Controllable Diastereodivergent Synthesis of Pyrrolo[2,1-a

Article pubs.acs.org/joc

Controllable Diastereodivergent Synthesis of Pyrrolo[2,1‑a]isoquinolines via Catalytic Intramolecular Acylsulfenylation of Activated Alkenes Wei Liu, Shan-Tao Du, Shu-Yue Wang, and Wei-Wei Liao* Department of Organic Chemistry, College of Chemistry, Jilin University, 2699 Qianjin Street, Changchun 130012, China S Supporting Information *

ABSTRACT: A controllable stereoselective synthesis of tetrahydropyrrolo[2,1-a]isoquinoline derivatives bearing a sulfur moiety was demonstrated with high diastereoselectivity through a catalytic intramolecular acylsulfenylation of activated alkenes. This approach involved a catalytic thia-Michael addition triggered intramolecular aldol-type tandem sequence. Both cis- and transproducts can be readily prepared in moderate to high yields with excellent diastereoselectivities in a catalytically atom-economic fashion under the optimized mild reaction conditions.

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INTRODUCTION Organosulfur compounds are widely present in nature and various biological systems1 and can also serve as useful synthetic scaffolds to a diverse array of building blocks.2 Therefore, it is of great significance for the construction of organosulfur compounds.3 Among them, intramolecular electrophilic sulfenocyclization represents one of the most efficient approaches to access carbocycles and heterocycles bearing sulfur moieties.4 In this transformation, the reaction of sulfur(II) electrophiles with electron-rich alkenes provides thiiranium ion intermediates, which can be trapped subsequently by a variety of nucleophiles and afford different cyclic sulfenofunctionalized products (Scheme 1a).4 The remarkable advances have been achieved on sulfenoamination,4a,b sulfenoetherification,4c and carbosulfenylation of olefins reactions.4d−f However, these sulfenium-initiated cyclizations require electron-rich alkenes and nucleophile components, and acylsulfenylation of electron-deficient alkenes could not be accomplished by using this approach. Considering the structural diversity of organosulfur compounds in nature and various biological systems, the development of an alternative strategy for the efficient construction of sulfenofunctionalized products including a cyclic structural framework via a catalytic acylsulfenylation of electron-deficient alkenes is highly appealing. Sulfa-Michael addition (SMA) triggered tandem reaction, in which a generated thioenolate intermediate can subsequently react with various electrophiles to give a diversity of organosulfur compounds, has acquired wide application in organic synthesis and biological processes.3c−e Inspired by our recent work on the metal-free intramolecular carbocyanation of electron-deficient alkenes and the stereoselective sulfa-Michael © 2017 American Chemical Society

Scheme 1. Synthetic Strategy

triggered tandem reaction,5 we envisioned that a novel intramolecular acylsulfenylation of electron-deficient alkenes could be established, in which a catalytic thia-Michael addition triggered intramolecular aldol-type tandem sequence would provide an organosulfur compound bearing a cyclic structural framework by utilizing a carbamothioate-based substrate (Scheme 1b, reaction 1). Pyrrolo[2,1-a]isoquinoline lactam systems frequently occurred in many natural products and biologically relevant Received: March 7, 2017 Published: April 25, 2017 4829

DOI: 10.1021/acs.joc.7b00551 J. Org. Chem. 2017, 82, 4829−4839

Article

The Journal of Organic Chemistry Table 1. Optimization of Reaction Conditionsa

mediator

solvent

T (°C)

t (h)

yield (%)b

drc (cis/trans)

BuLi/PhSH EtMgBr/PhSH t BuONa/PhSH t BuOK/PhSH PhSNa EtONa DBU/PhSH PBu3 PPh2Et PPhEt2 TBACN PhSNa PhSNa TBACN

THF THF THF THF THF THF THF THF THF THF THF THF THF NMP

0 0 0 0 0 0 0−30 0 60 0−30 0 0 0 0

5 5 0.5 0.5 0.5 2 24 1 22 8 2 5 0.5 1.5

25 − 94 93 92 83 77 61 50 57 63 82 92 64

1:1 − >19:1 >19:1 >19:1 >19:1 1:6 19/1). Products were obtained with dr >19/1 based on the 1H NMR analysis. bIsolated yields. cRun at −10 °C. dBased on the 1 H NMR analysis of the mixture 2 and 3.

while NMP was a suitable solvent for the transformation of 1a into a trans-product by using TBACN.10 Further optimization indicated that both the desired diastereoisomers 2a-cis and 2atrans can be obtained in comparable yields with excellent diastereoselectivities in the presence of the reducing loadings of mediators respectively by conducting these transformations in the more concentrated solution (Table 1, entries 12−14). The

relative configurations of diastereomeric pyrrolo[2,1-a]isoquinoline product 2a-cis and 2a-trans were determined on the basis of X-ray crystal structural analyses.11 With the optimized reaction conditions, the reaction scope of this diastereoselectivity-controllable acylsulfenylation reaction was examined (Table 2). Generally, controllable acylsulfenylation reactions furnished cis- and trans-tetrahydropyrrolo[2,14831


Article

The Journal of Organic Chemistry a]isoquinoline products with excellent diastereoselectivities regardless of cis- or trans-cyclization reaction conditions (Table 2, con. A and con. B). First, the cis-selective cyclizations were evaluated by using sodium thiophenolate (10 mol %) (path A). Various electron-withdrawing groups (R2) on the vinyl moiety were well tolerated, and methyl ester and ketone analogues gave the desired cis-prodcuts in good to high yields with excellent diastereoselectivities (Table 2, 2b-cis and 2c-cis). However, a bulky ester analogue such as tert-butyl ester afforded the product 2d-cis in a low yield (47%) with >19/1 diastereoselectivity, presumably due to the steric hindrance effect of the tert-butyl ester group (Table 2, entry 4). Substituents with different electronic natures on the aromatic ring (R3), such as methoxy and halogen, were tolerated (2e− 2j), and both para- and meta-substituent patterns on the aromatic ring had few effects on the chemical outcome and stereoselectivity of this transformation. For example, both substrates bearing para- and meta-methoxy substituted aromatic rings (R3) delivered the desired cis-products in high yields with excellent diastereoselectivities (2e-cis and 2h-cis), while analogues with para- or meta-bromo- and chloro-substituted aromatic rings (R3) also demonstrated comparable results with regards to the chemical outcomes and stereoselectivities (2f-cis, 2g-cis, and 2i-cis). However, the substituent at the orthoposition of aromatic rings (R3) had a considerable influence on this process. The treatment of ortho-bromo-substituted 1,2dihydroisoquinoline 1j with sodium thiophenolate (10 mol %) gave the desired acylsulfenylation cis-product 2j-cis in moderate yield and excellent diastereoselectivity under the optimal conditions, along with the decyanation product 3j in 36% yield, which may stem from the increasing steric strain of a fivemembered ring intermediate due to the introduction of an ortho-substituent (see Scheme 3). The reaction of 2,4-dichlorosubstituted 1,2-dihydroisoquinoline under the optimal conditions gave the desired product 2k-cis in good yield with excellent diastereoselectivity (Table 2, entry 11). The naphthyl substituted compound can also serve as a good substrate and provide product 2l-cis in 92% yield with a dr value >19/1(Table 2, entry 12). In addition, performing the cyclization reactions with 4-bromo-, 5-chloro-, 5-bromo-, and 6-bromo-substituted analogues respectively under optimal reaction conditions afforded the desired cis-products in high yields with excellent diastereoselectivities (2m-cis, 2n-cis, 2o-cis, and 2p-cis). Notably, treatment of α-unsubstituted allylic 1,2dihydroisoquinoline 1q (R3 = H) with sodium thiophenolate (10 mol %) under the optimized conditions furnished the desired product 2q-cis with excellent yield and diastereoselectivity (dr >19:1) (Table 2, entry 17). Subsequently, the cyclizations of allylic 1,2-dihydroisoquinolines which provided trans-products were examined by using TBACN (5 mol %) and NMP (con. B). The majority of α-substituted allylic 1,2dihydroisoquinolines can be employed as suitable substrates to provide the desired trans-products, except for ketone and tertbutyl ester analogues (R2) which did not give any desired transproducts (Table 2, entries 3−4). Compared to sodium thiophenolate catalyzed cis-cyclization, TBACN-catalyzed processes afforded moderate yields, albeit with excellent diastereoselectivities. However, the chemical yield and diastereoselectivity for TBACN-catalyzed cyclization of α-unsubstituted allylic 1,2-dihydroisoquinoline (1q) were comparable to those of the sodium thiophenolate catalyzed process, which furnished the desired trans-product 2q-trans with excellent yield and diastereoselectivity.

This protocol was also applied to substituted thiophenolates involving catalytic intramolecular acylsulfenylation which further extends the application of this tandem protocol for the preparation of various functionalized products (Table 3). Table 3. Substrate Scope of Tandem Reactiona

entry

R1

1

4-BrC6H4S

2

4-MeOC6H4S

1 1r 1r 1s 1s

con. t (h) A B A B

1.5 2 1.5 2

2

yield (%)b

drc

2r-cis 2r-trans 2s-cis 2s-trans

85 79 85 42

>19:1 >19:1 >19:1 >19:1

a

Condition A: reactions were performed with 1 (0.2 mmol) and EtONa (20 mol %) in THF (2 mL) at 0 °C under an inert atmosphere; condition B: reactions were performed with 1 (0.2 mmol) and TBACN (5 mol %) in NMP (0.5 mL) at 0 °C under an inert atmosphere. Diastereomeric pure 1 was employed (dr >19/1). b Isolated yields. cDetermined by 1H NMR analysis.

Treatment of para-bromophenyl-substituted allylic 1,2-dihydroisoquinoline 1r with EtONa (20 mol %) allowed expedient access to the cis-tetrahydropyrrolo[2,1-a]isoquinoline 2r-cis in good yield with >19/1 diastereoselectivity, in which 4bromobenzenethiote underwent a stereospecific acylsulfenylation transformation. On the other hand, a trans-cyclization of 1,2-dihydroisoquinoline 1r can also be achieved just by using TABCN (5 mol %), which provided the desired trans-product 2r-trans with comparable yield and diastereoselectivity. A paramethoxyphenyl carbothioate analogue can also serve as a suitable substrate for this controllable transformation, which afforded the desired cis- and trans-products with excellent selectivities by employing EtONa and TABCN as mediators respectively (Table 3, entry 2). In addition, the synthetic utility of this intramolecular acylsulfenylation product is illustrated as Scheme 2. The treatment of both 2a-cis and 2a-trans with mCPBA in CH2Cl2 afforded sulfones 4a-cis and 4a-trans in 78% and 85% yields with almost intact stereoselectivities, respectively. On the basis of the above experiments and X-ray crystal structural analyses of cis- and trans-products, a possible reaction pathway is proposed (Scheme 3). The conjugate addition of thiophenolate to the activated terminal alkene moiety of 1,2dihydroisoquinoline 1 would lead to enolate I. Due to the facial selectivity of enolate (I), subsequently a tandem intramolecular condensation between the enolate (Si-face, I-A) with the thioester group proceeded dominantly and gave intermediate II-A stereospecifically in the presence of metal cation such as Na+, which followed an elimination to afford the desired cisproduct 2-cis with thiophenolate. In this case, sodium cation may coordinate favorably to both the oxygen atom of the 4832


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The Journal of Organic Chemistry

(UV), KMnO4, p-anisaldehyde stain, and phosphomolybdic acid (PMA) stain; column chromatography purifications were carried out using silica gel. Proton nuclear magnetic resonance (1H NMR) spectra were recorded on a 300 or 500 MHz spectrometer in CDCl3, and carbon nuclear magnetic resonance (13C NMR) spectra were recorded on a 125 MHz spectrometer in CDCl3 unless otherwise noted. Mass spectra were recorded on the MicrOTOF Q. Melting points were measured on a melting point apparatus and were uncorrected. General Procedure for the Preparation of Allylic Substituted 1,2-Dihydroisoquinolines 1. To a dried 25 mL round-bottom flask under a N2 atmosphere were added DABCO (20 mol %), Reissert sulfur analogs (1 mmol), MBH carbonate (1.3 equiv), and CH3CN (5 mL) at 30 °C. Upon completion, the reaction mixture was concentrated in vacuo. The crude mixture was purified by column chromatography (silica gel, EtOAc/Petroleum ether (60−90 °C)) to provide the following compounds. A single isomer can be obtained by recrystallization if necessary. Ethyl 2,3-Dicyano-2-[2-(methoxycarbonyl)-1-phenylallyl]-4phenylpyridine-1(2H)-carboxylate (Table 1, 1a). White solid (461 mg, 96% yield, dr >19/1); Petroleum ether/EtOAc = 10/1; mp: 125− 126 °C. 1H NMR (500 MHz, CDCl3) δ 7.47−7.49 (m, 2H), 7.45− 7.42 (m, 3H), 7.28−7.25 (m, 1H), 7.20 (d, J = 7.1 Hz, 1H), 7.14 (t, J = 7.3 Hz, 1H), 7.07 (t, J = 7.6 Hz, 2H), 6.98−6.95 (m, 1H), 6.93−6.87 (m, 3H), 6.85 (d, 2H), 6.67 (s, 1H), 6.35 (d, J = 7.6 Hz, 1H), 5.03 (s, 1H), 4.21−4.10 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 166.7, 166.4, 136.5, 135.8, 134.7, 130.3, 130.0, 129.5, 129.4, 129.3, 128.7, 128.6, 128.1, 128.0, 127.9, 127.6, 126.9, 125.4, 122.7, 116.0, 113.6, 63.6, 61.4, 49.0, 14.2. HRMS (ESI): calcd for C29H25N2O3S ([M + H]+): 481.1580, found 481.1575. Methyl 2-((1-Cyano-2-((phenylthio)carbonyl)-1,2-dihydroisoquinolin-1-yl)(phenyl)methyl)acrylate (Table 1, 1b). White solid (443 mg, 95% yield, dr >19/1); Petroleum ether/EtOAc = 10/1; mp: 121−122 °C. 1H NMR (500 MHz, CDCl3) δ 7.52−7.46 (m, 2H), 7.45−7.38 (m, 3H), 7.30−7.24 (m, 1H), 7.20 (d, J = 7.3 Hz, 1H), 7.15 (t, J = 7.3 Hz, 1H), 7.07 (t, J = 7.6 Hz, 2H), 6.97 (t, J = 7.5 Hz, 1H), 6.94−6.87 (m, 3H), 6.85 (d, J = 8.1 Hz, 2H), 6.66 (s, 1H), 6.35 (d, J = 7.59, 1H), 5.02 (s, 1H), 3.71 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 167.2, 166.4, 136.2, 135.8, 134.5, 130.4, 130.1, 129.6, 129.5, 129.4, 128.7, 128.6, 128.1, 127.9, 127.6, 126.9, 125. 5, 122.7, 116.0, 113.7, 63.5, 52.5, 49.2. HRMS (ESI): calcd for C28H23N2O3S ([M + H]+): 467.1424, found 467.1427. S-Phenyl 1-Cyano-1-(2-methylene-3-oxo-1-phenylbutyl)isoquinoline-2(1H)-carbothioate (Table 1, 1c). White solid (356 mg, 79% yield, dr >19/1); Petroleum ether/EtOAc = 9/1; mp: 98−99 °C. 1H NMR (500 MHz, CDCl3) δ 7.51−7.38 (m, 5H), 7.25−7.20 (m, 1H), 7.17 (d, J = 7.3 Hz, 1H), 7.15−7.10 (m, 1H), 7.09−7.03 (m, 3H), 6.98 (d, J = 7.4 Hz, 2H), 6.96−6.90 (m, 2H), 6.81 (d, J = 7.6 Hz, 1H), 6.49 (s, 1H), 6.36 (d, J = 7.6 Hz, 1H), 5.21 (s, 1H), 2.33 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 198.6, 166.6, 144.7, 135.9, 135.1, 130.2, 130.1, 130.0, 129.5, 129.4, 128.5, 128.4, 128.0, 127.9, 127.8,

Scheme 2. Synthetic Transformation

thioester group and the enolate units of intermediate I-A.12 On the other hand, an alternative tandem intramolecular addition of enolate to CO of the thioester group can proceed from the Re-face of enolate I-B to produce intermediate II-B in the absence of a metal cation, presumably due to the repulsion between charged groups (cyano group and enolate moiety), which eventually gave trans-product 2-trans stereospecifically. In this pathway (con. B), a catalytic cyanide-Michael addition triggering an intramolecular aldol-type tandem sequence could generate metal ion-free thiophenolate as an authentic catalyst, which was supported by the fact that treatment of 1,2dihydroisoquinoline 1a with a catalytic amount of TBASPh (10 mol %) (TBASPh = tetrabutylammonium thiophenolate) in NMP gave the desired product 2a-trans in a similar yield (62%) and diastereoselectivity (>19/1).10

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CONCLUSION We have developed a controllable stereoselective synthesis of tetrahydropyrrolo[2,1-a]isoquinoline derivatives bearing a sulfur moiety with high diastereoselectivity in a catalytically atom-economic fashion. This approach involved a catalytic thiaMichael addition triggered intramolecular aldol-type tandem sequence. Both cis- and trans-products can be readily prepared in moderate to high yields with excellent diastereoselectivities under the optimized mild reaction conditions. The scope and versatility of the process were demonstrated, which will find potential utility in organic synthesis.

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EXPERIMENTAL SECTION

General Information. All reactions were carried out under inert atmospheric conditions unless otherwise noted, and solvents were dried according to established procedures. Reactions were monitored by thin layer chromatography (TLC) visualizing with ultraviolet light

Scheme 3. Plausible Reaction Mechanism

4833


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135.8, 135.6, 133.7, 131.2, 130.1, 129.9, 129.8, 129.5, 129.4, 128.7, 128.6, 128.2, 128.0, 127.7, 126.7, 125.7, 122.6, 121.8, 115.6, 113.7, 63.2, 52.6, 48.9. HRMS (ESI): calcd for C28H22BrN2O3S ([M + H]+): 545.0529, found 545.0532. Methyl 2-((2-Bromophenyl)(1-cyano-2-((phenylthio)carbonyl)1,2-dihydroisoquinolin-1-yl)methyl)acrylate (Table 1, 1j). White solid (517 mg, 95% yield, dr = 14/1); Petroleum ether/EtOAc = 10/1; mp: 122−123 °C. Major isomer: 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J = 7.7 Hz, 1H), 7.51−7.47 (m, 2H), 7.45−7.40 (m, 3H), 7.31−7.23 (m, 3H), 7.14 (d, J = 7.5 Hz, 1H), 7.04−6.98 (m, 3H), 6.90 (d, J = 7.5 Hz, 1H), 6.75 (s, 1H), 6.66 (s, 1H), 6.41 (d, J = 7.6 Hz, 1H), 5.83 (s, 1H), 3.74 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 167.1, 166.8, 136.5, 135.8, 134.4, 133.0, 131.2, 130.3, 130.1, 130.0, 129.7, 129.5, 129.4, 128.1, 127.6, 127.6, 127.1, 126.9, 125.6, 122.9, 116.4, 114.3, 63.5, 52.5, 46.5. HRMS (ESI): calcd for C28H22BrN2O3S ([M + H]+): 545.0529, found 545.0531. Methyl 2-((1-Cyano-2-((phenylthio)carbonyl)-1,2-dihydroisoquinolin-1-yl)(2,4-dichlorophenyl)methyl)acrylate (Table 1, 1k). White solid (427 mg, 80% yield, dr >19/1); Petroleum ether/EtOAc = 10/1; mp: 179−180 °C. 1H NMR (300 MHz, CDCl3) δ 7.74 (d, J = 8.6 Hz, 1H), 7.50−7.39 (m, 5H), 7.35−7.28 (m, 1H), 7.22 (dd, J = 8.6, 2.3 Hz, 1H), 7.18−7.13 (m, 1H), 7.10−7.04 (m, 2H), 6.98 (d, J = 7.5 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 6.79 (s, 1H), 6.66 (s, 1H), 6.41 (d, J = 7.6 Hz, 1H), 5.80 (s, 1H), 3.72 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 166.8, 137.7, 136.4, 135.8, 134.6, 131.9, 131.4, 130.1, 130.0, 129.9, 129.8, 129.4, 129.1, 127.9, 127.6, 127.4, 126.9, 126.8, 125.7, 122.8, 116.2, 114.5, 114.4, 114.3, 63.1, 52.5, 43.5. HRMS (ESI): calcd for C28H21Cl2N2O3S ([M + H]+): 535.0644, found 535.0647. Methyl 2-((1-Cyano-2-((phenylthio)carbonyl)-1,2-dihydroisoquinolin-1-yl) (naphthalen-2-yl)methyl)acrylate (Table 1, 1l). White solid (464 mg, 90% yield, dr >19/1); Petroleum ether/EtOAc = 10/1; mp: 155−156 °C. 1H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 7.4 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.52− 7.47 (m, 2H), 7.45−7.37 (m, 5H), 7.30 (s, 1H), 7.28−7.22 (m, 2H), 6.97 (dd, J = 8.5, 1.1 Hz, 1H), 6.94 (s, 1H), 6.89−6.83 (m, 3H), 6.72 (s, 1H), 6.38 (d, J = 7.6 Hz, 1H), 5.19 (s, 1H), 3.69 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 167.2, 166.5, 136.3, 135.8, 132.9, 132.8, 131.9, 130.1, 130.0, 129.6, 129.5, 129.4, 128.8, 128.7, 128.2, 128.1, 127.8, 127.7, 127.5, 127.4, 126.9, 126.4, 126.1, 125.5, 122.7, 116.0, 113.9, 63.4, 52.5, 49.5. HRMS (ESI): calcd for C32H25N2O3S ([M + H]+): 517.1580, found 517.1579. Methyl 2-((4-Bromo-1-cyano-2-((phenylthio)carbonyl)-1,2dihydroisoquinolin-1-yl)(phenyl)methyl)acrylate (Table 1, 1m). White solid (506 mg, 93% yield, dr >19/1); Petroleum ether/EtOAc = 10/1; mp: 140−141 °C. 1H NMR (300 MHz, CDCl3) δ 7.63 (dd, J = 7.8, 1.2 Hz, 1H), 7.52−7.36 (m, 6H), 7.22−7.13 (m, 2H), 7.12−7.03 (m, 3H), 6.95 (dd, J = 7.8, 1.0 Hz, 1H), 6.91−6.84 (m, 2H), 6.80 (s, 1H), 6.67 (s, 1H), 4.99 (s, 1H), 3.73 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 167.1, 166.0, 136.1, 135.7, 134.2, 130.3, 130.2, 129.9, 129.7, 129.5, 129.2, 129.0, 128.3, 128.1, 127.8, 126.4, 125.8, 123.2, 115.5, 108.9, 63.8, 52.6, 49.7. HRMS (ESI): calcd for C28H22BrN2O3S ([M + H]+): 545.0529, found 545.0528. Methyl 2-((5-Chloro-1-cyano-2-((phenylthio)carbonyl)-1,2dihydroisoquinolin-1-yl)(phenyl)methyl)acrylate (Table 1, 1n). White solid (475 mg, 95% yield, dr >19/1); Petroleum ether/EtOAc = 10/1; mp: 142−143 °C. 1H NMR (500 MHz, CDCl3) δ 7.51−7.45 (m, 2H), 7.46−7.40 (m, 3H), 7.32 (dd, J = 7.9, 0.8 Hz, 1H), 7.17 (t, J = 7.3 Hz, 1H), 7.10 (t, J = 7.6 Hz, 2H), 6.97 (d, J = 7.8 Hz, 1H), 6.92 (d, J = 7.4 Hz, 2H), 6.88 (t, J = 7.9 Hz, 1H), 6.86 (s, 1H), 6.83 (d, J = 7.8 Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 6.67 (s, 1H), 5.01 (s, 1H), 3.72 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 167.1, 166.7, 136.0, 135.8, 134.2, 130.6, 130.4, 130.2, 129.7, 129.5, 128.2, 128.1, 127.9, 126.8, 126.7, 126.6, 124.2, 115.7, 109.8, 63.5, 52.5, 48.8. HRMS (ESI): calcd for C28H22ClN2O3S ([M + H]+): 501.1034, found 501.1036. Methyl 2-((5-Bromo-1-cyano-2-((phenylthio)carbonyl)-1,2dihydroisoquinolin-1-yl)(phenyl)methyl)acrylate (Table 1, 1o). White solid (511 mg, 94% yield, dr >19/1); Petroleum ether/EtOAc = 10/1; mp: 138−139 °C. 1H NMR (500 MHz, CDCl3) δ 7.53−7.40 (m, 6H), 7.17 (t, J = 7.2 Hz, 1H), 7.10 (t, J = 7.6 Hz, 2H), 6.96 (d, J = 7.8 Hz, 1H), 6.92 (d, J = 7.6 Hz, 2H), 6.89−6.84 (m, 2H), 6.81 (t, J =

127.5, 126.7, 125.4, 122.8, 116.3, 113.5, 63.9, 46.3, 26.0. HRMS (ESI): calcd for C28H23N2O2S ([M + H]+): 451.1475, found 451.1468. tert-Butyl 2-((1-Cyano-2-((phenylthio)carbonyl)-1,2-dihydroisoquinolin-1-yl)(phenyl)methyl)acrylate (Table 1, 1d). White solid (457 mg, 90% yield, dr >19/1); Petroleum ether/EtOAc = 10/1; mp: 83−84 °C. 1H NMR (500 MHz, CDCl3) δ 7.51−7.47 (m, 2H), 7.46− 7.39 (m, 3H), 7.29−7.23 (m, 1H), 7.20 (d, J = 7.4 Hz, 1H), 7.14 (t, J = 7.3 Hz, 1H), 7.06 (t, J = 7.6 Hz, 2H), 6.96 (t, J = 7.6 Hz, 1H), 6.90 (t, J = 8.4 Hz, 3H), 6.85 (d, J = 7.6 Hz, 1H), 6.79 (s, 1H), 6.60 (s, 1H), 6.35 (d, J = 7.6 Hz, 1H), 5.01 (s, 1H), 1.42 (s, 9H).13C NMR (125 MHz, CDCl3) δ 166.3, 165.9, 137.7, 135.8, 135.1, 130.3, 130.0, 129.5, 129.4, 128.9, 128.8, 128.7, 128.0, 127.9, 127.6, 127.0, 125.4, 122.8, 116.1, 113.5, 81.5, 63.9, 48.7, 28.1. HRMS (ESI): calcd for C31H29N2O3S ([M + H]+): 509.1893, found 509.1898. Methyl 2-((1-Cyano-2-((phenylthio)carbonyl)-1,2-dihydroisoquinolin-1-yl)(4-methoxyphenyl)methyl)acrylate (Table 1, 1e). White solid (466 mg, 94% yield, dr = 16/1); Petroleum ether/EtOAc = 10/1; mp: 129−130 °C. Major isomer: 1H NMR (500 MHz, CDCl3) δ 7.51−7.45 (m, 2H), 7.43−7.39 (m, 3H), 7.29 (t, J = 7.4 Hz, 1H), 7.20 (d, J = 7.4 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 7.9 Hz, 1H), 6.83 (d, J = 7.6 Hz,1H), 6.81(s, 1H), 6.77 (d, J = 8.5 Hz, 2H), 6.64−6.58 (m, 3H), 6.34 (d, J = 7.6 Hz, 1H), 4.95 (s, 1H), 3.71 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 167.2, 166.4, 159.4, 136.6, 135.8, 131.5, 130.0, 129.5, 129.4, 129.0, 128.6, 128.1, 127.7, 126.9, 126.4, 125.4, 122.6, 116.0, 113.8, 113.3, 63.5, 55.3, 52.4, 48.7. HRMS (ESI): calcd for C29H25N2O4S ([M + H]+): 497.1530, found 497.1528. Methyl 2-((4-Bromophenyl)(1-cyano-2-((phenylthio)carbonyl)1,2-dihydroisoquinolin-1-yl)methyl)acrylate (Table 1, 1f). White solid (495 mg, 91% yield, dr = 15/1); Petroleum ether/EtOAc = 10/1; mp: 157−158 °C. Major isomer: 1H NMR (300 MHz, CDCl3) δ 7.51−7.41 (m, 5H), 7.35−7.29 (m, 1H), 7.25−7.17 (m, 3H), 7.09− 7.02 (m, 1H), 6.96−6.91 (m, 1H), 6.87−6.82 (m, 2H), 6.72 (d, J = 8.5 Hz, 2H), 6.67 (s, 1H), 6.38 (d, J = 7.5 Hz, 1H), 4.97 (s, 1H), 3.71 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 167.0, 166.5, 136.0, 135.8, 133.7, 132.0, 131.1, 130.1, 129.8, 129.5, 128.7, 128.5, 128.0, 127.9, 126.8, 125.6, 122.6, 122.5, 115.7, 113.8, 63.1, 52.5, 48.9. HRMS (ESI): calcd for C28H22BrN2O3S ([M + H]+): 545.0529, found 545.0536. Methyl 2-((4-Chlorophenyl)(1-cyano-2-((phenylthio)carbonyl)1,2-dihydroisoquinolin-1-yl)methyl)acrylate (Table 1, 1g). White solid (460 mg, 92% yield, dr = 14/1); Petroleum ether/EtOAc = 10/1; mp: 155−156 °C. Major isomer: 1H NMR (500 MHz, CDCl3) δ 7.52−7.38 (m, 5H), 7.34−7.29 (m, 1H), 7.23 (d, J = 7.3 Hz, 1H), 7.07−7.01 (m, 3H), 6.93 (d, J = 7.9 Hz, 1H), 6.87−6.83 (m, 2H), 6.78 (d, J = 8.4 Hz, 2H), 6.67 (s, 1H), 6.38 (d, J = 7.6 Hz, 1H), 4.98 (s, 1H), 3.71 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 166.9, 166.6, 135.9, 135.8, 134.2, 133.0, 131.7, 130.2, 129.8, 129.5, 129.4, 128.6, 128.4, 128.1, 128.0, 127.9, 126.7, 125.6, 122.6, 115.7, 113.9, 63.1, 52.6, 48.7. HRMS (ESI): calcd for C28H22ClN2O3S ([M + H]+): 501.1034, found 501.1038. Methyl 2-((1-Cyano-2-((phenylthio)carbonyl)-1,2-dihydroisoquinolin-1-yl)(3-methoxyphenyl)methyl)acrylate (Table 1, 1h). White solid (417 mg, 84% yield, dr = 15/1); Petroleum ether/EtOAc = 9/1; mp: 144−145 °C. Major isomer: 1H NMR (300 MHz, CDCl3) δ 7.50−7.40 (m, 5H), 7.33−7.27 (m, 1H), 7.23−7.20 (m, 1H), 7.05− 6.96 (m, 3H), 6.86 (s, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.72−6.69 (m, 1H), 6.66 (s, 1H), 6.56 (d, J = 7.7 Hz, 1H), 6.36 (d, J = 7.6 Hz, 1H), 6.33−6.31 (m, 1H), 4.99 (s, 1H), 3.72 (s, 3H), 3.59 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 167.2, 166.4, 159.0, 136.2, 135.9, 135.8, 130.1, 129.6, 129.5, 129.4, 128.8, 128.7, 128.2, 127.7, 126.9, 125.4, 122.7, 122.6, 116.0, 115.8, 114.2, 113.6, 113.5, 63.5, 55.2, 52.5, 49.2. HRMS (ESI): calcd for C29H25N2O4S ([M + H]+): 497.1530, found 497.1527. Methyl 2-((3-Bromophenyl)(1-cyano-2-((phenylthio)carbonyl)1,2-dihydroisoquinolin-1-yl)methyl)acrylate (Table 1, 1i). White solid (479 mg, 88% yield, dr = 14/1); Petroleum ether/EtOAc = 10/1; mp: 148−149 °C. Major isomer: 1H NMR (500 MHz, CDCl3) δ 7.49−7.47(m, 2H), 7.46−7.40 (m, 3H), 7.34 (t, J = 7.5 Hz, 1H), 7.29 (d, J = 7.1 Hz, 1H), 7.24 (d, J = 7.1 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 7.02−6.97 (m, 2H), 6.95 (d, J = 7.9 Hz, 1H), 6.84 (d, J = 7.9 Hz, 2H), 6.75 (s, 1H), 6.69 (s, 1H), 6.35 (d, J = 7.6 Hz, 1H), 4.98 (s, 1H), 3.72 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 166.9, 166.6, 136.8, 4834


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filtered, and concentrated in vacuo. The mixture was purified by column chromatography to provide the desired products 2-trans. Ethyl 10b-Cyano-3-oxo-1-phenyl-2-((phenylthio)methyl)1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2a-cis). White solid (89 mg, 92% yield, dr >19/1); Petroleum ether/EtOAc = 8/1; mp: 133−134 °C. 1H NMR (500 MHz, CDCl3) δ 7.42−7.32 (m, 4H), 7.31−7.20 (m, 8H), 7.19−7.14 (m, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 7.8 Hz, 1H), 6.38 (d, J = 7.6 Hz, 1H), 4.84 (s, 1H), 4.38−4.16 (m, 2H), 3.73 (d, J = 14.6 Hz, 1H), 3.26 (d, J = 14.6 Hz, 1H), 1.33 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 168.1, 167.7, 135.1, 132.6, 132.1, 131.3, 130.3, 130.1, 129.9, 129.5, 129.3, 129.0, 127.9, 126.8, 124.0, 120.8, 117.5, 114.2, 62.8, 59.7, 53.0, 36.9, 13.9. HRMS (ESI): calcd for C29H25N2O3S ([M + H]+): 481.1580, found 481.1581. Ethyl 10b-Cyano-3-oxo-1-phenyl-2-((phenylthio)methyl)1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2a-trans). White solid (61 mg, 64% yield, dr >19/1); Petroleum ether/EtOAc = 10/1; mp: 123−124 °C. 1H NMR (500 MHz, CDCl3) δ 7.81 (brs, 1H), 7.53−7.45 (m, 3H), 7.41−7.08 (m, 9H), 6.96 (d, J = 7.8 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.32 (d, J = 7.6 Hz, 1H), 4.85 (s, 1H), 4.34−4.05 (m, 2H), 3.75 (d, J = 13.6 Hz, 1H), 3.57 (d, J = 13.6 Hz, 1H), 1.17 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 168.5, 166.8, 136.6, 131.9, 130.5, 130.3, 130.2, 130.1, 129.7, 129.6, 129.2, 129.0, 126.9, 126.8, 124.1, 120.5, 118.3, 114.3, 62.9, 60.6, 58.8, 56.5, 34.9, 14.1. HRMS (ESI): calcd for C29H25N2O3S ([M + H]+): 481.1580, found 481.1585. Methyl 10b-Cyano-3-oxo-1-phenyl-2-((phenylthio)methyl)1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2b-cis). White solid (86 mg, 92% yield, dr >19/1); Petroleum ether/EtOAc = 9/1; mp: 158−159 °C. 1H NMR (500 MHz, CDCl3) δ 7.42−7.34 (m, 4H), 7.30−7.20 (m, 8H), 7.16 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H), 6.37 (d, J = 7.6 Hz, 1H), 4.84 (s, 1H), 3.82 (s, 3H), 3.73 (d, J = 14.5 Hz, 1H), 3.26 (d, J = 14.6 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 168.4, 167.5, 135.0, 132.6, 132.1, 131.2, 130.3, 130.2, 129.8, 129.6, 129.3, 129.1, 127.9, 126.8, 123.9, 120.8, 117.4, 114.2, 62.8, 59.7, 53.2, 52.6, 36.7. HRMS (ESI): calcd for C28H23N2O3S ([M + H]+): 467.1424, found 467.1427. Methyl 10b-Cyano-3-oxo-1-phenyl-2-((phenylthio)methyl)1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2b-trans). White solid (60 mg, 60% yield, dr >19/1); Petroleum ether/EtOAc = 10/1; mp: 149−151 °C. 1H NMR (500 MHz, CDCl3) δ 7.91 (brs, 1H), 7.50 (s, 3H), 7.38 (d, J = 7.7 Hz, 2H), 7.33 (t, J = 7.5 Hz, 1H), 7.29−7.24 (m, 3H), 7.23−7.17 (m, 2H), 7.13 (t, J = 7.6 Hz, 1H), 6.96 (d, J = 7.8 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.33 (d, J = 7.6 Hz, 1H), 4.86 (s, 1H), 3.72 (s, 3H), 3.72 (d, J = 13.7 Hz, 1H), 3.59 (d, J = 13.7 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 168.9, 166.7, 136.4, 131.8, 130.7, 130.3, 130.2, 130.1, 129.8, 129.7, 129.2, 129.0, 127.0, 126.9, 124.1, 120.4, 118.2, 114.4, 60.7, 58.8, 56.4, 53.5, 35.1. HRMS (ESI): calcd for C28H23N2O3S ([M + H]+): 467.1424, found 467.1421. 2-Acetyl-3-oxo-1-phenyl-2-((phenylthio)methyl)-1,2,3,10btetrahydropyrrolo[2,1-a]isoquinoline-10b-carbonitrile (Table 2, 2ccis). White solid (76 mg, 85% yield, dr >19/1); Petroleum ether/ EtOAc = 9/1; mp: 169−170 °C. 1H NMR (500 MHz, CDCl3) δ 7.44−7.22 (m, 12H), 7.16 (t, J = 7.6 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 6.38 (d, J = 7.6 Hz, 1H), 4.80 (s, 1H), 3.70 (d, J = 13.9 Hz, 1H), 3.31 (d, J = 13.9 Hz, 1H), 2.02 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 204.7, 169.1, 135.0, 132.7, 131.8, 130.9, 130.3, 130.2, 130.1, 129.6, 129.5, 129.4, 129.1, 128.1, 126.8, 123.9, 120.6, 117.3, 114.3, 67.7, 59.6, 53.5, 37.7, 30.1. HRMS (ESI): calcd for C28H23N2O2S ([M + H]+): 451.1475, found 451.1478. tert-Butyl 10b-Cyano-3-oxo-1-phenyl-2-((phenylthio)methyl)1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2d-cis). White solid (48 mg, 47% yield, dr >19/1); Petroleum ether/EtOAc = 12/1 to 8/1 gradient; mp: 128−129 °C. 1H NMR (500 MHz, CDCl3) δ 7.45−7.38 (m, 3H), 7.38−7.33 (m, 3H), 7.29−7.24 (m, 4H), 7.23−7.15 (m, 3H), 7.03 (d, J = 7.6 Hz, 1H), 6.99 (d, J = 7.9 Hz, 1H), 6.36 (d, J = 7.6 Hz, 1H), 4.84 (s, 1H), 3.69 (d, J = 14.5 Hz, 1H), 3.21 (d, J = 14.5 Hz, 1H), 1.52 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 168.2, 167.3, 135.1, 132.6, 132.2, 131.4, 130.4, 130.3,

7.9 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 6.67 (s, 1H), 5.01 (s, 1H), 3.72 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 167.1, 166.7, 136.0, 135.8, 134.2, 133.7, 130.4, 130.3, 130.2, 129.7, 129.5, 128.3, 128.3, 128.2, 128.1, 127.3, 126.6, 124.3, 120.8, 115.6, 112.3, 63.6, 52.6, 48.8. HRMS (ESI): calcd for C28H22BrN2O3S ([M + H]+): 545.0529, found 545.0534. Methyl 2-((6-Bromo-1-cyano-2-((phenylthio)carbonyl)-1,2dihydroisoquinolin-1-yl)(phenyl)methyl)acrylate (Table 1, 1p). White solid (435 mg, 80% yield, dr >19/1); Petroleum ether/EtOAc = 9/1; mp: 154−155 °C. 1H NMR (500 MHz, CDCl3) δ 7.51−7.46 (m, 2H), 7.45−7.39 (m, 3H), 7.35 (d, J = 2.0 Hz, 1H), 7.18 (t, J = 7.3 Hz, 1H), 7.12 (t, J = 7.5 Hz, 2H), 7.08 (dd, J = 8.4, 2.0 Hz, 1H), 6.94 (d, J = 7.4 Hz, 2H), 6.90 (d, J = 7.6 Hz, 1H), 6.81 (s, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.66 (s, 1H), 6.26 (d, J = 7.7 Hz, 1H), 4.99 (s, 1H), 3.72 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 167.2, 166.6, 136.0, 135.8, 134.3, 130.5, 130.3, 130.2, 129.8, 129.7, 129.5, 128.3, 128.2, 128.0, 127.4, 126.5, 124.1, 123.8, 115.8, 112.0, 63.3, 52.5, 48.9. HRMS (ESI): calcd for C28H22BrN2O3S ([M + H]+): 545.0529, found 545.0530. Ethyl 2-((1-Cyano-2-((phenylthio)carbonyl)-1,2-dihydroisoquinolin-1-yl)methyl)acrylate (Table 1, 1q). White solid (380 mg, 94% yield); Petroleum ether/EtOAc = 9/1; mp: 97−98 °C. 1H NMR (500 MHz, CDCl3) δ 7.60−7.54 (m, 2H), 7.52 (d, J = 7.7 Hz, 1H), 7.48−7.41 (m, 3H), 7.32−7.28 (m, 1H), 7.27−7.22 (m, 1H), 7.09−7.04 (m, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.27 (s, 1H), 5.86 (d, J = 8.0 Hz, 1H), 5.56 (s, 1H), 4.01−3.78 (m, 2H), 3.57 (d, J = 13.2 Hz, 1H), 2.97 (d, J = 13.3 Hz, 1H), 1.13 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 166.8, 166.1, 135.9, 133.4, 131.7, 130.2, 129.8, 129.5, 129.1, 128.0, 127.8, 127.2, 126.4, 125.4, 123.5, 117.2, 108.6, 61.6, 61.1, 39.9, 14.2. HRMS (ESI): calcd for C23H21N2O3S ([M + H]+): 405.1267, found 405.1269. Methyl 2-((2-(((4-Bromophenyl)thio)carbonyl)-1-cyano-1,2dihydroisoquinolin-1-yl)(phenyl)methyl)acrylate (Table 1, 1r). White solid (506 mg, 93% yield, dr >19/1); Petroleum ether/EtOAc = 9/1; mp: 142−143 °C. 1H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.31−7.26 (m, 1H), 7.21 (d, J = 7.1 Hz, 1H), 7.16 (t, J = 7.3 Hz, 1H), 7.07 (t, J = 7.6 Hz, 2H), 7.00− 6.95 (m, 1H), 6.92−6.86 (m, 3H), 6.85 (s, 1H), 6.80 (d, J = 7.6 Hz, 1H), 6.66 (s, 1H), 6.37 (d, J = 7.6 Hz, 1H), 5.00 (s, 1H), 3.71 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 167.2, 165.8, 137.2, 136.2, 134.4, 132.7, 130.3, 129.6, 129.5, 128.7, 128.5, 128.1, 128.0, 127.9, 127.7, 126.0, 125.5, 125.0, 122.3, 115.9, 114.1, 63.6, 52.5, 49.2. HRMS (ESI): calcd for C28H22BrN2O3S ([M + H]+): 545.0529, found 545.0534. Methyl 2-((1-Cyano-2-(((4-methoxyphenyl)thio)carbonyl)-1,2dihydroisoquinolin-1-yl)(phenyl)methyl)acrylate (Table 1, 1s). White solid (461 mg, 93% yield, dr >19/1); Petroleum ether/EtOAc = 10/1; mp: 141−142 °C. 1H NMR (500 MHz, CDCl3) δ 7.38 (d, J = 8.7 Hz, 2H), 7.30−7.24 (m, 1H), 7.20 (d, J = 7.3 Hz, 1H), 7.15 (t, J = 7.3 Hz, 1H), 7.07 (t, J = 7.6 Hz, 2H), 6.99−6.92 (m, 3H), 6.91−6.83 (m, 5H), 6.65 (s, 1H), 6.34 (d, J = 7.6 Hz, 1H), 5.01 (s, 1H), 3.82 (s, 3H), 3.71 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 167.3, 167.2, 161.2, 137.5, 136.1, 134.5, 130.3, 129.5, 129.4, 128.7, 128.0, 127.9, 127.8, 127.6, 125.4, 122.7, 117.2, 116.0, 115.1, 113.6, 63.4, 55.5, 52.5, 49.1. HRMS (ESI): calcd for C29H25N2O4S ([M + H]+): 497.1530, found 497.1531. General Procedure for Intramolecular Acylsulfenylation of Compounds 1. Method A: To a dried reaction tube were added 1 (0.2 mmoL) and PhSNa (10 mol %) in THF (0.5 mL) under a N2 atmosphere at 0 °C. The reaction was monitored by TLC. Upon completion, the reaction was quenched with saturated NH4Cl (3 mL), and H2O (7 mL) was added. The aqueous layer was extracted with EtOAc (6 mL × 3), and the combined organic extract was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The mixture was purified by column chromatography to provide the desired products 2-cis. Method B: To a dried reaction tube was added 1 (0.2 mmol) and TBACN (5 mol %) in NMP (0.5 mL) under a N2 atmosphere at 0 °C. The reaction was monitored by TLC. Upon completion, the reaction was quenched with saturated NH4Cl (3 mL), and H2O (7 mL) was added. The aqueous layer was extracted with EtOAc (6 mL × 3), and the combined organic extract was washed with saturated brine (10 mL), dried over Na2SO4, 4835


Article


6.93 (d, J = 7.6 Hz, 2H), 6.34 (d, J = 7.6 Hz, 1H), 4.89 (s, 1H), 3.74− 3.65 (m, 4H), 3.62 (d, J = 13.7 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 168.8, 166.4, 136.2, 136.0, 130.7, 130.5, 130.4, 130.1, 130.0, 129.9, 129.3, 129.1, 127.1, 127.0, 123.9, 120.3, 118.1, 114.5, 60.9, 58.8, 55.1, 53.6, 35.2. HRMS (ESI): calcd for C28H22ClN2O3S ([M + H]+): 501.1034, found 501.1043. Methyl 10b-Cyano-1-(3-methoxyphenyl)-3-oxo-2-((phenylthio)methyl)-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2h-cis). White solid (89 mg, 90% yield, dr >19/1); Petroleum ether/EtOAc = 8/1; mp: 163−164 °C. 1H NMR (500 MHz, CDCl3) δ 7.37 (t, J = 7.3 Hz, 1H), 7.32−7.16 (m, 8H), 7.05 (d, J = 7.6 Hz, 1H), 6.99 (d, J = 7.8 Hz, 1H), 6.97−6.91 (m, 2H), 6.80 (s, 1H), 6.37 (d, J = 7.6 Hz, 1H), 4.81 (s, 1H), 3.83 (s, 3H), 3.75 (s, 3H), 3.74 (d, J = 14.5 Hz, 1H), 3.28 (d, J = 14.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 168.3, 167.5, 160.3, 134.9, 133.4, 132.5, 131.1, 130.6, 130.2, 130.1, 129.3, 129.1, 127.9, 126.8, 124.0, 122.0, 120.7, 117.5, 115.1, 114.3, 62.7, 59.7, 55.4, 53.0, 52.7, 36.7. HRMS (ESI): calcd for C29H25N2O4S ([M + H]+): 497.1530, found 497.1531. Methyl 10b-Cyano-1-(3-methoxyphenyl)-3-oxo-2-((phenylthio)methyl)-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2h-trans). White solid (62 mg, 63% yield, dr >19/1); Petroleum ether/EtOAc = 10/1; mp: 159−160 °C. 1H NMR (500 MHz, CDCl3) δ 7.67 (brs, 1H), 7.43−7.38 (m, 3H), 7.34 (t, J = 7.5 Hz, 1H), 7.30−7.25 (m, 3H), 7.23−7.19 (m, 2H), 7.15 (t, J = 7.7 Hz, 1H), 7.05−6.99 (m, 2H), 6.91 (d, J = 7.6 Hz, 1H), 6.33 (d, J = 7.6 Hz, 1H), 4.84 (s, 1H), 3.84 (s, 3H), 3.76−3.70 (m, 1H), 3.72 (s, 3H), 3.62 (d, J = 14.3 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 168.9, 166.7, 160.3, 136.4, 133.1, 130.8, 130.6, 130.3, 130.1, 130.0, 129.2, 129.0, 126.9, 126.8, 124.1, 120.3, 118.3, 114.4, 77.4, 60.8, 58.8, 56.2, 55.5, 53.5, 34.9. HRMS (ESI): calcd for C29H25N2O4S ([M + H]+): 497.1530, found 497.1525. Methyl 1-(3-Bromophenyl)-10b-cyano-3-oxo-2-((phenylthio)methyl)-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2i-cis). White solid (93 mg, 85% yield, dr >19/1); Petroleum ether/EtOAc = 8/1; mp: 184−185 °C. 1H NMR (500 MHz, CDCl3) δ 7.54−7.53 (m, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.33− 7.20 (m, 9H), 7.11−7.06 (m, 2H), 6.88 (d, J = 7.8 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 4.80 (s, 1H), 3.84 (s, 3H), 3.75 (d, J = 14.8 Hz, 1H), 3.22 (d, J = 14.8 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 168.2, 167.3, 135.0, 134.4, 133.1, 132.8, 131.0, 130.8, 130.3, 130.2, 129.6, 129.2, 128.3, 127.9, 127.0, 123.8, 123.6, 120.7, 117.1, 114.4, 63.2, 59.7, 52.8, 52.2, 36.9. HRMS (ESI): calcd for C28H22BrN2O3S ([M + H]+): 545.0529, found 545.0532. Methyl 1-(3-Bromophenyl)-10b-cyano-3-oxo-2-((phenylthio)methyl)-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2i-trans). White solid (58.4 mg, 54% yield, dr >19/1); Petroleum ether/EtOAc = 10/1; mp: 152−153 °C. 1H NMR (500 MHz, CDCl3) δ 8.12 (brs, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.42−7.33 (m, 4H), 7.31−7.10 (m, 6H), 6.94 (dd, J = 14.4, 7.7 Hz, 2H), 6.34 (d, J = 7.6 Hz, 1H), 4.87 (s, 1H), 3.70 (s, 3H), 3.72−3.60 (m, 2H). 13C NMR (125 MHz, CDCl3) δ 168.6, 166.3, 136.2, 134.3, 132.9, 131.2, 130.7, 130.5, 130.0, 129.8, 129.3, 129.1, 127.1, 127.0, 123.9, 120.3, 118.0, 114.6, 61.0, 58.8, 55.0, 53.6, 35.2. HRMS (ESI): calcd for C28H22BrN2O3S ([M + H]+): 545.0529, found 545.0530. Methyl 1-(2-Bromophenyl)-10b-cyano-3-oxo-2-((phenylthio)methyl)-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2j-cis). White solid (98 mg, 2j-cis/3j = 1.5/1, 55% yield, 2j-cis: dr >19/1). Petroleum ether/EtOAc = 9/1. 1H NMR (500 MHz, CDCl3) δ 8.00 (dd, J = 8.1, 1.4 Hz, 1.5H, 1H of 2j-cis), 7.80 (dd, J = 8.1, 1.1 Hz, 1.5H, 1H of 2j-cis), 7.66 (s, 1H, 1H of 3j), 7.52−6.99 (m, 30 H, 12H of 2j-cis + 12H of 3j), 6.72 (d, J = 7.9 Hz, 1H, 1H of 3j), 6.37 (d, J = 7.6 Hz, 1.5H, 1H of 2j-cis), 5.75 (d, J = 8.0 Hz, 1H, 1H of 3j), 5.59 (s, 1.5H, 1H of 2j-cis), 3.87 (d, J = 13.9 Hz, 1H, 1H of 3j), 3.82 (s, 4.5H, 3H of 2j-cis), 3.66 (s, 3H, 3H of 3j), 3.63 (d, J = 14.0 Hz, 1.5H, 1H of 2j-cis), 3.42 (d, J = 13.9 Hz, 1H, 1H of 3j), 3.41 (d, J = 13.9 Hz, 1.5H, 1H of 2j-cis).13C NMR (125 MHz, CDCl3) δ 168.5, 167.6, 166.8, 166.3, 143.3, 135.6, 135.5, 134.8, 134.6, 133.1, 131.7, 131.1, 130.4, 130.3, 130.2, 130.1, 129.9, 129.9, 129.8, 129.6, 129.3, 129.2, 128.9, 128.3, 128.1, 127.4, 127.2, 127.1, 126.8, 125.5, 124.2, 124.0, 123.6, 120.5, 117.8, 117.2, 114.0, 108.5, 62.2, 61.0, 60.5, 52.7, 52.4, 51.4, 36.8, 36.0. 2j-cis: HRMS (ESI): calcd for C28H22BrN2O3S

130.1, 129.4, 129.3, 129.0, 127.8, 126.7, 124.0, 120.7, 117.7, 114.2, 85.7, 63.3, 59.7, 52.8, 37.3, 28.0. HRMS (ESI): calcd for C31H29N2O3S ([M + H]+): 509.1893, found 509.1891. Methyl 10b-Cyano-1-(4-methoxyphenyl)-3-oxo-2-((phenylthio)methyl)-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2e-cis). White solid (91 mg, 92% yield, dr >19/1); Petroleum ether/EtOAc = 8/1; mp: 134−135 °C. 1H NMR (500 MHz, CDCl3) δ 7.36 (t, J = 7.5 Hz, 1H), 7.31−7.20 (m, 6H), 7.20− 7.08 (m, 3H), 7.06 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.86 (d, J = 8.9 Hz, 2H), 6.37 (d, J = 7.6 Hz, 1H), 4.78 (s, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.72 (d, J = 14.5 Hz, 1H), 3.25 (d, J = 14.5 Hz, 1H). 13 C NMR (125 MHz, CDCl3) δ 168.5, 167.7, 160.4, 135.2, 132.5, 131.2, 131.1, 130.3, 130.1, 129.3, 129.0, 127.9, 126.8, 123.9, 123.6, 120.8, 117.5, 114.9, 114.3, 114.2, 62.7, 59.7, 55.4, 52.7, 52.6, 36.7. HRMS (ESI): calcd for C29H25N2O4S ([M + H]+): 497.1530, found 497.1522. Methyl 10b-Cyano-1-(4-methoxyphenyl)-3-oxo-2-((phenylthio)methyl)-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2e-trans). White solid (60 mg, 61% yield, dr >19/1); Petroleum ether/EtOAc = 10/1; mp: 137−138 °C. 1H NMR (500 MHz, CDCl3) δ 7.88 (brs, 1H), 7.39 (d, J = 7.6 Hz, 2H), 7.32 (t, J = 7.5 Hz, 1H), 7.30−7.24 (m, 3H), 7.22−7.17 (m, 2H), 7.14 (t, J = 7.7 Hz, 1H), 7.01 (t, J = 7.1 Hz, 3H), 6.92 (d, J = 7.6 Hz, 1H), 6.32 (d, J = 7.6 Hz, 1H), 4.80 (s, 1H), 3.87 (s, 3H), 3.73 (d, J = 13.7 Hz, 1H), 3.71 (s, 3H), 3.59 (d, J = 13.6 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 169.0, 166.8, 160.5, 136.5, 130.6, 130.3, 130.2, 130.1, 129.1, 129.0, 126.9, 126.8, 124.1, 123.4, 120.4, 118.3, 115.1, 114.3, 60.6, 58.8, 55.9, 55.5, 53.4, 35.1. HRMS (ESI): calcd for C29H25N2O4S ([M + H]+): 497.1530, found 497.1531. Methyl 1-(4-Bromophenyl)-10b-cyano-3-oxo-2-((phenylthio)methyl)-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2f-cis). White solid (101 mg, 93% yield, dr >19/1); Petroleum ether/EtOAc = 8/1; mp: 172−173 °C. 1H NMR (500 MHz, CDCl3) δ 7.48 (d, J = 8.7 Hz, 2H), 7.41−7.36 (m, 1H), 7.31− 7.16 (m, 7H), 7.05 (d, J = 7.6 Hz, 3H), 6.88 (d, J = 7.8 Hz, 1H), 6.38 (d, J = 7.6 Hz, 1H), 4.82 (s, 1H), 3.82 (s, 3H), 3.75 (d, J = 14.7 Hz, 1H), 3.22 (d, J = 14.7 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 168.2, 167.3, 135.1, 132.8, 132.7, 131.4, 131.0, 130.8, 130.3, 130.2, 129.5, 129.1, 128.1, 126.9, 124.1, 123.7, 120.7, 117.2, 114.3, 62.8, 59.6, 52.8, 52.4, 36.8. HRMS (ESI): calcd for C28H22BrN2O3S ([M + H]+): 545.0529, found 545.0530. Methyl 1-(4-bromophenyl)-10b-cyano-3-oxo-2-((phenylthio)methyl)-1,2,3,10b-tetrahydropyrrolo [2,1-a]isoquinoline-2-carboxylate (Table 2, 2f-trans). White solid (65 mg, 60% yield, dr >19/1); Petroleum ether/EtOAc = 10/1; mp: 161−162 °C. 1H NMR (500 MHz, CDCl3) δ 7.83 (brs, 1H), 7.63 (d, J = 8.9 Hz, 2H), 7.38−7.33 (m, 3H), 7.31−7.25 (m, 3H), 7.24−7.19 (m, 2H), 7.18−7.14 (m, 1H), 6.93 (d, J = 7.6 Hz, 2H), 6.34 (d, J = 7.6 Hz, 1H), 4.87 (s, 1H), 3.70 (s, 3H), 3.68 (d, J = 13.7 Hz, 1H), 3.62 (d, J = 13.7 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 168.7, 166.4, 136.2, 132.9, 131.0, 130.7, 130.5, 130.1, 129.9, 129.3, 129.1, 127.1, 127.0, 124.2, 123.9, 120.3, 118.1, 114.5, 60.9, 58.8, 55.2, 53.6, 35.2. HRMS (ESI): calcd for C28H22BrN2O3S ([M + H]+): 545.0529, found 545.0526. Methyl 1-(4-Chlorophenyl)-10b-cyano-3-oxo-2-((phenylthio)methyl)-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2g-cis). White solid (92 mg, 92% yield, dr >19/1); Petroleum ether/EtOAc = 8/1; mp: 201−202 °C. 1H NMR (500 MHz, CDCl3) δ 7.38 (t, J = 7.5 Hz, 1H), 7.32 (d, J = 8.7 Hz, 2H), 7.30−7.08 (m, 9H), 7.05 (d, J = 7.6 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 6.38 (d, J = 7.6 Hz, 1H), 4.84 (s, 1H), 3.82 (s, 3H), 3.75 (d, J = 14.7 Hz, 1H), 3.22 (d, J = 14.7 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 168.2, 167.3, 135.8, 135.0, 132.7, 131.1, 130.8, 130.5, 130.3, 130.2, 129.8, 129.4, 129.1, 128.0, 126.9, 123.7, 120.7, 117.2, 114.3, 62.8, 59.6, 52.8, 52.3, 36.8. HRMS (ESI): calcd for C28H22ClN2O3S ([M + H]+): 501.1034, found 501.1041. Methyl 1-(4-Chlorophenyl)-10b-cyano-3-oxo-2-((phenylthio)methyl)-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2g-trans). White solid (60 mg, 60% yield, dr >19/1); Petroleum ether/EtOAc = 10/1; mp: 72−73 °C. 1H NMR (500 MHz, CDCl3) δ 7.83 (brs, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.39−7.32 (m, 3H), 7.31−7.24 (m, 3H), 7.24−7.18 (m, 2H), 7.16 (t, J = 7.6 Hz, 1H), 4836


Article

The Journal of Organic Chemistry ([M + H]+): 545.0529, found 545.0536; 3j: HRMS (ESI): calcd for C27H21BrNO3S ([M + H]+): 518.0420, found 518.0424. Methyl 1-(2-Bromophenyl)-10b-cyano-3-oxo-2-((phenylthio)methyl)-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2j-trans). White solid (61 mg, 2j-trans/3j = 1.5:1, 34% yield, 2j-trans: dr >19/1); Petroleum ether/EtOAc = 10/1. 1H NMR (500 MHz, CDCl3) δ 8.32 (dd, J = 8.0, 1.3 Hz, 1.5H, 1H of 2j-trans), 7.79 (dd, J = 8.0, 1.0 Hz, 1.5H, 1H of 2j-trans), 7.66 (s, 1H, 1H of 3j), 7.53−6.99 (m, 28.5 H, 11H of 2j-trans + 12H of 3j), 6.90 (d, J = 7.8 Hz, 1.5H, 1H of 2j-trans), 6.72 (d, J = 8.0 Hz, 1H, 1H of 3j), 6.37 (d, J = 7.6 Hz, 1.5H, 1H of 2j-trans), 5.76 (d, J = 8.0 Hz, 1H, 1H of 3j), 5.55 (s, 1.5H, 1H of 2j-trans), 3.87 (d, J = 13.9 Hz, 1H, 1H of 3j), 3.72 (d, J = 13.5 Hz, 1.5H, 1H of 2j-trans), 3.71 (s, 4.5H, 3H of 2j-trans), 3.66 (s, 3H, 3H of 3j), 3.47−3.39 (m, 2.5H, 1H of 2j-trans + 1H of 3j). 13C NMR (125 MHz, CDCl3) δ 168.6, 167.7, 166.8, 166.3, 143.3, 135.9, 135.6, 134.9, 134.7, 133.1, 131.2, 131.1, 131.0, 130.8, 130.4, 130.2, 130.0, 129.9, 129.8, 129.6, 129.3, 129.2, 129.1, 128.9, 128.4, 128.2, 127.4, 127.3, 127.2, 127.1, 127.0, 126.9, 126.5, 125.5, 124.2, 123.7, 123.6, 120.6, 117.9, 117.8, 114.5, 108.6, 77.4, 60.6, 60.4, 58.5, 53.5, 52.5, 36.0, 35.3. 2j-trans: HRMS (ESI): calcd for C28H22BrN2O3S ([M + H]+): 545.0529, found 545.0537. Methyl 10b-Cyano-1-(2,4-dichlorophenyl)-3-oxo-2-((phenylthio)methyl)-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2k-cis). White solid (94 mg, 88% yield, dr >19/1); Petroleum ether/EtOAc = 8/1; mp: 151−152 °C. 1H NMR (500 MHz, CDCl3) δ 7.39 (t, J = 7.4 Hz, 1H), 7.32 (d, J = 8.8 Hz, 2H), 7.30−7.27 (m, 4H), 7.24−7.21 (m, 2H), 7.19 (t, J = 7.7 Hz, 1H), 7.12 (brs, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 6.38 (d, J = 7.6 Hz, 1H), 4.84 (s, 1H), 3.82 (s, 3H), 3.75 (d, J = 14.7 Hz, 1H), 3.22 (d, J = 14.7 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 168.3, 167.3, 135.9, 135.0, 132.7, 131.1, 130.9, 130.5, 130.3, 130.2, 129.8, 129.4, 129.1, 128.1, 126.9, 123.7, 120.7, 117.3, 114.3, 62.8, 59.7, 52.8, 52.3, 36.8. HRMS (ESI): calcd for C28H21Cl2N2O3S ([M + H]+): 535.0644, found 535.0645. Methyl 10b-Cyano-1-(2,4-dichlorophenyl)-3-oxo-2-((phenylthio)methyl)-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2k-trans). White solid (92 mg, 2k-trans/3k = 2.5:1, 62% yield, 2k-trans: dr >19/1); Petroleum ether/EtOAc = 10/1. 1H NMR (500 MHz, CDCl3) δ 8.30 (d, J = 8.6 Hz, 2.5H, 1H of 2k-trans), 7.62 (d, J = 2.2 Hz, 3.5H, 1H of 2k-trans + 1H of 3k), 7.52−7.47 (m, 2H, 2H of 3k), 7.44−7.20 (m, 27.5H, 9H of 2k-trans + 5H of 3k), 7.16 (dd, J = 8.3, 1.9 Hz, 1H, 1H of 3k), 7.08 (t, J = 7.5 Hz, 1H, 1H of 3k), 7.03 (d, J = 8.3 Hz, 1H, 1H of 3k), 7.00 (d, J = 7.6 Hz, 3.5H, 1H of 2ktrans + 1H of 3k), 6.83 (d, J = 7.8 Hz, 2.5H, 1H of 2k-trans), 6.70 (d, J = 7.9 Hz, 1H, 1H of 3k), 6.37 (d, J = 7.6 Hz, 2.5H, 1H of 2k-trans), 5.75 (d, J = 7.9 Hz, 1H, 1H of 3k), 5.50 (s, 2.5H, 1H of 2k-trans), 3.88 (d, J = 13.9 Hz, 1H, 1H of 3k), 3.69 (s, 7.5H, 3H of 2k-trans), 3.65 (d, J = 13.3 Hz, 2.5H, 1H of 2k-trans), 3.62 (s, 3H, 3H of 3k), 3.43 (d, J = 13.3 Hz, 2.5H, 1H of 2k-trans), 3.36 (d, J = 13.9 Hz, 1H, 1H of 3k). 13 C NMR (125 MHz, CDCl3) δ 168.6, 167.5, 166.6, 166.5, 140.3, 140.2, 136.7, 136.5, 135.7, 135.0, 134.9, 131.6, 131.0, 130.9, 130.6, 130.5, 130.2, 130.0, 129.9, 129.8, 129.7, 129.4, 129.3, 129.2, 129.0, 128.3, 128.2, 128.1, 127.3, 127.1, 125.5, 123.7, 123.3, 120.6, 117.7, 114.6, 108.5, 60.6, 60.2, 58.6, 53.6, 52.5, 50.3, 36.1, 35.3. 2k-trans: HRMS (ESI): calcd for C28H21Cl2N2O3S ([M + H]+): 535.0644, found 535.0644; 3k: HRMS (ESI): calcd for C27H20Cl2NO3S ([M + H]+): 508.0535, found 508.0535. Methyl 10b-Cyano-1-(naphthalen-2-yl)-3-oxo-2-((phenylthio)methyl)-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2l-cis). White solid (95 mg, 92% yield, dr >19/1); Petroleum ether/EtOAc = 8/1; mp: 205−206 °C. 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 7.4 Hz, 1H), 7.56−7.46 (m, 3H), 7.40−7.23 (m, 8H), 7.14−7.09 (m, 2H), 6.96 (d, J = 7.8 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 5.01 (s, 1H), 3.85 (s, 3H), 3.77 (d, J = 14.7 Hz, 1H), 3.28 (d, J = 14.7 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 168.5, 167.6, 135.6, 133.5, 133.4, 132.8, 131.2, 130.3, 130.2, 129.5, 129.4, 129.3, 129.1, 128.4, 128.0, 127.8, 127.3, 126.9, 126.8, 124.0, 120.8, 117.5, 114.3, 63.2, 59.7, 53.2, 52.7, 37.0. HRMS (ESI): calcd for C32H25N2O3S ([M + H]+): 517.1580, found 517.1573. Methyl 10b-Cyano-1-(naphthalen-2-yl)-3-oxo-2-((phenylthio)methyl)-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxy-

late (Table 2, 2l-trans). White solid (52 mg, 50% yield, dr >19/1); Petroleum ether/EtOAc = 10/1; mp: 195−196 °C.1H NMR (500 MHz, CDCl3) δ 8.66 (brs, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.95−7.86 (m, 2H), 7.61−7.52 (m, 2H), 7.35 (d, J = 7.5 Hz, 2H), 7.32−7.28 (m, 1H), 7.27−7.13 (m, 5H), 7.07 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.95 (d, J = 7.6 Hz, 1H), 6.34 (d, J = 7.6 Hz, 1H), 5.05 (s, 1H), 3.78 (d, J = 13.7 Hz, 1H), 3.72 (s, 3H), 3.66 (d, J = 13.7 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 169.1, 166.8, 136.4, 133.5, 130.7, 130.3, 130.2, 130.1, 129.6, 129.3, 129.2, 129.0, 128.7, 127.8, 127.4, 127.0, 126.9, 124.2, 120.4, 118.3, 114.5, 61.0, 59.0, 56.3, 53.5, 35.1. HRMS (ESI): calcd for C32H25N2O3S ([M + H]+): 517.1580, found 517.1572. Methyl 6-Bromo-10b-cyano-3-oxo-1-phenyl-2-((phenylthio)methyl)-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2m-cis). White solid (81 mg, 74% yield, dr >19/1); Petroleum ether/EtOAc = 8/1; mp: 159−160 °C. 1H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 7.9 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.44−7.39 (m, 2H), 7.36 (t, J = 7.4 Hz, 2H), 7.31−7.18 (m, 8H), 6.97 (d, J = 7.8 Hz, 1H), 4.86 (s, 1H), 3.83 (s, 3H), 3.73 (d, J = 14.7 Hz, 1H), 3.24 (d, J = 14.7 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 168.1, 166.7, 134.6, 132.7, 131.6, 131.4, 130.5, 130.3, 129.8, 129.7, 129.4, 129.3, 128.0, 127.1, 123.8, 121.7, 117.1, 110.1, 62.6, 59.4, 53.1, 52.8, 36.6. HRMS (ESI): calcd for C28H22BrN2O3S ([M + H]+): 545.0529, found 545.0532. Methyl 6-Bromo-10b-cyano-3-oxo-1-phenyl-2-((phenylthio)methyl)-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2m-trans). White solid (60 mg, 55% yield, dr >19/1); Petroleum ether/EtOAc = 10/1; mp: 163−164 °C. 1H NMR (500 MHz, CDCl3) δ 7.96 (brs, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.54 (s, 3H), 7.47 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 7.6 Hz, 2H), 7.34−7.28 (m, 4H), 7.27−7.22 (m, 2H), 7.02 (d, J = 7.7 Hz, 1H), 4.88 (s, 1H), 3.74 (s, 3H), 3.70 (d, J = 13.8 Hz, 1H), 3.62 (d, J = 13.8 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 168.7, 165.9, 136.1, 131.5, 130.7, 130.6, 130.5, 130.4, 129.9, 129.3, 129.1, 127.2, 127.1, 123.9, 121.3, 117.8, 110.3, 60.6, 58.6, 56.5, 53.6, 35.1. HRMS (ESI): calcd for C28H22BrN2O3S ([M + H]+): 545.0529, found 545.0526. Methyl 7-Chloro-10b-cyano-3-oxo-1-phenyl-2-((phenylthio)methyl)-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2n-cis). White solid (90 mg, 90% yield, dr >19/1); Petroleum ether/EtOAc = 8/1; mp: 165−166 °C.1H NMR (500 MHz, CDCl3) δ 7.44 (t, J = 7.6 Hz, 2H), 7.39 (t, J = 7.6 Hz, 2H), 7.35−7.23 (m, 7H), 7.17 (d, J = 7.8 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 4.88 (s, 1H), 3.85 (s, 3H), 3.77 (d, J = 14.6 Hz, 1H), 3.28 (d, J = 14.6 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 168.1, 167.3, 134.8, 132.8, 132.6, 132.0, 131.7, 131.1, 129.7, 129.6, 129.5, 129.4, 128.5, 128.0, 122.5, 122.0, 117.0, 110.3, 62.9, 59.6, 53.0, 52.7, 36.6. HRMS (ESI): calcd for C28H22ClN2O3S ([M + H]+): 501.1034, found 501.1031. Methyl 7-Chloro-10b-cyano-3-oxo-1-phenyl-2-((phenylthio)methyl)-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2n-trans). White solid (55 mg, 55% yield, dr >19/1); Petroleum ether/EtOAc = 10/1; mp: 178−179 °C. 1H NMR (500 MHz, CDCl3) δ 7.87 (brs, 2H), 7.57−7.51 (m, 3H), 7.41 (d, J = 7.9 Hz, 3H), 7.34−7.27 (m, 2H), 7.23 (t, J = 7.3 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 7.8 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 6.80 (d, J = 7.8 Hz, 1H), 4.89 (s, 1H), 3.75 (s, 3H), 3.71 (d, J = 13.8 Hz, 1H), 3.62 (d, J = 13.8 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 168.8, 166.5, 136.2, 132.1, 131.9, 131.6, 131.2, 130.7, 129.9, 129.8, 129.7, 129.0, 128.4, 127.0, 122.6, 121.7, 117.8, 110.6, 60.9, 58.8, 56.3, 53.5, 35.1. HRMS (ESI): calcd for C28H22ClN2O3S ([M + H]+): 501.1034, found 501.1032. Methyl 7-Bromo-10b-cyano-3-oxo-1-phenyl-2-((phenylthio)methyl)-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2o-cis). White solid (100 mg, 92% yield, dr >19/1); Petroleum ether/EtOAc = 8/1; mp: 160−161 °C. 1H NMR (500 MHz, CDCl3) δ 7.61 (d, J = 8.1 Hz, 1H), 7.43−7.39 (m, 1H), 7.36 (t, J = 7.6 Hz, 2H), 7.32−7.19 (m, 7H), 7.12 (d, J = 7.8 Hz, 1H), 7.01 (t, J = 7.9 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H), 4.84 (s, 1H), 3.82 (s, 3H), 3.74 (d, J = 14.6 Hz, 1H), 3.25 (d, J = 14.6 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 168.1, 167.3, 134.8, 134.5, 132.9, 132.6, 131.8, 130.0, 129.8, 129.7, 129.6, 129.4, 128.0, 123.2, 4837


Article


122.0, 120.6, 117.3, 114.2, 62.3, 59.6, 53.4, 52.8, 36.4. HRMS (ESI): calcd for C28H22BrN2O3S ([M + H]+): 545.0529, found 545.0521. Methyl 2-(((4-Bromophenyl)thio)methyl)-10b-cyano-3-oxo-1phenyl-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2r-trans). White solid (86 mg, 79% yield, dr >19/1); Petroleum ether/EtOAc = 10/1; mp: 186−187 °C. 1H NMR (500 MHz, CDCl3) δ 8.30−7.02 (brs, 2H), 7.51 (s, 3H), 7.39 (d, J = 8.5 Hz, 2H), 7.34 (t, J = 7.5 Hz, 1H), 7.27−7.21 (m, 3H), 7.14 (t, J = 7.9 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.35 (d, J = 7.6 Hz, 1H), 4.85 (s, 1H), 3.74 (s, 3H), 3.69 (d, J = 13.8 Hz, 1H), 3.54 (d, J = 13.8 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 168.8, 166.6, 135.6, 132.2, 132.1, 131.7, 130.4, 130.1, 129.9, 129.8, 129.7, 129.2, 127.0, 124.1, 121.0, 120.3, 118.3, 114.5, 60.6, 58.8, 56.4, 53.6, 35.0. HRMS (ESI): calcd for C28H22BrN2O3S ([M + H]+): 545.0529, found 545.0523. Methyl 10b-Cyano-2-(((4-methoxyphenyl)thio)methyl)-3-oxo-1phenyl-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2s-cis). White solid (84 mg, 85% yield, dr >19/1); Petroleum ether/EtOAc = 8/1; mp: 149−150 °C. 1H NMR (500 MHz, CDCl3) δ 7.44−7.29 (m, 6H), 7.27 (s, 1H), 7.23−7.14 (m, 3H), 7.04 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.72 (d, J = 8.6 Hz, 2H), 6.37 (d, J = 7.6 Hz, 1H), 4.93 (s, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.66 (d, J = 14.6 Hz, 1H), 3.17 (d, J = 14.7 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 168.4, 167.5, 159.9, 135.2, 132.2, 131.1, 130.3, 130.2, 129.6, 129.5, 129.1, 126.8, 125.0, 124.0, 120.8, 117.5, 114.8, 114.1, 62.7, 59.7, 55.5, 52.8, 52.6, 37.6. HRMS (ESI): calcd for C29H25N2O4S ([M + H]+): 497.1530, found 497.1535. Methyl 10b-Cyano-2-(((4-methoxyphenyl)thio)methyl)-3-oxo-1phenyl-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2s-trans). White solid (45 mg, 45% yield, dr >19/1); Petroleum ether/EtOAc = 10/1; mp: 145−146 °C. 1H NMR (500 MHz, CDCl3) δ 7.80 (brs, 2H), 7.52−7.47 (m, 3H), 7.37 (d, J = 8.7 Hz, 2H), 7.32 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 7.12 (t, J = 7.7 Hz, 1H), 6.95 (d, J = 7.6 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 6.33 (d, J = 7.6 Hz, 1H), 4.83 (s, 1H), 3.78 (s, 3H), 3.73 (s, 3H), 3.61 (d, J = 13.7 Hz, 1H), 3.51 (d, J = 13.7 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 169.0, 166.8, 159.4, 134.0, 131.8, 130.3, 130.1, 129.7, 129.6, 129.1, 126.9, 126.8, 124.1, 120.4, 118.2, 114.6, 114.3, 60.8, 58.8, 56.5, 55.4, 53.5, 36.8. HRMS (ESI): calcd for C29H25N2O4S ([M + H]+): 497.1530, found 497.1529. Procedure for the Preparation of Compounds 4. To a stirred solution of 2a (0.2 mmol) in DCM (2 mL) was added m-CPBA (0.44 mmol, 75.9 mg) in portion-wise addition at 0 °C. The reaction mixture was stirred at this temperature for 30 min, then warmed to room temperature, and stirred until completed. After completion, the reaction was diluted with DCM (8 mL) and washed with 5% aqueous K2CO3 (8 mL) and 5% NaHCO3 (10 mL) solution. The aqueous layer was extracted with DCM (3 × 10 mL), the combined organic layers were dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo. The mixture was purified by column chromatography (silica gel, EtOAc/Petroleum ether) to provide compound 4a. Ethyl 10b-Cyano-3-oxo-1-phenyl-2-((phenylsulfonyl)methyl)1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Scheme 2). White solid (80 mg, 78% yield, dr >19/1); Petroleum ether/EtOAc = 3/1; mp: 176−177 °C. 1H NMR (500 MHz, CDCl3) δ 7.97 (d, J = 7.3 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H), 7.62 (t, J = 7.2 Hz, 1H), 7.53−7.44 (m, 5H), 7.35 (t, J = 7.5 Hz, 1H), 7.25−7.18 (m, 2H), 7.12 (d, J = 7.8 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.39 (d, J = 7.6 Hz, 1H), 5.40 (s, 1H), 4.34−4.19 (m, 2H), 3.90 (d, J = 15.2 Hz, 1H), 3.74 (d, J = 15.2 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 166.7, 166.6, 139.9, 134.3, 131.9, 131.2, 130.2, 129.8, 129.7, 129.5, 129.4, 128.0, 126.9, 123.9, 120.4, 117.6, 114.6, 63.5, 59.9, 59.7, 55.7, 52.7, 13.8. HRMS (ESI): calcd for C29H25N2O5S ([M + H]+): 513.1479, found 513.1478. Ethyl 10b-Cyano-3-oxo-1-phenyl-2-((phenylsulfonyl)methyl)1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Scheme 2). White solid (87 mg, 85% yield, dr >19/1); Petroleum ether/EtOAc = 2/1; mp: 172−173 °C. 1H NMR (300 MHz, CDCl3) δ 8.13 (brs, 1H), 7.98−7.90 (m, 2H), 7.66−7.60 (m, 1H), 7.57−7.44 (m, 5H), 7.34 (td, J = 7.6, 1.2 Hz, 1H), 7.25−7.19 (m, 1H), 7.13 (td, J = 7.7, 1.4 Hz, 1H), 6.95−6.84 (m, 2H), 6.33 (d, J = 7.5 Hz, 1H), 4.70

122.3, 122.2, 117.1, 112.9, 63.0, 59.7, 53.0, 52.7, 36.6. HRMS (ESI): calcd for C28H22BrN2O3S ([M + H]+): 545.0529, found 545.0526. Methyl 7-Bromo-10b-cyano-3-oxo-1-phenyl-2-((phenylthio)methyl)-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2o-trans). White solid (58 mg, 53% yield, dr >19/1); Petroleum ether/EtOAc = 10/1; mp: 175−176 °C. 1H NMR (500 MHz, CDCl3) δ 7.81 (brs, 2H), 7.56 (d, J = 7.7 Hz, 1H), 7.53−7.47 (m, 3H), 7.38 (d, J = 8.0 Hz, 2H), 7.30−7.23 (m, 2H), 7.22−7.17 (m, 1H), 7.01−6.92 (m, 3H), 6.75 (d, J = 7.8 Hz, 1H), 4.86 (s, 1H), 3.72 (s, 3H), 3.68 (d, J = 13.8 Hz, 1H), 3.58 (d, J = 13.7 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 168.8, 166.4, 136.2, 134.6, 132.0, 131.6, 130.8, 130.1, 129.9, 129.8, 129.0, 127.1, 123.3, 122.4, 121.9, 117.8, 113.2, 61.0, 58.9, 56.2, 53.6, 35.1. HRMS (ESI): calcd for C28H22BrN2O3S ([M + H]+): 545.0529, found 545.0522. Methyl 8-Bromo-10b-cyano-3-oxo-1-phenyl-2-((phenylthio)methyl)-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2p-cis). White solid (101 mg, 93% yield, dr >19/1); Petroleum ether/EtOAc = 9/1; mp: 201−202 °C. 1H NMR (300 MHz, CDCl3) δ 7.49−7.15 (m, 12H), 7.10 (d, J = 7.6 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 6.30 (d, J = 7.6 Hz, 1H), 4.79 (s, 1H), 3.82 (s, 3H), 3.73 (d, J = 14.6 Hz, 1H), 3.24 (d, J = 14.6 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 168.2, 167.5, 134.9, 132.5, 132.3, 131.8, 131.6, 129.8, 129.7, 129.5, 129.4, 128.0, 125.5, 124.4, 122.1, 117.0, 112.8, 62.7, 59.5, 53.1, 52.7, 36.6. HRMS (ESI): calcd for C28H22BrN2O3S ([M + H]+): 545.0529, found 545.0533. Methyl 8-Bromo-10b-cyano-3-oxo-1-phenyl-2-((phenylthio)methyl)-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2p-trans). White solid (60 mg, 55% yield, dr >19/1); Petroleum ether/EtOAc = 10/1; mp: 179−180 °C. 1H NMR (500 MHz, CDCl3) δ 7.78 (brs, 2H), 7.50 (s, 3H), 7.42−7.33 (m, 3H), 7.30−7.23 (m, 3H), 7.19 (t, J = 7.2 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 6.25 (d, J = 7.6 Hz, 1H), 4.82 (s, 1H), 3.78− 3.65 (m, 4H), 3.59 (d, J = 13.7 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 168.8, 166.6, 136.3, 132.1, 131.9, 131.4, 130.7, 129.9, 129.6, 129.0, 128.8, 127.0, 125.6, 124.6, 121.7, 117.8, 113.0, 60.7, 58.6, 56.3, 53.5, 35.0. HRMS (ESI): calcd for C28H22BrN2O3S ([M + H]+): 545.0529, found 545.0534. Ethyl 10b-Cyano-3-oxo-2-((phenylthio)methyl)-1,2,3,10btetrahydropyrrolo[2,1-a]isoquinoline-2- carboxylate (Table 2, 2qcis). Colorless oil (75 mg, 96% yield, dr >19/1). Petroleum ether/ EtOAc = 8/1. 1H NMR (500 MHz, CDCl3) δ 7.47−7.36 (m, 2H), 7.35−7.30 (m, 2H), 7.28−7.22 (m, 4H), 7.16 (d, J = 7.5 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H), 6.33 (d, J = 7.6 Hz, 1H), 4.35−4.23 (m, 2H), 3.70 (d, J = 13.9 Hz, 1H), 3.62 (d, J = 13.5 Hz, 1H), 3.51 (d, J = 13.9 Hz, 1H), 3.05 (d, J = 13.5 Hz, 1H), 1.35 (t, J = 7.14 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 168.3, 167.7, 134.5, 131.5, 130.2, 130.1, 129.6, 129.2, 129.1, 127.5, 126.6, 123.6, 120.7, 118.0, 114.2, 63.2, 56.9, 55.8, 39.6, 39.4, 13.9. HRMS (ESI): calcd for C23H21N2O3S ([M + H]+): 405.1267, found 405.1263. Ethyl 10b-Cyano-3-oxo-2-((phenylthio)methyl)-1,2,3,10btetrahydropyrrolo[2,1-a]isoquinoline-2- carboxylate (Table 2, 2qtrans). Colorless oil (76.2 mg, 94% yield, dr >19/1). Petroleum ether/ EtOAc = 10/1. 1H NMR (500 MHz, CDCl3) δ 7.56−7.50 (m, 2H), 7.42−7.37 (m, 2H), 7.33 (t, J = 7.4 Hz, 2H), 7.28 (d, J = 7.2 Hz, 2H), 7.25−7.20 (m, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.32 (d, J = 7.6 Hz, 1H), 4.19−3.99 (m, 2H), 3.96 (d, J = 13.6 Hz, 1H), 3.61−3.52 (m, 2H), 3.47 (d, J = 13.8 Hz, 1H), 1.19 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 168.0, 167.5, 134.6, 131.9, 130.4, 130.1, 129.4, 129.1, 127.8, 126.7, 123.9, 120.6, 118.7, 114.6, 63.0, 57.6, 55.5, 38.2, 37.5, 14.0. HRMS (ESI): calcd for C23H21N2O3S ([M + H]+): 405.1267, found 405.1272. Methyl 2-(((4-Bromophenyl)thio)methyl)-10b-cyano-3-oxo-1phenyl-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (Table 2, 2r-cis). White solid (93 mg, 85% yield, dr >19/1); Petroleum ether/EtOAc = 8/1; mp:185−186 °C. 1H NMR (500 MHz, CDCl3) δ 7.46−7.35 (m, 6H), 7.31 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 6.7 Hz, 1H), 7.19 (t, J = 7.3 Hz, 1H), 7.14 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.38 (d, J = 7.6 Hz, 1H), 4.80 (s, 1H), 3.83 (s, 3H), 3.71 (d, J = 14.5 Hz, 1H), 3.25 (d, J = 14.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 168.2, 167.4, 133.8, 133.6, 132.3, 131.9, 131.0, 130.2, 130.1, 129.8, 129.7, 129.2, 126.9, 123.9, 4838


Article

The Journal of Organic Chemistry (s, 1H), 4.23−4.10 (m, 3H), 3.80 (d, J = 14.9 Hz, 1H), 1.17 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 167.4, 164.9, 140.3, 133.9, 131.2, 130.5, 130.2, 130.1, 129.9, 129.1, 129.0, 128.9, 128.6, 127.0, 124.0, 120.6, 117.8, 114.5, 63.3, 58.7, 57.4, 57.1, 55.8, 14.0. HRMS (ESI): calcd for C29H25N2O5S ([M + H]+): 513.1479, found 513.1478.

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(6) (a) Kuo, R.-Y.; Wu, C.-C.; Chang, F.-R.; Yeh, J.-L.; Chen, I.-J.; Wu, Y.-C. Bioorg. Med. Chem. Lett. 2003, 13, 821. (b) Wang, R. F.; Yang, X. W.; Ma, C. M.; Cai, S. Q.; Li, J. N.; Shoyama, Y. Heterocycles 2004, 63, 1443. (c) Pässler, U.; Knöller, H. J. In The Alkaloids: Chemistry and Biology; Knöller, H. J., Ed.; Elsevier: Amsterdam, 2011; Vol. 70; p 79 and and references cited therein. (7) Selected recent examples: (a) Fleury, J.-F.; Netchitaïlo, P.; Daïch, A. Synlett 2011, 2011, 1821. (b) Selvakumar, J.; Makriyannis, A.; Ramanathan, C. R. Org. Biomol. Chem. 2010, 8, 4056. (h) Moreno, L.; Párraga, J.; Galán, A.; Cabedo, N.; Primo, J.; Cortes, D. Bioorg. Med. Chem. 2012, 20, 6589 and references cited therein.. (8) Qin, T.-Y.; Cheng, L.; Ho-Chol, J.; Zhang, S. X.-A.; Liao, W.-W. Synthesis 2016, 48, 357. (9) For reviews of Lewis base-catalyzed allylic alkylation reactions of MBH adducts, see: (a) Liu, T.-Y.; Xie, M.; Chen, Y.-C. Chem. Soc. Rev. 2012, 41, 4101. (b) Rios, R. Catal. Sci. Technol. 2012, 2, 267. (c) Wei, Y.; Shi, M. Chem. Rev. 2013, 113, 6659. (10) See the Supporting Information for details. (11) For CCDC 1502062 (compound 2a-cis) and CCDC 1502063 (compound 2a-trans), see the Supporting Information for details. (12) The explicit mechanism of how Na or K cations other than Li and Mg cations improved selectivity in this reaction remains unclear at this stage. The role of Na cation could be confirmed further by the fact that treatment of 1b (0.2 mmol) with TBACN (5 mol %) and NaI (20 mol %) in THF (0.5 mL) provided the desired product 2b in 40% yield with cis/trans = 3/1 (rt, 10 h).

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b00551. Crystallographic data for 2a-cis (CIF) Crystallographic data for 2a-trans (CIF) NMR spectra of products 1a−1s, 2a−2s, and 4a−4b; Xray structures of compounds 2a-cis and 2a-trans (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Wei-Wei Liao: 0000-0001-6225-4258 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS W.-W.L. thanks NSFC (No. 21372096) and the Open Project of State Key Laboratory for Supramolecular Structure and Materials (sklssm201716) for financial support. We also thank for the help of Dr. Yan Yan on X-ray crystal structural analyses.

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REFERENCES

(1) (a) Nudelman, A., Ed. The Chemistry of Optically Active Sulfur Compounds; Gordon and Breach: New York, 1984. (b) Damani, L. A., Ed. Sulphur-Containing Drugs and Related Organic Compounds; Wiley: New York, 1989. (c) Fraústo da Silva, J. R., Williams, R. J. P., Eds. The Biological Chemistry of the Elements; Clarendon: Oxford, 2001. (d) Hansch, C., Sammes, P. G., Taylor, J. B., Eds. Comprehensive Medicinal Chemistry: the Rational Design, Mechanistic Study & Therapeutic Application of Chemical Compounds; Pergamon Press: Oxford, 1990. (2) For leading books, see: (a) Toru, T., Bolm, C., Eds. Organosulfur Chemistry in Asymmetric Synthesis; Wiley-VCH: Weinheim, Germany, 2008. (b) Page, P., Eds. Organosulfur Chemistry. Synthetic Aspects; Academic Press: London, 1995. (3) For selected reviews, see: (a) Arisawa, M.; Yamaguchi, M. Pure Appl. Chem. 2008, 80, 993. (b) Shen, C.; Zhang, P.-F.; Sun, Q.; Bai, S.Q; Hor, T. S. A.; Liu, X.-G. Chem. Soc. Rev. 2015, 44, 291. (c) Bichler, P.; Love, J.-A. Top. Organomet. Chem. 2010, 31, 39. (d) Chauhan, P.; Mahajan, S.; Enders, D. Chem. Rev. 2014, 114, 8807. (e) Yu, J.-S.; Huang, H.-M.; Ding, P.-G.; Hu, X.-S.; Zhou, F.; Zhou, J. ACS Catal. 2016, 6, 5319. (4) Sulfamination of alkenes: (a) Li, L.-J.; Li, Z.-Q.; Huang, D.-S.; Wang, H.-N.; Shi, Y.-A. RSC Adv. 2013, 3, 4523. (b) Denmark, S. E.; Chi, H.-M. J. Am. Chem. Soc. 2014, 136, 8915. Oxysulfenylation of alkenes: (c) Denmark, S. E.; Kornfilt, D. J. P.; Vogler, T. J. Am. Chem. Soc. 2011, 133, 15308. Carbosulfenylation of olefins: (d) Denmark, S. E.; Jaunet, A. J. Am. Chem. Soc. 2013, 135, 6419. (e) Denmark, S. E.; Jaunet, A. J. Org. Chem. 2014, 79, 140. (f) Denmark, S. E.; Chi, H. M. J. Am. Chem. Soc. 2014, 136, 3655. Intermolecular reaction: (g) Zhao, G.-L.; Rios, R.; Vesely, J.; Eriksson, L.; Córdova, A. Angew. Chem., Int. Ed. 2008, 47, 8468. (5) (a) Zhuang, Z.; Chen, J.-M.; Pan, F.; Liao, W.-W. Org. Lett. 2012, 14, 2354. (b) Chen, J.-M.; Zou, G.-F.; Liao, W.-W. Angew. Chem., Int. Ed. 2013, 52, 9296. (c) Chen, J.-M.; Xu, Q.-Q.; Liao, W.-W. Chem. Eur. J. 2014, 20, 13876. (d) Qin, T.-Y.; Cheng, L.; Zhang, S. X.-A.; Liao, W.-W. Chem. Commun. 2015, 51, 9714. 4839


Controllable Diastereodivergent Synthesis of Pyrrolo[2,1-a

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