Palladium(II)-catalyzed ortho-C–H olefination of phenylalanine and phenylethylamine derivatives directed by removable picolinamide group

Abstract

Palladium-catalyzed ortho-C–H olefination of phenylalanine and phenylethylamine derivatives assisted by a removable picolinamide group has been achieved. This protocol shows broad substrate scope, functional tolerance and moderate to high yields, thus affording a practical approach for the direct modification of phenylalanine and phenylethylamine derivatives.

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Introduction

Transition-metal-catalyzed direct C–H functionalization has captured wide attention because of its high efficiency in constructing carbon–carbon and carbon–heteroatom bonds,^1,2 and great progress has been made in C–H activation reactions with the assistance of various directing groups which can enhance the reactivity and achieve site selectivity in recent decades.^3,4 In particular, C–H functionalization of nitrogen-containing compounds, such as amino acid derivatives, is especially important and attractive considering their prevalence in natural products and therapeutic agents. Moreover, functionalized amino acid derivatives have also been widely used as building blocks in medicinal chemistry for their broad biological activities.⁵ Therefore, the synthesis of these structures is of great importance. Compared with the conventional de novo synthesis strategy, the direct functionalization of C–H bonds of various readily available amino acid derivatives generates a much more straightforward and convenient access to functionalized amino acid derivatives, providing a potential protocol for the direct modification of amino acid derivatives. Despite the remarkable achievements made in the C–H functionalization of amino acid derivatives in recent years,⁶ reports on the direct olefination of phenylalanine derivatives at the ortho-position are still rare, and only one kind of directing group, namely sulfonyl amide, was employed successfully to achieve the ortho-C–H olefination of phenylalanine derivatives (Scheme 1a).⁷ Although pioneering works reported by Yu's group in 2008 realized the ortho-alkenylation of phenylalanine derivatives assisted by a trifluoro-sulfonamide group, this reaction suffered from the disadvantages of moderate yields, long reaction time and limited examples.^7a Very recently, the ortho-olefination of phenylalanine derivatives was also developed using N-methyl-N-(2-pyridyl)sulfonyl as the directing group by Carretero's group, but only limited to electron-deficient alkenes.^7b It is noteworthy that both reported methods employed sulfonyl amide as the directing group. In the present work, we report the palladium-catalyzed ortho-olefination of phenylalanine derivatives directed by removable picolinamide group with various electron-deficient and electron-rich alkenes in moderate to high yields (Scheme 1b), thus generating a practical strategy for the direct modification of phenylalanine derivatives to produce olefinated phenylalanine derivatives as potential building blocks for drug discovery. Remarkably, our approach was also compatible with phenylethylamine derivatives, which further broadens the substrate scope and highlights the synthetic utility of this methodology. Our method provides an alternative strategy and additional complementarity to the preexisting methods for the ortho-olefination of phenylalanine and phenylethylamine derivatives.

Scheme 1 ortho-C–H Olefination of phenylalanine derivatives directed by sulfonyl amide and picolinamide groups.

Results and discussion

Initial screening experiments were performed employing 1a and 2a as the model substrates to optimize the reaction conditions (Table 1). We tested the reaction of 1a and 2a with Pd(OAc)₂ as catalyst in 1,4-dioxane at 110 °C for 20 h under an atmosphere of air at first, and the desired product 3a was obtained only in 4% yield with the starting materials recovered (entry 1). Pleasingly, 3a was achieved with a moderate yield (42%) when oxygen was employed as the oxidant (entry 2). It is worth noting that the addition of KHCO₃ as base can significantly improve the yield in the presence of oxidant (entry 3), this might be because KHCO₃ can accelerate the deprotonation process to promote this reaction. Subsequently, several common oxidants such as CuCl₂, Cu(OAc)₂, PhI(OAc)₂, K₂S₂O₈, DDQ and BQ were screened, however, none of them gave better yield than oxygen (entries 4–9). A further screening of the oxidants revealed that employment of silver salts such as AgNO₃, AgSO₃CF₃, AgOAc, AgCO₂CF₃, Ag₂O and Ag₂CO₃ generally can afford 3a in moderate to high yields (entries 10–15), and four of them (AgOAc, AgCO₂CF₃, Ag₂O and Ag₂CO₃) gave higher yield than oxygen (entries 12–15). Among the silver salts screened, Ag₂CO₃ was found to be the most efficient oxidant for this transformation with 89% yield (entry 15). In addition, an exploration of the bases discovered that KHCO₃ was the most suitable base for this reaction (entries 15–19). Besides, control experiments showed that Pd(OAc)₂ played a crucial and indispensable role in this ortho-C–H olefination reaction (entry 20). In this way, the optimal reaction conditions were identified using the catalytic system of Pd(OAc)₂/Ag₂CO₃/KHCO₃ in 1,4-dioxane at 110 °C for 20 h.

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst	Oxidant	Base	Yield^b (%)
a Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol, 2 equiv.), Pd(OAc)2 (0.03 mmol, 10 mol%), oxidant (0.6 mmol, 2 equiv.), and base (0.6 mmol, 2 equiv.) in 1,4-dioxane (2.0 ml) at 110 °C for 20 h in a 25 ml sealed tube.b Isolated yield.c No reaction.
1	Pd(OAc)2	—	—	4
2	Pd(OAc)2	1 atm O2	—	42
3	Pd(OAc)2	1 atm O2	KHCO3	68
4	Pd(OAc)2	CuCl2	KHCO3	7
5	Pd(OAc)2	Cu(OAc)2	KHCO3	36
6	Pd(OAc)2	PhI(OAc)2	KHCO3	Trace
7	Pd(OAc)2	K2S2O8	KHCO3	32
8	Pd(OAc)2	DDQ	KHCO3	Trace
9	Pd(OAc)2	BQ	KHCO3	67
10	Pd(OAc)2	AgNO3	KHCO3	41
11	Pd(OAc)2	AgSO3CF3	KHCO3	54
12	Pd(OAc)2	AgOAc	KHCO3	72
13	Pd(OAc)2	AgCO2CF3	KHCO3	81
14	Pd(OAc)2	Ag2O	KHCO3	83
15	Pd(OAc)2	Ag2CO3	KHCO3	89
16	Pd(OAc)2	Ag2CO3	K3PO4	78
17	Pd(OAc)2	Ag2CO3	NaHCO3	80
18	Pd(OAc)2	Ag2CO3	Na2CO3	82
19	Pd(OAc)2	Ag2CO3	K2CO3	76
20	—	Ag2CO3	KHCO3	NR^c

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After determining the optimal reaction conditions, we then examined the general applicability of the process. In general, the olefination process tolerated a variety of phenylalanine derivatives with various substituents at R₁ and alkenes with electron-donating or electron-withdrawing groups at R₂, and furnished the desired products in moderate to high yields (Table 2). The reactions of substrate 1a bearing a methoxy group in the ortho-position with different acrylates afforded the alkenylated products in high yields (3a–3e). Except for acrylates, other activated alkenes, such as vinyl sulfone (3f), vinyl phosphate (3g) and vinyl ketone (3h), could undergo this transformation with moderate to high yields. Notably, unactivated alkenes such as styrene (3i), 1-pentene (3j), 1-hexene (3k) and 1-octene (3l) were also suitable for this reaction, furnishing the corresponding products in moderate yields. Subsequently, the scope of phenylalanine derivatives was explored. Substrates carrying a substituent (Me, F, Cl, Br) in the ortho-position reacted smoothly and produced the corresponding products in good to high yields (3m–3q). When meta-substituted substrate was employed, the C–H olefination reaction took place at the less sterically hindered position with good yield (3r). The reactions of unsubstituted or para-substituted phenylalanine derivatives afforded a separable mixture of mono- and diolefination products, and exclusive diolefination products were obtained in good yields by increasing the amounts of catalyst, alkene, oxidant and base (3s–3u), this may attribute to the transformation of monoolefination products which were produced in the reaction process into diolefination products when excessive reagents were used.

Table 2 Reaction substrate scope of phenylalanine derivatives^a

a Reaction conditions: 1 (0.3 mmol), 2 (0.6 mmol, 2 equiv.), Pd(OAc)₂ (0.03 mmol, 10 mol%), Ag₂CO₃ (0.6 mmol, 2 equiv.), and KHCO₃ (0.6 mmol, 2 equiv.) in 1,4-dioxane (2.0 ml) at 110 °C for 20 h in a 25 ml sealed tube; isolated yields.b 2 (1.2 mmol, 4 equiv.), 48 h.c The ratio of mono- and diolefination products was determined by ¹HNMR.d 2a (0.9 mmol, 3 equiv.), Pd(OAc)₂ (0.045 mmol, 15 mol%), Ag₂CO₃ (0.9 mmol, 3 equiv.), and KHCO₃ (0.9 mmol, 3 equiv.).

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To further broaden the substrate scope of this process, phenylethylamine derivatives were tested as the reaction substrates. To our delight, this approach was also compatible with phenylethylamines (Table 3). The reactions of diverse substituted phenylethylamine derivatives with various alkenes proceeded smoothly under the optimal reaction conditions, affording the desired products in moderate to high yields (5a–5i). We also made our efforts to achieve the ortho-C–H olefination of peptides (5j–5k), albeit with unsuccessful results, this may attribute to the additional coordination of amide of the peptide bond with Pd(OAc)₂ which inactivated the catalyst.

Table 3 Reaction substrate scope of phenylethylamine derivatives^a

a Reaction conditions: 4 (0.3 mmol), 2 (0.6 mmol, 2 equiv.), Pd(OAc)₂ (0.03 mmol, 10 mol%), Ag₂CO₃ (0.6 mmol, 2 equiv.), and KHCO₃ (0.6 mmol, 2 equiv.) in 1,4-dioxane (2.0 ml) at 110 °C for 20 h in a 25 ml sealed tube; isolated yields.b The ratio of mono- and diolefination products was determined by ¹HNMR.c Methyl acrylate (0.9 mmol, 3 equiv.), Pd(OAc)₂ (0.045 mmol, 15 mol%), Ag₂CO₃ (0.9 mmol, 3 equiv.), and KHCO₃ (0.9 mmol, 3 equiv.).

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To further illustrate the practicality of this methodology, the C–H olefination reaction with 1a was carried out on a gram scale under optimal conditions. Impressively, the desired product 3a was achieved in 86% yield (Scheme 2a). In addition, the picolinamide directing group can be easily removed using the general and mature protocol reported by Chen (Scheme 2b).⁸ Besides, removal of the directing group of 5c and subsequent intramolecular cyclization gave the tetrahydroisoquinoine 5c-2 in 80% yield over two steps, interestingly, epoxide 5c-3 was obtained as the byproduct in extremely low yield (Scheme 2c). These aspects further highlight the advantages and potential application of this approach.

Scheme 2 Gram-scale olefination, removal of the directing group and derivatization.

The plausible mechanism of this ortho-C–H olefination reaction was outlined in Scheme 3. Coordination of amides A to Pd(OAc)₂ generates Pd(II) complex B, subsequent C–H bond activation at the ortho-position forms the Ar–Pd metastable intermediate C. Then, olefin coordination and 1,2-migratory insertion take place sequentially followed by β-H elimination, affording the olefination products F and a Pd(0) species. The reduced Pd(0) species was oxidized to Pd(II) oxidation state by Ag₂CO₃ to regenerate the Pd(II) catalyst. KHCO₃ may play as a base which can accelerate the deprotonation process to promote this reaction.

Scheme 3 Proposed reaction mechanism of this ortho-C–H olefination of phenylalanine and phenylethylamine derivatives.

Conclusions

In conclusion, we have developed an efficient and practical approach for the ortho-C–H olefination of phenylalanine and phenylethylamine derivatives with the assistance of removable picolinamide group. The broad substrate scope, functional tolerance, and moderate to high yields demonstrate the great potential of this method for the direct modification of phenylalanine and phenylethylamine derivatives. Other synthetic applications of this method are currently under investigation in our laboratory.

Experimental section

General information

The reagents were purchased from commercial suppliers and used without further purification. Analytical thin-layer chromatography (TLC) was performed on HSGF 254 (0.15–0.2 mm thickness), visualized by irradiation with UV light (254 nm). Column chromatography was performed using silica gel FCP 200–300. Melting points were measured with a micro melting point apparatus. Nuclear magnetic resonance spectra were recorded on a Brucker AMX-400 or AMX-500 MHz instrument (TMS as IS). Chemical shifts were reported in parts per million (ppm, δ) downfield from tetramethylsilane. Proton coupling patterns were described as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and broad (br). Low- and high-resolution mass spectra (LRMS and HRMS) were measured on a spectrometer.

Preparation and characterization data of compound 3

Procedure for the preparation of 3a. A 25 ml Schlenk tube equipped with a magnetic stir bar was charged with 2a (98.5 mg, 0.3 mmol), ethyl acrylate (65.2 μl, 0.6 mmol), Pd(OAc)₂ (6.7 mg, 0.03 mmol), Ag₂CO₃ (165.5 mg, 0.6 mmol), KHCO₃ (60.1 mg, 0.6 mmol) and 1,4-dioxane (2.0 ml) and then capped with a septa. After that, the tube was kept in the preheated oil bath at 110 °C for 20 h. After removal of the solvent, the residue was purified by flash chromatography on silica gel to give the desired product 3a as white solid.

Compounds 3b–3v and 5a–5i were prepared following the similar procedure carried out for 3a.
(S,E)-Ethyl-3-(2-(3-ethoxy-3-oxo-2-(picolinamido)propyl)-3-methoxyphenyl)acrylate (3a). White solid (113.9 mg, yield 89%), mp 125–126 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.83 (d, J = 7.6 Hz, 1H), 8.53 (d, J = 4.7 Hz, 1H), 8.12–8.01 (m, 2H), 7.82–7.73 (m, 1H), 7.43–7.34 (m, 1H), 7.24–7.18 (m, 1H), 7.18–7.12 (m, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.30 (d, J = 15.7 Hz, 1H), 4.88–4.75 (m, 1H), 4.30–4.13 (m, 4H), 3.91 (s, 3H), 3.50–3.33 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H), 1.27 (t, J = 7.0 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 171.57, 166.60, 164.36, 157.95, 149.57, 148.11, 141.42, 137.17, 135.56, 128.33, 126.23, 124.95, 122.28, 121.54, 119.31, 111.29, 61.47, 60.60, 55.75, 53.49, 27.97, 14.41, 14.19; LRMS (ESI): 427 [M + H]⁺; HRMS (ESI) calcd for C₂₃H₂₇N₂O₆ [M + H]⁺ 427.1869, found: 427.1866.
(S,E)-Methyl-3-(2-(3-ethoxy-3-oxo-2-(picolinamido)propyl)-3-methoxyphenyl)acrylate (3b). White solid (113.8 mg, yield 92%), mp 82–83 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.79 (d, J = 7.5 Hz, 1H), 8.49 (d, J = 4.4 Hz, 1H), 8.10–7.97 (m, 2H), 7.77–7.69 (m, 1H), 7.38–7.31 (m, 1H), 7.20–7.14 (m, 1H), 7.13–7.06 (m, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.27 (d, J = 15.7 Hz, 1H), 4.86–4.72 (m, 1H), 4.23–4.08 (m, 2H), 3.87 (s, 3H), 3.76 (s, 3H), 3.46–3.30 (m, 2H), 1.24 (t, J = 6.9 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 171.47, 166.94, 164.28, 157.89, 149.44, 148.06, 141.66, 137.11, 135.38, 128.29, 126.19, 124.91, 122.19, 120.94, 119.19, 111.32, 61.40, 55.69, 53.40, 51.70, 27.91, 14.08; LRMS (ESI): 413 [M + H]⁺; HRMS (ESI) calcd for C₂₂H₂₅N₂O₆ [M + H]⁺ 413.1713, found: 413.1709.
(S,E)-Butyl-3-(2-(3-ethoxy-3-oxo-2-(picolinamido)propyl)-3-methoxyphenyl)acrylate (3c). Pale yellow oil (111.8 mg, yield 82%). ¹H NMR (400 MHz, CDCl₃) δ 8.81 (d, J = 7.6 Hz, 1H), 8.50 (d, J = 4.4 Hz, 1H), 8.11–7.98 (m, 2H), 7.79–7.68 (m, 1H), 7.41–7.30 (m, 1H), 7.20–7.08 (m, 2H), 6.84 (d, J = 7.9 Hz, 1H), 6.28 (d, J = 15.7 Hz, 1H), 4.84–4.73 (m, 1H), 4.23–4.09 (m, 4H), 3.88 (s, 3H), 3.47–3.30 (m, 2H), 1.71–1.62 (m, 2H), 1.47–1.37 (m, 2H), 1.25 (t, J = 7.0 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 171.52, 166.66, 164.31, 157.91, 149.50, 148.07, 141.36, 137.13, 135.50, 128.28, 126.19, 124.88, 122.22, 121.47, 119.25, 111.25, 64.49, 61.42, 55.71, 53.43, 30.80, 27.92, 19.25, 14.14, 13.81; LRMS (ESI): 455 [M + H]⁺; HRMS (ESI) calcd for C₂₅H₃₁N₂O₆ [M + H]⁺ 455.2182, found: 455.2180.
(S,E)-tert-Butyl-3-(2-(3-ethoxy-3-oxo-2-(picolinamido)propyl)-3-methoxyphenyl)acrylate (3d). White solid (110.4 mg, yield 81%), mp 80–81 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.85 (d, J = 7.3 Hz, 1H), 8.53 (d, J = 4.2 Hz, 1H), 8.07 (d, J = 7.7 Hz, 1H), 7.96 (d, J = 15.6 Hz, 1H), 7.83–7.72 (m, 1H), 7.43–7.32 (m, 1H), 7.22–7.10 (m, 2H), 6.85 (d, J = 8.0 Hz, 1H), 6.24 (d, J = 15.7 Hz, 1H), 4.87–4.74 (m, 1H), 4.27–4.12 (m, 2H), 3.91 (s, 3H), 3.50–3.30 (m, 2H), 1.54 (s, 9H), 1.26 (t, J = 7.0 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 171.61, 165.93, 164.40, 157.91, 149.60, 148.11, 140.29, 137.17, 135.70, 128.25, 126.21, 124.78, 123.41, 122.28, 119.31, 111.06, 80.58, 61.45, 55.73, 53.53, 28.28, 27.87, 14.21; LRMS (ESI): 455 [M + H]⁺; HRMS (ESI) calcd for C₂₅H₃₁N₂O₆ [M + H]⁺ 455.2182, found: 455.2178.
(S,E)-Benzyl-3-(2-(3-ethoxy-3-oxo-2-(picolinamido)propyl)-3-methoxyphenyl)acrylate (3e). Pale yellow oil (124.6 mg, yield 85%). ¹H NMR (400 MHz, CDCl₃) δ 8.72 (d, J = 7.6 Hz, 1H), 8.37 (d, J = 4.2 Hz, 1H), 8.03 (d, J = 15.7 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.67–7.59 (m, 1H), 7.35–7.30 (m, 2H), 7.29–7.21 (m, 4H), 7.12–7.06 (m, 1H), 7.05–7.01 (m, 1H), 6.76 (d, J = 7.8 Hz, 1H), 6.24 (d, J = 15.7 Hz, 1H), 5.15 (s, 2H), 4.80–4.68 (m, 1H), 4.13–3.97 (m, 2H), 3.79 (s, 3H), 3.38–3.24 (m, 2H), 1.12 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 171.51, 166.38, 164.31, 157.95, 149.50, 148.09, 142.04, 137.13, 136.15, 135.41, 128.64, 128.33, 128.27, 126.20, 125.02, 122.24, 121.03, 119.28, 111.40, 66.38, 61.44, 55.73, 53.40, 28.01, 14.14; LRMS (ESI): 511 [M + Na]⁺; HRMS (ESI) calcd for C₂₈H₂₈N₂O₆Na [M + Na]⁺ 511.1845, found: 511.1840.
(S,E)-Ethyl-3-(2-methoxy-6-(2-(phenylsulfonyl)vinyl)phenyl)-2-(picolinamido)propanoate (3f). Pale yellow oil (75.7 mg, yield 52%). ¹H NMR (400 MHz, CDCl₃) δ 8.84 (d, J = 7.5 Hz, 1H), 8.58–8.51 (m, 1H), 8.13–8.03 (m, 2H), 8.03–7.95 (m, 2H), 7.80–7.75 (m, 1H), 7.62–7.52 (m, 3H), 7.39 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H), 7.23–7.14 (m, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 15.1 Hz, 1H), 4.80–4.68 (m, 1H), 4.27–4.14 (m, 2H), 3.91 (s, 3H), 3.46 (dd, J = 13.9, 9.6 Hz, 1H), 3.35 (dd, J = 14.0, 5.2 Hz, 1H), 1.27 (t, J = 6.7 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 171.47, 164.42, 158.11, 149.44, 148.22, 140.65, 139.73, 137.26, 133.51, 133.29, 130.44, 129.47, 128.56, 127.95, 126.34, 125.74, 122.30, 119.57, 112.21, 61.68, 55.87, 53.61, 28.25, 14.24; LRMS (ESI): 495 [M + H]⁺; HRMS (ESI) calcd for C₂₆H₂₇N₂O₆S [M + H]⁺ 495.1590, found: 495.1592.
(S,E)-Ethyl-3-(2-(2-(diethoxyphosphoryl)vinyl)-6-methoxyphenyl)-2-(picolinamido)propanoate (3g). Pale yellow oil (117.7 mg, yield 80%). ¹H NMR (400 MHz, CDCl₃) δ 8.87 (d, J = 7.4 Hz, 1H), 8.58–8.49 (m, 1H), 8.08–8.01 (m, 1H), 7.88–7.73 (m, 2H), 7.37 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.24–7.15 (m, 1H), 7.11 (d, J = 7.3 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.19 (dd, J = 18.7, 17.2 Hz, 1H), 4.82–4.67 (m, 1H), 4.24–4.08 (m, 6H), 3.91 (s, 3H), 3.43 (dd, J = 13.9, 10.0 Hz, 1H), 3.30 (dd, J = 13.9, 5.1 Hz, 1H), 1.36 (t, J = 7.1 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 171.55, 164.35, 157.81, 149.39, 148.08, 145.20 (d, J_C–P = 6.8 Hz), 137.15, 135.98 (d, J_C–P = 20.2 Hz), 128.28, 126.22, 124.39, 122.16, 119.00, 117.90 (d, J_C–P = 189.7 Hz), 111.21, 62.03 (d, J_C–P = 6.6 Hz), 61.98 (d, J_C–P = 6.3 Hz), 61.40, 55.70, 53.42, 27.79, 16.46, 16.41, 14.10; LRMS (ESI): 491 [M + H]⁺; HRMS (ESI) calcd for C₂₄H₃₂N₂O₇P [M + H]⁺ 491.1947, found: 491.1941.
(S,E)-Ethyl-3-(2-methoxy-6-(3-oxopent-1-en-1-yl)phenyl)-2-(picolinamido)propanoate (3h). White solid (103.4 mg, yield 84%), mp 81–82 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.83 (d, J = 7.3 Hz, 1H), 8.57–8.50 (m, 1H), 8.12–8.06 (m, 1H), 7.96 (d, J = 16.1 Hz, 1H), 7.84–7.76 (m, 1H), 7.41 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.25–7.15 (m, 2H), 6.92–6.86 (m, 1H), 6.55 (d, J = 16.1 Hz, 1H), 4.85–4.72 (m, 1H), 4.26–4.11 (m, 2H), 3.91 (s, 3H), 3.48 (dd, J = 14.0, 9.0 Hz, 1H), 3.37 (dd, J = 14.0, 5.4 Hz, 1H), 2.77 (q, J = 7.3 Hz, 2H), 1.24 (t, J = 7.2 Hz, 3H), 1.17 (t, J = 7.3 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 201.24, 171.64, 164.38, 158.04, 149.53, 148.18, 139.34, 137.33, 135.75, 129.76, 128.43, 126.38, 125.17, 122.36, 119.23, 111.43, 61.59, 55.81, 53.66, 33.08, 28.16, 14.23, 8.36; LRMS (ESI): 433 [M + Na]⁺; HRMS (ESI) calcd for C₂₃H₂₆N₂O₅Na [M + Na]⁺ 433.1739, found: 433.1738.
(S,E)-Ethyl-3-(2-methoxy-6-styrylphenyl)-2-(picolinamido)propanoate (3i). White solid (62.5 mg, yield 49%), mp 107–108 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.95 (d, J = 6.7 Hz, 1H), 8.49 (d, J = 4.7 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.78–7.71 (m, 1H), 7.59–7.48 (m, 3H), 7.41–7.33 (m, 3H), 7.29–7.20 (m, 3H), 6.98 (d, J = 16.0 Hz, 1H), 6.80 (d, J = 6.7 Hz, 1H), 4.86–4.74 (m, 1H), 4.28–4.12 (m, 2H), 3.93 (s, 3H), 3.50 (dd, J = 14.0, 9.5 Hz, 1H), 3.38 (dd, J = 14.0, 4.9 Hz, 1H), 1.28 (t, J = 7.2 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 172.01, 164.60, 157.85, 149.67, 148.12, 138.43, 137.50, 137.15, 131.80, 128.78, 128.11, 127.91, 126.87, 126.21, 125.54, 123.35, 122.32, 118.59, 109.17, 61.49, 55.70, 53.95, 28.04, 14.22; LRMS (ESI): 453 [M + Na]⁺; HRMS (ESI) calcd for C₂₆H₂₆N₂O₄Na [M + Na]⁺ 453.1790, found: 453.1786.
(S,E)-Ethyl-3-(2-methoxy-6-(pent-1-en-1-yl)phenyl)-2-(picolinamido)propanoate (3j). Pale yellow oil (63.3 mg, yield 53%). ¹H NMR (400 MHz, CDCl₃) δ 8.95 (d, J = 6.7 Hz, 1H), 8.54 (d, J = 4.4 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.83–7.73 (m, 1H), 7.39 (dd, J = 6.6, 4.8 Hz, 1H), 7.18–7.09 (m, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.78–6.64 (m, 2H), 6.17–6.04 (m, 1H), 4.79–4.65 (m, 1H), 4.27–4.14 (m, 2H), 3.92 (s, 3H), 3.40 (dd, J = 13.8, 10.1 Hz, 1H), 3.24 (dd, J = 13.8, 4.8 Hz, 1H), 2.30–2.10 (m, 2H), 1.55–1.46 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H), 0.97 (t, J = 7.4 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 172.17, 164.65, 157.66, 149.78, 148.13, 139.25, 137.20, 134.57, 127.90, 126.90, 126.22, 122.40, 122.34, 119.03, 108.44, 61.36, 55.64, 53.82, 35.50, 27.85, 22.50, 14.25, 13.92; LRMS (ESI): 397 [M + H]⁺; HRMS (ESI) calcd for C₂₃H₂₉N₂O₄ [M + H]⁺ 397.2127, found: 397.2119.
(S,E)-Ethyl-3-(2-(hex-1-en-1-yl)-6-methoxyphenyl)-2-(picolinamido)propanoate (3k). Pale yellow oil (69.2 mg, yield 56%). ¹H NMR (400 MHz, CDCl₃) δ 8.94 (d, J = 6.7 Hz, 1H), 8.58–8.47 (m, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.82–7.72 (m, 1H), 7.38 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.18–7.09 (m, 1H), 7.04 (d, J = 7.5 Hz, 1H), 6.77–6.64 (m, 2H), 6.18–6.02 (m, 1H), 4.77–4.67 (m, 1H), 4.26–4.15 (m, 2H), 3.92 (s, 3H), 3.40 (dd, J = 13.8, 10.2 Hz, 1H), 3.24 (dd, J = 13.8, 4.8 Hz, 1H), 2.29–2.16 (m, 2H), 1.49–1.35 (m, 4H), 1.26 (t, J = 7.2 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 172.17, 164.64, 157.67, 149.82, 148.13, 139.27, 137.19, 134.79, 127.89, 126.71, 126.20, 122.40, 122.34, 119.03, 108.43, 61.34, 55.64, 53.81, 33.12, 31.47, 27.86, 22.46, 14.27, 14.11; LRMS (ESI): 411 [M + H]⁺; HRMS (ESI) calcd for C₂₄H₃₁N₂O₄ [M + H]⁺ 411.2284, found: 411.2276.
(S,E)-Ethyl-3-(2-methyl-6-(oct-1-en-1-yl)phenyl)-2-(picolinamido)propanoate (3l). Pale yellow oil (77.3 mg, yield 61%). ¹H NMR (400 MHz, CDCl₃) δ 8.63–8.50 (m, 2H), 8.11 (d, J = 7.8 Hz, 1H), 7.85–7.75 (m, 1H), 7.41 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.24 (d, J = 7.4 Hz, 1H), 7.11–6.99 (m, 2H), 6.75 (d, J = 15.5 Hz, 1H), 6.11–5.97 (m, 1H), 4.99–4.84 (m, 1H), 4.20–3.99 (m, 2H), 3.30 (d, J = 7.9 Hz, 2H), 2.42 (s, 3H), 2.29–2.16 (m, 2H), 1.52–1.42 (m, 2H), 1.41–1.29 (m, 6H), 1.13 (t, J = 7.1 Hz, 3H), 0.89 (t, J = 6.9 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 172.24, 164.12, 149.54, 148.28, 138.57, 137.32, 137.09, 134.46, 132.09, 129.33, 127.86, 127.04, 126.37, 124.63, 122.35, 61.55, 52.68, 33.47, 32.47, 31.90, 29.44, 29.13, 22.79, 20.26, 14.25, 14.02; LRMS (ESI): 423 [M + H]⁺; HRMS (ESI) calcd for C₂₆H₃₅N₂O₃ [M + H]⁺ 423.2648, found: 423.2638.
(S,E)-Ethyl-3-(2-(3-ethoxy-3-oxo-2-(picolinamido)propyl)-3-methylphenyl)acrylate (3m). White solid (110.8 mg, yield 90%), mp 61–62 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.57–8.47 (m, 2H), 8.08 (d, J = 15.7 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.80–7.71 (m, 1H), 7.37 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.32 (d, J = 6.9 Hz, 1H), 7.19–7.08 (m, 2H), 6.20 (d, J = 15.6 Hz, 1H), 4.95–4.84 (m, 1H), 4.23 (q, J = 7.1 Hz, 2H), 4.16–4.05 (m, 2H), 3.43–3.28 (m, 2H), 2.44 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H), 1.14 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 171.39, 166.59, 163.85, 149.13, 148.17, 142.46, 137.77, 137.16, 134.76, 134.46, 132.19, 127.25, 126.27, 124.88, 122.12, 120.84, 61.59, 60.41, 52.66, 32.36, 20.06, 14.31, 13.91; LRMS (ESI): 411 [M + H]⁺; HRMS (ESI) calcd for C₂₃H₂₇N₂O₅ [M + H]⁺ 411.1920, found: 411.1915.
(S,E)-Ethyl-3-(2-(3-ethoxy-3-oxo-2-(picolinamido)propyl)-3-fluorophenyl)acrylate (3n). Pale yellow oil (114.4 mg, yield 92%). ¹H NMR (400 MHz, CDCl₃) δ 8.58–8.43 (m, 2H), 8.11–8.03 (m, 1H), 7.98 (d, J = 15.7 Hz, 1H), 7.82–7.73 (m, 1H), 7.41–7.35 (m, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.24–7.18 (m, 1H), 7.07–6.98 (m, 1H), 6.25 (d, J = 15.7 Hz, 1H), 5.04–4.89 (m, 1H), 4.23–4.12 (m, 4H), 3.49–3.31 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 171.06, 166.25, 164.05, 161.82 (d, J_C–F = 245.3 Hz), 149.25, 148.29, 140.37 (d, J_C–F = 3.1 Hz), 137.17, 136.64 (d, J_C–F = 4.0 Hz), 128.76 (d, J_C–F = 9.2 Hz), 126.33, 123.42 (d, J_C–F = 16.0 Hz), 122.63 (d, J_C–F = 2.9 Hz), 122.27, 121.95, 116.36 (d, J_C–F = 23.4 Hz), 61.82, 60.65, 52.59, 28.22, 14.34, 14.05; LRMS (ESI): 415 [M + H]⁺; HRMS (ESI) calcd for C₂₂H₂₄FN₂O₅ [M + H]⁺ 415.1669, found: 415.1659.
(S,E)-Ethyl-3-(3-chloro-2-(3-ethoxy-3-oxo-2-(picolinamido)propyl)phenyl)acrylate (3o). Pale yellow oil (113.7 mg, yield 88%). ¹H NMR (400 MHz, CDCl₃) δ 8.57 (d, J = 8.6 Hz, 1H), 8.54–8.49 (m, 1H), 8.11–8.01 (m, 2H), 7.80–7.72 (m, 1H), 7.42–7.33 (m, 3H), 7.20–7.12 (m, 1H), 6.21 (d, J = 15.7 Hz, 1H), 5.06–4.96 (m, 1H), 4.26–4.12 (m, 4H), 3.55 (dd, J = 14.1, 6.4 Hz, 1H), 3.47 (dd, J = 14.1, 8.8 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 171.07, 166.20, 163.97, 149.15, 148.21, 141.20, 137.16, 136.71, 135.95, 133.88, 130.79, 128.40, 126.30, 125.65, 122.35, 122.20, 61.80, 60.66, 52.27, 32.69, 14.31, 14.00; LRMS (ESI): 433 ([M + H]⁺, (Cl³⁷)), 431 ([M + H]⁺, (Cl³⁵)); HRMS (ESI) calcd for C₂₂H₂₄ClN₂O₅ [M + H]⁺ 431.1374, found: 431.1371.
(S,E)-Ethyl-3-(3-bromo-2-(3-ethoxy-3-oxo-2-(picolinamido)propyl)phenyl)acrylate (3p). Pale yellow oil (107.0 mg, yield 75%). ¹H NMR (400 MHz, CDCl₃) δ 8.59 (d, J = 8.7 Hz, 1H), 8.52 (d, J = 4.7 Hz, 1H), 8.11–8.00 (m, 2H), 7.80–7.72 (m, 1H), 7.55 (dd, J = 7.9, 0.9 Hz, 1H), 7.43–7.35 (m, 2H), 7.12–7.04 (m, 1H), 6.19 (d, J = 15.6 Hz, 1H), 5.07–4.98 (m, 1H), 4.28–4.20 (m, 2H), 4.20–4.13 (m, 2H), 3.58 (dd, J = 14.1, 6.3 Hz, 1H), 3.49 (dd, J = 14.1, 9.1 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 171.10, 166.22, 164.03, 149.27, 148.27, 141.54, 137.20, 136.91, 135.52, 134.31, 128.78, 126.85, 126.43, 126.32, 122.55, 122.27, 61.86, 60.73, 52.38, 35.49, 14.38, 14.07; LRMS (ESI): 477 ([M + H]⁺, (Br⁸¹)), 475 ([M + H]⁺, (Br⁷⁹)); HRMS (ESI) calcd for C₂₂H₂₄BrN₂O₅ [M + H]⁺ 475.0869, found: 475.0862.
(S,E)-Ethyl-3-(3,5-dichloro-2-(3-ethoxy-3-oxo-2-(picolinamido)propyl)phenyl)acrylate (3q). Pale yellow oil (98.1 mg, yield 70%). ¹H NMR (400 MHz, CDCl₃) δ 8.61–8.51 (m, 2H), 8.06 (d, J = 7.8 Hz, 1H), 8.00 (d, J = 15.7 Hz, 1H), 7.84–7.75 (m, 1H), 7.44–7.35 (m, 3H), 6.22 (d, J = 15.6 Hz, 1H), 5.06–4.96 (m, 1H), 4.29–4.16 (m, 4H), 3.52 (dd, J = 14.1, 6.2 Hz, 1H), 3.43 (dd, J = 14.1, 8.8 Hz, 1H), 1.34 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 170.98, 165.93, 164.07, 149.17, 148.33, 140.12, 137.95, 137.33, 136.72, 133.73, 132.61, 130.38, 126.45, 125.84, 123.58, 122.37, 62.05, 60.93, 52.14, 32.60, 14.39, 14.15; LRMS(ESI): 465 [M + H]⁺; HRMS (ESI) calcd for C₂₂H₂₃Cl₂N₂O₅ [M + H]⁺ 465.0984, found: 465.0981.
(S,E)-Ethyl-3-(4-chloro-2-(3-ethoxy-3-oxo-2-(picolinamido)propyl)phenyl)acrylate (3r). White solid (100.8 mg, yield 78%), mp 84–85 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.52–8.48 (m, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.11–8.06 (m, 1H), 7.90 (d, J = 15.8 Hz, 1H), 7.82–7.74 (m, 1H), 7.49–7.42 (m, 1H), 7.38 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.23–7.16 (m, 2H), 6.22 (d, J = 15.7 Hz, 1H), 5.05–4.93 (m, 1H), 4.21–4.07 (m, 4H), 3.37 (dd, J = 14.1, 6.2 Hz, 1H), 3.28 (dd, J = 14.1, 6.5 Hz, 1H), 1.26 (t, J = 7.1 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 170.75, 166.22, 163.93, 149.05, 148.24, 140.18, 137.65, 137.16, 135.63, 132.67, 130.95, 128.16, 127.87, 126.35, 122.22, 120.78, 61.80, 60.48, 53.26, 35.23, 14.23, 14.04; LRMS (ESI): 433 ([M + H]⁺, (Cl³⁷)), 431 ([M + H]⁺, (Cl³⁵)); HRMS (ESI) calcd for C₂₂H₂₄ClN₂O₅ [M + H]⁺ 431.1374, found: 431.1369.
(S,E)-Ethyl-3-(2-(3-ethoxy-3-oxo-2-(picolinamido)propyl)phenyl)acrylate (3s_mono). White solid (50.0 mg, yield 42%), mp 69–70 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.55–8.49 (m, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.15–8.08 (m, 1H), 8.01 (d, J = 15.7 Hz, 1H), 7.84–7.76 (m, 1H), 7.58–7.52 (m, 1H), 7.40 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 7.29–7.22 (m, 3H), 6.28 (d, J = 15.7 Hz, 1H), 5.06–4.98 (m, 1H), 4.22–4.10 (m, 4H), 3.47–3.30 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 171.20, 166.64, 164.02, 149.31, 148.32, 141.55, 137.24, 135.95, 134.26, 131.04, 130.05, 127.75, 127.02, 126.38, 122.34, 120.56, 61.73, 60.53, 53.54, 35.53, 14.38, 14.13; LRMS (ESI): 397 [M + H]⁺; HRMS (ESI) calcd for C₂₂H₂₅N₂O₅ [M + H]⁺ 397.1763, found: 397.1756.
(2E,2′E)-Diethyl-3,3′-(2-((S)-3-ethoxy-3-oxo-2-(picolinamido)propyl)-1,3-phenylene)diacrylate (3s_di). White solid (56.4 mg, yield 38%), mp 138–139 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.55–8.50 (m, 1H), 8.47 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 15.7 Hz, 2H), 8.07–8.00 (m, 1H), 7.82–7.74 (m, 1H), 7.53 (d, J = 7.8 Hz, 2H), 7.39 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.31–7.26 (m, 1H), 6.26 (d, J = 15.6 Hz, 2H), 4.97–4.83 (m, 1H), 4.28–4.22 (m, 4H), 4.22–4.10 (m, 2H), 3.56 (dd, J = 14.5, 5.6 Hz, 1H), 3.43 (dd, J = 14.4, 8.7 Hz, 1H), 1.34 (t, J = 7.1 Hz, 6H), 1.23 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 171.00, 166.44, 163.98, 149.21, 148.28, 141.73, 137.21, 135.72, 135.32, 128.78, 127.97, 126.34, 122.30, 122.17, 61.95, 60.72, 53.43, 31.97, 14.45, 14.13; LRMS (ESI): 495 [M + H]⁺; HRMS (ESI) calcd for C₂₇H₃₁N₂O₇ [M + H]⁺ 495.2131, found: 495.2128.
(S,E)-Ethyl-3-(2-(3-ethoxy-3-oxo-2-(picolinamido)propyl)-5-methylphenyl)acrylate (3t_mono). Pale yellow oil (44.3 mg, yield 36%). ¹H NMR (400 MHz, CDCl₃) δ 8.55–8.49 (m, 1H), 8.44 (d, J = 8.4 Hz, 1H), 8.14–8.08 (m, 1H), 7.97 (d, J = 15.8 Hz, 1H), 7.84–7.75 (m, 1H), 7.43–7.33 (m, 2H), 7.14–7.06 (m, 2H), 6.27 (d, J = 15.7 Hz, 1H), 5.06–4.93 (m, 1H), 4.22–4.08 (m, 4H), 3.40 (dd, J = 14.2, 6.0 Hz, 1H), 3.29 (dd, J = 14.2, 6.7 Hz, 1H), 2.31 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 171.24, 166.68, 163.99, 149.36, 148.31, 141.70, 137.28, 137.21, 133.99, 132.96, 130.99, 130.95, 127.57, 126.33, 122.33, 120.20, 61.69, 60.46, 53.61, 35.04, 21.15, 14.38, 14.15; LRMS (ESI): 411 [M + H]⁺; HRMS (ESI) calcd for C₂₃H₂₇N₂O₅ [M + H]⁺ 411.1920, found: 411.1916.
(2E,2′E)-Diethyl-3,3′-(2-((S)-3-ethoxy-3-oxo-2-(picolinamido)propyl)-5-methyl-1,3-phenylene)diacrylate (3t_di). White solid (68.7 mg, yield 45%), mp 101–102 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.53–8.47 (m, 1H), 8.43 (d, J = 8.6 Hz, 1H), 8.07 (d, J = 15.6 Hz, 2H), 8.03–7.99 (m, 1H), 7.81–7.71 (m, 1H), 7.40–7.30 (m, 3H), 6.23 (d, J = 15.6 Hz, 2H), 4.93–4.79 (m, 1H), 4.26–4.08 (m, 6H), 3.50 (dd, J = 14.5, 5.5 Hz, 1H), 3.37 (dd, J = 14.5, 8.6 Hz, 1H), 2.30 (s, 3H), 1.31 (t, J = 7.1 Hz, 6H), 1.23 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 170.95, 166.41, 163.90, 149.16, 148.19, 141.78, 137.36, 137.11, 135.42, 132.40, 129.48, 126.23, 122.21, 121.71, 61.82, 60.56, 53.47, 31.46, 21.09, 14.35, 14.04; LRMS (ESI): 509 [M + H]⁺; HRMS (ESI) calcd for C₂₈H₃₃N₂O₇ [M + H]⁺ 509.2288, found: 509.2281.
(S,E)-Ethyl-3-(5-chloro-2-(3-ethoxy-3-oxo-2-(picolinamido)propyl)phenyl)acrylate (3u_mono). Pale yellow oil (45.4 mg, yield 35%). ¹H NMR (400 MHz, CDCl₃) δ 8.58–8.50 (m, 1H), 8.45 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 15.8 Hz, 1H), 7.84–7.75 (m, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.40 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.25–7.20 (m, 1H), 7.19–7.14 (m, 1H), 6.26 (d, J = 15.7 Hz, 1H), 5.05–4.95 (m, 1H), 4.25–4.07 (m, 4H), 3.39 (dd, J = 14.2, 6.0 Hz, 1H), 3.28 (dd, J = 14.2, 6.7 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 170.94, 166.20, 163.99, 149.14, 148.32, 140.20, 137.29, 135.91, 134.36, 133.58, 132.36, 129.84, 126.86, 126.45, 122.35, 121.72, 61.87, 60.67, 53.31, 34.96, 14.32, 14.14; LRMS (ESI): 433 ([M + H]⁺, (Cl³⁷)), 431 ([M + H]⁺, (Cl³⁵)); HRMS (ESI) calcd for C₂₂H₂₄ClN₂O₅ [M + H]⁺ 431.1374, found: 431.1365.
(2E,2′E)-Diethyl-3,3′-(5-chloro-2-((S)-3-ethoxy-3-oxo-2-(picolinamido)propyl)-1,3-phenylene)diacrylate (3u_di). White solid (55.7 mg, yield 35%), mp 83–85 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.52 (d, J = 4.2 Hz, 1H), 8.47 (d, J = 8.7 Hz, 1H), 8.09–7.97 (m, 3H), 7.82–7.76 (m, 1H), 7.53–7.44 (m, 2H), 7.40 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 6.25 (d, J = 15.6 Hz, 2H), 4.94–4.82 (m, 1H), 4.30–4.12 (m, 6H), 3.51 (dd, J = 14.5, 5.5 Hz, 1H), 3.38 (dd, J = 14.5, 8.7 Hz, 1H), 1.34 (t, J = 7.1 Hz, 6H), 1.26 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 170.65, 165.93, 163.87, 148.96, 148.18, 140.34, 137.30, 137.17, 133.70, 133.67, 128.18, 126.31, 123.09, 122.22, 61.96, 60.73, 53.06, 31.60, 14.28, 14.01; LRMS (ESI): 531 ([M + H]⁺, (Cl³⁷)), 529 ([M + H]⁺, (Cl³⁵)); HRMS (ESI) calcd for C₂₇H₃₀ClN₂O₇ [M + H]⁺ 529.1742, found: 529.1744.
(S,E)-Ethyl-2-(picolinamido)-3-(2-styrylphenyl)propanoate (3v). Yellow oil (55.4 mg, 46%). ¹H NMR (400 MHz, CDCl₃) δ 8.58–8.47 (m, 1H), 8.46–8.37 (m, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.72–7.57 (m, 2H), 7.53–7.40 (m, 3H), 7.35–7.12 (m, 7H), 6.90 (d, J = 16.0 Hz, 1H), 5.11–4.93 (m, 1H), 4.24–4.02 (m, 2H), 3.52–3.29 (m, 2H), 1.16 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 171.55, 164.09, 149.28, 148.16, 137.47, 137.16, 137.11, 134.30, 130.96, 130.80, 128.68, 127.70, 127.68, 127.63, 126.77, 126.27, 126.06, 125.70, 122.29, 61.65, 53.79, 35.89, 14.13; LRMS (ESI): 401 [M + H]⁺; HRMS (ESI) calcd for C₂₅H₂₅N₂O₃ [M + H]⁺ 401.1865, found: 401.1860.
(E)-Methyl-3-(3-methyl-2-(2-(picolinamido)ethyl)phenyl)acrylate (5a). Pale yellow oil (86.6 mg, yield 89%). ¹H NMR (400 MHz, CDCl3) δ 8.59–8.49 (m, 1H), 8.31–8.17 (m, 2H), 8.11 (d, J = 15.7 Hz, 1H), 7.90–7.82 (m, 1H), 7.46–7.38 (m, 2H), 7.23 (d, J = 7.1 Hz, 1H), 7.20–7.13 (m, 1H), 6.31 (d, J = 15.7 Hz, 1H), 3.77 (s, 3H), 3.63–3.55 (m, 2H), 3.18–3.09 (m, 2H), 2.46 (s, 3H); ¹³C NMR (101 MHz, CDCl3) δ 167.17, 164.44, 149.80, 148.02, 142.76, 137.64, 137.24, 136.68, 134.04, 132.29, 126.83, 126.10, 124.79, 122.10, 120.06, 51.61, 39.40, 29.35, 19.94; LRMS (ESI): 325 [M + H]⁺; HRMS (ESI) calcd for C₁₉H₂₁N₂O₃ [M + H]⁺ 325.1552, found: 325.1548.
(E)-Ethyl-3-(3-methyl-2-(2-(picolinamido)ethyl)phenyl)acrylate (5b). Pale yellow oil (87.2 mg, yield 86%). ¹H NMR (400 MHz, CDCl3) δ 8.59–8.49 (m, 1H), 8.26–8.16 (m, 2H), 8.10 (d, J = 15.7 Hz, 1H), 7.89–7.80 (m, 1H), 7.46–7.38 (m, 2H), 7.23 (d, J = 7.1 Hz, 1H), 7.19–7.14 (m, 1H), 6.31 (d, J = 15.7 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.63–3.54 (m, 2H), 3.18–3.09 (m, 2H), 2.46 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl3) δ 166.92, 164.53, 149.92, 148.13, 142.62, 137.75, 137.37, 136.73, 134.25, 132.32, 126.93, 126.19, 124.92, 122.22, 120.68, 60.55, 39.50, 29.49, 20.06, 14.39; LRMS (ESI): 339 [M + H]⁺; HRMS (ESI) calcd for C₂₀H₂₃N₂O₃ [M + H]⁺ 339.1709, found: 339.1706.
(E)-N-(2-Methyl-6-(3-oxopent-1-en-1-yl)phenethyl)picolinamide (5c). White solid (89.5 mg, yield 93%), mp 86–87 °C. ¹H NMR (400 MHz, CDCl3) δ 8.57–8.47 (m, 1H), 8.31–8.22 (m, 1H), 8.20 (d, J = 7.8 Hz, 1H), 8.04 (d, J = 16.0 Hz, 1H), 7.90–7.82 (m, 1H), 7.47–7.40 (m, 2H), 7.23 (d, J = 7.1 Hz, 1H), 7.20–7.14 (m, 1H), 6.57 (d, J = 16.0 Hz, 1H), 3.63–3.55 (m, 2H), 3.19–3.11 (m, 2H), 2.72 (q, J = 7.3 Hz, 2H), 2.45 (s, 3H), 1.13 (t, J = 7.3 Hz, 3H); ¹³C NMR (101 MHz, CDCl3) δ 201.28, 164.66, 149.88, 148.19, 140.41, 137.68, 137.50, 137.01, 134.60, 132.43, 128.82, 127.02, 126.34, 124.92, 122.27, 39.56, 33.64, 29.51, 20.11, 8.32; LRMS (ESI): 323 [M + H]⁺; HRMS (ESI) calcd for C₂₀H₂₃N₂O₂ [M + H]⁺ 323.1760, found: 323.1762.
(E)-Methyl-3-(3-methyl-2-(2-(picolinamido)propyl)phenyl)acrylate (5d). Pale yellow oil (91.4 mg, yield 90%). ¹H NMR (400 MHz, CDCl3) δ 8.57–8.48 (m, 1H), 8.19 (d, J = 15.7 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.87–7.78 (m, 1H), 7.41 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.23–7.19 (m, 1H), 7.17–7.10 (m, 1H), 6.25 (d, J = 15.7 Hz, 1H), 4.45–4.31 (m, 1H), 3.81 (s, 3H), 3.21 (dd, J = 13.9, 6.6 Hz, 1H), 2.99 (dd, J = 13.9, 8.0 Hz, 1H), 2.49 (s, 3H), 1.25 (d, J = 6.7 Hz, 3H); ¹³C NMR (101 MHz, CDCl3) δ 167.47, 163.58, 149.98, 148.01, 143.81, 138.04, 137.46, 136.70, 134.64, 132.44, 126.89, 126.16, 124.95, 122.28, 119.93, 51.79, 46.35, 36.08, 20.42, 20.36; LRMS (ESI): 339 [M + H]⁺; HRMS (ESI) calcd for C₂₀H₂₃N₂O₃ [M + H]⁺ 339.1709, found: 339.1708.
(E)-Ethyl-3-(3-methyl-2-(2-(picolinamido)propyl)phenyl)acrylate (5e). Pale yellow oil (93.4 mg, yield 88%). ¹H NMR (400 MHz, CDCl3) δ 8.57–8.49 (m, 1H), 8.18 (d, J = 15.7 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.86–7.78 (m, 1H), 7.43–7.34 (m, 2H), 7.23–7.17 (m, 1H), 7.16–7.10 (m, 1H), 6.25 (d, J = 15.7 Hz, 1H), 4.44–4.32 (m, 1H), 4.31–4.23 (m, 2H), 3.21 (dd, J = 13.9, 6.6 Hz, 1H), 2.99 (dd, J = 13.9, 8.0 Hz, 1H), 2.49 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H), 1.25 (d, J = 6.7 Hz, 3H); ¹³C NMR (101 MHz, CDCl3) δ 167.08, 163.55, 149.96, 147.99, 143.54, 138.00, 137.48, 136.66, 134.71, 132.37, 126.87, 126.16, 124.95, 122.29, 120.38, 60.57, 46.35, 36.08, 20.42, 20.37, 14.47; LRMS (ESI): 353 [M + H]⁺; HRMS (ESI) calcd for C₂₁H₂₅N₂O₃ [M + H]⁺ 353.1865, found: 353.1860.
(E)-N-(1-(2-Methyl-6-(3-oxopent-1-en-1-yl)phenyl)propan-2-yl)picolinamide (5f). White solid (91.6 mg, yield 91%), mp 75–76 °C. ¹H NMR (400 MHz, CDCl3) δ 8.57–8.48 (m, 1H), 8.20–8.10 (m, 2H), 8.04 (d, J = 8.0 Hz, 1H), 7.88–7.79 (m, 1H), 7.45–7.39 (m, 2H), 7.24–7.18 (m, 1H), 7.18–7.11 (m, 1H), 6.56 (d, J = 15.9 Hz, 1H), 4.41–4.29 (m, 1H), 3.28 (dd, J = 13.9, 6.2 Hz, 1H), 2.96 (dd, J = 13.9, 8.4 Hz, 1H), 2.90–2.71 (m, 2H), 2.48 (s, 3H), 1.25 (d, J = 6.7 Hz, 3H), 1.18 (t, J = 7.3 Hz, 3H); ¹³C NMR (101 MHz, CDCl3) δ 201.49, 163.63, 149.96, 148.07, 141.14, 137.98, 137.51, 136.93, 134.81, 132.45, 128.59, 126.91, 126.25, 124.93, 122.28, 46.65, 35.97, 33.64, 20.64, 20.07, 8.39; LRMS (ESI): 337 [M + H]⁺; HRMS (ESI) calcd for C₂₁H₂₅N₂O₂ [M + H]⁺ 337.1916, found: 337.1914.
(E)-Methyl-3-(3-fluoro-2-(2-(picolinamido)ethyl)phenyl)acrylate (5g). White solid (80.8 mg, yield 82%), mp 77–79 °C. ¹H NMR (400 MHz, CDCl3) δ 8.53–8.46 (m, 1H), 8.23–8.08 (m, 2H), 7.98 (d, J = 15.8 Hz, 1H), 7.87–7.79 (m, 1H), 7.40 (ddd, J = 7.6, 4.8, 1.1 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.26–7.20 (m, 1H), 7.13–7.02 (m, 1H), 6.30 (d, J = 15.8 Hz, 1H), 3.74 (s, 3H), 3.70–3.64 (m, 2H), 3.17–3.12 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 166.83, 164.45, 161.72 (d, J_C–F = 245.2 Hz), 149.86, 148.05, 140.90 (d, J_C–F = 3.5 Hz), 137.41, 136.24 (d, J_C–F = 4.5 Hz), 128.28 (d, J_C–F = 9.1 Hz), 126.21, 126.02 (d, J_C–F = 16.1 Hz), 122.60 (d, J_C–F = 3.3 Hz), 122.34, 121.33, 116.68 (d, J_C–F = 23.3 Hz), 51.85, 39.72, 25.44; LRMS (ESI): 329 [M + H]⁺; HRMS (ESI) calcd for C₁₈H₁₈FN₂O₃ [M + H]⁺ 329.1301, found: 329.1296.
(E)-Methyl-3-(3-chloro-2-(2-(picolinamido)ethyl)phenyl)acrylate (5h). White solid (81.6 mg, yield 79%), mp 93–95 °C. ¹H NMR (400 MHz, CDCl3) δ 8.53–8.47 (m, 1H), 8.21–8.09 (m, 2H), 8.04 (d, J = 15.7 Hz, 1H), 7.87–7.80 (m, 1H), 7.47–7.37 (m, 3H), 7.24–7.16 (m, 1H), 6.26 (d, J = 15.7 Hz, 1H), 3.74 (s, 3H), 3.72–3.67 (m, 2H), 3.29 (t, J = 7.2 Hz, 2H); ¹³C NMR (101 MHz, CDCl3) δ 166.74, 164.52, 149.89, 148.09, 141.81, 137.36, 136.42, 136.16, 135.76, 131.10, 128.10, 126.21, 125.70, 122.31, 121.67, 51.86, 39.00, 29.99; LRMS (ESI): 347 ([M + H]⁺, (Cl³⁷)), 345 ([M + H]⁺, (Cl³⁵)); HRMS (ESI) calcd for C₁₈H₁₈ClN₂O₃ [M + H]⁺ 345.1006, found: 345.1003.
(E)-Methyl-3-(2-(2-(picolinamido)ethyl)phenyl)acrylate (5i_mono). Pale yellow oil (50.3 mg, yield 54%). ¹H NMR (400 MHz, CDCl3) δ 8.54–8.45 (m, 1H), 8.23–8.09 (m, 2H), 8.04 (d, J = 15.8 Hz, 1H), 7.88–7.79 (m, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.41 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.37–7.31 (m, 1H), 7.30–7.23 (m, 2H), 6.35 (d, J = 15.8 Hz, 1H), 3.77 (s, 3H), 3.72–3.65 (m, 2H), 3.10 (t, J = 7.3 Hz, 2H); ¹³C NMR (101 MHz, CDCl3) δ 167.28, 164.42, 149.88, 148.10, 141.93, 138.66, 137.45, 133.61, 130.65, 130.41, 127.33, 126.95, 126.25, 122.32, 119.94, 51.82, 40.69, 33.27; LRMS (ESI): 311 [M + H]⁺; HRMS (ESI) calcd for C₁₈H₁₉N₂O₃ [M + H]⁺ 311.1396, found: 311.1397.
(2E,2′E)-Dimethyl-3,3′-(2-(2-(picolinamido)ethyl)-1,3-phenylene)diacrylate (5i_di). White solid (35.5 mg, yield 30%), mp 106–107 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.50–8.44 (m, 1H), 8.16 (d, J = 7.8 Hz, 1H), 8.14–8.06 (m, 3H), 7.83–7.78 (m, 1H), 7.56 (d, J = 7.8 Hz, 2H), 7.39 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.31–7.27 (m, 1H), 6.29 (d, J = 15.7 Hz, 2H), 3.76 (s, 6H), 3.63–3.57 (m, 2H), 3.28–3.20 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 166.92, 164.52, 149.77, 148.06, 142.07, 137.60, 137.28, 135.22, 128.76, 127.54, 126.19, 122.28, 121.42, 51.85, 40.23, 28.93; LRMS (ESI): 395 [M + H]⁺; HRMS (ESI) calcd for C₂₂H₂₃N₂O₅ [M + H]⁺ 395.1607, found: 395.1601.

Compounds 3v-1, 5c-1, 5c-2 and 5c-3 were prepared according to similar procedures described in literature: Y.-S. Zhao and G. Chen, Org. Lett., 2011, 13, 4850–4853.
(S,E)-2-((tert-Butoxycarbonyl)amino)-3-(2-styrylphenyl)propanoic acid (3v-1). Yellow oil (41.8 mg, 82%). ¹H NMR (400 MHz, DMSO) δ 12.61 (s, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.68–7.60 (m, 2H), 7.56 (d, J = 16.2 Hz, 1H), 7.42–7.36 (m, 2H), 7.32–7.20 (m, 5H), 7.17 (d, J = 16.3 Hz, 1H), 4.14–4.04 (m, 1H), 3.29 (dd, J = 14.1, 4.2 Hz, 1H), 2.96 (dd, J = 14.0, 10.0 Hz, 1H), 1.31 (s, 9H); ¹³C NMR (101 MHz, DMSO) δ 173.62, 155.53, 137.31, 136.01, 135.73, 130.77, 130.12, 128.67, 127.72, 127.34, 126.96, 126.64, 125.38, 125.29, 78.10, 54.92, 34.23, 28.13; LRMS (ESI): 390 [M + Na]⁺; HRMS (ESI) calcd for C₂₂H₂₅NO₄Na [M + Na]⁺ 390.1681, found: 390.1675.
(E)-tert-Butyl-2-methyl-6-(3-oxopent-1-en-1-yl)phenethyl(picolinoyl)carbamate (5c-1). Pale yellow oil (115.4 mg, yield 91%). ¹H NMR (400 MHz, CDCl3) δ 8.62–8.55 (m, 1H), 8.23 (d, J = 16.2 Hz, 1H), 7.86–7.79 (m, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 7.3 Hz, 1H), 7.41 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.24–7.13 (m, 2H), 6.60 (d, J = 16.2 Hz, 1H), 3.99–3.88 (m, 2H), 3.26–3.15 (m, 2H), 2.96 (q, J = 7.3 Hz, 2H), 2.49 (s, 3H), 1.19 (t, J = 7.3 Hz, 3H), 1.15 (s, 9H); ¹³C NMR (101 MHz, CDCl3) δ 202.57, 171.55, 154.83, 153.06, 148.23, 140.97, 138.02, 137.13, 136.16, 134.78, 132.28, 129.85, 127.12, 125.39, 124.68, 122.89, 83.39, 45.14, 32.22, 28.57, 27.43, 19.96, 8.64; LRMS (ESI): 445 [M + Na]⁺; HRMS (ESI) calcd for C₂₅H₃₀N₂O₄Na [M + Na]⁺ 445.2103, found: 445.2099.
tert-Butyl-5-methyl-1-(2-oxobutyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (5c-2). White solid (76.3 mg, yield 88%), mp 104–106 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.20–6.92 (m, 3H), 5.72–5.48 (m, 1H), 4.36–3.97 (m, 1H), 3.38–3.12 (m, 1H), 2.98–2.38 (m, 6H), 2.23 (s, 3H), 1.45 (s, 9H), 1.06 (t, J = 7.2 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃, rotamer peaks exist in the spectra) δ 209.02, 208.59, 154.58, 154.36, 137.13, 136.96, 136.82, 136.61, 132.94, 132.78, 128.33, 126.04, 124.87, 124.64, 80.42, 80.01, 51.90, 51.39, 50.00, 49.84, 38.06, 37.15, 36.96, 35.87, 28.47, 25.98, 25.77, 19.48, 7.76; LRMS (ESI): 340 [M + Na]⁺; HRMS (ESI) calcd for C₁₉H₂₇NO₃Na [M + Na]⁺ 340.1889, found: 340.1884.
tert-Butyl-2-methyl-6-(3-propionyloxiran-2-yl)phenethylcarbamate (5c-3). White solid (8.3 mg, yield 9%), mp 90–91 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.21–7.00 (m, 3H), 4.85–4.71 (m, 1H), 4.48–4.36 (m, 1H), 3.45–3.29 (m, 1H), 3.27–3.15 (m, 2H), 2.98–2.83 (m, 2H), 2.62 (q, J = 7.2 Hz, 2H), 2.37 (s, 3H), 1.42 (s, 9H), 1.12 (t, J = 7.2 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 207.49, 156.05, 137.00, 135.54, 134.69, 130.73, 126.97, 122.53, 79.50, 62.99, 56.29, 40.26, 30.63, 30.15, 28.50, 19.56, 7.04; LRMS (ESI): 356 [M + Na]⁺; HRMS (ESI) calcd for C₁₉H₂₇NO₄Na [M + Na]⁺ 356.1838, found: 356.1832.

Acknowledgements

We gratefully acknowledge financial support from the National Natural Science Foundation of China (No. 21602022), the Open Project Program of Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province (No. ARRLKF15-01), Chengdu University New Faculty Start-up Funding (No. 2081915037) and Zhejiang Provincial Natural Science Foundation (No. LQ14B020004).

Notes and references

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3. Recent reviews for directing group assisted C–H functionalization: (a) R.-Y. Zhu, M.-E. Farmer, Y.-Q. Chen and J.-Q. Yu, Angew. Chem., Int. Ed., 2016, 55, 10578–10599; (b) D. A. Colby, A. S. Tsai, R. G. Bergman and J. A. Ellman, Acc. Chem. Res., 2011, 45, 814–825; (c) J. J. Mousseau and A. B. Charette, Acc. Chem. Res., 2013, 46, 412–424; (d) R. Giri, B.-F. Shi, K. M. Engle, N. Maugel and J.-Q. Yu, Chem. Soc. Rev., 2009, 38, 3242–3272; (e) A. Ros, R. Fernandez and J. M. Lassaletta, Chem. Soc. Rev., 2014, 43, 3229–3243; (f) J.-D. Liu, G.-S. Chen and Z. Tan, Adv. Synth. Catal., 2016, 358, 1174–1194; (g) C. S. Yeung and V. M. Dong, Chem. Rev., 2011, 111, 1215–1292; (h) G. Rousseau and B. Breit, Angew. Chem., Int. Ed., 2011, 50, 2450–2494; (i) L. Ackermann, Acc. Chem. Res., 2014, 47, 281–295; (j) A. P. Pulis and D. J. Procter, Angew. Chem., Int. Ed., 2016, 55, 9842–9860; (k) J. L. Roizen, M. E. Harvey and J. D. Bois, Acc. Chem. Res., 2012, 45, 911–922; (l) L. Ackermann, Chem. Rev., 2011, 111, 1315–1345; (m) C. Zheng and S.-L. You, RSC Adv., 2014, 4, 6173–6214; (n) G.-F. Zha, H.-L. Qin and E. A. B. Kantchev, RSC Adv., 2016, 6, 30875–30885; (o) T. S. Lobana, RSC Adv., 2015, 5, 37231–37274; (p) S. E. Kazzouli, J. Koubachi, N. E. Brahmia and G. Guillaumet, RSC Adv., 2015, 5, 15292–15327; (q) M. Zhang, Y. Zhang, X. Jie, H. Zhao, G. Li and W. Su, Org. Chem. Front., 2014, 1, 843–895; (r) G. Qiu and J. Wu, Org. Chem. Front., 2015, 2, 169–178.
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Footnote

† Electronic supplementary information (ESI) available: Experimental details and additional spectra. See DOI: 10.1039/c7ra02574b

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