Oxidative Heck Reaction as a Tool for Para-selective Olefination of

Publication Date (Web): September 6, 2017 .... To make sure that all stationary points are smoothly connected to each other, an IRC calculation was pe...
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Oxidative Heck Reaction as a Tool for Para-selective Olefination of Aniline: A DFT Supported Mechanism Firouz Matloubi Moghaddam,* Raheleh Pourkaveh, and Ashkan Karimi Laboratory of Organic Synthesis and Natural Products, Department of Chemistry, Sharif University of Technology, Azadi Street, P.O. Box 111559516, Tehran, Iran S Supporting Information *

ABSTRACT: This study describes the first para-selective palladium-catalyzed alkenylation of tertiary amines. This regioselective C−H activation was conducted without any chelation moieties. A series of olefins were reacted under mild reaction conditions at 60 °C, and the corresponding products were obtained in good yields with high selectivity.

great efforts have been devoted to this field, and considerable advancement has been achieved from following the pioneering work by Fujiwara and Moritanin.26 Until now, only a few reports have been published on selective oxidative functionalization of arenes.27−30 In 2007, Shi’s group reported Pdcatalyzed ortho-functionalization of substituted toluenes via ortho-olefination of N,N-dimethylbenzylamines (Scheme 1a).31 In 2009, Yu and co-workers published Pd-catalyzed metaselective olefination of electron-deficient arenes by applying bulky 2,6-dialkylpyridine as a ligand at 90 °C (Scheme 1b).32 The role of the pyridine ligand on the selectivity of the oxidative Heck reaction was also investigated by Sanford and co-workers.33 In 2011, Glorius et al. reported Rh-catalyzed olefination of bromobenzene at 140 °C (Scheme 1c).34 To the best of our knowledge, this is the first report of highly para-selective olefination of tertiary anilines via non-chelateassisted C−H activation catalyzed by palladium under mild reaction conditions. In addition, density functional theory (DFT) calculations were used to assess a plausible mechanism, and the biological activity of the reaction products was evaluated by QSAR methods. In an initial attempt, N,N-diethylamine was reacted with methyl acrylate in the presence of Cu(OAc)2 as oxidant, Pd(OAc)2 as catalyst, and DCE/HOAc as solvent. After being heated in an 80 °C oil bath for 5 h, the para-selective oxidative Heck coupling product was formed in 81% yield (Table S1, entry 1). It is important to note that the nitrogen of the tertiary amine did not play a chelation role in this case to activate the ortho-position of the aryl ring. Based on this result, several factors such as solvent, oxidant, reaction temperature, and the

C

arbon−carbon bond formation is a fundamental transformation in organic chemistry. There are two ways to approach this goal: C−X activation and C−H activation. There are many synthetic methods for C−C bond construction by means of C−X activation such as Stille,1 Kumada,2 Hiyama,3 and Negishi4 reactions which suffer from the toxicity of starting material, limited functional group tolerance, and harsh reaction conditions. There are also some major economic disadvantages associated with the use of organoboron compounds as those used in the Suzuki reaction.5 Among those methods, the Mizoroki−Heck reaction is a versatile tool and has received considerable attention.6 So far, a number of efficient catalytic systems have been reported to improve origin conditions;7,8 however, all these cross-coupling reactions require a good leaving group. Furthermore, using a halide promoter results in the formation of halide salts as a byproduct.9 In order to overcome this disadvantage, an atom-economic strategy is in high demand, and this is possible via direct olefination of C(sp2)−H.8−11 Therefore, C−H activation is a suitable candidate to control the regioselectivity.12,13 Hydroarylation of alkynes via transition metal catalysis is another way to introduce an olefin into arenes.14,15 Recently, using different directing groups such as carbamate,16,17 pyrimidine,18 pyridine,19,20 and carbonyl21,22 has attracted much attention to put a functional group in a special region. By this strategy, one C− H bond in a molecule can be preferentially activated over other present C−H bonds by forming cyclometalates. However, removing and assembling a directing group on a molecule requires extra synthetic procedures which can be considered a drawback for that method. Beyond directing groups, there is an emerging field in which simple arenes without chelation moieties can induce regioselectivity.23−25 Although arenes are quite unwilling coupling partners due to C−H bond strengths, © 2017 American Chemical Society

Received: July 1, 2017 Published: September 6, 2017 10635

DOI: 10.1021/acs.joc.7b01570 J. Org. Chem. 2017, 82, 10635−10640

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The Journal of Organic Chemistry

investigated. In this case, cyclohexenone produces the reaction in high yield and the aryl ring of diethyl aniline attached at the β position of the carbonyl group (entry 3). Acrylo nitrile, styrene, vinyl acetate, and ethyl cinnamate are other examples of terminal alkenes which gave good yields for this transformation (entries 4−7). Finally, N,N-diisopropylaniline as a sterically hindered substrate was employed, and desired product in excellent yield was obtained. In all cases, para- and transisomers were observed. Although there are some mechanistic studies on ortho-C−H activation, to the best of our knowledge, there is no study on para-C−H activation. As this is the first report on paraolefination of a tertiary aniline, a more logical mechanism was proposed by employing DFT calculations with the M06 functional to report a mechanism with an optimized geometry of the structures and their energy profile as shown in Figure 1 (for more detailed mechanism, see Figure S1). Briefly, the mechanism contains an electrophilic metalation at the para-site of the aromatic ring. We compared the insertion of Pd in different sites and found that para-insertion is the most favorable because the concentration of free amine is tuned by ACOH. In the next steps, a nucleophilic attack followed by a C−C cross-coupling occurred. The rate-determining step is the conversion of INT5 to INT6 through TS3. The energy barrier of this step is 74.3 kcal/mol, which is accessible in our reaction temperature (353 K). ΔH and ΔG of the reaction of dimethylaniline and styrene (as a sample for our theoretical investigation) are 106 and 101 kcal/mol, respectively (for more details, see Supporting Information). It is important to note that trans-stiblene derivatives are known to be inhibitors of TNFα-induced activation of NF-κB. NF-κB is a family of transcription factors that has an influence on the expression of numerous genes involved in immunity and inflammation.35 Based on the experimental results,36 we evaluated the activity of our reaction products by using a QSAR model. Different molecular descriptors were produced by PaDEL software,37 and the model was performed using the chemoface program.38 The best QSAR model was obtained with R2 = 0.942, RMSE = 0.135, and F = 114.3. According to our investigations, the products exhibit high activity against activation of NF-κB. Table S2 shows the predicted IC50 values obtained from the GA-MLR method. IC50 for the products is in the range of nM, and the most reactive compound is (E)-ethyl 3-(4-(diethylamino)phenyl)-2-phenyl acrylate (Table S2, entry 7), with a predicted IC50 of 0.13 nM. According to our QSAR studies, all of the products have biological activity against activation of NK-κB, and some of them show very high activity (IC50 < 10 nM). In vivo experimental evaluation of biological activity of our products to confirm our prediction is an ongoing project in our laboratory, and the results will be reported in future publications. In conclusion, to date, various methods have been developed to introduce olefins into arenes. This study showed the art of governing regioselectivity via palladium-catalyzed Heck-type strategy without using a coordinating element. Under optimized reaction conditions, a wide range of alkenes reacted efficiently with tertiary aromatic amine, and corresponding para-selective products formed in high yields. It is important to note that electronic and steric factors of simple arenes such as N,N-dimethylaniline, N,N-diethylaniline, and N,N-diisopropylaniline are responsible for such regioselective C−H bond functionalization. In the light of DFT studies, a rational mechanism was reported, and the bioactivity of the reaction

Scheme 1. Different Strategies for Regioselective Oxidative Olefination

amount of catalyst were optimized via reaction between N,Ndiethylaniline and methyl acrylate as a model reaction. In order to find the best oxidant, different organic and inorganic oxidants such as BQ, MnO2, Ag2O, Ag2CO3, oxone, K2S2O8, and Cu(OAc)2 were tested. Among them, Cu(OAc)2 was chosen as the best oxidant. We investigated the efficiency of different solvents (Table S1, entries 8−14). According to entries 1 and 14, controlling experiments were conducted. Results showed that HOAc is essential in achieving higher yields because, in its absence, a significantly lower yield was obtained. In the presence of HOAc, the concentration of tertiary aniline is tuning. Without this acidic condition, the tertiary amine nitrogen atom binds strongly to the Pd(II) ion due to its strong σ-donor property. In the next step, the amount of catalyst required for such a transformation was optimized. Increasing the amount of catalyst up to 5 mol % reduced the reaction time (entry 17). Exploring the effect of reaction temperature showed that decreasing to 60 °C was also efficient, and there was no sensible change in reaction yield observed. Finally, it was found that the presence of a transition metal is necessary for progressing the reaction (entry 18). Notably, palladium as a transition metal catalyst proved to be crucial, and the model reaction did not proceed when conducted in the presence of nickel (entry 19). With optimum conditions in hand, the scope of the reaction with different olefins was investigated. As shown in Table 1, both terminal and internal alkenes were suitable substrates. Different acrylic esters such as methyl and butyl were reacted in high yields (entries 1, 2, and 16). However, acrylic acid could not act as an efficient substrate under optimized reaction conditions. This observation may arise from strong binding of carboxylic acid oxygen to the Pd(II) ion. Apart from acyclic alkenes, cyclic ones were also 10636

DOI: 10.1021/acs.joc.7b01570 J. Org. Chem. 2017, 82, 10635−10640

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The Journal of Organic Chemistry Table 1. Para-olefination of Tertiary Anlinesa

a Reaction conditions: amine (0.5 mmol), alkene (0.8 mmol), Cu(OAc)2 (0.5 mmol), DCE/HOAc (1.5:1, 1 mL), Pd(OAc)2 (5 mol %) at 60 °C for 5 h. bIsolated yield.

mechanistic calculations, the LANL2DZ basis set40 was set for the palladium atoms and 6-31G*41 for the others. Calculations were performed in the gas phase and 298.15 K. Conformer distribution was studied by Spartan,42 and Gaussian0943 was used for other mechanistic calculations. First frequency was utilized to assess whether intermediates and transition states were in the true optimized structure. To make sure that all stationary points are smoothly connected to each other, an IRC calculation was performed.44 General Procedure for Para-olefination of Tertiaryamines. In a typical experiment, N,N-diethylaniline (0.5 mmol, 80 μL), alkene (0.8 mmol), Cu(OAc)2 (0.5 mmol, 100 mg), and Pd(OAc)2 (5 mol %, 5 mg) were added to a sealed tube equipped with a magnetic stirring bar followed by the addition of DCE/HOAc (1.5:1, 1 mL). The reaction mixture was stirred at 60 °C in an oil bath, and the completion of the reaction was monitored using TLC (n-hexane/ethyl acetate/methanol, 25:5:2). After being completed, the reaction mixture was cooled to room temperature and diluted with water and ethyl acetate (4 × 10 mL). The organic layer was dried over anhydrous MgSO4. The solution was then filtered, and the solvent was evaporated using a rotary evaporator. The residue was purified by thin layer

products against TNFα was also evaluated by the QSAR method.

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EXPERIMENTAL SECTION

General Information. All materials used are commercially available and were purchased from Merck and used without any additional purification. Palladium acetate was purchased from SigmaAldrich with 98% purity. 1H NMR and 13C NMR spectra were recorded on a Bruker (Avance DRX-500) spectrometer using CDCl3 as solvent at room temperature. Chemical shifts δ were reported in parts per million relative to tetramethylsilane as an internal standard. FTIR spectra of samples were taken using an ABB Bomem MB-100 FTIR spectrophotometer. Gas chromatography (GC) analyses were performed on an Agilent Technologies 6890 N, equipped with a 19019 J-413 HP-5, 5% phenyl methyl siloxane, capillary column (60.0 m × 250 μm × 1.00 μm). High-resolution mass spectroscopy was performed on a JEOL GC-mate II spectrometer. Computational Information. The molecular geometries and structures were optimized with the M06 functional of theory.39 In all 10637

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6.5 Hz), 2.77 (t, 2H, J = 6.0 Hz), 3.39−3.44 (q, 6H), 6.43 (s, 1H), 6.71 (d, 2H, J = 9.0 Hz), 7.51 (d, 2H, J = 9.0 Hz); 13C NMR (125 MHz, CDCl3, ppm) δ 12.501, 22.287, 27.857, 37.400, 44.671, 11.165, 127.904, 132.527, 140.199, 146.142, 150.139, 199.328; HRMS (EI) m/ z 243.1616 (M+• C16H21NO+• requires 243.1618). (E)-3-(4-(Diethylamino)phenyl)acrylonitrile (3bd): Yield 85.1 mg (85%), yellow solid; mp 97−98 °C; 1H NMR (500 MHz, CDCl3, ppm) δ 1.13 (t, 6H, J = 7.0 Hz), 3.75−3.80 (q, 4H, J = 7.0 Hz), 5.95 (d, 1H, J = 12.5 Hz), 7.18 (d, 2H, J = 7.5), 7.36 (d, 1H, J = 12.5 Hz), 7.43 (d, 2H, J = 7.5 Hz); 13C NMR (125 MHz, CDCl3, ppm) δ 12.488, 45.044, 93.140, 112.165, 119.859, 122.198, 128.314, 150.657, 151.176; HRMS (EI) m/z 200.1307 (M+• C13H16N2+• requires 200.1308). (E)-N,N-Diethyl-4-styrylaniline (3be): Yield 100.5 mg (80%), yellow solid; mp 85−86 °C; 1H NMR (500 MHz, CDCl3, ppm) δ 0.90 (t, 6H, J = 7.0 Hz), 3.44−3.48 (q, 4H, J = 7.0 Hz), 6.65 (d, 2H, J = 9.5 Hz), 7.46 (d, 1H, J = 18.0 Hz), 7.52 (d, 1H, J = 18.0 Hz), 7.56 (d, 2H, J = 9.5 Hz), 7.59−7.66 (m, 5H); 13C NMR (125 MHz, CDCl3, ppm) δ 12.504, 45.656, 112.165, 123.767, 127.444, 128.314, 128.622, 128.707, 128.891, 137.300, 148.661; HRMS (EI) m/z 251.1670 (M+• C18H21N+• requires 251.1669). (E)-4-(Diethylamino)styryl acetate (3bf): Yield 88.6 mg (76%), yellow oil; 1H NMR (500 MHz, CDCl3, ppm) δ 1.18 (t, 6H, J = 7.0 Hz), 2.36 (s, 3H), 3.39−3.44 (q, 4H, J = 7.0 Hz), 6.30 (d, 1H, J = 16.0 Hz), 6.64 (d, 2H, J = 9.0 Hz), 7.40 (d, 2H, J = 9.0 Hz), 7.62 (d, 1H, J = 16.0 Hz); 13C NMR (125 MHz, CDCl3, ppm) δ 12.488, 20.023, 45.044, 110.111, 11.703, 130.039, 136.344, 150.657, 151.176, 169.009; HRMS (EI) m/z 233.1409 (M+• C14H19NO2+• requires 233.1410). (E)-Ethyl 3-(4-(diethylamino)phenyl)-2-phenyl acrylate (3bg): Yield 132.6 mg (82%), yellow oil; 1H NMR (500 MHz, CDCl3, ppm) δ 0.98 (t, 6H, J = 7.0 Hz), 1.23 (t, 3H, J = 7.0 Hz), 3.39−3.43 (q, 4H, J = 7 Hz), 4.31−4.35 (q, 2H, J = 7.0 Hz), 6.45 (s, 1H), 6.66 (d, 2H, J = 9.0 Hz), 7.55 (d, 2H, J = 9.0 Hz), 7.79−7.99 (m, 5H); 13C NMR (125 MHz, CDCl3, ppm) δ 13.190, 14.765, 46.638, 61.679, 110.572, 117.254, 125.154, 128.229, 128.689, 131.447, 140.356, 148.303, 152.388, 166.518; HRMS (EI) m/z 323.1880 (M +• C21H25NO2+• requires 323.1880). (E)-Methyl 3-(4-(diethylamino)phenyl)-2-methyl acrylate (3bh): Yield 102.6 mg (83%), yellow oil; 1H NMR (500 MHz, CDCl3, ppm) δ 1.21 (t, 6H, J = 7 Hz), 2.19 (s, 3H), 3.39−3.43 (q, 4H, J = 7.0 Hz), 3.81 (s, 3H), 6.68 (d, 2H, J = 9.0 Hz), 7.38 (d, 2H, J = 9.0 Hz), 7.51 (s, 1H); 13C NMR (125 MHz, CDCl3, ppm) δ 13.139, 14.765, 46.085, 52.227, 110.572,120.589, 123.767, 132.169, 138.910, 147.404, 170.414; HRMS (EI) m/z 247.1567 (M+• C15H21NO2+• requires 247.1567). (E)-3-(4-(Diethylamino)phenyl)-2-methylacrylonitrile (3bi): Yield 83.6 mg (78%), yellow oil; 1H NMR (500 MHz, CDCl3, ppm) δ 1.21 (t, 6H, J = Hz), 2.92 (s, 3H), 3.39−3.44 (q, 4H, J = 7.0 Hz), 3.79 (s, 3H), 6.64 (d, 2H, J = 9.0 Hz), 7.40 (d, 2H, J = 9.0 Hz), 7.62 (s, 1H); 13 C NMR (125 MHz, CDCl3, ppm) δ 13.139, 13.801, 46.442, 110.352, 115.394, 117.109, 122.049, 132.062, 139.568, 146.962; HRMS (EI) m/ z 214.1463 (M+• C14H18N2+• requires 214.1465). (E)-N,N-Diethyl-4-(2-phenylprop-1-en-1-yl)aniline (3bj): Yield 102.2 mg (77%), yellow oil; 1H NMR (500 MHz, CDCl3, ppm) δ 1.21 (t, 6H, J = 7.0 Hz), 1.58 (s, 2H), 3.39−3.44 (q, 4H, J = 7.0 Hz), 6.65 (d, 2H, J = 9.5 Hz), 7.07 (s, 1H), 7.50 (t, 2H, J = 7.5 Hz), 7.63 (t, 2H, J = 7.5 Hz), 7.83 (d, 1H, J = 9.5 Hz), 8.00 (d, 2H, J = 7.5 Hz); 13C NMR (125 MHz, CDCl3, ppm) δ 13.139, 18.336, 46.228, 110.514, 121.926, 122.230, 126.510, 127.835, 127.978, 132.113, 132.958, 141.338, 146.962; HRMS (EI) m/z 265.1825 (M+• C19H23N+• requires 265.1825). (E)-4-(4-(Diethylamino)phenyl)but-3-en-2-one (3bk): Yield 91.3 mg (84%), yellow oil; 1H NMR (500 MHz, CDCl3, ppm) δ 1.22 (t, 6H, J = 7.0 Hz), 2.35 (s, 3H), 3.40−3.45 (q, 4H, J = 7.0 Hz), 6.53 (d, 1H, J = 16 Hz), 6.65 (d, 2H, J = 9.0 Hz), 7.43 (d, 2H, J = 9.0 Hz), 7.45 (d, 1H, J = 16 Hz); 13C NMR (125 MHz, CDCl3, ppm) δ 12.581, 29.112, 45.312, 112.124, 128.212, 129.512, 145.450, 150.117, 198.833; HRMS (EI) m/z 217.1461 (M+• C14H19NO+• requires 217.1461). (E)-Ethyl 3-(4-(diethylamino)phenyl)but-2-enoate (3bl): Yield 100.6 mg (77%), yellow oil; 1H NMR (500 MHz, CDCl3, ppm) δ 1.24 (t, 6H, J = 7.0 Hz), 1.42 (t, 3H, J = 7.5 Hz), 2.51 (3H, s), 3.45−

Figure 1. Plausible reaction mechanism for para-olefination of tertiary aniline. chromatography on 20 cm × 20 cm silica gel plates (n-hexane/ethyl acetate/methanol, 25:5:2). Some products such as 3ba, 3bb, 3bd, 3be, 3bk, 3aa, 3ab, 3ac, 3ad, and 3ae are known compounds and have been synthesized by other methods.45−54 (E)-Methyl 3-(4-(diethylamino)phenyl)acrylate (3ba): Yield 103.8 mg (89%), yellow solid; mp 41−42 °C; 1H NMR (500 MHz, CDCl3, ppm) δ 1.21 (t, 6H, J = 7.0 Hz), 3.39−3.44 (q, 4H, J = 7.0 Hz), 3.79 (s, 3H), 6.20 (d, 1H, J = 15.5), 6.64 (d, 2H, J = 9.0), 7.40 (d, 2H, J = 9.0), 7.62 (d, 1H, J = 15.5); 13C NMR (125 MHz, CDCl3, ppm) δ 13.139, 46.228, 51.828, 110.572, 115.678, 123.033, 131.906, 144.632, 148.922, 168.062; HRMS (EI) m/z 233.1413 (M+• C14H19NO2+• requires 233.1410). (E)-Butyl 3-(4-(diethylamino)phenyl)acrylate (3bb): Yield 119.8 mg (87%), yellow oil; 1H NMR (500 MHz, CDCl3, ppm) δ 0.90 (t, 3H, J = 7.0 Hz), 1.21 (t, 3H, J = 7.0 Hz), 1.49−1.60 (m, 2H), 1.69− 1.83 (m, 2H), 3.39−3.43 (q, 4H, J = 7.0 Hz), 4.23 (t, 2H, J = 7 Hz), 6.20 (d, 1H, J = 15.5 Hz), 6.68 (d, 2H, J = 9 Hz), 7.51 (d, 2H, J = 9 Hz), 7.62 (d, 1H, J = 15.5 Hz); 13C NMR (125 MHz, CDCl3, ppm) δ 12.767, 13.862, 20.127, 32.624, 45.733, 66.267, 112.824, 117.589, 128.921, 134.128, 145.083, 150.251, 169.160; HRMS (EI) m/z 275.1883 (M+• C17H25NO2+• requires 275.1880). 4′-(Diethylamino)-5,6-dihydro-[1,1′-biphenyl]-3(4H)-one (3bc): Yield 119.2 mg (89%), yellow oil; 1H NMR (500 MHz, CDCl3, ppm) δ 1.21 (t, 6H, J = 7.0 Hz), 2.12−2.19 (m, 2H), 2.47 (t, 2H, J = 10638

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3.49 (q, 4H, J = 7.0 Hz), 4.31−4.36 (q, 2H, J = 7.5 Hz), 5.41 (s, 1H), 7.72 (d, 2H, J = 9.0 Hz), 7.89 (d, 2H, J = 9.0 Hz); 13C NMR (125 MHz, CDCl3, ppm) δ 13.322, 14.884, 18.116, 46.228, 61.316, 112.406, 117.787, 126.189, 129.996, 148.070, 153.857, 168.565; HRMS (EI) m/ z 261.1726 (M+• C16H23NO2+• requires 261.1723). 4′-(Dimethylamino)-5,6-dihydro-[1,1′-biphenyl]-3(4H)-one (3aa): Yield 92.5 mg (86%), yellow solid; mp 136−137 °C; 1H NMR (500 MHz, CDCl3, ppm) δ 2.12−2.19 (m, 2H), 2.47 (t, 2H, J = 6.5 Hz), 2.77 (t, 2H, J = 6.0 Hz), 6.43 (s, 1H), 6.71 (d, 2H, J = 9.0 Hz), 7.51 (d, 2H, J = 9.0 Hz); 13C NMR (125 MHz, CDCl3, ppm) δ 22.165, 27.767, 37.565, 40.322, 112.580, 127.856, 132.661, 140.219, 146.322, 151.301, 200.029; HRMS (EI) m/z 215.1302 (M+• C14H17NO+• requires 215.1305). (E)-N,N-Dimethyl-4-(2-phenylprop-1-en-1-yl)aniline (3ab): Yield 99.7 mg (84%), yellow oil; 1H NMR (500 MHz, CDCl3, ppm) δ 1.58 (s, 3H), 2.92 (s, 6H), 6.65 (d, 2H, J = 9.5 Hz), 7.07 (s, 1H), 7.50 (t, 2H, J = 7.5 Hz), 7.63 (t, 2H, J = 7.5 Hz), 7.83 (d, 1H, J = 9.5 Hz), 8.00 (d, 2H, J = 7.5 Hz); 13C NMR (125 MHz, CDCl3, ppm) δ 18.547, 42.192, 112.406, 122.859, 126.510, 126.546, 127.799, 127.978, 130.392, 132.958, 141.691, 149.989; HRMS (EI) m/z 237.1512 (M+• C17H19N+• requires 237.1512). (E)-Methyl 3-(4-(dimethylamino)phenyl)acrylate (3ac): Yield 88.2 mg (86%), yellow solid; mp 134−136 °C; 1H NMR (500 MHz, CDCl3, ppm) δ 3.42 (s, 6H), 3.79 (s, 3H), 6.20 (d, 1H, J = 15.5), 6.64 (d, 2H, J = 9.0), 7.40 (d, 2H, J = 9.0), 7.62 (d, 1H, J = 15.5); 13C NMR (125 MHz, CDCl3, ppm) δ 13.322, 14.884, 18.116, 46.228, 61.316, 112.406, 117.787, 126.189, 129.996, 148.070, 153.857, 168.565; HRMS (EI) m/z 205.1094 (M+• C12H15NO2+• requires 205.1097). (E)-Butyl 3-(4-(dimethylamino)phenyl)acrylate (3ad): Yield 103.9 mg (84%), yellow oil; 1H NMR (500 MHz, CDCl3, ppm) δ 0.90 (t, 3H, J = 6.5 Hz), 1.15−122 (m, 2H), 1.28−1.40 (m, 2H), 3.40 (s, 6H), 3.79−3.84 (q, 2H), 6.20 (d, 1H, J = 15.5 Hz), 6.64 (d, 2H, J = 9.0 Hz), 7.40 (d, 2H, J = 9.0 Hz), 7.62 (d, 1H, J = 15.5 Hz); 13C NMR (125 MHz, CDCl3, ppm) δ 14.051, 19.828, 31.155, 40.065, 66.267, 112.625, 117.479, 129.001, 134.071, 145.155, 150.316, 170.071; HRMS (EI) m/ z 247.1567 (M+• C15H21NO2+• requires 247.1567). (E)-N,N-Dimethyl-4-styrylaniline (3ae): Yield 78.1 mg (70%), yellow solid; mp 147−148 °C; 1H NMR (500 MHz, CDCl3, ppm) δ 2.97 (s, 6H), 6.64 (d, 2H, J = 9.5 Hz), 7.45 (d, 1H, J = 18.0 Hz), 7.51 (d, 1H, J = 18.0 Hz), 7.55 (d, 2H, J = 9.5 Hz), 7.60−7.67 (m, 5H); 13C NMR (125 MHz, CDCl3, ppm) δ 40.065, 11.913, 122.704, 127.768, 128.390, 128.804, 128.891, 130.039, 138.031, 151.301; HRMS (EI) m/ z 223.1353 (M+• C16H17N+• requires 223.1356). (E)-Methyl 3-(4-(diisopropylamino)phenyl)acrylate (3ca): Yield 115.8 mg (90%), yellow oil; 1H NMR (500 MHz, CDCl3, ppm) δ 1.76 (d, 12H, J = 6.5 Hz), 2.77−2.85 (m, 2H), 3.67 (s, 3H), 6.37 (d, 1H, J = 16 Hz), 6.67 (d, 2H, J = 9 Hz), 7.26 (d, 2H, J = 9 Hz), 7.72 (d, 1H, J = 16 Hz); 13C NMR (125 MHz, CDCl3, ppm) δ 23.3, 52.5, 55.3, 114.4, 116.0, 122.7, 132.2, 144.6, 146.1, 169.4; HRMS (EI) m/z 261.1729 (M+• C16H23NO2+• requires 261.1723).

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ACKNOWLEDGMENTS We are grateful to Xiuling Cui for the HRMS analyses, and the Sharif University of Technology (SUT) for the research grant attributed to this project.

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REFERENCES

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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.7b01570. 1

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Note

H and 13C NMR spectra of the synthesized starting materials and products (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. 10639

DOI: 10.1021/acs.joc.7b01570 J. Org. Chem. 2017, 82, 10635−10640

Note

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