Norbornene-Catalyzed Meta-C–H Alkylation of Nosyl-Protected

Oct 9, 2018 - A Pd/norbornene-catalyzed direct meta-alkylation of nosyl-protected phenylalanine derivatives with alkyl iodides is reported in moderate...
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Cite This: J. Org. Chem. 2018, 83, 13211−13216

Pd(II)/Norbornene-Catalyzed Meta-C−H Alkylation of NosylProtected Phenylalanines Jieyu Liu, Qiuping Ding,* Wenjun Fang, Wanhui Wu, Yuanguang Zhang, and Yiyuan Peng Key Laboratory of Small Functional Organic Molecule, Ministry of Education and Jiangxi’s Key Laboratory of Green Chemistry, Jiangxi Normal University, Nanchang, Jiangxi 330022, P.R. of China

J. Org. Chem. 2018.83:13211-13216. Downloaded from pubs.acs.org by UNIV STRASBOURG on 11/02/18. For personal use only.

S Supporting Information *

ABSTRACT: A Pd/norbornene-catalyzed direct meta-alkylation of nosyl-protected phenylalanine derivatives with alkyl iodides is reported in moderate to good yields. The use of diisopropyl bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate is identified as a more suitable transient mediator. A simple pyridine ligand is also essential for this reaction to proceed. No racemization was observed in this meta-methylation reaction.

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INTRODUCTION α-Amino acids are versatile chiral building blocks presented widely in peptides, proteins, and biologically active natural products.1 Recently, great attention has been paid to phenylalanine, which is one of the essential amino acids in the human body and widely used in pharmaceuticals, pesticides, health foods, fine chemical products, and peptides.2 Therefore, the development of more effective new methodologies for synthesis or selective modification of phenylalanines and their derivatives is highly desirable due to their extensive applications. During the past decade, Pd-catalyzed directed C−H functionalization of phenylalanine derivatives have made great progress. In 2008, Yu first reported a Pd-catalyzed ortho-iodination of triflate protected phenylalanines where the corresponding products could undergo the subsequent Cucatalyzed intramolecular amination to afford the indolines. Meanwhile, they also developed the Pd-catalyzed triflamidedirected ortho-alkenylation of phenylalanine derivatives to give the precursors of tetrahydroisoquinolines.3 In 2010, Yu also reported the Pd-catalyzed ortho-acetoxylation of triflate protected phenylalanines.4 Chen and Yu, respectively, demonstrated intramolecular C−H amination of picolinamide (PA)- and N-SO2Py-protected phenylalanines using PhI(OAc)2 as a bystander oxidant to afford indolines.5 In 2015, the Carretero group reported the Pd-catalyzed directed orthoalkenylation of N-methyl-N-(SO2Py)-protected phenylalanine ethyl ester derivatives.6 In 2014, Shi reported Pd-catalyzed ortho-borylation of picolinamide (PA)-protected phenylalanines.7 In 2015, Zhao and Zeng described the Pd-catalyzed ortho-alkynylation of arylalkylamines assisted by an oxalyl amide directing group. Phenylalanine derivatives are compatible and provide the corresponding alkynylated products in good yields under the standard conditions.8 In 2015, Shi and co-workers developed the Pd-catalyzed intramolecular amidation of phenylalanine derived dipeptides.9 In 2017, Yu reported © 2018 American Chemical Society

the Pd-catalyzed meta-selective C−H arylation of nosylprotected phenylalanine derivatives promoted by the combination of norbornene- and pyridine-based ligands.10 Recently, remarkable progress has been achieved in transition-metal-catalyzed meta-C(sp2)−H bond alkylation with directing groups. The advances of meta-C−H alkylation involves three primary aspects: (1) The Ackermann group developed Ru-catalyzed meta-alkylation of arenes with a directing group via σ-activation.11 (2) The Maiti group developed C−H alkylation of arenes bearing an organic linker pyrimidine-based template as directing group.12 (3) The Yu group developed Pd/norbornene-co-catalyzed meta-selective alkylation of arenes via tandem C−H activation and Catellani reactions.13,14 For instance, the Yu group recently reported a Pd(II)-catalyzed chiral norbornene-mediated enantioselective alkylation as well as arylation of homobenzylamines.14b These techniques were limited to certain substrates, so further approach for development of meta-C−H alkylation is still highly desirable. Based on previously reported meta-C−H arylation of nosyl-protected phenethylamines, benzylamines, and 2-arylanilines (Scheme 1a),10 we herein report a ligandenabled palladium(II)-catalyzed meta-C−H alkylation of nosylprotected phenethylamines using a modified norbornene as a transient mediator (Scheme 1b).

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RESULTS AND DISCUSSION Base on previously established C−H arylation reactions of nosyl-protected phenethylamines, our initial investigations began with nosyl-protected phenylalanine 1a and iodomethane 2a (Table 1). Under previous arylation reaction conditions [Pd(OAc)2 (10 mol %), AgOAc (3.0 equiv), pyridine (10 mol %), norbornene (NBE1, 10 mol %), TBME, 80 °C, 24 h], only trace amounts of meta-dialkylated product 3aa were observed. Received: July 28, 2018 Published: October 9, 2018 13211

DOI: 10.1021/acs.joc.8b01933 J. Org. Chem. 2018, 83, 13211−13216

Article

The Journal of Organic Chemistry Scheme 1. Pd-Catalyzed Meta-C−H Functionalization of Nosyl-Protected Phenethylamines

Table 2. Evaluation of Ligands for Meta-C−H Alkylation of Nosyl-Protected Phenylalanines

Table 1. Screening of Norbornene for Meta-C−H Alkylation of Nosyl-Protected Phenylalaninea,b

whereas no desired product was observed in the presence of Ag2O, Ag2CO3, AgTFA, and AgOTf. Subsequently, we explored the scope of phenylalanine derivatives using iodomethane 2a (3.5 equiv) as coupling partner under the optimal conditions [Pd(OAc)2 (10 mol %), pyridine (20 mol %), NBE5 (1.5 equiv), AgOAc (3.0 equiv), TBME, 80 °C, 24 h] (Scheme 2). Substrates bearing both electron-donating and withdrawing groups (such as Me, MeO, F, Cl, and Br) on the aryl ring all worked smoothly for this alkylation reaction, providing meta-monomethylated products (3ba−ia) in moderate to good yields with high regioselectivity. Generally, electron-donating substituents could improve the reactivity of this transformation. It is noteworthy that the methylation of substrates with a bromo substituent under the standard conditions affords the C−H functionalization products in moderate yields, keeping the C−Br bond intact. To further evaluate the synthetic utility of this strategy, then we next examined the scope of alkyl iodides to obtain structurally versatile meta-alkylated phenylalanines. Iodoethane 2b was evaluated affording the meta-ethylated products in lower yields (2bb and 2gb) due to the formation of side products, cyclobutane derivatives, which were isolated and characterized by their NMR spectra. To our delight, ethyl iodoacetate16 2c is tolerated under the standard conditions. The reactions of various phenylalanine derivatives were found to be well-tolerated in this protocol to provide monofunctionalization products 3bc−jc in moderate to excellent yields. Then we examined several other alkylation reagents, such as n PrI, CNCH2I, CF3CH2I, and some ArCH2I, only trace amounts of desired proudcts were observed under standard conditions. Attesting to the effectiveness and practicability of this reaction, L-phenylalanine-derived 1a was used as substrate under the standard reaction conditions, and the results showed that no racemization was observed in this meta-methylation reaction (3aa, >99% ee; see the SI for HPLC data). On the basis of previous Pd/norbornene-catalyzed C−H functionalization reports,10,13,14 we proposed a plausible mechanism for this meta-C(sp2)−H alkylation (Figure 1). Initially, Pd(II)-catalyzed ortho-C(sp2)−H activation of substrate 1 resulted in a six-membered palladacycle I which can subsequently react with norbornene to form intermediate II. Second, the insertion of norbornene and the meta-C−H

a Reaction conditions: phenylalanine 1a (0.1 mmol), MeI 2a (0.3 mmol, 3.0 equiv), Pd(OAc)2 (10 mol %), pyridine (20 mol %), norbornene (1.5 equiv), AgOAc (0.3 mmol, 3.0 equiv), TBME (1.0 mL), 80 °C, 24 h. bYield of product was determined by 1H NMR using dibromomethane as an internal standard.

Fortunately, meta-alkylated product was obtained in 54% yield (di/mono, 5/1) when the amount of NBE1 was increased to 1.5 equiv. Recently, Yu reported that the modified norbornene (NBE-CO2Me, NBE2) could effectively improve meta-C−H alkylation reactions.13b Therefore, we investigated the reaction using several formate-modified norbornenes (Table 1, NBE2− NBE5). The results indicated that diisopropyl bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate (NBE5)15 was identified to be the best one, affording the dialkylated product 3aa in 80% yield determined by 1H NMR, with 10% yield of meta-monoalkylated product, whereas NBE2−NBE4 gave the desired product in lower and only moderate yields, while no reaction was observed in the absence of norbornene. It is known that the presence of catalytic amounts of pyridine ligand is crucial, which dominates this transformation efficiently. Subsequently, we systematically screened the pyridine- and quinoline-type ligands using NBE5 as a transient mediator (Table 2). Interesting, pyridines bearing both electron-withdrawing and -donating substituents (L2−L6) provided the desired products in lower yields. The result of simple quinoline (L7) was inferior compared to that of the simple pyridine. No reaction was observed when 8methylquinoline (L8) and 1,10-phenanthroline (L9) were used as ligands. Control experiments showed that only trace amounts of products were observed in the absence of ligand. Taking account of the direct effect of solvent on this reaction, we evaluated some common solvents (see the Supporting Information, Table S1). Regretfully, poor selectivities and yields were obtained with other solvents such as DCE, toluene, THF, t‑BuOH, CH3CN, and 1,4-dioxane. Among the silver oxidants examined, AgOAc afforded the best results, 13212

DOI: 10.1021/acs.joc.8b01933 J. Org. Chem. 2018, 83, 13211−13216

Article

The Journal of Organic Chemistry Scheme 2. Meta-Alkylation of Substituted Phenylalaninesa,b

subsequently undergo reductive elimination and β-carbon elimination to afford NBE5 and intermediates VI. Finally, the latter transform to meta-alkylation product 3 and regenerate the palladium(II) catalyst. It is worth noting that intermediates III and IV can undergo reductive elimination to produce the side products, cyclobutane derivatives, which were isolated in some cases and characterized by NMR spectrum. In summary, we have developed a Pd(II)-catalyzed metaC(sp2)-H alkylation of N-nosyl-protected phenylalanine derivatives using diisopropyl bicyclo[2.2.1]hept-5-ene-2,3dicarboxylate (NBE5) as a transient mediator, and simple pyridine as ligand in the presence of AgOAc. This protocol features moderate substrate scope, functional group tolerance, and no racemization. The acquired insight from this study will guide further development of this emerging meta-C−H functionalization strategy. Investigation of the applications of this Pd(II)/NBE5 co-catalyzed meta-C(sp2)−H functionalization of other substrates are currently underway in our laboratory.

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EXPERIMENTAL SECTION

Nuclear magnetic resonance (NMR) spectra are recorded in parts per million from internal tetramethylsilane on the δ scale. 1H and 13C NMR spectra were recorded on a Bruker AV-400 spectrometer operating at 400 and 100 MHz, respectively. All chemical shift values are quoted in ppm and coupling constants quoted in hertz. Highresolution mass spectrometry (HRMS) spectra were obtained on a micrOTOF II instrument. Synthesis of N-Nosyl Amino Acid Methyl Esters 1b−i According to the Reported Procedures.10 4-Nitrobenzenesulfonyl chloride (NsCl, 1.0 mmol, 1.0 equiv) was added to a cooled (0 °C) solution of amino acid methyl ester hydrochloride (1.0 mmol, 1.0 equiv) and triethylamine (TEA, 3.0 mmol, 3.0 equiv) in DCM (5 mL). After being stirred at room temperature for 12 h, the reaction mixture was poured into H2O. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to column chromatography (EtOAc/ hexanes = 1:2) to give 1b−i. Methyl 2-(4-nitrophenylsulfonamido)-3-(m-tolyl)propanoate (1b): 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.8 Hz, 2H), 7.82 (d, J = 8.8 Hz, 2H), 7.11 (t, J = 8.0 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.85−6.81(m, 2H), 5.26 (s, 1H, N−H), 4.30−4.20 (m, 1H), 3.63 (s, 3H), 3.07 (dd, J = 5.2, 14.0 Hz, 1H), 2.92 (dd, J = 7.6, 14.0 Hz, 1H), 2.25 (s, 3H). The 1H NMR data were identical with those reported in the literature.10 Methyl 3-(3-methoxyphenyl)-2-(4-nitrophenylsulfonamido)propanoate (1c): 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H), 7.12 (t, J = 8.0 Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H), 6.63 (d, J = 7.2 Hz, 1H), 6.51 (s, 1H), 5.47 (d, J = 5.2 Hz, 1H, N−H), 4.29−4.19 (m, 1H), 3.71 (s, 3H), 3.65 (s, 3H), 3.08 (dd, J = 4.4, 13.6 Hz, 1H), 2.89 (dd, J = 7.6, 13.6 Hz, 1H). The 1H NMR data were identical with those reported in the literature.10 Methyl 3-(3-bromophenyl)-2-(4-nitrophenylsulfonamido)propanoate (1d): 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 9.2 Hz, 2H), 7.82 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 7.07 (t, J = 7.6 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 5.73 (d, J = 5.4 Hz, 1H, N−H), 4.26−4.18 (m, 1H), 3.66 (s, 3H), 3.08 (dd, J = 4.8, 14.0 Hz, 1H), 2.87 (dd, J = 8.4, 14.0 Hz, 1H). The 1H NMR data were identical with those reported in the literature.10 Methyl 2-(4-nitrophenylsulfonamido)-3-(o-tolyl)propanoate (1e): 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H), 7.13−7.08 (m, 1H), 7.05−6.99 (m, 2H), 6.94 (d, J = 7.2 Hz, 1H), 5.35 (d, J = 9.2 Hz, 1H, N−H), 4.25−4.18 (m, 1H), 3.63 (s, 3H), 3.13 (dd, J = 5.2, 14.0 Hz, 1H), 2.90 (dd, J = 8.8, 14.4 Hz, 1H), 2.25 (s, 3H). The 1H NMR data were identical with those reported in the literature.10 Methyl 3-(2-methoxyphenyl)-2-(4-nitrophenylsulfonamido)propanoate (1f): 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.8

a

Reaction conditions: substrate phenylalanines 1 (0.2 mmol), R2I 2 (3.5 equiv), Pd(OAc)2 (10 mol %), pyridine (20 mol %), NBE5 (1.5 equiv), AgOAc (3.0 equiv), TBME (1.0 mL), 80 °C, 24 h. bIsolated yield.

Figure 1. Proposed mechanism of meta-C(sp2)−H alkylation.

activation could lead to the intermediate III. Third, intermediate III would undergo oxidative addition with the alkyl iodide to form Pd(IV) species IV, which can 13213

DOI: 10.1021/acs.joc.8b01933 J. Org. Chem. 2018, 83, 13211−13216

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The Journal of Organic Chemistry

(d, J = 9.2 Hz, 1H, N−H), 4.23−4.17 (m, 1H), 3.66 (s, 3H), 3.09 (dd, J = 5.2, 14.0 Hz, 1H), 2.82 (dd, J = 9.2, 14.0 Hz, 1H), 2.19 (s, 3H), 2.17 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.7, 149.8, 145.5, 135.5, 133.2, 130.9, 130.6, 128.1, 127.9, 123.9, 56.5, 52.7, 36.6, 20.7, 18.7; HRMS (ESI) m/z [M + H]+ calcd for C18H21N2O6S 393.1120, found 393.1124. Methyl 3-(2-Methoxy-5-methylphenyl)-2-(4nitrophenylsulfonamido)propanoate (3fa). Isolated as a yellow solid (64.4 mg, 79% yield): mp 123−125 °C; 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.8 Hz, 2H), 6.95 (dd, J = 1.2, 8.4 Hz, 1H), 6.73 (s, 1H), 6.61 (d, J = 8.3 Hz, 1H), 5.57 (d, J = 8.6 Hz, 1H, N−H), 4.23−4.17 (m, 1H), 3.75 (s, 3H), 3.67 (s, 3H), 2.97−2.92 (m, 2H), 2.16 (s, 3H); 13C NMR (1001 MHz, CDCl3) δ 171.6, 155.2, 149.7, 145.7, 131.9, 130.3, 129.1, 128.0, 123.8, 123.3, 110.6, 56.6, 55.6, 52.6, 33.5, 20.2; HRMS (ESI) m/z [M + H]+ calcd for C18H21N2O7S 409.1069, found 409.1072. Methyl 3-(2-Fluoro-5-methylphenyl)-2-(4nitrophenylsulfonamido)propanoate (3ga). Isolated as a yellow solid (39.6 mg, 50% yield): mp 106−108 °C; 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 8.8 Hz, 2H), 6.97− 6.94 (m, 1H), 6.86−6.83 (m, 1H), 6.81−6.74 (m, 1H), 5.42 (d, J = 9.2 Hz, 1H, N−H), 4.27−4.21 (m, 1H), 3.64 (s, 3H), 3.04 (dd, J = 5.6, 14.0 Hz, 1H), 2.96 (dd, J = 8.0, 14.0 Hz, 1H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.1, 159.3 (d,1JC−F = 241.6 Hz), 149.9, 145.6, 133.8 (d,4JC−F = 3.6 Hz), 132.1 (d,4JC−F = 4.1 Hz), 129.7 (d,3JC−F = 7.8 Hz), 128.1, 124.0, 121.5 (d,2JC−F = 15.5 Hz), 115.5 (d,2JC−F = 21.9 Hz), 56.1, 52.8, 32.8, 20.5; HRMS (ESI) m/z [M + H]+ calcd for C17H18FN2O6S 397.0870, found 397.0876. Methyl 3-(2-Chloro-5-methylphenyl)-2-(4nitrophenylsulfonamido)propanoate (3ha). Isolated as a yellow solid (35.4 mg, 43% yield): mp 119−120 °C; 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 9.2 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.0 Hz, 1H), 6.93−6.88 (m, 1H), 6.87−6.58 (m, 1H), 5.46 (dd, J = 4.8, 8.8 Hz, 1H, N−H), 4.35−4.29 (m, 1H), 3.68 (s, 3H), 3.16 (dd, J = 5.2, 14.0 Hz, 1H), 2.93 (dd, J = 10.0, 14.0 Hz, 1H), 2.21 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 171.4, 149.8, 145.5, 136.9, 132.7, 132.3, 131.1, 129.5, 129.4, 128.0, 124.0, 55.9, 52.9, 36.7, 20.64; HRMS (ESI) m/z [M + H]+ calcd for C17H18ClN2O6S 413.0574, found 413.0578. Methyl 3-(2-Bromo-5-methylphenyl)-2-(4nitrophenylsulfonamido)propanoate (3ia). Isolated as a yellow solid (38.3 mg, 42% yield): mp 130−132 °C; 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 9.2 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.0 Hz, 1H), 6.87 (s, 1H), 6.82 (d, J = 8.4 Hz, 1H), 5.62 (d, J = 10.0 Hz, 1H, N−H), 4.38−4.32 (m, 1H), 3.70 (s, 3H), 3.18 (dd, J = 5.2, 14.0 Hz, 1H), 2.91 (dd, J = 10.0, 14.0 Hz, 1H), 2.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.5, 149.8, 145.4, 137.6, 134.5, 132.7, 132.5, 129.8, 128.0, 123.9, 121.2, 56.0, 52.9, 39.0, 20.6; HRMS (ESI) m/z [M + H]+ calcd for C17H18BrN2O6S 457.0069, found 457.0072. Methyl 3-(3-Ethyl-5-methylphenyl)-2-(4nitrophenylsulfonamido)propanoate (3bb). Isolated as a colorless solid (19.5 mg, 24% yield): white solid; mp 84−86 °C; 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 8.8 Hz, 2H), 6.84 (s, 1H), 6.65 (s, 1H), 6.64 (s, 1H), 5.33 (d, J = 9.6 Hz, 1H, N− H), 4.26−4.20 (m, 1H), 3.64 (s, 3H), 3.04 (dd, J = 5.2, 14.0 Hz, 1H), 2.87 (dd, J = 7.6, 13.6 Hz, 1H), 2.50 (q, J = 7.6 Hz, 2H), 2.21 (s, 3H), 1.16 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.2, 149.9, 145.7, 144.7, 138.3, 134.7, 128.1, 127.8, 127.3, 125.9, 124.0, 57.2, 52.6, 39.1, 28.6, 21.2, 15.5; HRMS (ESI) m/z [M + H]+ calcd for C19H23N2O6S 407.1277, found 407.1282. Methyl 3-(5-Ethyl-2-fluorophenyl)-2-(4nitrophenylsulfonamido)propanoate (3gb). Isolated as a yellow solid (22.1 mg, 27% yield): mp 71−73 °C; 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.8 Hz, 2H), 7.02− 6.97 (m, 1H), 6.88 (d, J = 7.2 Hz, 1H), 6.84−6.78 (m, 1H), 5.33 (d, J = 9.6 Hz, 1H, N−H), 4.29−4.22 (m, 1H), 3.64 (s, 3H), 3.06 (dd, J = 5.6, 14.0 Hz, 1H), 2.99 (dd, J = 8.0, 13.6 Hz, 1H), 2.53 (q, J = 7.6 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.1, 159.4 (d,1JC−F = 241.7 Hz), 150.0, 145.7, 140.2 ((d,4JC−F = 3.4 Hz)), 130.9 (d,4JC−F = 4.1 Hz), 128.6 (d,3JC−F = 8.1 Hz), 128.1, 124.1, 121.6

Hz, 2H), 7.73 (d, J = 8.8 Hz, 2H), 7.18 (t, J = 8.0 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 6.79 (t, J = 7.6 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 5.59 (d, J = 7.6 Hz, 1H, N−H), 4.30−4.20 (m, 1H), 3.76 (s, 3H), 3.65 (s, 3H), 3.04 (dd, J = 4.8, 13.6 Hz, 1H), 2.96 (dd, J = 8.8, 13.6 Hz, 1H). The 1H NMR data were identical with those reported in the literature.10 Methyl 3-(2-fluorophenyl)-2-(4-nitrophenylsulfonamido)propanoate (1g): 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.24−7.17 (m, 1H), 7.11 (t, J = 7.2 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.92 (t, J = 9.6 Hz, 1H), 5.33 (d, J = 9.6 Hz, 1H, N−H), 4.30−4.23 (m, 1H), 3.63 (s, 3H), 3.10 (dd, J = 5.6, 13.6 Hz, 1H), 3.03 (dd, J = 7.6, 14.0 Hz, 1H). The 1H NMR data were identical with those reported in the literature.10 Methyl 3-(2-chlorophenyl)-2-(4-nitrophenylsulfonamido)propanoate (1h): 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 7.2 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.33−7.27 (m, 2H), 5.65 (d, J = 8.8 Hz, 1H, N−H), 4.31−4.23 (m, 1H), 3.63 (s, 3H), 3.19 (dd, J = 4.8, 14.0 Hz, 1H), 3.03 (dd, J = 7.2, 13.6 Hz, 1H). The 1H NMR data were identical with those reported in the literature.10 Methyl 3-(2-bromophenyl)-2-(4-nitrophenylsulfonamido)propanoate (1i): 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 7.6 Hz, 1H), 7.17− 7.12 (m, 1H), 7.11−7.08 (m, 1H), 7.07−7.02 (m, 1H), 5.50 (d, J = 10.0 Hz, 1H, N−H), 4.40−4.32 (m, 1H), 3.68 (s, 3H), 3.23 (dd, J = 5.2, 13.6 Hz, 1H), 2.98 (dd, J = 10.0, 14.0 Hz, 1H). The 1H NMR data were identical with those reported in the literature.10 General Procedure for Meta-C(sp2)−H Alkylation of Phenylalanines. The starting material phenylalanine 1 (0.20 mmol), Pd(OAc)2 (0.02 mmol, 4.4 mg), and AgOAc (0.60 mmol, 100.0 mg) were added in a tube under air (10 mL) with a magnetic stir bar. Then to the reaction mixture were added pyridine (0.04 mmol, 4.4 μL), diisopropyl bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate (NBE5) (0.3 mmol, 79.8 mg), alkyl iodide 2 (0.60 mmol), and TBME (2.0 mL). The reaction mixture was heated to 80 °C for 24 h under vigorous stirring. Upon completion, the reaction mixture was purified by preparative TLC using an eluent of petroleum ether/ethyl acetate (4/1 to 6/1) to give the desired meta-alkylated products 3. Methyl 3-(3,5-Dimethylphenyl)-2-(4-nitrophenylsulfonamido)propanoate (3ba). Isolated as a yellow solid (64.3 mg, 82% yield): mp 137−139 °C; 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 6.82 (s, 1H), 6.61 (s, 2H), 5.29 (d, J = 9.2 Hz, 1H, N−H), 4.24−4.20 (m, 1H), 3.64 (s, 3H), 3.02 (dd, J = 5.2, 14.0 Hz 1H), 2.84 (dd, J = 7.8, 14.0 Hz, 1H), 2.20 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 171.2, 149.9, 145.6, 138.3, 134.7, 129.0, 128.2, 127.1, 123.9, 57.2, 52.7, 39.1, 21.1; HRMS (ESI) m/z [M + H]+ calcd for C18H21N2O6S 393.1120, found 393.1122. Methyl 3-(3-Methoxy-5-methylphenyl)-2-(4nitrophenylsulfonamido)propanoate (3ca). Isolated as a yellow solid (57.9 mg, 71% yield): mp 117−119 °C; 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.8 Hz, 2H), 7.79 (d, J = 8.8 Hz, 2H), 6.50 (s, 1H), 6.41 (s, 1H), 6.31 (s, 1H), 5.51 (d, J = 6.0 Hz, 1H, N−H), 4.29−4.15 (m, 1H), 3.69 (s, 3H), 3.66 (s, 3H), 3.03 (dd, J = 4.8, 13.6 Hz, 1H), 2.81 (dd, J = 8.2, 14.0 Hz, 1H), 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.3, 159.7, 149.8, 145.5, 139.8, 136.1, 128.0, 123.9, 122.4, 113.2, 112.1, 57.2, 55.0, 52.7, 39.0, 21.4. HRMS (ESI) m/z [M + H]+ calcd for C18H21N2O7S 409.1069, found 409.1070. Methyl 3-(3-Bromo-5-methylphenyl)-2-(4nitrophenylsulfonamido)propanoate (3da). Isolated as a yellow solid (36.5 mg, 40% yield): mp 104−105 °C; 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 8.8 Hz, 2H), 7.14 (s, 1H), 6.91 (s, 1H), 6.78 (s, 1H), 5.32 (d, J = 9.2 Hz, 1H, N−H), 4.24−4.19 (m, 1H), 3.67 (s, 3H), 3.04 (dd, J = 4.8, 14.0 Hz, 1H), 2.83 (dd, J = 8.0, 14.0 Hz, 1H), 2.23 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.9, 150.0, 145.4, 140.5, 136.9, 131.1, 129.3, 128.8, 128.1, 124.1, 122.5, 57.1, 52.9, 38.8, 21.0; HRMS (ESI) m/z [M + H]+ calcd for C17H18BrN2O6S 457.0069, found 457.0068. Methyl 3-(2,5-Dimethylphenyl)-2-(4-nitrophenylsulfonamido)propanoate (3ea). Isolated as a yellow solid (62.7 mg, 80% yield): mp 120−122 °C; 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 6.92−6.86 (m, 2H), 6.72 (s, 1H), 5.51 13214

DOI: 10.1021/acs.joc.8b01933 J. Org. Chem. 2018, 83, 13211−13216

Article

The Journal of Organic Chemistry (d,2JC−F = 15.6 Hz), 115.1 (d,2JC−F = 21.9 Hz), 56.2, 52.8, 33.0, 27.9, 15.6; HRMS (ESI) m/z [M + H]+ calcd for C18H20FN2O6S 411.1026, found 411.1030. Methyl 3-(3-(2-Ethoxy-2-oxoethyl)-5-methylphenyl)-2-(4nitrophenylsulfonamido)propanoate (3bc). Isolated as a yellow solid (85.3 mg, 92% yield): mp 91−92 °C; 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 8.8 Hz, 2H), 6.91 (s, 1H), 6.79 (s, 1H), 6.69 (s, 1H), 5.55 (d, J = 9.2 Hz, 1H, N−H), 4.25−4.20 (m, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.64 (s, 3H), 3.49 (s, 2H), 3.04 (dd, J = 5.2, 14.0 Hz, 1H), 2.88 (dd, J = 7.6, 13.6 Hz, 1H), 2.18 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.5, 171.2, 149.8, 145.6, 138.6, 135.1, 134.5, 129.1, 128.6, 128.1, 127.4, 124.0, 61.0, 57.1, 52.7, 40.9, 38.9, 21.1, 14.1; HRMS (ESI) m/z [M + H]+ calcd for C21H25N2O8S 465.1332, found 465.1340. Methyl 3-(3-(2-Ethoxy-2-oxoethyl)-5-methoxyphenyl)-2-(4nitrophenylsulfonamido)propanoate (3cc). Isolated as a yellow solid (72.9 mg, 76% yield): mp 94−96 °C; 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 6.63 (s, 1H), 6.57 (s, 1H), 6.36 (s, 1H), 5.50−5.45 (m, 1H, N−H), 4.25− 4.14 (m, 3H), 3.67 (s, 3H), 3.66 (s, 3H), 3.51 (s, 2H), 3.05 (dd, J = 4.8, 14.0 Hz, 1H), 2.85 (dd, J = 8.0, 14.0 Hz, 1H), 1.28 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.3, 171.1, 159.8, 149.8, 145.5, 136.6, 135.9, 128.1, 124.0, 122.7, 113.7, 113.6, 61.1, 57.1, 55.1, 52.8, 41.1, 39.0, 14.2; HRMS (ESI) m/z [M + H]+ calcd for C21H25N2O9S 481.1281, found 481.1286. Methyl 3-(5-(2-Ethoxy-2-oxoethyl)-2-methylphenyl)-2-(4nitrophenylsulfonamido)propanoate (3ec). Isolated as a yellow solid (72.4 mg, 78% yield): mp 89−91 °C; 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.91 (s, 1H), 5.65−5.56 (m, 1H, N−H), 4.22−4.12 (m, 3H), 3.65 (s, 3H), 3.48 (s, 2H), 3.11 (dd, J = 5.2, 14.0 Hz, 1H), 2.87 (dd, J = 8.8, 14.0 Hz, 1H), 2.17 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.6, 149.8, 145.4, 135.1, 133.7, 132.0, 131.2, 130.8, 128.4, 128.1, 124.0, 61.0, 56.3, 52.8, 40.6, 36.6, 18.8, 14.2; HRMS (ESI) m/z [M + H]+ calcd for C21H25N2O8S 465.1332, found 465.1335. Methyl 3-(5-(2-Ethoxy-2-oxoethyl)-2-methoxyphenyl)-2-(4nitrophenylsulfonamido)propanoate (3fc). Isolated as a yellow solid (70.1 mg, 73% yield): mp 98−100 °C; 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 9.2 Hz, 2H), 7.73 (d, J = 8.8 Hz, 2H), 7.06 (dd, J = 2.0, 8.0 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 5.64 (d, J = 8.8 Hz, 1H, N−H), 4.24 (td, J = 4.8, 9.2 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.71 (s, 3H), 3.66 (s, 3H), 3.46 (s, 2H), 3.02 (dd, J = 4.8, 13.6 Hz, 1H), 2.91 (dd, J = 9.6, 13.6 Hz, 1H), 1.28 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.7, 171.6, 156.3, 149.7, 145.7, 132.3, 129.6, 128.0, 126.6, 123.9, 123.7, 110.5, 60.9, 56.1, 55.5, 52.6, 40.1, 33.8, 14.2; HRMS (ESI) m/z [M + H]+ calcd for C21H25N2O9S 481.1281, found 481.1284. Methyl 3-(5-(2-Ethoxy-2-oxoethyl)-2-fluorophenyl)-2-(4nitrophenylsulfonamido)propanoate (3gc). Isolated as a yellow solid (40.2 mg, 43% yield): mp 88−90 °C; 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.8 Hz, 2H), 7.12− 7.05 (m, 1H), 7.03 (d, J = 6.8 Hz, 1H), 6.82 (t, J = 9.0 Hz, 1H), 5.45 (d, J = 9.6 Hz, 1H, N−H), 4.26 (dd, J = 8.4, 14.4 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.65 (s, 3H), 3.52 (s, 2H), 3.07 (dd, J = 5.2, 14.0 Hz, 1H), 2.99 (dd, J = 8.0, 13.6 Hz, 1H), 1.27 (t, J = 7.2 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 171.2, 171.0, 160.2 (d,1JC−F = 244.0 Hz), 149.9, 145.5, 132.7 (d,4JC−F = 4.5 Hz), 130.3, 130.2 (d,1JC−F = 5.4 Hz), 128.2, 124.1, 122.1(d,2JC−F = 16.1 Hz), 115.4 (d,2JC−F = 22.3 Hz), 99.9, 61.1, 55.9, 52.9, 40.2, 32.9, 14.2; HRMS (ESI) m/z [M + H]+ calcd for C20H22FN2O8S 469.1081, found 469.1088. Methyl 3-(2-Chloro-5-(2-ethoxy-2-oxoethyl)phenyl)-2-(4nitrophenylsulfonamido)propanoate (3hc). Isolated as a yellow solid (35.8 mg, 37% yield): mp 93−95 °C; 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.0 Hz, 1H), 7.07−6.99 (m, 2H), 5.55 (d, J = 9.6 Hz, 1H, N−H), 4.36−4.30 (m, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.68 (s, 3H), 3.52 (s, 2H), 3.19 (dd, J = 5.2, 14.0 Hz, 1H), 2.95 (dd, J = 9.6, 14.0 Hz, 1H), 1.28 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.3, 171.0, 149.8, 145.3, 133.2, 133.1, 132.9, 132.8, 129.8, 129.7, 128.2,

124.0, 61.2, 55.5, 53.0, 40.3, 36.8, 14.2; HRMS (ESI) m/z [M + H]+ calcd for C20H22ClN2O8S 485.0785, found 485.0792. Methyl 3-(2-Bromo-5-(2-ethoxy-2-oxoethyl)phenyl)-2-(4nitrophenylsulfonamido)propanoate (3ic). Isolated as a yellow solid (61.2 mg, 57% yield): mp 98−100 °C; 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.24 (J = 8.4 Hz, 1H), 7.05 (d, J = 1.2 Hz, 1H), 6.94 (dd, J = 1.2, 8.0 Hz, 1H), 5.70 (d, J = 9.6 Hz, 1H, N−H), 4.38−4.32 (m, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.70 (s, 3H), 3.50 (s, 2H), 3.20 (dd, J = 4.8, 14.0 Hz, 1H), 2.93 (dd, J = 10.0, 14.0 Hz, 1H), 1.28 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.5, 170.9, 149.8, 145.2, 134.9, 133.9, 133.0, 132.9, 130.0, 128.1, 124.0, 123.0, 61.2, 55.5, 53.0, 40.3, 39.0, 14.1; HRMS (ESI) m/z [M + H]+ calcd for C20H22BrN2O8S 529.0280, found 529.0289. Methyl 3-(3-(2-Ethoxy-2-oxoethyl)-5-fluorophenyl)-2-(4nitrophenylsulfonamido)propanoate (3jc). Isolated as a yellow solid (36.5 mg, 39% yield): mp 96−98 °C; 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 9.2 Hz, 1H), 6.80 (s, 1H), 6.61 (d, J = 8.8 Hz, 1H), 5.52 (d, J = 9.2 Hz, 1H, N−H), 4.24 (dd, J = 7.2, 13.6 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.64 (s, 3H), 3.53 (s, 2H), 3.09 (dd, J = 4.8, 14.0 Hz, 1H), 2.93 (dd, J = 7.6, 14.0 Hz, 1H), 1.28 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.8 (2C), 150.0, 145.4, 137.4 (d, 3JC−F = 7.8 Hz), 136.8 (d, 3JC−F = 8.0 Hz), 128.2, 126.2, 124.2, 115.4 (d, 2JC−F = 21.8 Hz), 114.8 (d, 2JC−F = 21.2 Hz), 61.2, 56.8, 52.9, 40.7, 38.8, 14.1; HRMS (ESI) m/z [M + H]+ calcd for C20H22FN2O8S 469.1081, found 469.1083. Diisopropyl 5-(3-Methoxy-2-(4-nitrophenylsulfonamido)-3-oxopropyl)-7-methyl-1,2,3,4,4a,8b-hexahydro-1,4-methanobiphenylene-2,3-dicarboxylate (Side Products, Cyclobutane Derivatives). Isolated as a yellow solid (19.3 mg, 15% yield): 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 8.8 Hz, 2H), 6.70 (s, 1H), 6.62 (s, 1H), 5.74 (d, J = 9.6 Hz, 1H), 5.06−4.99 (m, 2H), 4.25−4.19 (m, 1H), 3.68−3.64 (m, 4H), 3.40 (d, J = 3.2 Hz, 1H), 3.07 (dd, J = 4.4, 12.0 Hz, 1H), 2.94 (dd, J = 4.0, 11.6 Hz, 1H), 2.88 (dd, J = 5.2, 14.0 Hz, 1H), 2.79 (dd, J = 8.0, 13.6 Hz, 1H), 2.55 (s, 2H), 2.22 (s, 3H), 1.30−1.24 (m, 12H), 1.04−0.96 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 171.6, 171.4, 172, 149.8, 146.0, 145.3, 141.4, 138.1, 129.3, 128.8, 127.9, 124.0, 121.6, 67.8, 67.7, 57.2, 52.8, 45.9, 45.8, 43.9, 43.2, 40.2, 39.5, 35.0, 33.2, 22.0, 21.9, 21.8, 21.7; HRMS (ESI) m/z [M + H]+ calcd for C32H39N2O10S 643.2325, found 643.2319.

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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.8b01933. 1 H NMR and 13C NMR of new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Qiuping Ding: 0000-0002-1154-7621 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the National Natural Science Foundation of China (21662017) and the Natural Science Foundation of Jiangxi Province of China (20171BAB2030007) is gratefully acknowledged.

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REFERENCES

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