Synthesis of Amides and Nitriles from Vinyl Azides and p-Quinone

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Synthesis of Amides and Nitriles from Vinyl Azides and para-Quinone Methides Chen Lin, Yangyong Shen, Bo Huang, Yu Liu, and Sunliang Cui J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00145 • Publication Date (Web): 16 Mar 2017 Downloaded from http://pubs.acs.org on March 16, 2017

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The Journal of Organic Chemistry

Synthesis of Amides and Nitriles from Vinyl Azides and paraQuinone Methides Chen Lin,† Yangyong Shen,† Bo Huang,† Yu Liu,‡ and Sunliang Cui*,† †

Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China Sate Key Laboratory of Plant Physiology and Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou 310058, China Supporting Information Placeholder ‡

ABSTRACT: A divergent synthesis of amides and nitriles from vinyl azides and para-Quinone Methides (p-QMs) were developed. The p-QMs could be activated by BF3-Et2O and then nucleophilic attacked by vinyl azides for leading to divergent rearrangement toward amides and nitriles.

Vinyl azides have acted as powerful synthons for the construction of nitrogen heterocycles, and recently a simple access to vinyl azides from alkynes has been invented by Bi.1 Hassner and Moore revealed that the vinyl azides could be protonated and undergo Schmidt-type migration to generate nitrilium ion with the elimination of nitrogen gas.2 Recently, Chiba and coworkers reported that the vinyl azides could also act as enamine-type nucleophile and undergo Schmidt-type migration for synthesis of amides.3 Bi then applied this method for the construction of 4-yamides.4 These protocols showed that the vinyl azides could serve as amide precursor in a mild reaction condition. Very recently, Liu revealed that vinyl azides could alternatively serve as ketone precursors in radical reaction.5 Meanwhile, Jiao and co-workers established an impressive silver-catalyzed direct approach to nitriles via vinyl azides intermediates.6 Therefore, the exploration of new reactivities of vinyl azides toward divergent synthesis remains important and interesting. para-Quinone methides (p-QMs) are structurally characterized by assembly of carbonyl and olefinic moieties, exhibiting unique chemical reactivity toward phenol synthesis.7 Recently, the p-QMs have been widely investigated in various addition reaction as versatile Michael acceptor.8 Fan and co-workers have developed the asymmetric addition reaction of malonates to p-QMs for accessing chiral functionalized diarylmethines.9 Meanwhile, Jørgensen, Liao, Tortosa and Li have independently developed the asymmetric addition reaction of p-QMs with enamines, borane and thioester.10 Interestingly, Deng, Enders and Fan also reported an asymmetric addition of pQMs with glycine Schiff base and oxindoles.11 On the other hand, Yao and Lin explored the addition of p-QMs with dicyano olefins, sulphur ylides and vinyl cyclopropanes.12 In continuation of our efforts in heterocycles synthesis and p-QMs transformation,13 we hypothesized that the combination of vinyl azides and p-QMs might lead to interesting

Figure 1.Synthesis of Amides and Nitriles from Vinyl Azides and p-QMs.

products formation. Herein, we would like to report a facile synthesis of amides and nitriles from vinyl azides and p-QMs (Figure 1). And it should be noted that the vinyl azides were first observed as nitriles precursor. We commenced our study by investigating the reaction of phenyl substituted vinyl azide 1a and para-quinone methide 2a, and BF3-Et2O was used as Lewis acid (Table 1). When the reaction was conducted without additives, no products were observed (entry 1). The addition of TFA was found to lead to trace product formation (entry 2). Gratifyingly, when 1

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equivalent amount of AcOH was utilized as additive (entry 3), an amide product 3a was isolated in 32% yield. The next attempt to increase the temperature to room temperature resulted in an improvement of the yield to 40% (entry 4). When AcOH was added in 2 equivalent amounts, 3a could be obtained in 59% yield (entry 5). Variation of the additive from AcOH to H2O would dramatically improve the yield to 75%, probably because H2O could convert the nitrilium immediate to amide motif more efficiently (entry 6). When the temperature was increased to 60 oC, the yield would be dimished to 42% (entry 7). When MeOH was used as additive (entry 8), the amide product could only be formed in 17% yield.

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in good yields (3r-3s). Considering the wealth of these phenol containing amides in biological research, this method provides a simple and efficient method toward their construction. Table 2. Synthesis of Amidesa

Table 1. Reaction Optimizationa

Entry

Additive

T (oC)

Yield (%)

1b

none

rt

0

2b

TFA

0

< 5%

3b

AcOH

0

32

4b

AcOH

rt

40

5c

AcOH

rt

59

6c

H2O

rt

75

7c

H2O

60

42

MeOH

rt

17

c

8 a

Reaction condition: 1a (0.4 mmol), 2a (0.2 mmol), BF3Et2O (0.4 mmol), 1 hr, yields refer to isolated products. b additive (0.2 mmol). cadditive (0.4 mmol). With the optimized reaction condition in hand, we set out to investigate the substrate scope (Table 2). Various p-QMs could proceed well in this process. For example, the 4substituted p-QMs, regardless of the electron-donating or electron-withdrawing substitution, could proceed smoothly with vinyl azide 1a to deliver the phenol containing amides in good yields, with valuable substitution like methoxy, chloro, ester, cyano, and nitro (3b-3g). Additionally, the ortho-, meta- and polysubstituted p-QMs were also well amenable in this process (3h-3j). Moreover, the structure of 3e was confirmed by X-ray analysis.14 In addition, the heterocyclic and fused aryl moieties like 2-naphthyl, thiophene tethered p-QMs were found applicable to furnish the amides in good yields (3k-3l). Interestingly, the alkyl substituted p-QM 1g was also found compatible to this process to deliver the amide 3m in excellent yield. On the other hand, various vinyl azides were also employed to explore the generality of this amide synthesis protocol. As depicted in Table 2, the functionalized aromatic ring tethered vinyl azides served as amides precursors well to afford the corresponding products in good to excellent yields (3n-3q). Furthermore, the 2-naphthyl and butyl substituted vinyl azides were also found applicable to generate the amides

a

Reaction conditions: 1 (0.4 mmol), 2 (0.2 mmol), BF3-Et2O (0.4 mmol), H2O (0.4 mmol), DCM, rt, 1 hr, yields refer to isolated products.

Interestingly, when the tertiary alcohol tethered vinyl azide 1h was subject to this process with 2a, a sole product 4a was formed. The characterization excluded 4a as amide product. The next removal of H2O gave the same results and 4a could be isolated in 71% yield. The standard identification showed that the product should be a nitrile compound. This indicated that the alcohol moiety was cleaved and this process was different from the previous rearrangement. Next, a variety of pQMs, with diverse functional group, 2-naphthyl and thiophene, were utilized to test the generality of this scope (Table 3). As shown in Table 3, the p-QMs could all convert to the phenol containing nitriles upon the reaction with 1h. The structure of 4j was confirmed by X-ray analysis.15 Thus the vinyl azide 1h acted as an acetonitrile precursor in this process, which could be further extended in nitriles synthesis. To unravel the synthetic utility, the de-tert-butylation was conducted (Figure 2). For example, when the amide 3a was treated with AlCl3, it could be easily de-tert-butylated to deliver the product 5 in excellent yield, which represents a privileged structure motif in medicinal chemistry. Meanwhile, the nitrile 4a could convert to 6 with the same method. Therefore, this method could provide direct approach in the construction of these compounds.

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Table 3. Synthesis of Nitrilesa

In summary, a divergent synthesis of amides and nitriles from p-QMs and vinyl azides were developed. The process is mild and efficient, along with broad substrate scope. Moreover, the vinyl azides not only act as amide precursor, but also serve as nitriles precursor, which could be further extended in divergent synthesis.

EXPERIMENTAL SECTION

a Reaction conditions: 1h (0.4 mmol), 2 (0.2 mmol), BF3-Et2O (0.4 mmol), DCM, rt, 1 hr, yields refer to isolated products.

Figure 2. De-tert-butylation of Amides and Nitriles. The possible reaction mechanism was depicted in Figure 3. The p-QMs were activated by BF3-Et2O and attacked by vinyl azides 1 to be intermediate A. A divergent transformation occurs at this stage. For the phenyl and alkyl substituted vinyl azides, A undergoes the Schmidt rearrangement to form nitrilium ion B, which is added by H2O to form amide product 3. Respecting to 1h, C occurs elimination rather than the Schmidt rearrangement, with release of nitrogen gas and acetone to give nitrile product 4. Thus these processes constitute the divergent synthesis of amides and nitriles.

Figure 3. Possible Reaction Mechanism.

General Methods. Infrared spectra were obtained on a FTIR spectrometer. 1H NMR and 13C NMR spectra were recorded on BRUKER AVANCE III 400, BRUKER AVANCE III 500 and BRUKER AVANCE III 600 spectrometer. CDCl3 and (CD3)2CO were used as solvent. Chemical shifts were referenced relative to residual solvent. The following abbreviations are used to describe peak patterns where appropriate: br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dq = double quartet. Coupling constants (J) are reported in Hertz (Hz). HRMS were performed on Waters GCT Premier Time of Flight Mass Spectrometer (EI). Melting points were measured with micro melting point apparatus. Ethyl acetate (EA), Petroleum ether (PE), BF3-Et2O and Dichloromethane (DCM) were commercial available. All Vinyl azides (1a-1h) and p-QMs (2a-2q) were prepared according to the literature.16,17 Typical Procedure for Synthesis of 3a. A Schlenk tube containing 2a (58.8 mg, 0.2mmol), the mixture of 1a (0.4 mmol), H2O (7.2 mg, 0.4 mmol), and DCM (2 mL) were added. Then, BF3-Et2O (0.4 mmol) was added dropwise via syringe and the reaction was kept at room temperature for about 1 hr. Then the solution was diluted with EA and transferred to a round bottom flask. Silica was added to the flask and volatiles were evaporated under vacuum. The purification was performed by flash column chromatography on silica gel using EA/PE (v/v, 1:10) as eluent to get 3a as a white solid. (64.4 mg, 75% yield). 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-N,3diphenylpropanamide (3a). White solid (64.4 mg, 75% yield), mp 193-195oC, Rf = 0.2 (EA/PE, v/v = 1:20). 1H NMR (CDCl3, 500MHz), δ: 7.32-7.31 (m, 4H), 7.23-7.20 (m, 5H), 7.07-7.04 (m, 3H), 6.73 (s, 1H), 5.10 (s, 1H), 4.50 (t, J = 8.0 Hz,1H), 3.04 (d, J = 8.0 Hz, 2H), 1.38 (s, 18H); 13C NMR (CDCl3, 100MHz) δ: 169.9, 152.6, 144.0, 137.8, 136.2, 134.1, 129.0, 128.8, 127.8, 126.7, 124.8, 119.9, 47.9, 45.5, 34.5, 30.4; IR (KBr) v: 3646, 3437, 3286, 2953, 1661, 1598, 1546, 1437, 1322, 1234, 1150, 755, 692 cm-1; HRMS (EI) (m/z): calcd for C29H35NO2 (M+): 429.2668; Found: 429.2672. 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-N-phenyl-3-(ptolyl)propanamide (3b).White solid (60.2 mg, 68% yield), mp 211-213 oC, Rf = 0.2 (EA/PE, v/v = 1:20). 1H NMR (CDCl3, 500MHz), δ: 7.30-7.23 (m, 6H), 7.16-7.15 (m, 2H), 7.11 (s, 2H), 7.09-7.06 (m, 1H), 6.87 (s, 1H), 5.14 (s,1H), 4.49 (t, J = 7.5 Hz,1H), 3.07 (d, J = 7.5 Hz, 2H), 2.35 (s, 3H), 1.39 (s, 18H); 13C NMR (CDCl3, 100MHz) δ: 170.0, 152.6, 141.0, 137.8, 136.2, 134.3, 129.5, 129.0, 127.6, 124.3, 124.3, 119.9, 47.5, 45.5, 34.5, 30.4, 21.1; IR (KBr) v: 3635, 3452, 3265, 2947, 1661, 1598, 1541, 1431, 1317, 1239, 1160, 1035, 749, 686 cm-1; HRMS (EI) (m/z): calcd for C30H37NO2 (M+): 443.2824; Found: 443.2826.

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3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-(4methoxyphenyl)-N-phenylpropanamide (3c). White solid (69.8 mg, 76% yield), mp 191-192 oC, Rf = 0.2 (EA/PE, v/v = 1:10). 1H NMR (CDCl3, 400MHz), δ: 7.24-7.21 (m, 6H), 7.067.02 (m, 3H), 6.86-6.81 (m, 3H), 5.10 (s,1H), 4.45 (t, J = 7.8 Hz,1H), 3.78 (s, 3H), 3.01 (d, J = 7.8 Hz, 2H), 1.39 (s, 18H); 13 C NMR (CDCl3, 100MHz) δ: 170.0, 158.3, 152.5, 137.8, 136.2, 136.1, 134.4, 129.0, 128.8, 124.3, 119.9, 114.2, 55.4, 47.1, 45.6, 34.5, 30.4; IR (KBr) v: 3635, 3467, 3281, 2948, 1661, 1609, 1546, 1505, 1442, 1249, 1176, 1035, 749, 693 cm1 ; HRMS (EI) (m/z): calcd for C30H37NO3 (M+): 459.2773; Found: 459.2776.

3-(2-Chlorophenyl)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)N-phenylpropanamide (3h). White solid (69.6 mg, 75% yield), mp 223-226 oC, Rf = 0.3 (EA/PE, v/v = 1:10). 1H NMR (CDCl3, 500MHz), δ: 7.32-7.34 (m, 2H), 7.28-7.26 (m, 2H), 7.25-7.22 (m, 3H), 7.17-7.12 (m, 3H), 7.06-7.03 (m, 1H), 6.90 (s, 1H), 5.12 (s, 1H), 5.00 (t, J = 7.5 Hz, 1H), 3.08 (d, J = 7.5 Hz, 2H), 1.38 (s, 18H); 13C NMR (CDCl3, 100MHz) δ: 169.3, 152.7, 141.4, 137.8 136.2, 134.1, 132.4, 129.0, 128.1, 127.9, 127.2, 124.6, 124.4,119.9, 44.2, 43.7, 34.5, 30.4; IR (KBr) v: 3630, 3437, 3286, 2958, 1661, 1598, 1535, 1437, 1364, 1311, 1150, 749, 687 cm-1; HRMS (EI) (m/z): calcd for C29H34ClNO2 (M+): 463.2278; Found: 463.2282.

3-(4-Chlorophenyl)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)N-phenylpropanamide (3d). White solid (73.3 mg, 79% yield), mp 213-215 oC, Rf = 0.2 (EA/PE, v/v = 1:20). 1H NMR (CDCl3, 500MHz), δ: 7.28-7.22 (m, 8H), 7.07-7.03 (m, 3H), 6.83 (s, 1H), 5.13 (s,1H), 4.51 (t, J = 7.5 Hz, 1H), 3.02 (dd, J1 = 7.5 Hz, J2 = 14.0 Hz, 1H), 2.98 (dd, J1 = 7.5 Hz, J2 = 14.0 Hz, 1H), 1.38 (s, 18H); 13C NMR (CDCl3, 100MHz) δ: 169.5, 152.7, 142.6, 137.7, 136.4, 133.7, 132.3, 129.2, 129.0, 128.8, 124.5, 124.3, 120.0, 47.0, 45.1, 34.5, 30.4; IR (KBr) v: 3640, 3427, 3291, 2958, 1656, 1598, 1546, 1499, 1160, 1108, 759, 692 cm-1; HRMS (EI) (m/z): calcd for C29H34ClNO2 (M+): 463.2278; Found: 463.2284.

3-(3-Bromophenyl)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)N-phenylpropanamide (3i). White solid (81.2 mg, 80% yield), mp 216-218 oC, Rf = 0.3 (EA/PE, v/v = 1:10). 1H NMR (CDCl3, 600MHz), δ: 7.44 (s, 1H), 7.34-7.33 (m, 1H), 7.267.23 (m, 5H), 7.18-7.16 (m, 1H), 7.07-7.03 (m, 3H), 6.81 (s, 1H), 5.13 (s, 1H), 4.50 (t, J = 7.8 Hz,1H), 3.00 (q, J1 = 1.2 Hz, J2 = 7.8 Hz, 2H), 1.38 (s, 18H); 13C NMR (CDCl3, 150MHz) δ: 169.4, 152.8, 146.5, 137.7, 136.4, 133.4, 131.0, 130.3, 129.8, 129.1, 126.5, 124.5, 124.4, 122.8, 120.0, 47.4, 45.1, 34.6, 30.4; IR (KBr) v: 3630, 3483, 3285, 2956, 2364, 1655, 1599, 1549, 1497, 1431, 1366, 1158, 748, 692 cm-1; HRMS (EI) (m/z): calcd for C29H34BrNO2 (M+): 507.1773; Found: 507.1769.

Methyl-4-(1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-oxo-3(phenylamino)propyl)benzoate (3e). White solid (55.5 mg, 57% yield), mp 197-198 oC, Rf = 0.1 (EA/PE, v/v = 1:10). 1H NMR (CDCl3, 400MHz), δ: 7.98-7.96 (m, 2H), 7.38-7.36 (m, 2H), 7.28-7.22 (m, 4H), 7.07-7.03 (m, 3H), 6.94 (s, 1H), 5.13 (s, 1H), 4.60 (t, J = 7.6 Hz,1H), 3.9 (s, 3H), 3.052 (d, J = 7.6 Hz, 2H), 1.37 (s, 18H); 13C NMR (CDCl3, 100MHz) δ: 169.4, 167.2, 152.8, 149.4, 137.7, 136.4, 133.4, 130.1, 129.0, 128.48, 127.9, 124.5, 119.9, 52.2, 47.6, 44.5, 34.5, 30.4; IR (KBr) v: 3609, 3354, 2948, 1687, 1608.8, 1525, 1437, 1291, 1114, 1024, 785, 687 cm-1; HRMS (EI) (m/z): calcd for C31H37NO4 (M+): 487.2773; Found: 487.2776.

3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-(3,4dimethoxyphenyl)-N-phenylpropanamide (3j). Colorless oil (59.6 mg, 61% yield), Rf = 0.3 (EA/PE, v/v = 1:5). 1H NMR (CDCl3, 400MHz), δ: 7.26-7.24 (m, 4H), 7.08-7.04 (m, 3H), 6.86-6.81 (m, 4H), 5.11 (s, 1H), 4.45 (t, J = 7.6 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.01 (d, J = 7.6 Hz, 2H), 1.39 (s, 18H); 13 C NMR (CDCl3, 100MHz) δ: 170.0, 152.6, 149.0, 147.7 137.8, 136.6, 136.2, 134.2, 129.0, 124.3, 124.3, 119.5, 111.5, 111.3, 56.0, 55.9, 47.4, 45.8, 34.5, 30.4; IR (KBr) v: 3620, 3458, 3312, 2942, 1666, 1520, 1431, 1365, 1324, 1243, 1140, 1025, 1158, 755 cm-1; HRMS (EI) (m/z): calcd for C31H39NO4 (M+): 489.2879; Found: 489.2875.

3-(4-Cyanophenyl)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)N-phenylpropanamide (3f). White solid (66.2 mg, 73% yield), mp 96-98 oC, Rf = 0.2 (EA/PE, v/v = 1:10). 1H NMR (CDCl3, 500MHz), δ: 7.59-7.57 (m, 2H), 7.41-7.39 (m, 2H), 7.30-7.24 (m, 4H), 7.09-7.06 (m, 1H), 7.00 (s, 3H), 5.16 (s,1H), 4.62 (t, J = 8.0 Hz,1H), 3.06 (dd, J1 = 8.0 Hz, J2 = 14.5 Hz, 1H), 3.01 (dd, J1 = 8.0 Hz, J2 = 14.5 Hz, 1H), 1.38 (s, 18H); 13C NMR (CDCl3, 100MHz) δ: 169.1, 152.9, 149.8, 137.6, 136.5, 132.8, 132.5, 129.1, 128.7, 124.6, 124.3, 120.0, 110.3, 47.5, 44.4, 34.5, 30.3; IR (KBr) v: 3637, 3453, 2953, 2224, 1661, 1604, 1546, 1442, 1239, 1134, 754, 697 cm-1; HRMS (EI) (m/z): calcd for C30H34N2O2 (M+): 454.2620; Found: 454.2622.

3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-(naphthalen-2-yl)N-phenylpropanamide (3k). White solid (59.4 mg, 62% yield), mp 230-231 oC, Rf = 0.2 (EA/PE, v/v = 1:10). 1H NMR (CDCl3, 500MHz), δ: 8.25-8.23 (m, 1H), 7.86-7.84 (m, 1H), 7.76-7.74 (m, 1H), 7.53-7.43 (m, 4H), 7.23-7.22(m, 4H), 7.147.12 (m, 2H), 7.05-7.03 (m, 1H), 6.80 (s, 1H), 5.34 (dd, J1 = 6.5 Hz, J2 = 8.5 Hz,1H), 5.08 (s, 1H), 3.19 (dd, J1 = 6.5 Hz, J2 = 14.2 Hz, 1H), 3.13 (dd, J1 = 8.5 Hz, J2 = 14.2 Hz, 1H), 1.34 (s, 18H); 13C NMR (CDCl3, 150MHz) δ: 170.0, 152.6, 139.8, 137.8 136.2, 134.2, 133.6, 131.7, 129.0, 128.9, 127.5, 126.3, 125.70, 125.4, 124.5, 124.3, 124.1, 124.0, 119.8, 45.6, 43.1, 34.5, 30.4; IR (KBr) v: 3635, 3453, 3271, 3068, 2951,1660, 1594, 1543, 1493, 1437, 1366, 1239, 1148, 961, 758 cm-1; HRMS (EI) (m/z): calcd for C33H37NO2 (M+): 479.2824; Found: 479.2826.

3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-(4-nitrophenyl)N-phenylpropanamide (3g). White solid (73.9 mg, 78% yield), mp 108-110 oC, Rf = 0.1 (EA/PE, v/v = 1:10). 1H NMR (CDCl3, 500MHz), δ: 8.16-8.14 (m, 2H), 7.47-7.45 (m, 2H), 7.32-7.30 (m, 2H), 7.27-7.24 (m, 2H), 7.09-7.05 (m, 2H), 7.01 (s, 2H), 5.17 (s, 1H), 4.68 (t, J = 7.8 Hz, 1H), 3.08-3.06 (m, 2H), 1.38 (s, 18H); 13C NMR (CDCl3, 100MHz) δ: 169.7, 153.0, 152.0, 146.6 137.6, 136.6, 132.7, 129.1, 128.7, 124.6, 124.3, 124.0, 120.0, 47.3, 44.3, 34.5, 30.3; IR (KBr) v: 3630, 3406, 3291, 2963, 1666, 1598, 1525, 1437, 1348, 1233, 1160, 755, 697 cm-1; HRMS (EI) (m/z): calcd for C29H34N2O4 (M+): 474.2519; Found: 474.2515.

3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-N-phenyl-3(thiophen-2-yl)propanamide (3l). White solid (63.5 mg, 73% yield), mp 172-175 oC, Rf = 0.3 (EA/PE, v/v = 1:10). 1H NMR (CDCl3, 500MHz), δ: 7.27-7.23 (m, 4H), 7.18-7.14 (m, 3H), 7.07-7.04 (m, 1H), 6.93-6.90 (m, 2H), 6.86(s, 1H), 5.15 (s, 1H), 4.76 (t, J = 7.5 Hz, 1H), 3.08 (dd, J1 = 8.0 Hz, J2 = 14.0 Hz, 1H), 3.00 (dd, J1 = 7.5 Hz, J2 = 14.0 Hz, 1H), 1.40 (s, 18H); 13C NMR (CDCl3, 100MHz) δ: 169.2, 152.9, 148.1, 137.7 136.3, 133.7, 129.0, 126.9, 124.4, 124.0, 119.9, 47.1,

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43.7, 34.5, 30.4; IR (KBr) v: 3630,3281, 3057, 2953, 2903, 2864, 1666, 1598, 1551, 1437, 1312, 1234, 1150, 968, 754, 692 cm-1; HRMS (EI) (m/z): calcd for C27H33NO2S (M+): 435.2232; Found: 435.2229. 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-Nphenylbutanamide (3m). White solid (63.1 mg, 86% yield), mp 177-179 oC, Rf = 0.2 (EA/PE, v/v = 1:10). 1H NMR (CDCl3, 400MHz), δ: 7.31-7.23 (m, 4H), 7.06-7.03 (m, 3H), 6.77 (s, 1H), 5.12 (s, 1H), 3.26 (m, 1H), 2.61 (dd, J1 = 7.2 Hz, J2 = 14.0 Hz, 1H), 2.54 (dd, J1 = 7.2 Hz, J2 = 14.0 Hz, 1H), 1.42 (s, 18H), 1.37 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 100MHz) δ: 170.4, 152.5, 137.9, 136.3, 136.10, 129.0, 124.2, 123.3, 119.7, 47.7, 37.3, 34.5, 30.4, 21.9; IR (KBr) v: 3646, 3437, 3265, 3135, 2958, 1656, 1598, 1540, 1494, 1364, 1317, 1228, 1145, 957, 749, 683 cm-1; HRMS (EI) (m/z): calcd for C24H33NO2 (M+): 367.2511; Found: 367.2513. 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-phenyl-N-(ptolyl)propanamide (3n). White solid (63.8 mg, 72% yield), mp 212-214 oC, Rf = 0.2 (EA/PE, v/v = 1:20). 1H NMR (CDCl3, 400MHz), δ: 7.32-7.30 (m, 4H), 7.23-7.20 (m, 1H), 7.11-7.08 (m, 4H), 7.04-7.02 (m, 2H), 6.78 (s, 1H), 5.11 (s, 1H), 4.50 (t, J = 7.6 Hz, 1H), 3.03 (d, J = 7.6 Hz, 2H), 2.27 (s, 3H), 1.39 (s, 18H); 13C NMR (CDCl3, 100MHz) δ: 169.7, 152.5, 144.0, 136.1 135.1, 134.1, 133.9, 129.4, 126.6, 124.3, 120.0, 47.8, 45.3, 34.5, 30.4, 20.9; IR (KBr) v: 3646, 3437, 3281, 3175, 2958, 1655, 1604, 1541, 1437, 1322, 1234, 1176, 1145, 817, 701 cm-1; HRMS (EI) (m/z): calcd for C30H37NO2 (M+): 443.2824; Found: 443.2828. 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-N-(4methoxyphenyl)-3-phenylpropanamide (3o). White solid (56.9 mg, 65% yield), mp 187-189 oC, Rf = 0.2 (EA/PE, v/v = 1:10). 1H NMR (CDCl3, 400MHz), δ: 7.32-7.30 (m, 4H), 7.237.19 (m, 1H), 7.11-7.07 (m, 4H), 6.79-6.75 (m, 2H), 6.69(s, 1H), 5.10 (s, 1H), 4.50 (t, J = 7.6 Hz, 1H), 3.75 (s, 3H), 3.02 (d, J = 7.6 Hz, 2H), 1.39 (s, 18H); 13C NMR (CDCl3, 100MHz) δ: 169.7, 156.5, 152.5, 144.0 136.1, 134.1, 130.8, 128.7, 127.8, 124.3, 121.9, 114.1, 55.5, 47.9, 45.2, 34.5, 30.4; IR (KBr) v: 3635, 3255, 3135, 3073, 2952, 1650, 1603, 1525, 1447, 1233, 1160, 1030, 827, 697 cm-1; HRMS (EI) (m/z): calcd for C30H37NO3 (M+): 459.2773; Found: 459.2775.

137.7, 136.2, 133.9, 129.7, 128.9, 124.3, 120.1, 119.9, 113.96, 111.8, 50.3, 47.9, 45.4, 35.5, 30.4; IR (KBr) v: 3630, 3473, 3290, 2956, 1659, 1604, 1543, 1488, 1371, 1316, 1158, 1047, 753, 708 cm-1; HRMS (EI) (m/z): calcd for C30H37NO3 (M+): 459.2773; Found: 459.2773. 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-N-(naphthalen-1yl)-3-phenylpropanamide (3r). White solid (90.1 mg, 94% yield), mp 152-154 oC, Rf = 0.2 (EA/PE, v/v = 1:10). 1H NMR (CDCl3, 600MHz), δ: 7.79-7.77 (m, 2H), 7.08 (s, 2H), 7.647.62 (m, 1H), 7.42-7.25 (m, 8H), 7.18 (s,1H), 6.76-6.75 (m, 1H), 5.17(s, 1H), 4.56 (t, J = 7.8 Hz, 1H), 3.26 (dd, J1 = 8.4 Hz, J2 = 14.0 Hz, 1H), 3.21 (dd, J1 = 7.8 Hz, J2 = 14.0 Hz, 1H), 1.39 (s, 18H); 13C NMR (CDCl3, 150MHz) δ: 170.4, 152.8, 144.2, 136.4, 134.0, 133.8, 132.2, 132.1, 128.9, 128.5, 127.8, 126.7, 126.3, 125.9, 125.7, 125.7, 124.4, 120.8, 120.5, 48.2, 45.3, 34.5, 30.4; IR (KBr) v: 3635,3418, 3255, 3053, 2961, 2364, 2319, 1655,1543, 1503, 1432, 1240, 1159, 1031, 885, 778, 697 cm-1; HRMS (EI) (m/z): calcd for C33H37NO2 (M+): 479.2824; Found: 479.2824. N-Butyl-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-3phenylpropanamide (3s). White solid (49.9 mg, 61% yield), mp 144-146 oC, Rf = 0.2 (EA/PE, v/v = 1:5). 1H NMR (CDCl3, 400MHz), δ: 7.30-7.24 (m, 4H), 7.19-7.15 (m, 1H), 7.03 (s, 2H), 5.13 (s, 1H), 5.06(s, 1H), 4.41 (t, J = 7.6 Hz, 1H), 3.143.03 (m, 2H), 2.89-2.80 (m, 2H), 1.39 (s, 18H), 1.23-1.16 (m, 2H), 1.11-1.02 (m, 2H), 0.79 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100MHz) δ: 171.4, 152.4, 144.2, 135.9, 134.2, 128.64, 127.8, 126.4, 124.3, 47.8, 44.4, 39.1, 34.5, 31.5, 30.4, 19.8, 13.8; IR (KBr) v: 3646, 3312, 3083, 2942, 1640, 1551, 1431, 1233, 1156, 1031, 885, 697 cm-1; HRMS (EI) (m/z): calcd for C27H39NO2 (M+): 409.2981; Found: 409.2980. Typical Procedure for Synthesis of 4a. A Schlenk tube containing 2a (58.8 mg, 0.2mmol), the mixture of 1h (0.4 mmol), and DCM (2 mL) were added. Then BF3-Et2O (0.4 mmol) was added dropwise via syringe and the reaction was kept at room temperature for about 1 h. Then the solution was diluted with EA and transferred to a round bottom flask. Silica was added to the flask and volatiles were evaporated under vacuum. The purification was performed by flash column chromatography on silica gel using EA/PE (v/v, 1:20) as eluent to get 4a as a white solid. (47.5 mg, 71% yield) .

N-(4-Chlorophenyl)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)3-phenylpropanamide (3p). White solid (86.3 mg, 93% yield), mp 209-210 oC, Rf = 0.2 (EA/PE, v/v = 1:10). 1H NMR (CDCl3, 500MHz), δ: 7.33-7.29 (m, 4H), 7.24-7.15 (m, 5H), 7.06 (s, 2H), 6.75 (s, 1H), 5.12(s, 1H), 4.48 (t, J = 7.5 Hz, 1H), 3.04 (d, J = 7.5 Hz, 2H), 1.38 (s, 18H); 13C NMR (CDCl3, 100MHz) δ: 169.9, 152.6, 143.8, 136.2 133.9, 129.2, 129.0, 128.8, 127.8, 126.7, 124.3, 121.0, 47.8, 45.3, 34.5, 30.3; IR (KBr) v: 3635,3448, 3276, 2958, 1656, 1598, 1541, 1489, 1390, 1239, 1156, 1023, 827, 697 cm-1; HRMS (EI) (m/z): calcd for C29H34ClNO2 (M+): 463.2278; Found: 463.2275.

3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3phenylpropanenitrile (4a). White solid (47.5 mg, 71% yield), mp 130-133 oC, Rf = 0.4 (EA/PE, v/v = 1:20). 1H NMR (CDCl3, 400MHz), δ: 7.35-7.31 (m, 2H), 7.26-7.23 (m, 3H), 7.00 (s, 2H), 5.14 (s, 1H), 4.28 (t, J = 7.6 Hz, 1H), 2.86 (d, J = 7.6 Hz, 2H), 1.39 (s, 18H); 13C NMR (CDCl3, 100MHz) δ: 153.0, 141.8, 136.1, 132.0, 128.9, 127.6, 127.3, 124.2, 118.9, 47.3, 34.5, 30.3, 24.9; IR (KBr) v: 3635, 3427, 2958, 2244, 1436, 1228, 1150, 885, 707 cm-1; HRMS (EI) (m/z): calcd for C23H29NO (M+): 335.2249; Found: 335.2251.

3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-N-(3methoxyphenyl)-3-phenylpropanamide (3q). White solid (63.3 mg, 69% yield), mp 188-190 oC, Rf = 0.2 (EA/PE, v/v = 1:10). 1H NMR (CDCl3, 600MHz), δ: 7.25-7.22 (m, 5H), 7.08 (s, 2H), 7.06-7.03 (m, 1H), 6.92-6.91 (m, 1H), 6.85 (s, 1H), 6.83(s, 1H), 6.77-6.45 (m, 1H), 5.11 (s, 1H), 4.47 (t, J = 7.8 Hz, 1H), 3.77 (s, 3H), 3.02 (d, J = 7.8 Hz, 2H), 1.39 (s, 18H); 13 C NMR (CDCl3, 150MHz) δ: 169.8, 159.9, 152.6, 145.7,

3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-(4methoxyphenyl)propanenitrile (4b). White solid (59.8 mg, 82% yield), mp 113-115 oC, Rf = 0.2 (EA/PE, v/v = 1:20). 1H NMR (CDCl3, 400MHz), δ: 7.19-7.17 (m, 2H), 7.00 (s, 2H), 6.90-6.87 (m, 2H), 5.14 (s, 1H), 4.25 (t, J = 7.8 Hz, 1H), 3.80 (s, 3H), 2.96 (d, J = 7.8 Hz, 2H), 1.41 (s, 18H); 13C NMR (CDCl3, 150MHz) δ: 158.7, 152.9, 136.2, 134.0, 132.4, 128.7, 124.1, 118.9, 114.2, 55.4, 46.5, 34.5, 30.3, 25.2; IR (KBr) v: 3640,3442, 2961, 2237, 1437, 1244, 1178, 1128, 834, 748 cm-

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1

; HRMS (EI) (m/z): calcd for C24H31NO2 (M+): 365.2355; Found: 365.2356.

3-([1,1'-Biphenyl]-4-yl)-3-(3,5-di-tert-butyl-4hydroxyphenyl)propanenitrile (4c). White solid (69.9 mg, 85% yield), mp 170-172 oC, Rf = 0.4 (EA/PE, v/v = 1:10). 1H NMR (CDCl3, 400MHz), δ: 7.59-7.57 (m, 4H), 7.45-7.42 (m, 2H), 7.36-7.33 (m, 3H), 7.05 (s, 2H), 5.17 (s, 1H), 4.34 (t, J = 7.6 Hz, 1H), 3.03 (d, J = 7.6 Hz, 2H), 1.42 (s, 18H); 13C NMR (CDCl3, 150MHz) δ: 153.1, 140.9, 140.7, 140.1, 136.3, 132.0, 128.0, 127.6, 127.4, 127.1, 124.2, 118.9, 47.2, 34.5, 30.3, 25.0; IR (KBr) v: 3635, 3468, 2961, 2292, 1482, 1431, 1396, 1320, 1234, 1153, 839, 773, 702 cm-1; HRMS (EI) (m/z): calcd for C29H33NO (M+): 411.2562; Found: 411.2564. 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-(4nitrophenyl)propanenitrile (4d). White solid (60.0 mg, 79% yield), mp 113-114 oC, Rf = 0.2 (EA/PE, v/v = 1:10). 1H NMR (CDCl3, 600MHz), δ: 8.23-8.21 (m, 2H), 7.45-7.44 (m, 2H), 6.97 (s, 2H), 5.23 (s, 1H), 4.41 (t, J = 7.8 Hz, 1H), 3.04 (d, J = 7.8 Hz, 2H), 1.40 (s, 18H); 13C NMR (CDCl3, 150MHz) δ: 153.5, 149.1, 147.2, 136.7, 130.5, 128.7, 124.2, 118.0, 47.1, 34.5, 30.3, 24.5; IR (KBr) v: 3625, 3458, 2971, 2225, 1518, 1442, 1346, 1148, 854, 707 cm-1; HRMS (EI) (m/z): calcd for C23H28N2O3 (M+): 380.2100; Found: 380.2104. 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-(2fluorophenyl)propanenitrile (4e). White solid (49.4 mg, 70% yield), mp 100-103 oC, Rf = 0.3 (EA/PE, v/v = 1:20). 1H NMR (CDCl3, 400MHz), δ: 7.29-7.21 (m, 2H), 7.15-7.05 (m, 4H), 5.17 (s, 1H), 4.59 (t, J = 7.6 Hz, 1H), 3.08 (dd, J1 = 7.6 Hz, J2 = 16.4 Hz, 1H), 3.02 (dd, J1 = 7.6 Hz, J2 = 16.4 Hz, 1H), 1.41 (s, 18H); 13C NMR (CDCl3, 100MHz) δ: 160.6 (d, J = 22.0 Hz), 153.1, 136.2, 130.6, 129.0 (d, J = 9.0 Hz), 128.91 (d, J = 14 Hz), 128.88 (d, J = 4.0 Hz), 124.6 (d, J = 4.0 Hz), 124.2, 118.7, 116.1 (d, J = 22.0 Hz), 41.1, 34.5, 30.2, 23.6; 19F NMR (CDCl3, 376MHz) δ: -116.8; IR (KBr) v: 3630, 3406, 3291, 2963, 2295, 1525, 1437, 1348, 1234, 1160, 755, 697 cm-1; HRMS (EI) (m/z): calcd for C23H28FNO (M+): 353.2153; Found: 353.2156. 3-(3-Bromophenyl)-3-(3,5-di-tert-butyl-4hydroxyphenyl)propanenitrile (4f). White solid (60.2 mg, 67% yield), mp 127-128 oC, Rf = 0.3 (EA/PE, v/v = 1:20). 1H NMR (CDCl3, 400MHz), δ: 7.42-7.39 (m, 2H), 7.23-7.21 (m, 2H), 6.98 (s, 2H), 5.19 (s, 1H), 4.25 (t, J = 7.6 Hz, 1H), 2.79 (d, J = 7.6 Hz, 2H), 1.41 (s, 18H); 13C NMR (CDCl3, 150MHz) δ: 153.2, 144.1, 136.4, 131.2, 131.0, 130.5, 130.4, 126.2, 124.1, 123.0, 118.4, 47.0, 34.5, 30.3, 24.8; IR (KBr) v: 3619, 3408, 3073, 2942, 2244, 1494, 1442, 1311, 1238, 1145, 755 cm-1; HRMS (EI) (m/z): calcd for C23H28BrNO (M+): 413.1354; Found: 413.1359. 3-(2-Cyano-1-(3,5-di-tert-butyl-4hydroxyphenyl)ethyl)benzonitrile (4g). White solid (57.6 mg, 80% yield), mp 138-139 oC, Rf = 0.2 (EA/PE, v/v = 1:10). 1H NMR (CDCl3, 600MHz), δ: 7.58-7.47 (m, 4H), 6.95 (s, 2H), 5.23 (s, 1H), 4.33 (t, J = 7.2 Hz, 1H), 3.01 (d, J = 7.2 Hz, 2H), 1.41 (s, 18H); 13C NMR (CDCl3, 150MHz) δ: 153.5, 143.1, 136.7, 132.2, 131.5, 131.1, 130.6, 129.8, 124.1, 118.7, 118.1, 113.1, 46.9, 34.6, 30.3, 24.6; IR (KBr) v: 3569, 3068, 2956, 2338, 2247, 1437, 1342, 1239, 1107, 875, 723, 687 cm-1; HRMS (EI) (m/z): calcd for C24H28N2O (M+): 360.2202; Found: 360.2200.

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3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-(2,6dichlorophenyl)propanenitrile (4h). White solid (51.7 mg, 64% yield), mp 126-128 oC, Rf = 0.2 (EA/PE, v/v = 1:20). 1H NMR (CDCl3, 400MHz), δ: 7.35 (d, J = 8.0 Hz, 2H), 7.17 (t, J = 8.0 Hz, 1H), 7.05 (s, 2H), 5.40 (dd, J1 = 7.6 Hz, J2 = 9.6 Hz, 1H), 5.15 (s, 1H), 3.50 (dd, J1 = 9.6 Hz, J2 = 16.8 Hz, 1H), 3.34 (dd, J1 = 7.6 Hz, J2 = 16.8 Hz, 1H), 1.39 (s, 18H); 13C NMR (CDCl3, 100MHz) δ: 152.8, 136.6, 135.8, 129.2, 128.8, 124.0, 118.6, 42.5, 34.5, 30.3, 20.4; IR (KBr) v: 3630, 3437, 2942, 2239, 1436, 1342, 1243, 1139, 879, 770 cm-1; HRMS (EI) (m/z): calcd for C23H27Cl2NO (M+): 403.1470; Found: 403.1475. 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-(3,4dimethoxyphenyl)propanenitrile (4i). White solid (60.8 mg, 77% yield), mp 147-148 oC, Rf = 0.1 (EA/PE, v/v = 1:10). 1H NMR (CDCl3, 600MHz), δ: 7.03 (s, 2H), 6.86-6.81 (m, 2H), 6.77 (s, 1H), 5.16 (s, 1H), 4.24 (t, J = 7.2 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 2.97 (d, J = 7.2 Hz, 2H), 1.41 (s, 18H); 13C NMR (CDCl3, 150MHz) δ: 153.0, 149.1, 148.3, 136.2, 134.4, 132.1, 124.1, 119.6, 119.0, 111.4, 111.3, 56.0, 46.9, 34.5, 30.3, 25.3; IR (KBr) v: 3632, 3457, 2925, 2232, 1433, 1318, 1257, 1154, 880, 764, 690 cm-1; HRMS (EI) (m/z): calcd for C25H33NO3 (M+): 395.2460; Found: 395.2464. 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-(2,4,5trimethoxyphenyl)propanenitrile (4j). White solid (40.0 mg, 47% yield), mp 140-141 oC, Rf = 0.1 (EA/PE, v/v = 1:5). 1H NMR (CDCl3, 400MHz), δ: 7.09 (s, 2H), 6.64 (s, 1H), 6.53 (s, 1H), 5.14 (s, 1H), 4.60 (t, J = 7.2 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.75 (s, 3H), 3.06 (dd, J1 = 7.2 Hz, J2 = 14.4 Hz, 1H), 2.95 (dd, J1 = 7.6 Hz, J2 = 14.4 Hz, 1H), 1.42 (s, 18H); 13C NMR (CDCl3, 150MHz) δ: 152.8, 151.3, 148.9, 143.0, 136.0, 131.6, 124.5, 121.7, 119.4, 113.1, 97.8, 56.8, 56.4, 56.3, 41.0, 34.5, 30.4, 23.6; IR (KBr) v: 3614, 3442, 2961, 2237, 1523, 1437, 1396, 1310, 1209, 1132, 1037, 859, 763 cm-1; HRMS (EI) (m/z): calcd for C26H35NO4 (M+): 425.2566; Found: 425.2564. 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-(naphthalen-2yl)propanenitrile (4k). White solid (71.6 mg, 93% yield), mp 161-162 oC, Rf = 0.3 (EA/PE, v/v = 1:20). 1H NMR (CDCl3, 400MHz), δ: 8.06-8.03 (m, 1H), 7.89-7.87 (m, 1H), 7.81-7.8 (m, 1H), 7.53-7.47 (m, 3H), 7.41-7.39 (m, 1H), 7.09 (s, 2H), 5.14-5.01 (m, 2H), 3.17 (dd, J1 = 7.2 Hz, J2 = 12.4 Hz, 1H), 3.10 (dd, J1 = 8.0 Hz, J2 = 12.4 Hz, 1H), 1.38 (s, 18H); 13C NMR (CDCl3, 150MHz) δ: 153.0, 137.4, 136.2, 134.2, 131.7, 131.4, 129.1, 128.1, 126.5, 125.8, 125.4, 124.4, 124.2, 123.3, 119.0, 42.9, 34.5, 30.3, 25.0; IR (KBr) v: 3519, 3068, 2947, 2242, 1436, 1361, 1158, 869, 768, 652 cm-1; HRMS (EI) (m/z): calcd for C27H31NO (M+): 385.2406; Found: 385.2406. 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-(thiophen-2yl)propanenitrile (4l). White solid (53.9 mg, 79% yield), mp 97-98 oC, Rf = 0.4 (EA/PE, v/v = 1:10). 1H NMR (CDCl3, 400MHz), δ: 7.22-7.21 (m, 1H), 7.10 (s, 2H), 6.98-6.96 (m, 2H), 5.19 (s, 1H), 4.51 (t, J = 7.2 Hz, 1H), 3.04 (dd, J1 = 7.6 Hz, J2 = 12.8 Hz, 1H), 2.99 (dd, J1 = 7.2 Hz, J2 = 12.8 Hz, 1H), 1.42 (s, 18H); 13C NMR (CDCl3, 150MHz) δ: 153.4, 145.7, 136.3, 131.7, 127.0, 125.1, 124.8, 124.1, 118.4, 43.3, 34.5, 30.4, 26.8; IR (KBr) v: 3635, 3468, 2961, 2247, 1437, 1366, 1315, 1239, 1158, 885, 839, 708 cm-1; HRMS (EI) (m/z): calcd for C21H27NOS (M+): 341.1813; Found: 341.1815.

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Typical Procedure for Synthesis of 5. AlCl3 (2.6 g, 20.0 mmol) was added to a two-neck round bottom flask, which was evacuated and purged with Argon three times and anhydrous benzene (10.0 mL) was added. Then benzene (10.0 mL) solution of 3a (87.8 mg, 0.2 mmol) was added to the solution, the reaction was kept at 60 oC for 2 h. Then water (20 mL) was added to quench the reaction, and the aqueous phase was extracted with EA (10 mL) for three times. The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was next purified in flash column chromatography on silica gel (EA/PE, v/v = 1:2) as eluent to get 5 as a white solid (55.4 mg, 83% yield); mp 171-172 oC; 1H NMR (CD3COCD3, 400MHz), δ: 9.08 (s, 1H), 8.12 (s, 1H), 7.56-7.54 (m, 2H), 7.32-7.21 (m, 9H), 7.016.97 (m, 1H), 6.75-6.73 (m, 2H), 4.61 (t, J = 7.8 Hz, 1H), 3.09 (d, J = 8.0 Hz, 2H); 13C NMR (CD3COCD3, 150MHz) δ: 170.0, 156.7, 145.9, 140.3, 136.1, 129.6, 129.4, 129.1, 128.6, 126.9, 124.0, 120.0, 116.0, 47.3, 44.2; IR (KBr) v: 3584, 3286, 1654, 1538, 1432, 1315, 1168, 1092, 956, 819, 758, 692 cm-1; HRMS (EI) (m/z): calcd for C21H19NO2 (M+): 317.1416; Found: 317.1418. Typical Procedure for Synthesis of 6. AlCl3 (2.6 g, 20.0 mmol) was added to a two-neck round bottom flask, which was evacuated and purged with Argon three times and anhydrous benzene (10.0 mL) was added. Then benzene (10.0 mL) solution of 4a (66.8 mg, 0.2 mmol) was added to the solution, and the reaction was kept at 60 oC for 2 h. Then water (20 mL) was added to quench the reaction, and the aqueous phase was extracted with EA (10 mL) for three times. The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was next purified in flash column chromatography on silica gel (EA/PE, v/v = 1:5) as eluent to get 6 as a white solid (37.5 mg, 84% yield); mp 82-84 oC; 1H NMR (CDCl3, 400MHz), δ: 7.35-7.32 (m, 2H), 7.28-7.21 (m, 3H), 7.10-7.08 (m, 2H), 6.79-6.77 (m, 2H), 5.34-5.22 (m, 1H), 4.32 (t, J = 7.8 Hz, 1H), 3.00 (d, J = 7.8 Hz, 2H); 13C NMR (CDCl3, 150MHz) δ: 155.1, 141.6, 133.4, 129.0, 128.9, 127.5, 127.4, 118.8, 115.8, 46.5, 24.6; IR (KBr) v: 3387,2258, 1452, 1350, 1265, 1214, 1092, 819, 768, 708 cm-1; HRMS (EI) (m/z): calcd for C15H13NO (M+): 223.0997; Found: 223.0997.

ASSOCIATED CONTENT Supporting Information The supporting Information is available free of charge on the ACS Piblications website at DOI: 10.1021/. Full experimental procedures, CIF files, and spectra data (PDF).

AUTHOR INFORMATION Corresponding Author [email protected]

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT We are grateful for the financial support from National Natural Science Foundation of China (21472163 and 31400224).

REFERENCES (1) For reviews of vinyl azides, see: (a) Jung, N.; Bräse, S. Angew. Chem., Int. Ed. 2012, 51, 12169. (b) Chiba, S. Chimia 2012, 66, 377. (c) Chiba, S. Synlett. 2011, 21. (d) Banert, K. in Organic Azides: Syntheses and Applications (Eds: Bräse, S.; Banert, K.), Wiley, Hoboken, 2010, p. 115. (e) Stokes, B. J.; Driver, T. G. Eur. J. Org. Chem. 2011, 22, 4071. (f) Driver, T. G. Org. Biomol. Chem. 2010, 8, 3831. (g) Liu, Z.; Liu, J.; Zhang, L.; Liao, P.; Song, J.; Bi, X. Angew. Chem., Int. Ed. 2014, 53, 5305. (h) Liu, Z.; Liao, P.; Bi, X. Org. Lett. 2014, 16, 3668. (i) Hu, B.; DiMagno, S. G. Org. Biomol. Chem. 2015, 13, 3844. (2) (a) Hassner,A.;Ferdinandi, E. S.;Isbister, R. J. J. Am. Chem. Soc. 1970, 92, 1672. (b) Moore, H. W.; Shelden, H. R.; Weyler, Jr. W. Tetraderon Lett. 1969, 10, 1243. (3) (a) Zhang, F.-L.; Wang, Y.-F.;Lonca, G. H.; Zhu, X.; Chiba, S. Angew. Chem., Int. Ed. 2014, 53, 4390. (b) Zhang, F.-L.; Zhu, X.; Chiba, S. Org. Lett. 2015, 17, 3138. (c) Wang, Y.-F.; Hu, M.; Hayashi, H.; Xing, B.; Chiba, S. Org. Lett.2016, 18, 992. (4) Zhang, Z.; Kumar, R. K.; Li, G.; Wu, D.; Bi, X. Org. Lett. 2015, 17, 6190. (5) Wu, S.-W.; Liu, F. Org. Lett. 2016, 18, 3642. (6) Shen, T.; Wang, T.; Qin, C.; Jiao, N. Angew. Chem., Int. Ed. 2013, 52, 6677. (7) For reviews, see: (a) Turner, A. B. Q. Chem. Soc. Rev.1964, 18, 347. (b) Peter, M. G. Angew. Chem., Int. Ed. 1989, 28, 555. (c) “Quinone Methides”: Wagner, H.-U.; Gompper, R. in The Chemistry of Quinonoid Compounds, Editor: S. Patai, Wiley, New York, 1974; Vol. 2, pp. 1145. (8) (a) Angle, S. R.; Turnbull, K. D. J. Am. Chem. Soc. 1989, 111, 1136. (b) Angle, S. R.; Louie, M. S.; Yang, W. Tetrahedron Lett. 1989, 30, 1193. (c) Ramanjaneyulu, B. T.; Mahesh, S.; Anand, R. V. Org. Lett.2015, 17,3952. (d) Reddy, V.; Anand, R. V. Org. Lett. 2015, 17, 3390. (9) Chu, W.-D.; Zhang, L.-F.; Bao, X.; Zhao, X.-H.; Zeng, C.; Du, J.-Y.; Zhang, G.-B.; Wang, F.-X.; Ma, X.-Y.; Fan, C.-A. Angew. Chem., Int. Ed. 2013, 52, 9229. (10) (a) Caruana, L.; Kniep, F.; Johansen, T. K.; Poulsen, P. H.; Jørgensen, K. A. J. Am. Chem. Soc.2014, 136, 15929. (b) Lou, Y.; Cao, P.; Jia, T.; Zhang, Y.; Wang, M.; Liao, J. Angew. Chem., Int. Ed. 2015, 54, 12134. (c) Dong, N.; Zhang, Z.-P.; Xue, X.-S.; Li, X.; Cheng, J.-P. Angew. Chem., Int. Ed. 2016, 55, 1460. (d) Jarava-Barrera, C.; Parra, A.; López, A.; Cruz-Acosta, F.; Collado-Sanz, D.; Cárdenas, D. J.; Tortosa, M. Acs. Catal. 2016, 6, 442.

(11) (a) He, F.-S; Jin, J.-H.; Yang, Z.-T.; Yu, X.; Fossey, J. S.; Deng, W.-P. ACS. Catal. 2016, 6, 652. (b) Zhao, K.; Zhi, Y.; Wang, A.; Enders, D. ACS. Catal. 2016, 6, 657. (c) Deng, Y.-H.; Zhang, X.Z.; Yu, K.-Y. Yan, X.; Du, J.-Y.; Huang, H.; Fan, C.-A. Chem. Commun. 2016, 52, 4183. (d) Zhang, X.-Z.; Deng, Y.-H.; Yan, X.; Yu, K.L.; Wang, X.-F; Ma, X.-Y.; Fan, C.-A. J. Org. Chem. 2016, 81, 5655. (12) (a) Li, X.; Xu, X.; Wei, W.; Lin, A.; Yao, H. Org. Lett. 2016, 18, 428. (b) Gai, K.; Fang, X.; Li, X.; Xu, J.; Wu, X.; Lin, A.; Yao, H. Chem. Commun. 2015, 51, 15831. (c) Yuan, Z.; Wei, W.; Lin, A.; Yao, H. Org. Lett. 2016, 18, 3370. (d) Yuan, Z.; Fang, X.; Li, X.; Wu, J.; Yao, H.; Lin, A. J. Org. Chem. 2015, 80, 11123. (e) Zhang, X.-Z.; Du, J.-Y.; Deng, Y.-H.; Chu, W.-D.; Yan, X.; Yu, K.-Y.; Fan, C.-A. J. Org. Chem. 2016, 81, 2598. (13) (a) Shen, Y.; Qi, J.; Mao, Z.; Cui, S. Org. Lett. 2016, 18, 2722. (b) Cui, S.; Zhang, Y.; Wang, D.; Wu, Q. Chem. Sci. 2013, 4, 3912. (c) Zhang, Y.; Wu, Q.; Cui, S. Org. Lett. 2015, 17, 2494. (d) Cui, S.; Zhang, Y.; Wu, Q. Chem. Sci. 2013, 4, 3421. (e) Zhang, Y.; Wu, Q.; Cui, S. Chem. Sci. 2014,5, 297. (f) Zheng, J.; Zhang, Y.; Cui, S. Org. Lett. 2014, 16, 3560. (g) Wu, Q.; Zhang, Y.; Cui, S. Org. Lett.2014, 16, 1350. (h) Zhang, Y.; Zheng, J.; Cui, S. J. Org. Chem. 2014, 79, 6490. (i) Zheng, J.; Wang, D.; Cui, S. Org. Lett. 2015, 17, 4572. (j) Zheng, J.; Deng, Z.; Zhang, Y.; Cui, S. Adv. Synth. Catal. 2016, 358, 746. (k) Zheng, J.; Qi, J.; Cui, S. Org. Lett. 2016, 18, 128. (l) Zheng, J.; Zhang, Y.; Wang, D.; Cui, S. Org. Lett. 2016, 18, 1768. (14) CCDC 1476217. (15) CCDC 1495420.

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(16) (a) Chu, W. D.; Zhang, L. F.; X. H.; Zeng, C.; Du, J. Y.; Zhang, G. B.; Wang, F. X.; Ma, X. Y.; Fan, C. A. Angew. Chem., Int. Ed. 2013, 52, 9229. (b) Muñiz, K.; Hövelmann, C. H.; Streuff, J. J. Am. Chem. Soc. 2008, 130, 763. (17) Liu, Z. H.; Liao, P. Q.; Bi, X. H. Org. Lett. 2014, 16, 3668.

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Synthesis of Amides and Nitriles from Vinyl Azides and p-Quinone

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