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May 15, 2019 - (2C), 72.7, 54.4, 51.8, 50.5, 29.1, 28.4, 27.0 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H23ClN2 327.1623; found 227.1621...
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Cite This: J. Org. Chem. 2019, 84, 6547−6556

Copper-Catalyzed Diamination of Oxime Ester-Tethered Unactivated Alkenes with Unprotected Amines Lin Wang and Chuan Wang* Hefei National Laboratory for Physical Science at the Microscale, Department of Chemistry, Center for Excellence in Molecular Synthesis, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 20237, P. R. China

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ABSTRACT: In this protocol, a redox-neutral Cu-catalyzed two-component vicinal diamination of oxime ester-tethered unactivated alkenes has been developed. This operationally simple method employs unprotected amines as the source of nucleophilic nitrogen and requires no additional ligand, enabling the efficient synthesis of diverse pyrrolines under mild and oxidant-free conditions. On the basis of the control experiments, a radical reaction pathway was proposed for this Cu-catalyzed reaction.

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INTRODUCTION Diamination of alkenes is one of the most important reactions in organic synthesis,1 as it provides a direct entry to vicinal diamines, which are contained as a characteristic motif in a large number of naturally occurring products and synthetic biologically active compounds.2 In the last decades, numerous strategies have been established for catalytic diamination of unactivated olefins, such as the Pd-, Ni-, Rh-, or Cu-catalyzed oxidative diamination,3 Pd- or Cu-catalyzed diamination using diaziridinones,4 Pd-catalyzed diamination employing N-fluorobenzenesulfonimide,5 Cu-catalyzed diamination using O-acyl hydroxylamines,6 Ti-catalyzed diamination employing a bis(imido)osmium complex,7 Rh- or Fe-catalyzed Ritter-type diamination,8 as well as aryl iodide-promoted diamination.9 Despite the tremendous progress in this area, the direct use of unprotected amines as nitrogen source in the catalytic diamination reaction of unactivated alkenes is still very rare,3j,k because amines are susceptible to oxidation under oxidative conditions.10 Oxime esters or ethers tethering a pendant olefinic unit are successfully employed in a series of two-component difunctionalizations of unactivated alkenes under transition metal or photocatalysis, furnishing a variety of functionalized N-containing heterocyclic compounds as products (Scheme 1A).11,12 Herein, we envisage a Cu-catalyzed oxidant-free diamination of tethered unactivated alkenes, in which oxime esters and unprotected amines are utilized as the electrophilic and nucleophilic nitrogen source, respectively, providing an access to diverse amino-substituted pyrrolines (Scheme 1B).

Scheme 1. Previous Work of the Use of Oxime EstersTethered Alkenes in Difunctionalization Reactions (A) and Cu-Catalyzed Diamination of Oxime Ester-Tethered Alkenes with Amines

(entries 1−5). It turned out that all the Cu(I)-salts were able to catalyze the desired diamination reaction and the best outcome in terms of the efficiency was achieved under the catalysis of [Cu(MeCN)4]PF6 (entry 5). Next, a brief solvent screening was undertaken, delivering no improved result (entries 6−8). The use of inorganic bases resulted in dramatically decreased yields (entries 9 and 10). Furthermore, lowering the temperature to 60 °C led to significant diminishing of the yield (entry 11), while raising the temperature to 100 °C had little influence (entry 12). Subsequently, the leaving groups LG of the oxime esters substrates were examined and no better results were obtained in these cases (entries 13−15). Performing the reaction with 1.5 equiv of the oxime ester 1a-1 with extended reaction time (10 h) increased the reaction yield to 85% based on aniline (entries 16). Finally, the yield was improved to an excellent level by further increasing the amount of the oxime ester to 2

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RESULTS AND DISCUSSION For optimization of the reaction conditions, we used the acetyl O-oxime 1a-1 incorporating a terminal olefin and 1.5 equiv of aniline (2a) as standard substrates (Table 1). Initially, an array of Cu-salts were investigated as catalysts using NEt3 as base and dimethoxyethane (DME) as solvent at 80 °C for 5 h © 2019 American Chemical Society

Received: April 4, 2019 Published: May 15, 2019 6547

DOI: 10.1021/acs.joc.9b00936 J. Org. Chem. 2019, 84, 6547−6556

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Table 1. Cu-Salts, Solvents, Bases, and Temperature Screening for the Diamination Reactiona

entry

Cu salt

solvent

base

yield (%)b

1 2 3 4 5 6 7 8 9 10 11c 12d 13e 14f 15g 16h 17i 18k

CuBr CuI CuCN CuCl [Cu(MeCN)4]PF6 [Cu(MeCN)4]PF6 [Cu(MeCN)4]PF6 [Cu(MeCN)4]PF6 [Cu(MeCN)4]PF6 [Cu(MeCN)4]PF6 [Cu(MeCN)4]PF6 [Cu(MeCN)4]PF6 [Cu(MeCN)4]PF6 [Cu(MeCN)4]PF6 [Cu(MeCN)4]PF6 [Cu(MeCN)4]PF6 [Cu(MeCN)4]PF6 [Cu(MeCN)4]PF6

DME DME DME DME DME DMF DCE 1,4-dioxane DME DME DME DME DME DME DME DME DME DME

NEt3 NEt3 NEt3 NEt3 NEt3 NEt3 NEt3 NEt3 K2CO3 K3PO4 NEt3 NEt3 NEt3 NEt3 NEt3 NEt3 NEt3 NEt3

55 66 21 65 72 58 68 65 traces 18 32 71 60 55 32 85 95 (88j) 83

Scheme 2. Evaluation of the Substrate Scope of the CuCatalyzed Diamination by Varying the Structure of the Oxime Estersa,b

a Unless otherwise specified, reactions were performed on a 0.1 mmol scale of the oxime ester 1a-1 using 1.5 equiv of aniline (2a), 20 mol % Cu-salt and 3 equiv of base at 80 °C for 5 h in 1.0 mL of the solvent. b Yields of 3a were based on the 1H NMR-spectroscopy using 1,3,5trimethoxybenzene as an internal standard. cReaction was performed at 60 °C. dReaction was performed at 100 °C. eOxime ester 1a-2 was employed instead of 1a-1. fOxime ester 1a-3 was employed instead of 1a-1. gOxime ester 1a-4 was employed instead of 1a-1. h1.5 equiv of oxime ester 1a-1 was employed with reaction time of 10 h. i2 equiv of oxime ester 1a-1 was employed with reaction time of 16 h. jYield of the isolated product 3a after flash chromatography. kReaction was performed with 10 mol % [Cu(MeCN)4]PF6.

a Unless otherwise specified, reactions were performed on a 0.2 mmol scale of aniline (2a) using 2 equiv of O-acetyl oximes 1, 20 mol % [Cu(MeCN)4]PF6 and 3 equiv of NEt3 at 80 °C for 16 h in 2.0 mL of DME. bYields of the isolated products after flash chromatography or preparative thin layer chromatography. cReaction was performed on a 5 mmol scale of aniline (2a). dO-Benzoyl oximes were used instead the O-acetyl oximes.

equiv and the reaction time to 16 h (entry 17). Lowering the catalyst loading to 10 mol % led to a diminished yield (entry 18). With the optimal reaction conditions in hand, we started to evaluate the substrate spectrum of this Cu-catalyzed diamination. First, a series of aromatic and heteroaromatic O-acetyl or O-benzoyl oximes tethering a terminal olefinic unit and two geminal substituents were reacted with aniline (2a) (Scheme 2). To our delight, all the reactions proceeded smoothly under the optimal reaction conditions, affording the diamination products 3a-g in moderate to excellent yields. Furthermore, a panel of representative alkenes bearing different substitution patterns of the olefinic unit were used as precursors in this Cucatalyzed reaction. In all the cases of geminal disubstituted alkenes, the desired products 3h-j were furnished in excellent yields. Of note is that the reaction employing the monosubstituted alkene also provided the diamination product 3k, albeit in a lower yield. Unfortunately, the oxime esters without geminal disubstitution or containing an internal alkene moiety turned out to be unsuccessful substrates. In the former case, no cyclization occurred and the reactions delivered the corresponding ketones as the hydrolysis product of the oxime

esters, instead. In contrast, aza-Heck-products were obtained when the internal alkenes were employed as the precursors.13−15 Subsequently, we continued to study the substrate scope of this Cu-catalyzed reaction by varying the structure of the amines (Scheme 3). Gratifyingly, both electron-donating and -withdrawing substituents on different position of the phenyl ring were well tolerated, providing the corresponding products 3l-ab in good to high yields. Remarkably, in the case of anilines bearing an alcoholic moiety the diamination reaction demonstrated excellent chemoselectivity and proceeded only with amine as the nucleophile (3ac). Moreover, this method was applicable to β-naphthyl amine, heterocyclic amines, and secondary aromatic amines as aminating agents and the corresponding products 3ad-ak were obtained in moderately good yields. One limitation of this method was observed in the case of aliphatic amines, which turned out to be unsuitable substrates. To shed light on the mechanism of this Cu-catalyzed reaction, we first conducted a control experiment using 6548

DOI: 10.1021/acs.joc.9b00936 J. Org. Chem. 2019, 84, 6547−6556

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Scheme 3. Evaluation of the Substrate Scope of the CuCatalyzed Diamination by Varying the Structure of the Aminesa,b

Scheme 4. Control Experiments for the Cu-Catalyzed Diaminationa,b

a

Yield based on the oxime ester. bYield based on aniline.

Scheme 5. Proposed Catalytic Cycle of the Cu-Catalyzed Diamination

a Unless otherwise specified, reactions were performed on a 0.2 mmol scale of amines 2 using 2 equiv of the oxime ester 1a-1, 20 mol % [Cu(MeCN)4]PF6 and 3 equiv of NEt3 at 80 °C for 16 h in 2.0 mL of DME. bYields of the isolated products after flash chromatography or preparative thin layer chromatography. cReactions time: 10 h. dThe OBenzoyl oxime 1a-2 was used instead the O-acetyl oxime 1a-1.

TEMPO as a radical scavenger (Scheme 4A). In this case, the diamination reaction was completely shut down and a TEMPO adduct 4 was isolated in moderate yield. Moreover, a radical clock reaction employing an oxime ester incorporating a cyclopropyl-substituted olefinic unit was performed under the standard reaction conditions (Scheme 4B). In this case, the formation of the 1,2-diamination product 3al was not observed, while the ring opening products 5 and 6 were both afforded in moderate yields. These results suggest that our reaction probably proceeds in a radical pathway. On the basis of the experimental results mentioned already, we proposed a plausible mechanism for this Cu-catalyzed diamination (Scheme 5). Initially, the oxime esters 1 interact with a Cu(I) complex I to give a cage II consisting of a Cu(II)species and an alkyl radical, which can recombine each other rapidly via a radical addition. The subsequent ligand-exchange of the resultant Cu-species III with amines 2 in assistance of NEt3 leads to the formation of a Cu(III)-intermediate IV. Finally, the reductive elimination from the complex IV provides the products 3 and the Cu(I) I species for the next catalytic cycle.

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SUMMARY In summary, we developed a Cu-catalyzed two-component diamination of oxime ester-tethered unactivated alkenes with unprotected amines as coupling partners, requiring no additional ligand. This redox-neutral reaction offers an efficient entry to a variety of pyrrolines under mild and oxidant-free conditions. Mechanistic studies indicate a radical pathway for the cyclization step.

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EXPERIMENTAL SECTION

Unless otherwise stated, all reactions were set up on a 10 mL tube and carried out under the protection of nitrogen. Cu(MeCN)4PF6 was purchased from TCI and used as received. All amines and solvents were purchased from Adamas or Energy Chemical. Other commercial reagents were purchased from Sigma-Aldrich, Alfa Aesar, TCI, Strem, Acros, and Energy Chemical, and were used as received. Reactions were monitored through thin layer chromatography [Merck 60 F254 6549

DOI: 10.1021/acs.joc.9b00936 J. Org. Chem. 2019, 84, 6547−6556

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colorless oil (52 mg, 81%). 1H NMR (400 MHz, Chloroform-d) δ = 7.79−7.67 (m, 2H), 7.21−7.09 (m, 2H), 6.90 (d, J = 9.0 Hz, 2H), 6.73−6.57 (m, 3H), 4.11−3.86 (brs, 1H), 3.83 (s, 3H), 3.32 (d, J = 11.6 Hz, 1H), 3.12 (d, J = 11.6 Hz, 1H), 2.07 (d, J = 13.0 Hz, 1H), 1.82 (d, J = 13.0 Hz, 1H), 1.47 (s, 3H), 1.42 (s, 3H), 1.36 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 177.8, 160.7, 148.9, 129.7 (2C), 129.1 (2C), 127.0, 117.1, 113.5 (2C), 112.9 (2C), 71.7, 55.3, 54.5, 51.5, 51.0, 29.4, 28.7, 27.2 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H26N2O 323.2118; found 323.2117. N-((2,4,4-Trimethyl-5-(naphthalen-2-yl)-3,4-dihydro-2H-pyrrol2-yl)methyl)aniline (3e). This compound was isolated by flash chromatography on silica gel (Petroleum ether:EtOAc = 15:1) as a colorless oil (43 mg, 63%). 1H NMR (400 MHz, Chloroform-d) δ = 8.16−8.12 (m, 1H), 7.91−7.79 (m, 4H), 7.58−7.40 (m, 2H), 7.22− 7.12 (m, 2H), 6.76−6.62 (m, 3H), 4.11−3.86 (brs, 1H), 3.38 (d, J = 11.7 Hz, 1H), 3.18 (d, J = 11.8 Hz, 1H), 2.13 (d, J = 13.1 Hz, 1H), 1.88 (d, J = 13.0 Hz, 1H), 1.53 (s, 3H), 1.48 (s, 3H), 1.42 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 178.6, 148.9, 133.7, 132.8, 132.1, 129.2 (2C), 128.6, 127.9, 127.7, 127.6, 126.8, 126.3, 125.7, 117.2, 113.0 (2C), 72.4, 54.5, 51.9, 50.8, 29.5, 28.7, 27.2 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C24H26N2 343.2169; found 343.2160. N-((5-(Furan-2-yl)-2,4,4-trimethyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)aniline (3f). This compound was isolated by flash chromatography on silica gel (Petroleum ether:EtOAc = 10:1) as a colorless oil (38 mg, 66%). 1H NMR (400 MHz, Chloroform-d) δ = 7.53 (d, J = 1.4 Hz, 1H), 7.19−7.11 (m, 2H), 6.95−6.86 (m, 1H), 6.67 (t, J = 7.3 Hz, 1H), 6.63 (d, J = 8.0 Hz, 2H), 6.51−6.45 (m, 1H), 3.87 (t, J = 5.0 Hz, 1H), 3.32 (dd, J = 12.0, 5.0 Hz, 1H), 3.17 (dd, J = 12.0, 5.0 Hz, 1H), 2.06 (d, J = 13.1 Hz, 1H), 1.78 (d, J = 13.2 Hz, 1H), 1.46 (s, 3H), 1.43 (s, 3H), 1.41 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 169.0, 148.8, 148.7, 144.0, 129.1 (2C), 117.1, 113.1, 112.9 (2C), 111.3, 73.7, 54.2, 51.1, 49.7, 29.0, 28.4, 27.5 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H22N2O 283.1805; found 283.1800. N-((3-Methyl-1-phenyl-2-azaspiro[4.4]non-1-en-3yl)methyl)aniline (3g). This compound was isolated by flash chromatography on silica gel (Petroleum ether:EtOAc = 15:1) as a colorless oil (51 mg, 80% when using 1g-1; 41 mg, 65% when using 1g-2). 1H NMR (400 MHz, Chloroform-d) δ = 7.70−7.55 (m, 2H), 7.42−7.30 (m, 3H), 7.22−7.09 (m, 2H), 6.73−6.58 (m, 3H), 4.11−3.86 (brs, 1H), 3.34 (d, J = 11.6 Hz, 1H), 3.16 (d, J = 11.6 Hz, 1H), 2.22−2.05 (m, 2H), 2.02 (d, J = 12.8 Hz, 1H), 1.86 (d, J = 12.8 Hz, 1H), 1.79−1.58 (m, 6H), 1.42 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 178.1, 148.8, 134.8, 129.3, 129.2 (2C), 128.2 (2C), 128.1 (2C), 117.1, 112.9 (2C), 73.0, 62.0, 54.3, 51.1, 39.5, 39.2, 26.9, 25.4, 25.3 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H26N2 319.2169; found 319.2161. N-((2-Ethyl-4,4-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)aniline (3h). This compound was isolated by flash chromatography on silica gel (Petroleum ether:EtOAc = 15:1) as a colorless oil (57 mg, 93%). 1H NMR (400 MHz, Chloroform-d) δ = 7.70−7.57 (m, 2H), 7.45−7.28 (m, 3H), 7.21−7.08 (m, 2H), 6.73− 6.57 (m, 3H), 4.02 (t, J = 5.9 Hz, 1H), 3.36 (dd, J = 11.6, 5.9 Hz, 1H), 3.10 (dd, J = 11.6, 5.0 Hz, 1H), 1.97−1.81 (m, 3H), 1.80−1.69 (m, 1H), 1.38 (s, 3H), 1.36 (s, 3H), 0.94 (t, J = 7.5 Hz, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 179.2, 148.9, 135.0, 129.3, 129.2 (2C), 128.2 (2C), 128.0 (2C), 117.1, 112.9 (2C), 75.8, 52.5, 51.7, 47.4, 31.4, 28.9, 28.7, 8.8 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H26N2 307.2169; found 307.2168. N-((2-Isopropyl-4,4-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2yl)methyl)aniline (3i). This compound was isolated by flash chromatography on silica gel (Petroleum ether:EtOAc = 15:1) as a colorless oil (61 mg, 95%). 1H NMR (400 MHz, Chloroform-d) δ = 7.65−7.54 (m, 2H), 7.45−7.32 (m, 3H), 7.21−7.09 (m, 2H), 6.67 (tt, J = 7.3, 1.1 Hz, 1H), 6.65−6.60 (m, 2H), 4.11−3.86 (brs, 1H), 3.45 (d, J = 11.6 Hz, 1H), 3.12 (d, J = 11.5 Hz, 1H), 2.52−2.32 (m, 1H), 1.96 (d, J = 13.5 Hz, 1H), 1.68 (d, J = 13.5 Hz, 1H), 1.39 (s, 3H), 1.32 (s, 3H), 0.96 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H) ppm. 13 C {1H} NMR (101 MHz, Chloroform-d) δ = 178.9, 148.9, 135.0,

precoated with silica gel (0.2 mm thickness)] and the spots were visualized using UV radiation (254 nm) on Spectroline Model ENF24061/F 254 nm. Other visualization methods include staining with a basic solution of potassium permanganate, followed by heating. 1H NMR and 13C NMR spectra were recorded on a Bruker Advance 400 M NMR spectrometers at ambient temperature in CDCl3 at 400 and 101 MHz. The chemical shifts are given in ppm relative to tetramethylsilane [1H: δ (SiMe4) = 0.00 ppm] as an internal standard or relative to the resonance of the solvent [1H: δ (CDCl3) = 7.26, 13 C: δ (CDCl3) = 77.16 ppm]. Multiplicities were given as s (singlet); d (doublet); t (triplet); q (quartet); dd (doublet of doublets); dt (doublet of triplets); m (multiplets). Coupling constants are reported as J values in Hz. High resolution mass spectral analysis (HRMS) was performed on Waters XEVO G2 Q-TOF. Flash chromatography was performed using 300−400 mesh silica gel with the indicated solvent system. General Experimental Procedure for the Cu-Catalyzed Diamination. A mixture of Cu(MeCN)4PF6 (13.9 mg, 20 mol %), dry triethylamine (83 uL, 3.0 equiv), γ,δ-unsaturated O-acetyl oximes (0.4 mmol, 2.0 equiv) and amines (0.2 mmol, 1.0 equiv) in dry DME (2.0 mL) was stirred in a sealed tube at 80 °C with the heating block for 16 h under nitrogen atmosphere. Upon completion of the reaction, the solvent was then removed under vacuum. The residue was purified through flash chromatography or preparative TLC on silica gel or basic aluminum oxide (pH 9.0−10.0) to afford the corresponding pyrrolines 3 as product. (Notes: O-benzoyl oximes were used for 3b-g, 3k, and 3o. Reaction time was 10 h for 3m-o, 3qu, and 3w. Aza-Heck products were formed in the cases of 3am and 3an.) N-((2,4,4-Trimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)aniline (3a). This compound was isolated by flash chromatography on silica gel (Petroleum ether:EtOAc = 10:1) as a colorless oil (52 mg, 88%). 1H NMR (400 MHz, Chloroform-d) δ = 7.71−7.62 (m, 2H), 7.44−7.32 (m, 3H), 7.22−7.10 (m, 2H), 6.74− 6.60 (m, 3H), 4.10−3.86 (brs, 1H), 3.34 (d, J = 11.7 Hz, 1H), 3.15 (d, J = 11.7 Hz, 1H), 2.09 (d, J = 13.0 Hz, 1H), 1.85 (d, J = 13.0 Hz, 1H), 1.45 (s, 3H), 1.44 (s, 3H), 1.33 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 179.1, 148.9, 134.8, 129.5, 129.2 (2C), 128.3 (2C), 128.1 (2C), 117.2, 113.0 (2C), 72.3, 54.5, 51.9, 50.5, 29.3, 28.5, 27.2 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H24N2 293.2012; found 293.2011. N-((5-(4-Fluorophenyl)-2,4,4-trimethyl-3,4-dihydro-2H-pyrrol-2yl)methyl)aniline (3b). This compound was isolated by flash chromatography on silica gel (Petroleum ether:EtOAc = 15:1) as a colorless oil (47 mg, 75%). 1H NMR (400 MHz, Chloroform-d) δ = 7.76−7.62 (m, 2H), 7.23−7.12 (m, 2H), 7.12−6.99 (m, 2H), 6.99− 6.66 (m, 1H), 6.66−6.60 (m, 2H), 4.11−3.85 (brs, 1H), 3.33 (d, J = 11.8 Hz, 1H), 3.13 (d, J = 11.8 Hz, 1H), 2.08 (d, J = 13.0 Hz, 1H), 1.84 (d, J = 13.0 Hz, 1H), 1.44 (s, 3H), 1.43 (s, 3H), 1.33 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 177.6, 163.6 (d, J = 248.0 Hz), 148.8, 130.8 (d, J = 6.1 Hz), 130.1 (d, J = 8.0 Hz, 2C), 129.2 (2C), 117.2, 115.2 (d, J = 22.0 Hz, 2C), 112.9 (2C), 72.3, 54.5, 51.7, 50.7, 29.2, 28.5, 27.1 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H23FN2 311.1918; found 311.1919. N-((5-(3-Chlorophenyl)-2,4,4-trimethyl-3,4-dihydro-2H-pyrrol-2yl)methyl)aniline (3c). This compound was isolated by flash chromatography on silica gel (Petroleum ether:EtOAc = 15:1) as a colorless oil (59 mg, 90% when using 1c-1, 50 mg, 77% when using 1c-2). 1H NMR (400 MHz, Chloroform-d) δ = 7.67 (t, J = 1.8 Hz, 1H), 7.54 (dt, J = 7.7, 1.4 Hz, 1H), 7.41−7.35 (m, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.22−7.11 (m, 2H), 6.73−6.60 (m, 3H), 4.11−3.86 (brs, 1H), 3.35 (d, J = 11.9 Hz, 1H), 3.14 (d, J = 11.9 Hz, 1H), 2.08 (d, J = 13.1 Hz, 1H), 1.85 (d, J = 13.1 Hz, 1H), 1.43 (s, 6H), 1.32 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 177.6, 148.7, 136.5, 134.3, 129.5, 129.4, 129.2 (2C), 128.2, 126.0, 117.3, 112.9 (2C), 72.7, 54.4, 51.8, 50.5, 29.1, 28.4, 27.0 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H23ClN2 327.1623; found 227.1621. N-((5-(4-Methoxyphenyl)-2,4,4-trimethyl-3,4-dihydro-2H-pyrrol2-yl)methyl)aniline (3d). This compound was isolated by flash chromatography on silica gel (Petroleum ether:EtOAc = 8:1) as a 6550

DOI: 10.1021/acs.joc.9b00936 J. Org. Chem. 2019, 84, 6547−6556

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5.85−5.82(m, 2H), 4.13−3.86 (brs, 1H), 3.74 (s, 6H), 3.31 (d, J = 10.7 Hz, 1H), 3.12 (d, J = 10.7 Hz, 1H), 2.06 (d, J = 13.0 Hz, 1H), 1.84 (d, J = 13.0 Hz, 1H), 1.44 (s, 3H), 1.43 (s, 3H), 1.34 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 179.0, 161.7 (2C), 150.8, 134.8, 129.5, 128.2 (2C), 128.0 (2C), 91.7 (2C), 89.7, 72.2, 55.2 (2C), 54.6, 51.9, 50.6, 29.2, 28.6, 27.1 ppm. HRMS (ESITOF) m/z: [M + H]+ Calcd for C22H28N2O2 353.2224; found 353.2224. 3-(Methylthio)-N-((2,4,4-trimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)aniline (3p). This compound was isolated by flash chromatography on silica gel (Petroleum ether:EtOAc = 10:1) as a colorless oil (51 mg, 75%). 1H NMR (400 MHz, Chloroform-d) δ = 7.75−7.61 (m, 2H), 7.44−7.34 (m, 3H), 7.08 (t, J = 7.9 Hz, 1H), 6.59 (ddd, J = 7.7, 1.8, 0.9 Hz, 1H), 6.55 (t, J = 2.0 Hz, 1H), 6.43 (ddd, J = 8.1, 2.4, 0.9 Hz, 1H), 4.03 (t, J = 5.7 Hz, 1H), 3.33 (dd, J = 11.7, 5.7 Hz, 1H), 3.13 (dd, J = 11.6, 5.9 Hz, 1H), 2.45 (s, 3H), 2.06 (d, J = 13.0 Hz, 1H), 1.85 (d, J = 13.0 Hz, 1H), 1.44 (s, 3H), 1.43 (s, 3H), 1.34 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 179.0, 149.2, 139.1, 134.7, 129.5, 129.4, 128.2 (2C), 128.0 (2C), 115.3, 110.8, 110.2, 72.2, 54.4, 51.8, 50.6, 29.2, 28.5, 27.1, 15.8 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H26N2S 339.1889; found 339.1884. 4-Fluoro-N-((2,4,4-trimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2yl)methyl)aniline (3q). This compound was isolated by preparative TLC on silica gel (Petroleum ether:EtOAc = 10:1) as a colorless oil (47 mg, 75%). 1H NMR (400 MHz, Chloroform-d) δ = 7.71−7.61 (m, 2H), 7.41−7.36 (m, 3H), 6.92−6.81 (m, 2H), 6.64−6.51 (m, 2H), 3.98−3.78 (brs, 1H), 3.30 (d, J = 11.5 Hz, 1H), 3.08 (d, J = 11.5 Hz, 1H), 2.07 (d, J = 13.0 Hz, 1H), 1.85 (d, J = 13.0 Hz, 1H), 1.45 (s, 3H), 1.44 (s, 3H), 1.34 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 179.1, 155.7 (d, J = 233.0 Hz), 145.3 (d, J = 1.1 Hz), 134.8, 129.5, 128.3 (2C), 128.0 (2C), 115.6 (d, J = 22.0 Hz, 2C), 113.7 (d, J = 8.0 Hz, 2C), 72.3, 55.3, 51.9, 50.6, 29.3, 28.5, 27.2 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H23FN2 311.1918; found 311.1914. 3-Chloro-N-((2,4,4-trimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2yl)methyl)aniline (3r). This compound was isolated by preparative TLC on silica gel (Petroleum ether:EtOAc = 10:1) as a colorless oil (61 mg, 92%). 1H NMR (400 MHz, Chloroform-d) δ = 7.78−7.59 (m, 2H), 7.48−7.30 (m, 3H), 7.05 (t, J = 7.9 Hz, 1H), 6.69−6.56 (m, 2H), 6.53−6.46 (m, 1H), 4.11 (t, J = 5.9 Hz, 1H), 3.32 (dd, J = 11.8, 5.7 Hz, 1H), 3.10 (dd, J = 11.7, 5.9 Hz, 1H), 2.03 (d, J = 13.0 Hz, 1H), 1.85 (d, J = 13.1 Hz, 1H), 1.45 (s, 3H), 1.43 (s, 3H), 1.33 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 179.1, 150.0, 135.0, 134.7, 130.1, 129.6, 128.3 (2C), 128.0 (2C), 117.0, 112.4, 111.4, 72.2, 54.3, 51.9, 50.6, 29.2, 28.6, 27.1 ppm. HRMS (ESITOF) m/z: [M + H]+ Calcd for C20H23ClN2 327.1623; found 327.1620. 4-Chloro-N-((2,4,4-trimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2yl)methyl)aniline (3s). This compound was isolated by preparative TLC on silica gel (Petroleum ether:EtOAc = 10:1) as a colorless oil (57 mg, 87%). 1H NMR (400 MHz, Chloroform-d) δ = 7.70−7.62 (m, 2H), 7.44−7.34 (m, 3H), 7.14−7.05 (m, 2H), 6.59−6.52 (m, 2H), 4.02 (t, J = 5.7 Hz, 1H), 3.31 (dd, J = 11.7, 5.7 Hz, 1H), 3.09 (dd, J = 11.7, 5.9 Hz, 1H), 2.04 (d, J = 13.0 Hz, 1H), 1.85 (d, J = 13.0 Hz, 1H), 1.44 (s, 3H), 1.43 (s, 3H), 1.33 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 179.1, 147.5, 134.7, 129.5, 129.0 (2C), 128.3 (2C), 128.0 (2C), 121.6, 114.0 (2C), 72.3, 54.7, 51.9, 50.6, 29.2, 28.5, 27.1 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H23ClN2 327.1623; found 327.1617. 3-Bromo-N-((2,4,4-trimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2yl)methyl)aniline (3t). This compound was isolated by preparative TLC on silica gel (Petroleum ether:EtOAc = 10:1) as a colorless oil (70 mg, 93%). 1H NMR (400 MHz, Chloroform-d) δ = 7.75−7.61 (m, 2H), 7.42−7.35 (m, 3H), 6.99 (t, J = 8.2 Hz, 1H), 6.81−6.72 (m, 2H), 6.54 (ddd, J = 8.2, 2.3, 1.0 Hz, 1H), 4.11 (t, J = 6.0 Hz, 1H), 3.31 (dd, J = 11.8, 5.6 Hz, 1H), 3.09 (dd, J = 11.8, 5.7 Hz, 1H), 2.03 (d, J = 13.1 Hz, 1H), 1.85 (d, J = 13.0 Hz, 1H), 1.45 (s, 3H), 1.42 (s, 3H), 1.33 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 179.1, 150.1, 134.7, 130.4, 129.5, 128.3 (2C), 128.0 (2C), 123.3,

129.2, 129.1 (2C), 128.2 (2C), 127.9 (2C), 117.0, 112.9 (2C), 78.9, 52.0, 51.6, 44.0, 32.7, 29.0, 27.9, 17.7 (2C) ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H28N2 321.2325; found 321.2325. N-((2-Benzyl-4,4-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)aniline (3j). This compound was isolated by flash chromatography on silica gel (Petroleum ether:EtOAc = 15:1) as a colorless oil (68 mg, 92%). 1H NMR (400 MHz, Chloroform-d) δ = 7.58−7.55 (m, 2H), 7.44−7.32 (m, 3H), 7.29−7.16(m, 7H), 6.72− 6.65 (m, 3H), 4.17 (t, J = 4.6 Hz, 1H), 3.46 (dd, J = 11.8, 4.6 Hz, 1H), 3.23−3.07 (m, 2H), 3.00 (d, J = 13.2 Hz, 1H), 2.02 (d, J = 13.4 Hz, 1H), 1.77 (d, J = 13.4 Hz, 1H), 1.26 (s, 3H), 0.78 (s, 3H) ppm. 13 C {1H} NMR (101 MHz, Chloroform-d) δ = 179.8, 148.7, 137.8, 135.0, 131.1 (2C), 129.2 (3C), 128.2 (2C), 127.9 (4C), 126.4, 117.3, 113.0 (2C), 76.5, 53.7, 52.0, 46.3, 44.5, 28.9, 27.3 ppm. HRMS (ESITOF) m/z: [M + H]+ Calcd for C26H28N2 369.2325; found 369.2322. N-((4,4-Dimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)aniline (3k). This compound was isolated by flash chromatography on silica gel (Petroleum ether:EtOAc = 15:1) as a colorless oil (28 mg, 50%). 1H NMR (400 MHz, Chloroform-d) δ = 7.69 (dd, J = 6.6, 2.3 Hz, 2H), 7.44−7.32 (m, 3H), 7.19 (t, J = 7.4 Hz, 2H), 6.75−6.65 (m, 3H), 4.33−4.26 (m, 2H), 3.45 (dd, J = 11.9, 5.0 Hz, 1H), 3.21 (dd, J = 11.9, 7.8 Hz, 1H), 2.10 (dd, J = 12.5, 6.8 Hz, 1H), 1.69 (dd, J = 12.5, 8.9 Hz, 1H), 1.37 (s, 3H), 1.36 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 180.7, 148.5, 134.6, 129.6, 129.2 (2C), 128.2 (2C), 127.8 (2C), 117.3, 113.1 (2C), 67.4, 50.6, 49.4, 45.6, 27.2, 26.0 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H22N2 279.1856; found 279.1849. 2,4,6-Trimethyl-N-((2,4,4-trimethyl-5-phenyl-3,4-dihydro-2Hpyrrol-2-yl)methyl)aniline (3l). This compound was isolated by flash chromatography on silica gel (Petroleum ether:EtOAc = 10:1) as a colorless oil (54 mg, 81%). 1H NMR (400 MHz, Chloroform-d) δ = 7.80−7.61 (m, 2H), 7.44−7.29 (m, 3H), 6.88−6.76 (m, 2H), 3.21− 3.10 (brs, 1H), 3.10 (d, J = 11.1 Hz, 1H), 2.86 (d, J = 11.1 Hz, 1H), 2.35 (d, J = 12.8 Hz, 1H), 2.28 (s, 6H), 2.22 (s, 3H), 1.82 (d, J = 12.8 Hz, 1H), 1.50 (s, 3H), 1.45 (s, 3H), 1.36 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 178.8, 143.6, 134.9, 131.4, 130.2, 129.39 (2C), 129.38 (2C), 128.2 (2C), 128.0 (2C), 72.5, 58.5, 51.9, 50.1, 29.5, 28.3, 27.1, 20.6, 18.2 (2C) ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C23H30N2 335.2482; found 335.2491. 2-Methoxy-N-((2,4,4-trimethyl-5-phenyl-3,4-dihydro-2H-pyrrol2-yl)methyl)aniline (3m). This compound was isolated by preparative TLC on silica gel (Petroleum ether:EtOAc = 10:1) as a colorless oil (58 mg, 89%). 1H NMR (400 MHz, Chloroform-d) δ = 7.70−7.59 (m, 2H), 7.43−7.31 (m, 3H), 6.86 (td, J = 7.7, 1.4 Hz, 1H), 6.75 (dd, J = 7.9, 1.4 Hz, 1H), 6.69−6.59 (m, 2H), 4.50−4.30 (brs, 1H), 3.81 (s, 3H), 3.39−3.27 (d, J = 12.0 Hz, 1H), 3.21 (d, J = 12.0 Hz, 1H), 2.14 (d, J = 13.0 Hz, 1H), 1.82 (d, J = 13.0 Hz, 1H), 1.46 (s, 3H), 1.45 (s, 3H), 1.29 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 179.2, 146.9, 138.9, 135.2, 129.2, 128.2 (2C), 128.0 (2C), 121.2, 116.1, 109.8, 109.5, 72.7, 55.5, 54.0, 52.0, 50.0, 29.4, 28.2, 27.3 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H26N2O 323.2118; found 323.2122. 3-Methoxy-N-((2,4,4-trimethyl-5-phenyl-3,4-dihydro-2H-pyrrol2-yl)methyl)aniline (3n). This compound was isolated by preparative TLC on silica gel (Petroleum ether:EtOAc = 10:1) as a colorless oil (51 mg, 78%). 1H NMR (400 MHz, Chloroform-d) δ = 7.76−7.63 (m, 2H), 7.45−7.34 (m, 3H), 7.07 (t, J = 8.1 Hz, 1H), 6.29−6.26 (m, 1H), 6.26−6.23 (m, 1H), 6.20 (t, J = 2.3 Hz, 1H), 4.11−3.85 (brs, 1H), 3.76 (s, 3H), 3.32 (d, J = 11.8 Hz, 1H), 3.13 (d, J = 11.8 Hz, 1H), 2.07 (d, J = 13.0 Hz, 1H), 1.84 (d, J = 13.0 Hz, 1H), 1.44 (s, 3H), 1.43 (s, 3H), 1.33 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 179.0, 160.8, 150.3, 134.8, 130.0, 129.5, 128.2 (2C), 128.0 (2C), 106.1, 102.4, 98.9, 72.3, 55.1, 54.5, 51.9, 50.6, 29.3, 28.5, 27.1 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H26N2O 323.2118; found 323.2112. 3,5-Dimethoxy-N-((2,4,4-trimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)aniline (3o). This compound was isolated by preparative TLC on silica gel (Petroleum ether:EtOAc = 10:1) as a colorless oil (55 mg, 77%). 1H NMR (400 MHz, Chloroform-d) δ = 7.74−7.62 (m, 2H), 7.45−7.33 (m, 3H), 5.87 (t, J = 2.1 Hz, 1H), 6551

DOI: 10.1021/acs.joc.9b00936 J. Org. Chem. 2019, 84, 6547−6556

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3.48−3.28 (m, 2H), 2.16 (d, J = 13.2 Hz, 1H), 1.85 (d, J = 13.1 Hz, 1H), 1.47 (s, 3H), 1.45 (s, 3H), 1.30 (s, 3H) ppm.13C {1H} NMR (101 MHz, Chloroform-d) δ = 179.4, 168.9, 151.4, 135.1, 134.5, 131.6, 129.2, 128.1 (2C), 128.0 (2C), 114.3, 111.5, 109.9, 72.5, 53.2, 52.1, 51.4, 49.6, 29.3, 28.1, 27.3 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H26N2O2 351.2067; found 351.2068. 4-(Methylsulfonyl)-N-((2,4,4-trimethyl-5-phenyl-3,4-dihydro-2Hpyrrol-2-yl)methyl)aniline (3aa). This compound was isolated by preparative TLC on silica gel (Petroleum ether:EtOAc = 1:2) as a colorless oil (63 mg, 85%). 1H NMR (400 MHz, Chloroform-d) δ = 7.81−7.60 (m, 4H), 7.50−7.33 (m, 3H), 6.78−6.55 (m, 2H), 4.77 (t, J = 5.7 Hz, 1H), 3.43 (dd, J = 12.2, 6.1 Hz, 1H), 3.18 (dd, J = 12.2, 5.4 Hz, 1H), 2.99 (s, 3H), 1.99 (d, J = 13.2 Hz, 1H), 1.89 (d, J = 13.1 Hz, 1H), 1.45 (s, 3H), 1.44 (s, 3H), 1.34 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 179.3, 152.8, 134.5, 129.7, 129.3 (2C), 128.3 (2C), 128.0 (2C), 126.9, 111.9 (2C), 72.1, 53.7, 51.9, 50.6, 45.0, 29.1, 28.6, 26.9 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H26N2O2S 371.1788; found 371.1786. 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-N-((2,4,4-trimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)aniline (3ab). This compound was isolated by flash chromatography on silica gel (Petroleum ether:EtOAc = 10:1) as a colorless oil (67 mg, 80%). 1H NMR (400 MHz, Chloroform-d) δ = 7.71−7.65 (m, 2H), 7.65−7.58 (m, 2H), 7.46−7.31 (m, 3H), 6.68−6.49 (m, 2H), 4.20 (t, J = 5.9 Hz, 1H), 3.38 (dd, J = 12.1, 5.6 Hz, 1H), 3.19 (dd, J = 12.0, 6.2 Hz, 1H), 2.04 (d, J = 13.0 Hz, 1H), 1.83 (d, J = 13.0 Hz, 1H), 1.44 (s, 3H), 1.42 (s, 3H), 1.32 (s, 15H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 179.1, 151.3, 136.3 (2C), 134.7, 129.4 (2C), 128.2 (2C), 128.0 (2C), 111.9 (2C), 83.1 (2C), 72.3, 53.8, 51.9, 50.4, 29.2, 28.4, 27.0, 24.8 (4C) ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C26H35BN2O2 419.2864; found 419.2873. (3-(((2,4,4-Trimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)amino)phenyl)methanol (3ac). This compound was isolated by preparative TLC on silica gel (Petroleum ether:EtOAc = 1:1) as a colorless oil (34 mg, 52%). 1H NMR (400 MHz, Chloroform-d) δ = 7.67−7.59 (m, 2H), 7.44−7.33 (m, 3H), 7.13 (t, J = 7.7 Hz, 1H), 6.68−6.60 (m, 2H), 6.56 (ddd, J = 8.1, 2.5, 1.0 Hz, 1H), 4.56 (s, 2H), 3.57−3.37 (brs, 1H), 3.35 (d, J = 11.9 Hz, 1H), 3.14 (d, J = 11.9 Hz, 1H), 2.07 (d, J = 13.0 Hz, 1H), 1.83 (d, J = 13.0 Hz, 1H), 1.43 (s, 6H), 1.32 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 179.4, 149.1, 142.2, 134.6, 129.5, 129.3, 128.2 (2C), 128.0 (2C), 115.6, 112.3, 111.2, 72.4, 65.4, 54.3, 51.8, 50.3, 29.2, 28.4, 27.0 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H26N2O 323.2118; found 323.2112. N-((2,4,4-Trimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)naphthalen-2-amine (3ad). This compound was isolated by preparative TLC on silica gel (Petroleum ether:EtOAc = 10:1) as a colorless oil (35 mg, 50%). 1H NMR (400 MHz, Chloroform-d) δ = 7.72−7.67 (m, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.7 Hz, 2H), 7.43−7.30 (m, 4H), 7.17 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 6.91 (dd, J = 8.8, 2.4 Hz, 1H), 6.85 (d, J = 2.3 Hz, 1H), 4.30−4.10 (brs, 1H), 3.45 (d, J = 11.8 Hz, 1H), 3.26 (d, J = 11.8 Hz, 1H), 2.12 (d, J = 13.1 Hz, 1H), 1.88 (d, J = 13.0 Hz, 1H), 1.48 (s, 3H), 1.45 (s, 3H), 1.35 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ =179.2, 146.5, 135.2, 134.8, 129.5, 128.8, 128.2 (2C), 128.0 (2C), 127.6, 127.4, 126.2, 125.8, 121.8, 118.3, 104.3, 72.3, 54.5, 51.9, 50.6, 29.2, 28.5, 27.2 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C24H26N2 343.2169; found 343.2163. Ethyl-6-(((2,4,4-trimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)amino)benzofuran-2-carboxylate (3ae). This compound was isolated by preparative TLC on silica gel (Petroleum ether:EtOAc = 5:1) as a colorless oil (51 mg, 61%). 1H NMR (400 MHz, Chloroform-d) δ = 7.75−7.59 (m, 2H), 7.45−7.30 (m, 5H), 6.89− 6.72 (m, 2H), 4.42 (q, J = 7.1 Hz, 2H), 4.14−3.94 (brs, 1H), 3.36 (d, J = 11.4 Hz, 1H), 3.14 (d, J = 11.5 Hz, 1H), 2.11 (d, J = 13.1 Hz, 1H), 1.88 (d, J = 13.0 Hz, 1H), 1.47 (s, 3H), 1.46 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H), 1.35 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroformd) δ = 179.1, 159.7, 149.8, 145.8, 145.6, 134.7, 129.5, 128.2 (2C), 128.0 (2C), 127.8, 117.1, 113.7, 112.7, 102.5, 72.2, 61.3, 55.4, 51.8,

119.9, 115.3, 111.8, 72.2, 54.3, 51.9, 50.6, 29.2, 28.5, 27.1 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H23BrN2 371.1117; found 371.1113. 4-Bromo-N-((2,4,4-trimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2yl)methyl)aniline (3u). This compound was isolated by preparative TLC on silica gel (Petroleum ether:EtOAc = 10:1) as a colorless oil (66 mg, 88%). 1H NMR (400 MHz, Chloroform-d) δ = 7.69−7.59 (m, 2H), 7.44−7.34 (m, 3H), 7.27−7.18 (m, 2H), 6.56−6.47 (m, 2H), 4.04 (t, J = 6.0 Hz, 1H), 3.31 (dd, J = 11.8, 5.5 Hz, 1H), 3.08 (dd, J = 11.7, 5.6 Hz, 1H), 2.03 (d, J = 13.1 Hz, 1H), 1.86 (d, J = 13.1 Hz, 1H), 1.44 (s, 3H), 1.42 (s, 3H), 1.33 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 179.1, 147.9, 134.7, 131.2 (2C), 129.5, 128.3 (2C), 128.0 (2C), 114.5 (2C), 108.6, 72.3, 54.5, 51.9, 50.6, 29.2, 28.5, 27.1 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H23BrN2 371.1117; found 371.1115. 4-Iodo-N-((2,4,4-trimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)aniline (3v). This compound was isolated by flash chromatography on silica gel (Petroleum ether:EtOAc = 10:1) as a colorless oil (72 mg, 86%). 1H NMR (400 MHz, Chloroform-d) δ = 7.71−7.57 (m, 2H), 7.47−7.29 (m, 5H), 6.49−6.34 (m, 2H), 4.06 (t, J = 6.0 Hz, 1H), 3.31 (dd, J = 11.8, 5.9 Hz, 1H), 3.08 (dd, J = 11.8, 6.0 Hz, 1H), 2.02 (d, J = 13.0 Hz, 1H), 1.84 (d, J = 13.0 Hz, 1H), 1.44 (s, 3H), 1.42 (s, 3H), 1.32 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 179.1, 148.4, 137.7 (2C), 134.7, 129.5, 128.2 (2C), 128.0 (2C), 115.1 (2C), 77.5, 72.2, 54.3, 51.8, 50.5, 29.2, 28.5, 27.0 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H23IN2 419.0979; found 419.0972. 4-(Trifluoromethyl)-N-((2,4,4-trimethyl-5-phenyl-3,4-dihydro2H-pyrrol-2-yl)methyl)aniline (3w). This compound was isolated by preparative TLC on silica gel (Petroleum ether:EtOAc = 10:1) as a colorless oil (66 mg, 92%). 1H NMR (400 MHz, Chloroform-d) δ = 7.70−7.57 (m, 2H), 7.46−7.28 (m, 5H), 6.64 (d, J = 8.5 Hz, 2H), 4.39 (t, J = 5.7 Hz, 1H), 3.39 (dd, J = 12.0, 5.9 Hz, 1H), 3.16 (dd, J = 12.0, 5.7 Hz, 1H), 2.02 (d, J = 13.1 Hz, 1H), 1.88 (d, J = 13.1 Hz, 1H), 1.45 (s, 3H), 1.43 (s, 3H), 1.33 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 179.2, 151.2, 134.6, 129.6, 128.3 (2C), 128.0 (2C), 126.6 (q, J = 4.0 Hz, 2C), 125.0 (q, J = 268.6 Hz), 118.5 (q, J = 32.0 Hz), 112.0 (2C), 72.2, 54.0, 51.9, 50.6, 29.2, 28.5, 27.0 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H23F3N2 361.1886; found 361.1888. 4-(((2,4,4-Trimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)amino)benzonitrile (3x). This compound was isolated by preparative TLC on silica gel (Petroleum ether:EtOAc = 5:1) as a colorless oil (55 mg, 85%). 1H NMR (400 MHz, Chloroform-d) δ = 7.69−7.59 (m, 2H), 7.42−7.39 (m, 5H), 6.63−6.57 (m, 2H), 4.67 (t, J = 5.8 Hz, 1H), 3.39 (dd, J = 12.1, 6.1 Hz, 1H), 3.15 (dd, J = 12.2, 5.4 Hz, 1H), 1.98 (d, J = 13.1 Hz, 1H), 1.89 (d, J = 13.1 Hz, 1H), 1.45 (s, 3H), 1.43 (s, 3H), 1.33 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 179.3, 151.8, 134.4, 133.7 (2C), 129.6, 128.3 (2C), 127.9 (2C), 120.6, 112.3 (2C), 98.4, 72.1, 53.6, 51.9, 50.6, 29.1, 28.5, 26.9 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H23N3 318.1965; found 318.1958. 4-Nitro-N-((2,4,4-trimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)aniline (3y). This compound was isolated by flash chromatography on silica gel (Petroleum ether:EtOAc = 3:1) as a colorless oil (56 mg, 82%). 1H NMR (400 MHz, Chloroform-d) δ = 8.17−7.97 (m, 2H), 7.73−7.59 (m, 2H), 7.49−7.34 (m, 3H), 6.67− 6.51 (m, 2H), 5.02 (t, J = 5.7 Hz, 1H), 3.46 (dd, J = 12.3, 6.2 Hz, 1H), 3.21 (dd, J = 12.3, 5.2 Hz, 1H), 1.98 (d, J = 13.2 Hz, 1H), 1.92 (d, J = 13.2 Hz, 1H), 1.46 (s, 3H), 1.44 (s, 3H), 1.34 (s, 3H) ppm. 13 C {1H} NMR (101 MHz, Chloroform-d) δ = 179.5, 153.8, 137.8, 134.3, 129.8, 128.3 (2C), 127.9 (2C), 126.4 (2C), 111.2 (2C), 71.9, 53.8, 51.9, 50.7, 29.1, 28.6, 26.9 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H23N3O2 338.1863; found 338.1855. Methyl-2-(((2,4,4-trimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2yl)methyl)amino)benzoate (3z). This compound was isolated by preparative TLC on silica gel (Petroleum ether:EtOAc = 10:1) as a colorless oil (53 mg, 75%). 1H NMR (400 MHz, Chloroform-d) δ = 7.90−7.85 (m, 2H), 7.73−7.57 (m, 2H), 7.42−7.27 (m, 4H), 6.82− 6.72 (m, 1H), 6.56 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 3.81 (s, 3H), 6552

DOI: 10.1021/acs.joc.9b00936 J. Org. Chem. 2019, 84, 6547−6556

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50.6, 29.2, 28.6, 27.2, 14.4 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C25H28N2O3 405.2173; found 405.2172. N-((2,4,4-Trimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)pyridin-2-amine (3af). This compound was isolated by preparative TLC on silica gel (Petroleum ether:EtOAc = 3:1) as a colorless oil (35 mg, 60%). 1H NMR (400 MHz, Chloroform-d) δ = 8.10−8.04 (m, 1H), 7.71−7.63 (m, 2H), 7.45−7.31 (m, 4H), 6.62− 6.48 (m, 1H), 6.46−6.40 (m, 1H), 4.78 (t, J = 6.0 Hz, 1H), 3.60 (dd, J = 12.7, 5.7 Hz, 1H), 3.44 (dd, J = 12.7, 6.3 Hz, 1H), 2.06 (d, J = 13.1 Hz, 1H), 1.84 (d, J = 13.1 Hz, 1H), 1.43 (s, 3H), 1.42 (s, 3H), 1.31 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 179.0, 159.1, 147.9, 137.2, 134.8, 129.4, 128.2 (2C), 128.0 (2C), 112.6, 107.7, 72.5, 52.0, 51.9, 50.2, 29.3, 28.4, 27.0 ppm. HRMS (ESITOF) m/z: [M + H]+ Calcd for C19H23N3 294.1965; found 294.1959. N-((2,4,4-trimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)pyridin-3-amine (3ag). This compound was isolated by preparative TLC on silica gel (Petroleum ether:EtOAc = 1:2) as a colorless oil (34 mg, 58%). 1H NMR (400 MHz, Chloroform-d) δ = 8.09−8.03 (m, 1H), 7.94 (dd, J = 4.6, 1.4 Hz, 1H), 7.71−7.63 (m, 2H), 7.45− 7.34 (m, 3H), 7.11−7.02 (m, 1H), 6.92 (ddd, J = 8.3, 2.9, 1.4 Hz, 1H), 4.10 (t, J = 6.1 Hz, 1H), 3.36 (dd, J = 11.8, 6.0 Hz, 1H), 3.13 (dd, J = 11.8, 5.9 Hz, 1H), 2.05 (d, J = 13.1 Hz, 1H), 1.88 (d, J = 13.0 Hz, 1H), 1.45 (s, 3H), 1.44 (s, 3H), 1.35 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 179.2, 144.8, 138.6, 136.2, 134.6, 129.6, 128.3 (2C), 128.0 (2C), 123.7, 118.7, 72.2, 54.1, 51.9, 50.6, 29.2, 28.6, 27.1 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H23N3 294.1965; found 294.1964. 2-Chloro-N-((2,4,4-trimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2yl)methyl)pyridin-4-amine (3ah). This compound was isolated by flash chromatography on basic aluminum oxide (pH = 9.0−10.0) (Petroleum ether:EtOAc = 1:1) as a colorless oil (46 mg, 70%). 1H NMR (400 MHz, Chloroform-d) δ = 7.92 (d, J = 5.8 Hz, 1H), 7.73− 7.58 (m, 2H), 7.48−7.32 (m, 3H), 6.50 (d, J = 2.2 Hz, 1H), 6.39 (dd, J = 5.8, 2.2 Hz, 1H), 4.80 (t, J = 5.9 Hz, 1H), 3.38 (dd, J = 12.3, 6.1 Hz, 1H), 3.13 (dd, J = 12.3, 5.2 Hz, 1H), 1.95 (d, J = 13.2 Hz, 1H), 1.89 (d, J = 13.1 Hz, 1H), 1.46 (s, 3H), 1.41 (s, 3H), 1.34 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 179.4, 155.8, 152.3, 149.2, 134.3, 129.7, 128.3 (2C), 127.9 (2C), 107.4, 106.0, 71.9, 53.1, 51.9, 50.6, 29.1, 28.6, 26.8 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H22ClN3 328.1575; found 328.1571. N-((2,4,4-Trimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)isoquinolin-5-amine (3ai). This compound was isolated by preparative TLC on silica gel (Petroleum ether:EtOAc = 1:1) as a colorless oil (37 mg, 53%). 1H NMR (400 MHz, Chloroform-d) δ = 8.86 (dd, J = 4.2, 1.6 Hz, 1H), 8.17 (ddd, J = 8.5, 1.7, 0.9 Hz, 1H), 7.80−7.65 (m, 2H), 7.57 (dd, J = 8.4, 7.6 Hz, 1H), 7.48 (dt, J = 8.5, 1.0 Hz, 1H), 7.44−7.36 (m, 3H), 7.30 (dd, J = 8.5, 4.2 Hz, 1H), 6.68 (dd, J = 7.6, 1.0 Hz, 1H), 4.83 (t, J = 3.7 Hz, 1H), 3.49 (dd, J = 11.3, 3.7 Hz, 1H), 3.26 (dd, J = 11.4, 3.7 Hz, 1H), 2.16 (d, J = 13.1 Hz, 1H), 1.94 (d, J = 13.0 Hz, 1H), 1.54 (s, 3H), 1.50 (s, 3H), 1.37 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 179.3, 149.9, 149.2, 144.3, 134.6, 130.4, 129.6, 128.8, 128.3 (2C), 128.0 (2C), 119.3, 118.8, 118.4, 104.8, 71.9, 54.7, 51.9, 51.0, 29.2, 28.7, 27.3 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C23H25N3 344.2121; found 344.2119. 4-((2,4,4-Trimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)3,4-dihydro-2H-benzo[b][1,4]oxazine (3aj). This compound was isolated by flash chromatography on basic aluminum oxide (pH = 9.0−10.0) (Petroleum ether:EtOAc = 20:1) as a colorless oil (29 mg, 42%). 1H NMR (400 MHz, Chloroform-d) δ = 7.71−7.58 (m, 2H), 7.43−7.31 (m, 3H), 6.88−6.73 (m, 3H), 6.60 (ddd, J = 7.9, 6.4, 2.3 Hz, 1H), 4.24−4.08 (m, 2H), 3.58−3.42 (m, 3H), 3.36 (d, J = 15.0 Hz, 1H), 2.16 (d, J = 12.9 Hz, 1H), 1.79 (d, J = 12.9 Hz, 1H), 1.46 (s, 3H), 1.39 (s, 3H), 1.26 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 177.5, 143.9, 136.7, 134.8, 129.3, 128.2 (2C), 127.9 (2C), 121.3, 117.4, 116.4, 113.0, 74.6, 64.2, 61.9, 51.8, 49.5, 49.3, 29.3, 28.4, 27.1 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H26N2O 335.2118; found 335.2114. 3-Methoxy-N-methyl-N-((2,4,4-trimethyl-5-phenyl-3,4-dihydro2H-pyrrol-2-yl)methyl)-aniline (3ak). This compound was isolated by

preparative TLC on silica gel (Petroleum ether:EtOAc = 8:1) as a colorless oil (29 mg, 43%). 1H NMR (400 MHz, Chloroform-d) δ = 7.73−7.53 (m, 2H), 7.45−7.29 (m, 3H), 7.12 (t, J = 8.2 Hz, 1H), 6.39 (ddd, J = 8.4, 2.5, 0.8 Hz, 1H), 6.31 (t, J = 2.4 Hz, 1H), 6.26 (ddd, J = 8.1, 2.3, 0.7 Hz, 1H), 3.78 (s, 3H), 3.57 (d, J = 15.2 Hz, 1H), 3.47 (d, J = 15.2 Hz, 1H), 2.98 (s, 3H), 2.12 (d, J = 13.0 Hz, 1H), 1.73 (d, J = 13.0 Hz, 1H), 1.44 (s, 3H), 1.37 (s, 3H), 1.18 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 177.1, 160.6, 152.2, 135.0, 129.5, 129.2, 128.1 (2C), 127.9 (2C), 105.3, 100.6, 98.7, 74.8, 62.4, 55.1, 51.9, 49.0, 40.0, 29.2, 28.2, 27.4 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H28N2O 337.2274; found 337.2272. (E)-2-(But-1-en-1-yl)-4,4-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrole (3am). This compound was isolated by flash chromatography on silica gel (Petroleum ether:EtOAc = 20:1) as a colorless oil (71 mg, 78%). 1H NMR (400 MHz, Chloroform-d) δ = 7.80−7.65 (m, 2H), 7.43−7.31 (m, 3H), 5.80−5.73 (m, 1H), 5.61−5.55(m, 1H), 4.54− 4.45 (m, 1H), 2.17−2.00 (m, 3H), 1.71 (dd, J = 12.5, 8.5 Hz, 1H), 1.37 (s, 3H), 1.36 (s, 3H), 1.02 (t, J = 7.4 Hz, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 179.6, 134.8, 133.1, 131.1, 129.3, 128.0 (2C), 127.9 (2C), 69.6, 50.4, 48.6, 27.2, 25.7, 25.4, 13.5 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H21N 228.1747; found 228.1741. 4,4-Dimethyl-5-phenyl-2-(prop-1-en-2-yl)-3,4-dihydro-2H-pyrrole (3an). This compound was isolated by flash chromatography on silica gel (Petroleum ether:EtOAc = 20:1) as a colorless oil (80 mg, 94%). 1H NMR (400 MHz, Chloroform-d) δ = 7.84−7.59 (m, 2H), 7.44−7.29 (m, 3H), 5.03 (s, 1H), 4.86 (s, 1H), 4.56−4.42 (m, 1H), 2.13 (dd, J = 12.4, 7.2 Hz, 1H), 1.81 (s, 3H), 1.74 (dd, J = 12.4, 9.1 Hz, 1H), 1.39 (s, 3H), 1.35 (s, 3H). 13C {1H} NMR (101 MHz, Chloroform-d) δ = 179.6, 147.0, 134.8, 129.4, 128.2 (2C), 127.9 (2C), 110.0, 72.3, 50.4, 47.3, 27.1, 25.9, 19.9. HRMS (ESI-TOF) m/ z: [M + H]+ Calcd for C15H19N 215.1590; found 214.1585. Experimental Procedure for the 5 mmol-Scale Reaction for Synthesis of 3a. A mixture of Cu(MeCN)4PF6 (373 mg, 1.0 mmol, 20 mol %), dry triethylamine (2.1 mL, 15 mmol, 3.0 equiv), γ,δunsaturated oxime ester 1a-1 (10 mmol, 2.60 g, 2.0 equiv), and aniline (2a) (480 μl, 5 mmol, 1.0 equiv) in dry DME (50.0 mL, 0.1 M) was stirred in a sealed 100 mL round-bottomed flask at 80 °C with oil bath for 16 h under nitrogen atmosphere, before the solvent was removed under vacuum. The residue was purified through column chromatography (Petroleum ether:EtOAc = 10:1) to afford the pyrroline 3a as a colorless oil (1.24 g, 85%). Preparation of the γ,δ-Unsaturated Oxime Esters. γ,δUnsaturated oxime esters 1a-1, 1a-2, 1a-3, 1a-4, 1b, 1c-2, 1d−f, 1g-2, 1k, 1l, and 1m were synthesized according to our previous work,12k,16 while 1n and 1p were synthesized according to the reported method.12d,16 The NMR spectroscopy data of all the known compounds are consistent with those reported. Procedure for the Synthesis of γ,δ-Unsaturated Oxime Esters 1h-j and 1o.17 Step 1: A mixture of isobutyrophenone (1.48 g, 10 mmol, 1.0 equiv) and potassium tert-butoxide (1.68 g, 15 mmol, 1.5 equiv) in tert-butyl alcohol (30 mL, 3 mL/mmol) was heated under reflux with oil bath for 10 min, before allyl bromides18 (12 mmol, 1.2 equiv) were added dropwise into the solution. After the reaction was complete according to the TLC analysis, the mixture was cooled to room temperature, treated with water (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined extracts were washed with brine, dried over MgSO4, filtered, and removed under reduced pressure. The crude products were used in the next step without further purifications. Step 2: To a solution of γ,δ-unsaturated ketones (crude, 10 mmol, 1.0 equiv) in MeOH (30 mL, 3 mL/mmol) was added NaOAc (1.64 g, 20 mmol, 2.0 equiv) and hydroxylamine hydrochloride (1.39 g, 20 mmol, 2.0 equiv). The mixture was then stirred under reflux with oil bath. After the reaction was complete according to the TLC analysis, the mixture was cooled to ambient temperature and concentrated in vacuo. The residual was treated with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined extracts were washed with brine, dried over MgSO4, filtered, and removed under reduced pressure. The crude products 6553

DOI: 10.1021/acs.joc.9b00936 J. Org. Chem. 2019, 84, 6547−6556

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dried over MgSO4, filtered, and removed under reduced pressure. The crude product was purified through flash chromatography on silica gel to give the corresponding γ,δ-unsaturated O-acetyl oximes. 1-(3-Chlorophenyl)-2,2,4-trimethylpent-4-en-1-one O-acetyl oxime (1c-1). This compound was isolated by flash chromatography on silica gel (Petroleum ether:EtOAc = 50:1) as a colorless oil (689 mg, 47% over 2 steps). 1H NMR (400 MHz, Chloroform-d) δ = 7.39−7.30 (m, 2H), 7.11−7.06 (m, 1H), 7.00−6.95 (m, 1H), 4.95 (s, 1H), 4.82 (s, 1H), 2.30 (s, 2H), 1.94 (s, 3H), 1.80 (s, 3H), 1.25 (s, 6H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 172.4, 168.6, 141.9, 134.7, 134.0, 129.3, 128.4, 126.6, 125.0, 115.1, 46.8, 41.3, 26.3 (2C), 25.3, 19.6 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H21ClNO2 294.1255; found 294.1262. (1-(2-Methylallyl)cyclopentyl)(phenyl)methanone O-acetyl oxime (1g-1). This compound was isolated by flash chromatography on silica gel (Petroleum ether:EtOAc = 50:1) as a colorless oil (727 mg, 51% over 2 steps). 1H NMR (400 MHz, Chloroform-d) δ = 7.43−7.31(m, 3H), 7.19−7.06 (m, 2H), 4.95 (s, 1H), 4.93 (s, 1H), 2.27 (s, 2H), 2.25−2.16 (m, 2H), 1.92 (s, 3H), 1.83−1.57 (m, 9H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 172.5, 169.0, 142.8, 133.4, 128.2, 127.8 (2C), 126.5 (2C), 113.6, 52.9, 44.4, 36.3 (2C), 24.7, 23.6 (2C), 19.7 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C28H24NO2 286.1802; found 286.1810. Procedure for the Control Experiment with TEMPO. A mixture of Cu(MeCN)4PF6 (14.9 mg, 0.04 mmol, 20 mol %), dry triethylamine (83 uL, 0.6 mmol, 3.0 equiv), TEMPO (62.5 mg, 0.4 mmol, 2 equiv), γ,δ-unsaturated oxime esters 1a-1 (103.7 mg, 0.4 mmol, 2.0 equiv), and aniline 2a (18 uL, 0.2 mmol, 1.0 equiv) in dry DME (2.0 mL) was stirred in a sealed tube at 80 °C with the heating block for 16 h under nitrogen atmosphere, before the solvent was removed under vacuum. The residue was purified by preparative TLC on silica gel (Petroleum ether:EtOAc = 10:1) to give the corresponding product 4. 2,2,6,6-Tetramethyl-1-((2,4,4-trimethyl-5-phenyl-3,4-dihydro2H-pyrrol-2-yl)methoxy) piperidine (4). This compound was isolated as a colorless oil (93 mg, 65%). 1H NMR (400 MHz, Chloroform-d) δ = 7.73−7.60 (m, 2H), 7.37−7.34 (m, 3H), 3.91 (d, J = 8.4 Hz, 1H), 3.80 (d, J = 8.4 Hz, 1H), 2.36 (d, J = 12.9 Hz, 1H), 1.69 (d, J = 12.9 Hz, 1H), 1.60−1.38 (m, 5H), 1.44 (s, 3H), 1.35 (s, 3H), 1.34− 1.28(m, 1H), 1.33 (s, 3H), 1.25 (s, 3H), 1.21 (s, 3H), 1.14 (s, 3H), 1.09 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 177.8, 135.4, 128.9, 128.1 (2C), 128.0 (2C), 82.7, 72.5, 60.0 (2C), 51.9, 48.9, 39.7 (2C), 33.3, 33.1, 29.6, 27.9, 26.7, 20.6, 20.3, 17.0 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C23H36N2 357.2900; found 357.2896. Procedure for the Radical Clock Reaction. A mixture of Cu(MeCN)4PF6 (14.9 mg, 0.04 mmol, 20 mol %), dry triethylamine (83uL, 0.6 mmol, 3.0 equiv), γ,δ-unsaturated oxime ester 1l (139.0 mg, 0.4 mmol, 2.0 equiv) and aniline 2a (18 μL, 0.2 mmol, 1.0 equiv) in dry DME (2.0 mL) was stirred in a sealed tube at 80 °C with the heating block for 16 h under nitrogen atmosphere, before the solvent was removed under vacuum. The residue was purified by preparative TLC on silica gel (Petroleum ether:EtOAc = 10:1) to give the corresponding products 5 and 6. 2-(Buta-1,3-dien-1-yl)-4,4-dimethyl-5-phenyl-3,4-dihydro-2Hpyrrole (5). This compound was isolated as a E/Z mixture (colorless oil, 32 mg, 36%). Major isomer: 1H NMR (400 MHz, Chloroform-d) δ = 7.75−7.72 (m, 2H), 7.45−7.33 (m, 3H), 6.45−6.25 (m, 2H), 5.95−5.84 (m, 1H), 5.22−5.17 (m, 1H), 5.10−5.03 (m, 1H), 4.67− 4.55 (m, 1H), 2.19−2.14 (m, 1H), 1.77−1.72 (m, 1H), 1.37 (s, 6H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 180.0, 136.8, 136.3, 130.9, 129.5, 128.1 (3C), 127.9 (2C), 116.5, 69.0, 50.5, 48.4, 27.1, 25.7 ppm. Minor isomer: 1H NMR (400 MHz, Chloroform-d) δ = 7.75−7.72 (m, 2H), 7.45−7.33 (m, 3H), 6.84−6.74 (m, 1H), 6.19− 6.07 (m, 1H), 5.55−5.49 (m, 1H), 5.30−5.24 (m, 1H), 5.19−5.16 (m, 1H), 5.02−4.95 (m, 1H), 2.23−2.18 (m, 1H), 1.72−1.67 (m, 1H), 1.39 (s, 3H), 1.37 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 180.3, 134.6, 134.3, 132.3, 129.9, 128.1 (3C), 127.9 (2C), 118.3, 65.1, 50.6, 49.3, 27.1, 25.7 ppm. HRMS (ESITOF) m/z: [M + H]+ Calcd for C16H19N 226.1590; found 226.1592.

were used in the next step without further purifications. Step 3: To a mixture of ketoximes (crude, 10 mmol, 1.0 equiv) and NEt3 (2.8 mL, 20 mmol, 2.0 equiv) in DCM (30 mL, 3 mL/mmol) at room temperature was added dropwise benzoyl chloride or acetyl chloride (12 mmol, 1.2 equiv). After stirring overnight, the mixture was concentrated in vacuo. The residual was treated with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined extracts were washed with brine, dried over MgSO4, filtered, and removed under reduced pressure. The crude products were purified through flash chromatography on silica gel to give the corresponding γ,δunsaturated oxime esters. 2,2-Dimethyl-4-methylene-1-phenylhexan-1-one O-acetyl oxime (1h). This compound was isolated by flash chromatography on silica gel (Petroleum ether:EtOAc = 50:1) as a colorless oil (819 mg, 30% over 3 steps). 1H NMR (400 MHz, Chloroform-d) δ = 7.43−7.32 (m, 3H), 7.13−7.00 (m, 2H), 4.96 (s, 1H), 4.89 (s, 1H), 2.31 (s, 2H), 2.05 (q, J = 7.5 Hz, 2H), 1.90 (s, 3H), 1.25 (s, 6H), 1.02 (t, J = 7.4 Hz, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 174.4, 168.8, 147.6, 133.1, 128.2, 127.8 (2C), 126.6 (2C), 112.4, 45.3, 41.4, 31.0, 26.3 (2C), 19.6, 12.6 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H24NO2 274.1802; found 274.1807. 2,2,5-Trimethyl-4-methylene-1-phenylhexan-1-one O-acetyl oxime (1i). This compound was isolated by flash chromatography on silica gel (Petroleum ether:EtOAc = 50:1) as a colorless oil (1.00 g, 35% over 3 steps). 1H NMR (400 MHz, Chloroform-d) δ = 7.41− 7.31 (m, 3H), 7.13−7.02 (m, 2H), 5.00 (s, 1H), 4.92 (s, 1H), 2.27 (s, 2H), 2.21−2.09 (m, 1H), 1.91 (s, 3H), 1.26 (s, 6H), 1.01 (d, J = 6.82 Hz, 6H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 174.6, 168.8, 152.2, 133.0, 128.2, 127.8 (2C), 126.6 (2C), 110.4, 43.8, 41.4, 35.3, 26.3 (2C), 22.0 (2C), 19.6 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C28H26NO2 288.1958; found 288.1964. 4-Benzyl-2,2-dimethyl-1-phenylpent-4-en-1-one O-acetyl oxime (1j). This compound was isolated by flash chromatography on silica gel (Petroleum ether:EtOAc = 50:1) as a colorless oil (670 mg, 20% over 3 steps). 1H NMR (400 MHz, Chloroform-d) δ = 7.36−7.31 (m, 3H), 7.30−7.25 (m, 2H), 7.23−7.19 (m, 1H), 7.17−7.13 (m, 2H), 7.04−6.97 (m, 2H), 5.07 (s, 1H), 4.97 (s, 1H), 3.37 (s, 2H), 2.24 (s, 2H), 1.89 (s, 3H), 1.27 (s, 6H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 174.2, 168.8, 145.2, 139.4, 133.0, 129.1 (2C), 128.3 (2C), 128.2, 127.8 (2C), 126.6 (2C), 126.1, 115.9, 45.3, 44.2, 41.5, 26.5 (2C), 19.6 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H26NO2 336.1958; found 336.1965. (4E)-2,2-Dimethyl-1-phenyloct-4-en-1-one O-benzoyl oxime (1o). This compound was isolated by flash chromatography on silica gel (Petroleum ether:EtOAc = 50:1) as a colorless oil (1.40 g, 40% over 3 steps). 1H NMR (400 MHz, Chloroform-d) δ = 7.58−7.50 (m, 2H), 7.48−7.37 (m, 4H), 7.30−7.22 (m, 2H), 7.18−7.10 (m, 2H), 5.60−5.40 (m, 2H), 2.36−2.26 (m, 2H), 2.08−1.95 (m, 2H), 1.48− 1.33 (m, 2H), 1.27 (s, 6H), 0.89 (t, J = 7.4 Hz, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 174.8, 163.6, 134.4, 133.5, 132.8, 129.3 (2C), 129.1, 128.2 (2C), 128.1, 127.9 (2C), 126.7 (2C), 125.3, 43.0, 41.6, 34.8, 25.5 (2C), 22.6, 13.6 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C23H28NO2 350.2115; found 350.2120. Procedure for the Synthesis of γ,δ-Unsaturated O-Acetyl Oximes 1c-1 and 1g-1.17 Step 1: A mixture of potassium hydroxide (1.0 g, 25 mmol, 5.0 equiv), the corresponding γ,δ-unsaturated Obenzoyl oximes12k 1c-2 or 1g-2 (5 mmol, 1.0 equiv) in the solvent (H2O:MeOH:THF = 1:1:2, 20 mL) was stirred under reflux with oil bath for 1 h. After the reaction was complete, the mixture was cooled to ambient temperature, treated with water (20 mL), and extracted with ethyl acetate (30 mL × 3). The combined extracts were washed with brine, dried over MgSO4, filtered through a basic aluminum oxide pad, and removed under reduced pressure. The crude products were used in the next step without other purified. Step 2: To a mixture of ketoxime (crude, 5.0 mmol, 1.0 equiv) and NEt3 (1.4 mL, 10.0 mmol, 2.0 equiv) in DCM (15 mL, 3 mL/mmol) at room temperature was added dropwise acetyl chloride (6.0 mmol, 1.2 equiv). After stirring overnight, the mixture was concentrated in vacuo. The residual was extracted from water (20 mL) with ethyl acetate (30 mL × 3). The combined extracts were washed with brine, 6554

DOI: 10.1021/acs.joc.9b00936 J. Org. Chem. 2019, 84, 6547−6556

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N-(4-(4,4-Dimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)but-3en-1-yl)aniline (6). Two isomers of this compound were separated by preparative TLC on silica gel as colorless oils (combined yield: 34 mg, 53%). Major isomer: 1H NMR (400 MHz, Chloroform-d) δ = 7.77− 7.67 (m, 2H), 7.42−7.31 (m, 3H), 7.23−7.06 (m, 2H), 6.73−6.66 (m, 1H), 6.65−6.53 (m, 2H), 5.75−5.73 (m, 2H), 4.57−4.51 (m, 1H), 3.83−3.63 (brs, 1H), 3.20 (t, J = 6.7 Hz, 2H), 2.46−2.33 (m, 2H), 2.14 (dd, J = 12.5, 7.1 Hz, 1H), 1.71 (dd, J = 12.5, 8.5 Hz, 1H), 1.37 (s, 3H), 1.36 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 180.0, 148.2, 135.1, 134.7, 129.5, 129.2 (2C), 128.1 (2C), 127.9 (3C), 117.2, 112.9 (2C), 69.3, 50.5, 48.6, 43.1, 32.3, 27.2, 25.7 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H26N2 319.2169; found 319.2163. Minor isomer: 1H NMR (400 MHz, Chloroform-d) δ = 7.77−7.67 (m, 2H), 7.44−7.34 (m, 3H), 7.17−7.08 (m, 2H), 6.69−6.62 (m, 1H), 6.62−6.51 (m, 2H), 5.62− 5.59 (m, 2H), 4.84−4.79 (m, 1H), 4.37−4.17 (brs, 1H), 3.30−3.12 (m, 2H), 2.67−2.58 (m, 1H), 2.56−2.48(m, 1H), 2.14 (dd, J = 12.5, 7.1 Hz, 1H), 1.68 (dd, J = 12.5, 8.6 Hz, 1H), 1.37 (s, 3H), 1.34 (s, 3H) ppm. 13C {1H} NMR (101 MHz, Chloroform-d) δ = 180.1, 148.4, 134.9, 134.6, 129.5, 129.1 (2C), 128.6, 128.1 (2C), 128.0 (2C), 116.9, 112.7 (2C), 64.6, 50.8, 49.0, 43.1, 27.7, 27.2, 25.7 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H26N2 319.2169; found 319.2170.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.9b00936. Information on substrate preparation and NMR spectra for all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Chuan Wang: 0000-0002-9219-1785 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work is supported by “1000-Youth Talents Plan” start-up funding, National Science Foundation of China (Grant No. 21772183), the Fundamental Research Funds for the Central Universities (WK2060190086), as well as the University of Science and Technology of China.

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REFERENCES

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DOI: 10.1021/acs.joc.9b00936 J. Org. Chem. 2019, 84, 6547−6556

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DOI: 10.1021/acs.joc.9b00936 J. Org. Chem. 2019, 84, 6547−6556