.9 (C), 146.4 (d, J = 255.0 Hz, CF), 129.8 (C), 123.0 (d, J = 7.6 Hz, CH), 122.0 (C), 121.3 (C), 120.6 (C), 114.7 (C), 111.1 (2 × CH), 56.4 (CH3), 44.8 (CH2), 26.5 (CH2); IR (neat) νmax 1666s, 1461s, 1264s, 1038m cm−1; MS m/z (%) relative intensity 280 [(M + 1)+, 7], 279 (M+, 8), 178 (100); HRMS (ESI-TOF) calcd for C14H13ClFNO2 [M + H]+ 280.0541, found 280.0540.

isomers of 7d (133 mg, 82%, E:Z isomer = 1:3.7) as a yellow viscous oil after column chromatography (SiO2, 100% henanes then 20% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3, Z-isomer was marked*) δ 7.16 (d, J = 8.4 Hz, 1H and 1H*), 6.61 (dd, J = 2.1, 8.4 Hz, 1H and 1H*), 6.51 (d, J = 2.1 Hz, 1H and 1H*), 6.10 (br. s, 1H), 5.82 (br. s, 1H*), 3.74 (dd, J = 9.5, 17.1 Hz, 1H*), 3.68−3.54 (m, 5H and 3H*), 3.44 (br. s, 2H*), 3.30 (d, J = 14.6 Hz, 1H), 3.01−2.76 (m, 2H and 2H*), 2.76−2.64 (m, 1H and 1H*), 2.59−2.46 (m, 1H and 1H*), 0.00 (s, 9H and 9H*); 19F NMR (376 MHz, CDCl3, Z-isomer was marked*) δ −96.2 (dd, J = 16.3, 251.2 Hz, 1F*), −98.4 (dd, J = 6.1, 251.2 Hz, 1F*), −99.4 (dd, J = 16.5, 244.4 Hz, 1F), −103.3 (dd, J = 6.0, 244.4 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3, Z-isomer was marked*) δ 159.7 (C and C*), 150.2 (t, J = 21.7 Hz, C), 149.6 (t, J = 22.9 Hz, C*), 137.3 (C and C*), 132.8 (CH*), 128.9 (CH), 128.0 (CH*), 127.9 (CH), 123.8 (dd, J = 250.4, 255.8 Hz, CF2*), 123.1 (C), 122.9 (C*), 122.3 (dd, J = 249.2, 254.7 Hz, CF2), 114.6 (CH), 114.5 (CH*), 113.1 (CH and CH*), 68.4 (t, J = 24.7 Hz, CH*), 67.0 (t, J = 24.2 Hz, CH), 60.6 (CH2*), 56.9 (CH2), 56.1 (CH3 and CH3*), 49.4 (CH2), 48.9 (CH2*), 30.4 (CH2*), 30.3 (CH2), 0.7 (3 × CH3*), 0.0 (3 × CH3); IR (neat) νmax 1487m, 1280s, 1248s, 1062s, 1011s cm−1; MS m/z (%) relative intensity 324 [(M + 1)+, 13], 323 (M+, 54), 250 (100); HRMS (ESI-TOF) calcd for C17H24F2NOSi [M + H]+ 324.1595, found 324.1605. 7-Chloro-1,1-difluoro-8-methoxy-2-((trimethylsilyl)methylene)1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline (7e). According to the general procedure D, the reaction of 4e (233 mg, 0.5 mmol), Bu3SnH (0.24 mL, 0.88 mmol), and AIBN (25 mg, 0.15 mmol) in dry toluene (30 mL) under reflux conditions for 16 h gave a mixture of isomers of 7e (157 mg, 88%, E:Z isomer = 1:4.4) as a colorless viscous oil after column chromatography (SiO2, 100% henanes then 20% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3, Z-isomer was marked*) δ 7.26 (d, J = 8.5 Hz, 1H and 1H*), 6.84 (d, J = 8.4 Hz, 1H and 1H*), 6.28 (s, 1H), 6.01 (s, 1H*), 3.89 (s, 3H and 4H*), 3.80 (d, J = 14.6 Hz, 1H), 3.73 (dd, J = 8.1, 16.7 Hz, 1H), 3.63 (d, J = 14.3 Hz, 1H*), 3.55 (d, J = 14.3 Hz, 1H*), 3.40 (d, J = 14.6 Hz, 1H), 3.25− 2.98 (m, 2H and 2H*), 2.96−2.84 (m, 1H and 1H*), 2.75−2.60 (m, 1H and 1H*), 0.17 (s, 9H and 9H*); 19F NMR (376 MHz, CDCl3, Zisomer was marked*) δ −96.8 (dd, J = 15.4, 248.3 Hz, 1F*), −98.3 (dd, J = 6.1, 248.3 Hz, 1F*), −99.7 (dd, J = 15.4, 244.9 Hz, 1F), −103.1 (dd, J = 5.6, 244.9 Hz, 1F); 13C{H}NMR (100 MHz, CDCl3, Z-isomer was marked*) δ 154.1 (C and C*), 148.8 (t, J = 21.4 Hz, C), 148.1 (t, J = 21.2 Hz, C*), 136.3 (C*), 134.7 (CH), 132.0 (CH*), 128.2 (CH), 124.5 (CH*), 124.4 (CH and C), 123.7 (C), 123.6 (C*), 122.5 (dd, J = 249.4, 255.9 Hz, CF2*), 122.2 (C*), 121.1 (dd, J = 249.1, 255.0 Hz, CF2), 109.5 (CH), 109.2 (CH*), 67.5 (t, J = 24.6 Hz, CH*), 66.1 (t, J = 24.2 Hz, CH), 59.4 (CH2*), 56.1 (CH3 and CH3*), 55.7 (CH2), 48.1 (CH2), 47.7 (CH2*), 27.7 (CH2 and CH2*), −0.3 (3 × CH3*), −1.0 (3 × CH3); IR (neat) νmax 1487m, 1280s, 1247s, 1063s, 1041s cm−1; MS m/z (%) relative intensity 358 [(M + 1)+, 38], 357 (M+, 95), 284 (100); HRMS (ESI-TOF) calcd for C17H23ClF2NOSi [M + H]+ 358.1205, found 358.1207. Synthesis of Compounds 8. General Procedure E. A mixture of 7 (0.1 mmol) and TBAF·3H2O (158 mg, 0.5 mmol) in acetonitrile (1.0 mL) was stirred for 24 h under O2 atmosphere (balloon). The solvent was removed in vacuo to give a crude product, which was further purified by column chromatography (SiO2). 1-Fluoro-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2carbaldehyde (8a). According to the general procedure E, the reaction of the isomeric mixture of 7a (36 mg, 0.1 mmol), TBAF·3H2O (158 mg, 0.5 mmol) in acetonitrile (1.0 mL) under O2 atmosphere (balloon) for 72 h gave 8a (20 mg, 73%) as a brown viscous oil after column chromatography (SiO2, 25% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) δ 9.72 (s, 1H), 7.16 (s, 1H), 6.98 (d, J = 3.5 Hz, 1H), 6.66 (s, 1H), 4.00 (t, J = 6.5 Hz, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 2.96 (t, J = 6.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ −164.8 (s, 1F); 13C{H}NMR (100 MHz, CDCl3) δ 183.0 (CH), 148.5 (C), 148.0 (C), 145.7 (d, J = 252.7 Hz, CF), 122.7 (C), 121.8 (d, J = 2.9 Hz, CH), 119.1 (d, J = 4.1 Hz, C), 115.2 (d, J = 18.8 Hz, C), 114.3 (d, J = 9.3 Hz, C), 111.3 (CH), 107.0 (d, J = 6.9 Hz, CH), 56.0 (2 × CH3), 45.6 (CH2), 28.7 (CH2); IR (neat) νmax 1657s, 1601m, 1522s, 780

DOI: 10.1021/acs.joc.7b02783 J. Org. Chem. 2018, 83, 765−782

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The Journal of Organic Chemistry

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Reutrakul, V.; Pohmakotr, M. Eur. J. Org. Chem. 2015, 2015, 2879− 2888. (j) Wolstenhulme, J. R.; Gouverneur, V. Acc. Chem. Res. 2014, 47, 3560−3570 and references cited. (4) For selected recent references for the reaction using NFSI, see: (a) Varun, B. V.; Prabhu, K. R. J. Org. Chem. 2017, 82, 9525−9536. (b) Gutierrez, D. A.; Lee, W.-C. C.; Shen, Y.; Li, J. J. Tetrahedron Lett. 2016, 57, 5372−5376. (c) Emma, M. G.; Lombardo, M.; Trombini, C.; Quintavalla, A. Eur. J. Org. Chem. 2016, 2016, 3223−3232. (d) Albertshofer, K.; Mani, N. S. J. Org. Chem. 2016, 81, 1269−1276. (e) Testa, C.; Gigot, É.; Genc, S.; Decréau, R.; Roger, J.; Hierso, J. Angew. Chem., Int. Ed. 2016, 55, 5555−5559. (f) Testa, C.; Roger, J.; Scheib, S.; Fleurat-Lessard, P.; Hierso, J.-C. Adv. Synth. Catal. 2015, 357, 2913−2923. (g) Ding, Q.; Ye, C.; Pu, S.; Cao, B. Tetrahedron 2014, 70, 409−416. (5) For selected recent references for trifluoromethylation, see: (a) Liu, X.; Xu, C.; Wang, M.; Liu, Q. Chem. Rev. 2015, 115, 683−730 and references cited. (b) Pandey, V. K.; Anbarasan, P. J. Org. Chem. 2014, 79, 4154−4160. (c) Masusai, C.; Soorukram, D.; Kuhakarn, C.; Tuchinda, P.; Pakawatchai, C.; Saithong, S.; Reutrakul, V.; Pohmakotr, M. Org. Biomol. Chem. 2013, 11, 6650−6658. (d) Kawai, H.; Yuan, Z.; Tokunaga, E.; Shibata, N. Org. Biomol. Chem. 2013, 11, 1446−1450. (e) Zhang, Y.; Fujiu, M.; Serizawa, H.; Mikami, K. J. Fluorine Chem. 2013, 156, 367−371. (f) Hoffmann-Röder, A.; Seiler, P.; Diederich, F. Org. Biomol. Chem. 2004, 2, 2267−2269 and references cited. (g) Folléas, B.; Marek, I.; Normant, J.-F.; Jalmes, L. S. Tetrahedron Lett. 1998, 39, 2973−2976. (h) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc. 1989, 111, 393−395. (6) For selected recent references for gem-difluoromethylation, see: (a) Korvorapun, K.; Soorukram, D.; Kuhakarn, C.; Tuchinda, P.; Reutrakul, V.; Pohmakotr, M. Chem. - Asian J. 2015, 10, 948−968. (b) Thaharn, W.; Soorukram, D.; Kuhakarn, C.; Tuchinda, P.; Pakawatchai, C.; Saithong, S.; Reutrakul, V.; Pohmakotr, M. J. Org. Chem. 2015, 80, 816−827. (c) Masusai, C.; Soorukram, D.; Kuhakarn, C.; Tuchinda, P.; Pakawatchai, C.; Saithong, S.; Reutrakul, V.; Pohmakotr, M. J. Org. Chem. 2015, 80, 1577−1592. (d) Soorukram, D.; Kuhakarn, C.; Reutrakul, V.; Pohmakotr, M. Synlett 2014, 25, 2558−2573 and references cited. (e) Thaharn, W.; Soorukram, D.; Kuhakarn, C.; Tuchinda, P.; Reutrakul, V.; Pohmakotr, M. Angew. Chem., Int. Ed. 2014, 53, 2212−2215. (f) Punirun, T.; Soorukram, D.; Kuhakarn, C.; Reutrakul, V.; Pohmakotr, M. Eur. J. Org. Chem. 2014, 2014, 4162−4169. (7) (a) Aikawa, K.; Maruyama, K.; Nitta, J.; Hashimoto, R.; Mikami, K. Org. Lett. 2016, 18, 3354−3357. (b) Aikawa, K.; Maruyama, K.; Honda, K.; Mikami, K. Org. Lett. 2015, 17, 4882−4885. (c) Wang, X.; Liu, G.; Xu, X.-H.; Shibata, N.; Tokunaga, E.; Shibata, N. Angew. Chem., Int. Ed. 2014, 53, 1827−1831. (d) Liu, G.; Wang, X.; Lu, X.; Xu, X.-H.; Tokunaga, E.; Shibata, N. ChemistryOpen 2012, 1, 227−231. (e) Zhu, L.; Li, Y.; Zhao, Y.; Hu, J. Tetrahedron Lett. 2010, 51, 6150− 6152. (f) Mikami, K.; Tomita, Y.; Itoh, Y. Angew. Chem., Int. Ed. 2010, 49, 3819−3822. (g) Li, Y.; Hu, J. J. Fluorine Chem. 2008, 129, 382− 385. (h) Burton, D. J.; Hartgraves, G. A. J. Fluorine Chem. 2007, 128, 1198−1215. (8) Chu, L.; Zhang, X.; Qing, F.-L. Org. Lett. 2009, 11, 2197−2200. (9) Li, W.; Zhu, X.; Mao, H.; Tang, Z.; Cheng, Y.; Zhu, C. Chem. Commun. 2014, 50, 7521−7523. (10) Chen, Q.; Zhou, J.; Wang, Y.; Wang, C.; Liu, X.; Xu, Z.; Lin, L.; Wang, R. Org. Lett. 2015, 17, 4212−4215. (11) For selected examples for oxidative functionalization of Tetrahydroisoquinolines, see: (a) Fu, N.; Li, L.; Yang, Q.; Luo, S. Org. Lett. 2017, 19, 2122−2125. (b) Yang, L.; Zhang-Negrerie, D.; Zhao, K.; Du, Y. J. Org. Chem. 2016, 81, 3372−3379. (c) Yan, C.; Li, L.; Liu, Y.; Wang, Q. Org. Lett. 2016, 18, 4686−4689. (d) Liu, X.; Sun, S.; Meng, Z.; Lou, H.; Liu, L. Org. Lett. 2015, 17, 2396−2399. (e) Wang, T.; Schrempp, M.; Berndhauser, A.; Schiemann, O.; Menche, D. Org. Lett. 2015, 17, 3982−3985. (f) Huang, H.-M.; Li, Y.J.; Ye, Q.; Yu, W.-B.; Han, L.; Jia, J.-H.; Gao, J.-R. J. Org. Chem. 2014, 79, 1084−1092. (g) Xie, Z.; Liu, L.; Chen, W.; Zheng, H.; Xu, Q.; Yuan, H.; Lou, H. Angew. Chem., Int. Ed. 2014, 53, 3904−3908. (h) Tanoue, A.; Yoo, W.-J.; Kobayashi, S. Org. Lett. 2014, 16, 2346−

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02783. Spectroscopic data of all compounds (copies of 1H, 13C and 19F NMR), the HMQC and NOESY spectra of 7aA, 7aB (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Tel: (+)-66-2-2015158. Fax: (+)-66-2-6445126. E-mail: [email protected]. ORCID

Chutima Kuhakarn: 0000-0003-4638-4356 Manat Pohmakotr: 0000-0002-6174-1211 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge financial supports from the Office of the Higher Education Commission and Mahidol University under the National Research Universities Initiative, the Center of Excellence for Innovation in Chemistry (PERCH−CIC), Thailand Research Found (IRN58W0005), The Franco-Thai Cooperation Program in Higher Education and Research (PHC-Siam 2017) and the Royal Golden Jubilee Ph.D. Program (Grant No. PHD/0121/2554 to T.P. and M.P.).

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REFERENCES

(1) (a) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. J. Med. Chem. 2015, 58, 8315−8359. (b) Bégué, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine; John Wiley & Sons: New York, 2008. (c) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320−330. (d) Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2005, 44, 214−231 and references cited. (e) Bégué, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine; John Wiley & Sons: New York, 2008. (f) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320−330. (g) Hiyama, T., Ed.; Organofluorine Compounds, Chemistry and Applications; Springer: New York, 2000. (2) For selected recent references, see: (a) Ojima, I. Fluorine in Medicinal Chemistry and Chemical Biology; Blackwell: Oxford, 2009. (b) Phillips, B.; Cai, R.; Delaney, W.; Du, Z.; Ji, M.; Jin, H.; Lee, J.; Li, J.; Niedziela-Majka, A.; Mish, M.; Pyun, H.-J.; Saugier, J.; Tirunagari, N.; Wang, J.; Yang, H.; Wu, Q.; Sheng, C.; Zonte, C. J. Med. Chem. 2014, 57, 2161−2166. (c) Giornal, F.; Pazenok, S.; Rodefeld, L.; Lui, N.; Vors, J.-P.; Leroux, F. R. J. Fluorine Chem. 2013, 152, 2−11. (d) O’Hagan, D. J. Fluorine Chem. 2010, 131, 1071−1081. (e) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308−319. (f) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320−330. (g) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359−4369. (3) For selected recent references for the reaction using Selecfluor, see: (a) Ma, X.; Diane, M.; Ralph, G.; Chen, C.; Biscoe, M. R. Angew. Chem., Int. Ed. 2017, 56, 12663−12667. (b) Liua, N.; Tiana, Q.-P.; Yanga, Q.; Yang, S.-D. Synlett 2016, 27, 2621−2625. (c) Jadhav, A. M.; Huple, D. B.; Singh, R. R.; Liu, R. Adv. Synth. Catal. 2016, 358, 1017− 1022. (d) Ulmer, A.; Brunner, C.; Arnold, A. M.; Pöthig, A.; Gulder, T. Chem. - Eur. J. 2016, 22, 3660−3664. (e) Liu, P.; Gao, Y.; Gu, W.; Shen, Z.; Sun, P. J. Org. Chem. 2015, 80, 11559−11565. (f) Sandford, C.; Rasappan, R.; Aggarwal, V. K. J. Am. Chem. Soc. 2015, 137, 10100− 10103. (g) Zhao, J.-F.; Duan, X.-H.; Yang, H.; Guo, L.-N. J. Org. Chem. 2015, 80, 11149−11155. (h) Egami, H.; Asada, J.; Sato, K.; Hashizume, D.; Kawato, Y.; Hamashima, Y. J. Am. Chem. Soc. 2015, 137, 10132−10135. (i) Phae-nok, S.; Soorukram, D.; Kuhakarn, C.; 781

DOI: 10.1021/acs.joc.7b02783 J. Org. Chem. 2018, 83, 765−782

Article

The Journal of Organic Chemistry 2349. (i) Min, C.; Sanchawala, A.; Seide, D. Org. Lett. 2014, 16, 2756− 2759. (j) Ueda, H.; Yoshida, K.; Tokuyama, H. Org. Lett. 2014, 16, 4194−4197. (k) Ma, Y.; Zhang, G.; Zhang, J.; Yang, D.; Wang, R. Org. Lett. 2014, 16, 5358−5361. (l) Huo, C.; Xie, H.; Wu, M.; Jia, X.; Wang, X.; Chen, F.; Tang, J. Chem. - Eur. J. 2015, 21, 5723−5726. (m) Huo, C.; Wu, M.; Jia, X.; Xie, H.; Yuan, Y.; Tang, J. J. Org. Chem. 2014, 79, 9860−9864. (n) Huo, C.; Wang, C.; Wu, M.; Jia, X.; Wang, X.; Yuan, Y.; Xie, H. Org. Biomol. Chem. 2014, 12, 3123−3128. (12) For selected recent references for Cu-catalyzed oxidative functionalization of tetrahydroisoquinolines, see: (a) Liu, Y.; Wang, C.; Xue, D.; Xiao, M.; Li, C.; Xiao, J. Chem. - Eur. J. 2017, 23, 3051− 3061. (b) Girard, S. A.; Knauber, T.; Li, C.-J. Angew. Chem., Int. Ed. 2014, 53, 74−100 and references cited. (c) Zhang, G.; Ma, Y.; Cheng, G.; Liu, D.; Wang, R. Org. Lett. 2014, 16, 656−659. (d) Boess, E.; Schmitz, C.; Klussmann, M. J. Am. Chem. Soc. 2012, 134, 5317−5325. (e) Su, W.; Yu, J.; Li, Z.; Jiang, Z. J. Org. Chem. 2011, 76, 9144−9150. (f) Mitsudera, H.; Li, C.-J. Tetrahedron Lett. 2011, 52, 1898−1900. (g) Jiang, H.; Chen, H.; Wang, A.; Liu, X. Chem. Commun. 2010, 46, 7259−7261. (h) Baslé, O.; Li, C.-J. Chem. Commun. 2009, 27, 4124− 4126. (13) Xie, Z.; Zan, X.; Sun, S.; Pan, X.; Liu, L. Org. Lett. 2016, 18, 3944−3947. (14) (a) Yan, C.; Liu, Y.; Wang, Q. Org. Lett. 2015, 17, 5714−5717. (b) Yan, C.; Liu, Y.; Wang, Q. RSC Adv. 2014, 4, 60075−60078. (c) Neel, A. J.; Hehn, J. P.; Tripet, P. F.; Toste, F. D. J. Am. Chem. Soc. 2013, 135, 14044−14047. (15) Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 4397−4400. (16) Orgren, L. R.; Maverick, E. E.; Marvin, C. C. J. Org. Chem. 2015, 80, 12635−12640. (17) (a) Ogiyama, T.; Yonezawa, K.; Inoue, M.; Watanabe, T.; Sugano, Y.; Gotoh, T.; Kiso, T.; Koakutsu, A.; Kakimoto, S.; Shishikura, J. Bioorg. Med. Chem. 2015, 23, 4624−4637. (b) Dhanasekaran, S.; Bisai, V.; Unhale, R. A.; Suneja, A.; Singh, V. K. Org. Lett. 2014, 16, 6068−6071. (c) Ye, Z.-S.; Guo, R.-N.; Cai, X.-F.; Chen, M.W.; Shi, L.; Zhou, Y.-G. Angew. Chem., Int. Ed. 2013, 52, 3685−3689. (18) (a) Zard, S. Z. Radical Reactions in Organic Synthesis; Oxford University Press: New York, 2003. (b) Chen, M.-J.; Tsai, Y.-M. Tetrahedron Lett. 2007, 48, 6271−6274. (c) Li, Y.; Hu, J. Angew. Chem., Int. Ed. 2005, 44, 5882−5886. (d) Bryans, J. S.; Large, J. M.; Parsons, A. F. J. Chem. Soc., Perkin Trans. 1 1999, 2905−2910. (e) Keusenkothen, P. F.; Smith, M. B. Tetrahedron 1992, 48, 2977− 2992. (f) Knapp, S.; Gibson, F. S. J. Org. Chem. 1992, 57, 4802−4809. (g) Knapp, S.; Gibson, F. S.; Choe, Y. H. Tetrahedron Lett. 1990, 31, 5397−5400. (19) These observations are in accordance with our previously reported work: Bootwicha, T.; Panichakul, D.; Kuhakarn, C.; Parbpai, S.; Kongsaeree, P.; Tuchinda, P.; Reutrakul, V.; Pohmakotr, M. J. Org. Chem. 2009, 74, 3798−3805. See also, ref 6e. (20) The reaction of 7a (0.1 mmol) with H2O2 (30% aq. solution, 1.5 equiv) was completed in 8 h to provide 8a in 74% yield. (21) Bojarski, A. j.; Mokrosz, M. J.; Minol, S. C.; Kozioł, A.; Wesołowska, A.; Tatarczyńska, E.; Kłodzińska, A.; Chojnacka-Wójcik, E. Bioorg. Med. Chem. 2002, 10, 87−95 and references cited.

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DOI: 10.1021/acs.joc.7b02783 J. Org. Chem. 2018, 83, 765−782