Base-Promoted Cascade Reactions of 3-(1-Alkynyl)chromones with

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Base-Promoted Cascade Reactions of 3‑(1-Alkynyl)chromones with Pyridinium Ylides to Chromeno[2,3‑d]azepine Derivatives Yu-Fang Zhang, Wen-Di Duan, Jingjing Chen, and Youhong Hu* State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China

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S Supporting Information *

ABSTRACT: A base-promoted cascade reaction of 3-(1-alkynyl)chromones with pyridinium ylides has been developed to afford a novel chromeno[2,3-d]azepine scaffold in an efficient and economic manner. This tandem process involves multiple reactions including a Michael addition/deprotonation/alkyne−allene isomerization/ cyclization and the subsequent 1,2-addition under mild conditions without a transition metal catalyst.

T

Scheme 1. Proposed Mechanism

andem reactions provide an efficient approach to generate molecular complexity from easily prepared intermediates, especially when applied to strategies toward otherwise difficult to access heterocyclic compounds.1 Based on multiple reactive sites in substrates, tandem reactions can be used rapidly to construct diverse scaffolds to generate unique compound libraries for drug discovery.2 Chromone fragments are common synthetic intermediates in organic synthesis and important core units found in various biologically active compounds.3 Based on the versatile reactivity of 3-(1-alkynyl)chromones, our research group has been engaged in the generation of natural-product-like chromone-fused scaffolds through cascade reactions. For example, a number of nucleophilic units were employed in base-promoted tandem ring-opening and ring-closing reactions of 3-(1-alkynyl)chromones 4 to construct functionalized xanthones. Recognizing that, as carbon nucleophiles, pyridinium ylides could undergo various reactions5 such as 1,3dipolar cycloadditions,6 Michael additions,7 or cyclopropanations,8 we hypothesized that pyridinium ylides with 3-(1alkynyl)chromones could promote Michael addition/ringopening/deprotonation/alkyne−allene isomerization/cyclization and the subsequent 1,2-addition (Scheme 1). It was noted that the stepwise nucleophilic 1,2-addition of D might proceed at a cyano group to generate the anion E as in our previously reported process,4d which could be further cyclized to form complex xanthone-fused compound F. Alternatively, the carbanion D′ derived from cyclization of C might directly attack at the 2-position of the pyridinium ring to generate the novel chromeno[2,3-d]azepine skeleton G. Initially, we investigated the reaction of 3-(1-alkynyl)chromone 1a and 1-(cyanomethyl)pyridin-1-ium bromide 2a· H+Br− using DBU (3 equiv) as a base in DMF at room temperature (Table 1, entry 1). Interestingly, a novel product 3a was obtained in a moderate yield (55%). The structure of 3a was confirmed by X-ray crystallography as a novel © XXXX American Chemical Society

chromeno[2,3-d]azepine G scaffold.10 Formation of xanthone-fused compound F was not observed. This result implied that only isomer D′, depicted in Scheme 1, was formed selectively after cyclization of C. The subsequent 1,2addition of D′ occurred at the CN bond of the pyridinium moiety to produce the corresponding chromeno[2,3-d]azepine G. Encouraged by this promising result, we examined the roles of the solvent, base, and pyridinium to optimize the conditions of this domino reaction (Table 1). Four of the most common solvents were tested, but none of them led to higher yields (Table 1, entries 1−4). Among the bases screened (entries 4− 6), Et3N produced the desired product in 44% yield with less byproduct. By increasing the amount of Et3N from 3 to 10 equiv, the reaction gave 3a in 56% yield with recovered starting material 1a. When increasing the amount of pyridinium salt 2a· H+Br− from 1.0 to 1.5 equiv, the reaction was completed with Received: December 18, 2018

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DOI: 10.1021/acs.joc.8b03210 J. Org. Chem. XXXX, XXX, XXX−XXX

Note

The Journal of Organic Chemistry Table 1. Optimization of Reaction Conditionsa

Scheme 2. Tandem Reaction of Various 3-(1Alkynyl)chromones with Pyridinium Ylide 2aa

entry

solvent

base (equiv)

ylide (equiv)

yieldb (%)

1 2 3 4 5 6 7 8 9

DMF DMSO THF DCM DMF DMF DMF DMF DCM

DBU (3.0) DBU (3.0) DBU (3.0) DBU (3.0) t-BuOK (3.0) Et3N (3.0) Et3N (10) Et3N (10) Et3N (10)

1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.5 1.5

55 29 29 33 27 44 56 85 93

a

Unless noted, the reaction was carried out with 0.2 mmol of 1a and 2a·H+Br− in the presence of base in 2.0 mL of solvent for 1 h. b Isolated yield.

a significantly improved yield of 85%. Changing the solvent to DCM slightly increased the yield to 93%. Using the optimized reaction conditions (Table 1, entry 9), we extended the scope of this tandem reaction by using various 3-(1-alkynyl)chromones 1 (Scheme 2). Good to excellent yields were obtained when R1 was an aryl group. It was noted that there were no obvious steric or electronic effects of the aryl group on the domino process (3a−3g). In addition, the reaction yield was satisfactory when R1 was a heteroaryl group (3h,3i). However, when R1 was an aliphatic chain, the tandem process was slow, and the desired products were obtained in 45 and 36% yield (3j, 3k), respectively. When compared with aryl rings, electron-donating alkyl groups could impact the cyclization of C to D′ significantly and prolonged the reaction time. In addition, reactions with various R2 substituents on the aryl ring of the chromone moiety proceeded smoothly (3l− 3o). Obviously, substrates bearing electron-withdrawing groups (F, Cl) at the 6-position of the chromone resulted in yields better than those of electron-donating groups (3l, 3o, vs 3m). Furthermore, the scope of various substituted pyridinium ylides 2b−2e was investigated (Scheme 3). Generally, pyridinium salts with CO2Et and CONMe2 substituents could afford cycloadducts 3 in 81 and 36% yield, respectively. Due to the low nucleophilicity of carboxamido-substituted pyridinium ylide 2c, the reaction of 2c·H+Br− with 1a was carried out in the presence of DBU as a stronger base to give 3ac in a reasonable yield. Surprisingly, acetyl- and benzoylsubstituted pyridinium ylides (2d·H+Cl− and 2e·H+Br−) gave the uncyclized betaine 4 in high yields. The structure of compound 4a was determined by X-ray crystal structure analysis and was a zwitterion.10 Prolonging the reaction time or increasing the reaction temperature generated a more complex mixture of product of unidentified structure. Based on the information in the crystal structure of 4a, the stable conjugated zwitterion 4a formed by enolization could not proceed through the process of deprotonation/alkyne−allene isomerization (Scheme 1). In summary, we have developed a base-promoted tandem reaction of 3-(1-alkynyl)chromones with pyridinium ylides to afford novel chromeno[2,3-d]azepine scaffolds in an efficient and atom- and step-economic manner. This reaction provided access to a new class of polycyclic heterocycles consisting of

a

The reaction was carried out with 0.2 mmol of 1 and 1.5 equiv of 2a· H+Br− in the presence of 10 equiv of Et3N in 2.0 mL of DCM at rt for 1−2 h. bThe reaction was carried out for 12 h.

Scheme 3. Tandem Reaction of 3-(1-Alkynyl)chromone 1a with Various Pyridinium Ylides 2

B

DOI: 10.1021/acs.joc.8b03210 J. Org. Chem. XXXX, XXX, XXX−XXX

Note

The Journal of Organic Chemistry

51.4−56.0 °C; 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.0 Hz, 1H), 8.10 (s, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.40−7.46 (m, 2H), 2.44 (td, J = 7.0, 1.6 Hz, 2H), 1.71−1.60 (m, 2H), 1.06 (td, J = 7.3, 1.4 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 177.3, 158.9, 157.4, 135.2, 127.7, 126.9, 125.0, 119.5, 113.2, 97.9, 72.0, 23.5, 23.1, 15.0; HRMS (ESI) m/z [M + H]+ calcd for C14H13O2 213.0910; found 213.0916. 7-Bromo-3-(phenylethynyl)-4H-chromen-4-one (1n): pale yellow solid, 98 mg, 15% yield, eluent ratio (petroleum ether/ethyl acetate = 10:1), mp 162.9−163.6 °C; 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H), 7.56−7.58 (m, 3H), 7.37−7.35 (m, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 174.8, 157.9, 156.1, 132.0, 129.6, 129.0, 128.5, 127.9, 122.6, 121.5, 112.1, 95.7, 79.1; HRMS (ESI) m/z [M + H]+ calcd for C17H10BrO2 324.9859; found 324.9853. 6,8-Dichloro-3-(phenylethynyl)-4H-chromen-4-one (1o): pale yellow solid, 145 mg, 46% yield, eluent ratio (petroleum ether/ethyl acetate = 5:1), mp 203.6−205.4 °C; 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 8.14 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.57 (dd, J = 6.8, 2.8 Hz, 2H), 7.35−7.37 (m, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 173.7, 157.7, 150.5, 134.3, 132.0, 131.6, 129.1, 128.5, 125.4, 124.7, 124.5, 122.4, 112.1, 96.3, 78.6; HRMS (ESI) m/z [M + H]+ calcd for C17H9Cl2O2 314.9974; found 314.9985. General Procedure for the Synthesis of Pyridinium Salt 2c· H+Br−. 1-(2-(Dimethylamino)-2-oxoethyl)pyridin-1-ium bromide(2c· H+Br−): To a solution of pyridine (242 μL, 3.0 mmol) in THF (0.2 M) was added 2-bromo-N,N-dimethylacetamide (0.5 g, 3.0 mmol). The solution was stirred at room temperature overnight; next, the solvent was evaporated, and the residue was washed with ether. Recrystallization from EtOH afforded pyridinium salt 2c·H+Br− as a white solid (382 mg, 52% yield, mp 180.1−180.9 °C): 1H NMR (400 MHz, DMSO-d6) δ 9.01 (t, J = 4.6 Hz, 2H), 8.69 (t, J = 7.7 Hz, 1H), 8.22 (t, J = 6.9 Hz, 2H), 5.91 (d, J = 8.9 Hz, 2H), 3.08 (s, 3H), 2.90 (s, 3H); 13C{1H} NMR (125 MHz, DMSO-d6) δ 164.5, 146.2, 146.1, 127.5, 61.2, 35.8, 35.5; HRMS (ESI) m/z calcd for [C9H13N2O]+ 165.1022; found 165.1020. General Procedure for the Synthesis of 3a−3o, 3ab,3ac, and 4a,4b. Representative procedure for the preparation of 14-oxo6-phenyl-6,6α-dihydro-14H-chromeno[2,3-d]pyrido[1,2-α]azepine12-carbonitrile (3a): To a solution of 1-(cyanomethyl)pyridin-1-ium bromide 2a·H+Br− (60 mg, 0.3 mmol) in dry DCM (2 mL) was added dry Et3N (278 μL, 2.0 mmol) at room temperature under nitrogen atmosphere. After being stirred for 5 min, 3-(1-alkynyl)chromone 1a (49 mg, 0.2 mmol) was added, and the resulting mixture was stirred for 1 h at room temperature (monitored by TLC). The mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate (10:1, v/v) as an eluent to afford the product 3a as a yellow solid (68 mg, 93% yield, mp 182.5−183.4 °C); 1H NMR (400 MHz, CDCl3) δ 8.31 (dd, J = 8.0, 1.5 Hz, 1H), 7.73−7.63 (m, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.29 (d, J = 4.5 Hz, 2H), 7.20 (t, J = 7.5 Hz, 2H), 6.96 (d, J = 7.4 Hz, 2H), 6.34 (d, J = 7.5 Hz, 1H), 6.13 (dd, J = 9.6, 5.9 Hz, 1H), 5.72 (dd, J = 9.6, 5.0 Hz, 1H), 4.67 (t, J = 6.6 Hz, 1H), 4.49 (s, 1H), 4.06 (d, J = 4.9 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 176.0, 169.3, 155.2, 134.6, 134.4, 129.3, 129.0, 128.2, 128.1, 126.7, 125.4, 123.9, 121.6, 117.97, 117.95, 117.8, 116.44, 116.35, 109.0, 100.3, 62.2, 59.2; HRMS (ESI) m/z [M−H]− calcd for C24H15N2O2 363.1139; found 363.1133. Characterization Data of 3b−3o, 3ab,3ac, and 4a,4b. 6-(2Methoxyphenyl)-14-oxo-6,6a-dihydro-14H-chromeno[2,3-d]pyrido[1,2-α]azepine-12-carbonitrile (3b): yellow solid, 66 mg, 84% yield, eluent ratio (petroleum ether/ethyl acetate = 10:1), mp 159.2− 160.3 °C; 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.36 (dd, J = 16.1, 8.2 Hz, 2H), 7.20−7.26 (m, 2H), 6.87 (d, J = 8.3 Hz, 1H), 6.74 (t, J = 7.5 Hz, 1H), 6.51 (d, J = 7.6 Hz, 1H), 6.36 (d, J = 7.5 Hz, 1H), 5.87 (dd, J = 9.9, 5.8 Hz, 1H), 5.66 (dd, J = 9.6, 4.9 Hz, 1H), 5.27 (s, 1H), 4.62 (t, J = 6.7 Hz, 1H), 4.21 (d, J = 4.9 Hz, 1H), 3.85 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 176.0, 170.3, 158.5, 155.1, 134.2, 129.2, 129.1, 128.5,

four fused rings, which expanded upon the natural-product-like xanthone skeleton. Further library generation and biological evaluation of the diversified chromeno[2,3-d]azepines are under investigation.

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EXPERIMENTAL SECTION

General Methods. NMR spectra were recorded on a Bruker spectrometer (400 MHz for 1H, 125 or 150 MHz for 13C). Chemical shifts are reported in δ parts per million (ppm), and the signals are described as br (broad), s (singlet), d (doublet), t (triplet), q (quartet), and m (multiple). Coupling constants (J values) are given in hertz (Hz). HRMS were recorded on a Q-TOF mass spectrometer with ESI resource. All of the reagents were used directly as obtained commercially. 3-(1-Alkynyl)chromones 1a, 1d, 1f, 1g, 1i, 1k−m,4a,9 and pyridinium salts 2a·H+Br−, 2b·H+Br−, 2d·H+Cl−, and 2e·H+Br−6c are known, which were synthesized according to reported procedures. General Procedure for the Synthesis of 3-(1-Alkynyl)chromones (1b, 1c, 1e, 1h, 1j, 1n, and 1o). To a solution of 3iodo-4H-chromen-4-one (554 mg, 2.0 mmol) and 1-ethynyl-2methoxybenzene (310 μL, 2.4 mmol) in Et3N (10 mL) were added PdCl2(PPh3)2 (14 mg, 1 mol %) and CuI (1.9 mg, 0.5 mol %) under nitrogen atmosphere. After being stirred at room temperature overnight (monitored by TLC), the mixture was diluted with CH2Cl2 and washed with 1 M HCl and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (10:1, v/v) as an eluent to afford the 3-(1-alkynyl)chromone 1b as a pale yellow solid (171 mg, 31% yield). Characterization Data of 3-(1-Alkynyl)chromones (1b, 1c, 1e, 1h, 1j, 1n, and 1o). 3-((2-Methoxyphenyl)ethynyl)-4Hchromen-4-one (1b): pale yellow solid, 171 mg, 31% yield, eluent ratio (petroleum ether/ethyl acetate = 10:1), mp 104.3−105.1 °C; 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.1 Hz, 1H), 8.26 (s, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 6.94 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 3.92 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 175.4, 160.2, 157.9, 156.1, 134.0, 130.3, 126.4, 125.8, 123.7, 120.6, 118.3, 112.1, 111.8, 110.8, 91.7, 83.5, 56.0; HRMS (ESI) m/z [M + H]+ calcd for C18H13O3 277.0859; found 277.0862. 3-((3-Methoxyphenyl)ethynyl)-4H-chromen-4-one (1c): yellow solid, 149 mg, 27% yield, eluent ratio (petroleum ether/ethyl acetate = 10:1), mp 116.3−118.0 °C; 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 7.7 Hz, 1H), 8.25 (s, 1H), 7.70 (t, J = 7.5 Hz, 1H), 7.40−7.52 (m, 2H), 7.28−7.14 (m, 2H), 7.11 (s, 1H), 6.91 (d, J = 7.8 Hz, 1H), 3.82 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 176.8, 160.7, 159.4, 157.4, 135.4, 130.8, 127.7, 127.2, 125.8, 125.1, 125.0, 119.7, 117.8, 117.0, 112.8, 96.4, 80.7, 56.8; HRMS (ESI) m/z [M + H]+ calcd for C18H13O3 277.0859; found 277.0866. 3-((2-(Trifluoromethyl)phenyl)ethynyl)-4H-chromen-4-one (1e): pale yellow solid, 295 mg, 47% yield, eluent ratio (petroleum ether/ ethyl acetate = 10:1), mp 125.9−127.1 °C; 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.0 Hz, 1H), 8.25 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.67−7.75 (m, 2H), 7.57−7.40 (m, 4H); 13C{1H} NMR (125 MHz, CDCl3) δ 175.1, 158.6, 156.1, 134.3, 134.2, 131.59 (q, JCF = 30.5 Hz), 131.58, 128.5, 126.4, 126.02, 125.97 (q, JCF = 5.2 Hz), 123.7 (q, JCF = 271.3 Hz), 123.8, 121.1, 120.4, 118.4, 111.2, 90.8, 85.5; HRMS (ESI) m/z [M + H]+ calcd for C18H10F3O2 315.0627; found 315.0634. 3-(Pyridin-4-ylethynyl)-4H-chromen-4-one (1h): mauve solid, 99 mg, 20% yield, eluent ratio (petroleum ether/ethyl acetate = 2:1), mp 139.4−140.7 °C; 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 5.9 Hz, 2H), 8.33−8.26 (m, 2H), 7.73 (t, J = 7.8 Hz, 1H), 7.46−7.52 (m, 2H), 7.43 (d, J = 6.0 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 175.1, 158.9, 156.1, 149.9, 134.4, 130.9, 126.4, 126.2, 125.7, 123.7, 118.4, 110.8, 92.4, 84.4; HRMS (ESI) m/z [M + H]+ calcd for C16H10NO2 248.0706; found 248.0706. 3-(Pent-1-yn-1-yl)-4H-chromen-4-one (1j): yellow solid, 106 mg, 25% yield, eluent ratio (petroleum ether/ethyl acetate = 10:1), mp C

DOI: 10.1021/acs.joc.8b03210 J. Org. Chem. XXXX, XXX, XXX−XXX

Note

The Journal of Organic Chemistry

14-Oxo-6-(pyridin-4-yl)-6,6a-dihydro-14H-chromeno[2,3-d]pyrido[1,2-α]azepine-12-carbonitrile (3h): yellow solid, 61 mg, 83% yield, eluent ratio (petroleum ether/ethyl acetate = 2:1), mp 150.3− 152.0 °C; 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 6.1 Hz, 2H), 8.29 (dd, J = 8.0, 1.5 Hz, 1H), 7.68 (ddd, J = 8.6, 7.3, 1.6 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.29 (s, 1H), 6.92 (d, J = 6.1 Hz, 2H), 6.35 (d, J = 7.4 Hz, 1H), 6.18 (dd, J = 9.6, 5.9 Hz, 1H), 5.75 (dd, J = 9.6, 5.1 Hz, 1H), 4.70 (t, J = 6.7 Hz, 1H), 4.48 (s, 1H), 4.09 (d, J = 5.0 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 175.7, 167.0, 155.2, 149.5, 143.1, 134.6, 129.4, 126.8, 125.7, 124.4, 124.1, 121.6, 118.1, 117.9, 117.5, 116.5, 116.0, 109.1, 100.9, 61.7, 59.1; HRMS (ESI) m/z [M + H]+ calcd for C23H16N3O2 366.1237; found 366.1244. 14-Oxo-6-(pyrimidin-5-yl)-6,6a-dihydro-14H-chromeno[2,3-d]pyrido[1,2-α]azepine-12-carbonitrile (3i): brown solid, 50 mg, 68% yield, eluent ratio (petroleum ether/ethyl acetate = 2:1), mp 159.3− 161.4 °C; 1H NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 8.33 (s, 2H), 8.29 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.33 (s, 1H), 6.40 (d, J = 7.5 Hz, 1H), 6.19 (dd, J = 9.5, 5.8 Hz, 1H), 5.73 (dd, J = 9.6, 5.1 Hz, 1H), 4.72 (t, J = 6.7 Hz, 1H), 4.42 (s, 1H), 4.13 (d, J = 5.1 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 175.4, 166.4, 158.3, 156.3, 155.2, 134.8, 129.2, 129.0, 126.8, 125.9, 124.9, 121.5, 118.1, 117.8, 116.7, 116.5, 115.8, 109.8, 100.7, 58.5, 58.0; HRMS (ESI) m/z [M + H]+ calcd for C22H15N4O2 367.1190; found 367.1193. 14-Oxo-6-propyl-6,6a-dihydro-14H-chromeno[2,3-d]pyrido[1,2α]azepine-12-carbonitrile (3j): yellow solid, 30 mg, 45% yield, eluent ratio (petroleum ether/ethyl acetate = 15:1), mp 176.5−177.8 °C; 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 7.8 Hz, 1H), 7.70 (t, J = 7.9 Hz, 1H), 7.42−7.46 (m, 2H), 7.10 (s, 1H), 6.99 (d, J = 7.4 Hz, 1H), 6.25 (dd, J = 9.8, 5.9 Hz, 1H), 5.65 (dd, J = 9.6, 4.7 Hz, 1H), 5.13 (t, J = 6.7 Hz, 1H), 3.83 (d, J = 4.6 Hz, 1H), 3.30 (dd, J = 11.0, 3.9 Hz, 1H), 1.77−1.66 (m, 1H), 1.51−1.41 (m, 1H), 1.36−1.40 (m, 1H), 1.08−0.96 (m, 1H), 0.92 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 176.0, 170.4, 155.0, 134.1, 129.6, 126.7, 125.4, 123.1, 121.7, 120.1, 117.9, 116.5, 115.7, 115.3, 107.8, 99.5, 58.7, 57.6, 29.6, 21.1, 14.1; HRMS (ESI) m/z [M − H]− calcd for C21H17N2O2 329.1296; found 329.1287. 6-(tert-Butyl)-14-oxo-6,6a-dihydro-14H-chromeno[2,3-d]pyrido[1,2-α]azepine-12-carbonitrile (3k): yellow solid, 25 mg, 36% yield, eluent ratio (petroleum ether/ethyl acetate = 15:1), mp 144.0−145.1 °C; 1H NMR (400 MHz, CDCl3) δ 8.28 (dd, J = 8.1, 1.2 Hz, 1H), 7.69 (t, J = 7.1 Hz, 1H), 7.42 (dd, J = 7.8, 5.3 Hz, 2H), 7.05 (s, 1H), 6.95 (d, J = 7.6 Hz, 1H), 6.10−6.02 (m, 1H), 5.64 (dd, J = 9.6, 4.8 Hz, 1H), 5.29 (t, J = 6.6 Hz, 1H), 4.08 (d, J = 4.1 Hz, 1H), 3.29 (s, 1H), 1.02 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3) δ 176.0, 168.90, 154.8, 134.0, 128.50, 126.60, 125.3, 124.0, 122.1, 121.5, 117.8, 117.7, 116. 6, 116.0, 107.3, 101.1, 66.3, 59.4, 40.1, 29.7; HRMS (ESI) m/z [M − H]− calcd for C22H19N2O2 343.1452; found 343.1449. 2-Fluoro-14-oxo-6-phenyl-6,6a-dihydro-14H-chromeno[2,3-d]pyrido[1,2-α]azepine-12-carbonitrile (3l): yellow solid, 70 mg, 92% yield, eluent ratio (petroleum ether/ethyl acetate = 10:1), mp 164.3− 166.7 °C; 1H NMR (400 MHz, CDCl3) δ 7.91 (ddd, J = 8.2, 2.4, 1.1 Hz, 1H), 7.40−7.34 (m, 2H), 7.29−7.24 (m, 1H), 7.23 (s, 1H), 7.18 (t, J = 7.5 Hz, 2H), 6.92 (d, J = 7.2 Hz, 2H), 6.31 (d, J = 7.5 Hz, 1H), 6.11 (dd, J = 9.6, 5.9 Hz, 1H), 5.70 (dd, J = 9.6, 5.1 Hz, 1H), 4.66 (t, J = 6.7 Hz, 1H), 4.46 (s, 1H), 4.02 (d, J = 5.0 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 175.3 (d, JCF = 2.1 Hz), 169.3, 159.6 (d, JCF = 247.3 Hz), 151.4, 134.4, 128.7 (d, JCF = 156.0 Hz), 128.6 (d, JCF = 106.0 Hz), 123.9, 122.72, 122.66 (d, JCF = 7.6 Hz), 122.55, 120.2 (d, JCF = 8.1 Hz), 118.0, 117.2, 116.8, 116.2, 111.5, 111.4, 108.5, 100.4, 62.1, 59.2; HRMS (ESI) m/z [M − H]− calcd for C24H14FN2O2 381.1045; found 381.1046. 2-Methoxy-14-oxo-6-phenyl-6,6a-dihydro-14H-chromeno[2,3d]pyrido[1,2-α]azepine-12-carbonitrile (3m): yellow solid, 51 mg, 65% yield, eluent ratio (petroleum ether/ethyl acetate = 10:1), mp 180.9−182.0 °C; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 2.9 Hz, 1H), 7.31−7.23 (m, 4H), 7.18 (t, J = 7.5 Hz, 2H), 6.93 (d, J = 7.2 Hz, 2H), 6.31 (d, J = 7.7 Hz, 1H), 6.10 (dd, J = 9.4, 5.8 Hz, 1H), 5.69 (dd, J = 9.6, 5.0 Hz, 1H), 4.64 (t, J = 6.6 Hz, 1H), 4.45 (s, 1H), 4.04

126.5, 125.3, 124.5, 121.4, 120.6, 119.6, 118.0, 116.8, 116.5, 110.7, 109.3, 100.1, 59.5, 55.7, 54.2; HRMS (ESI) m/z [M − H]− calcd for C25H17N2O3 393.1245; found 393.1252. 6-(3-Methoxyphenyl)-14-oxo-6,6α-dihydro-14H-chromeno[2,3d]pyrido[1,2-α]azepine-12-carbonitrile (3c): yellow solid, 64 mg, 81% yield, eluent ratio (petroleum ether/ethyl acetate = 10:1), mp 182.0−183.2 °C; 1H NMR (400 MHz, CDCl3) δ 8.28 (dd, J = 8.0, 1.5 Hz, 1H), 7.65 (ddd, J = 8.6, 7.2, 1.6 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.26 (s, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.79 (dd, J = 8.2, 2.0 Hz, 1H), 6.51 (dd, J = 12.1, 5.0 Hz, 2H), 6.35 (d, J = 7.5 Hz, 1H), 6.12 (dd, J = 9.6, 5.9 Hz, 1H), 5.70 (dd, J = 9.6, 5.1 Hz, 1H), 4.70 (t, J = 6.6 Hz, 1H), 4.45 (s, 1H), 4.02 (d, J = 5.0 Hz, 1H), 3.72 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 175.9, 169.1, 159.2, 155.2, 135.8, 134.3, 129.4, 129.1, 126.7, 125.4, 123.8, 121.6, 121.2, 118.1, 117.9, 117.7, 116.4, 116.3, 115.2, 113.2, 108.9, 100.4, 62.2, 59.2, 55.3; HRMS (ESI) m/z [M − H]− calcd for C25H17N2O3 393.1245; found 393.1242. 6-(4-Methoxyphenyl)-14-oxo-6,6a-dihydro-14H-chromeno[2,3d]pyrido[1,2-α]azepine-12-carbonitrile (3d): yellow solid, 72 mg, 91% yield, eluent ratio (petroleum ether/ethyl acetate = 10:1), mp 170.1−172.3 °C; 1H NMR (400 MHz, CDCl3) δ 8.27 (dd, J = 8.0, 1.6 Hz, 1H), 7.64 (ddd, J = 8.8, 7.2, 1.7 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.24 (s, 1H), 6.84 (d, J = 8.7 Hz, 2H), 6.70 (d, J = 8.8 Hz, 2H), 6.33 (d, J = 7.5 Hz, 1H), 6.09 (dd, J = 9.6, 5.9 Hz, 1H), 5.67 (dd, J = 9.6, 5.1 Hz, 1H), 4.68 (t, J = 6.3 Hz, 1H), 4.40 (s, 1H), 3.99 (d, J = 4.9 Hz, 1H), 3.75 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 176.0, 169.8, 159.6, 155.2, 134.3, 130.0, 129.3, 126.8, 126.6, 125.4, 123.8, 121.6, 118.1, 118.0, 117.5, 116.4 116.4, 113.6, 108.9, 100.3, 61.4, 59.2, 55.3; HRMS (ESI) m/z [M − H]− calcd for C25H17N2O3 393.1245; found 393.1243. 14-Oxo-6-(2-(trifluoromethyl)phenyl)-6,6a-dihydro-14Hchromeno[2,3-d]pyrido[1,2-α]azepine-12-carbonitrile (3e): yellow solid, 66 mg, 76% yield, eluent ratio (petroleum ether/ethyl acetate = 10:1), mp 169.8−172.9 °C; 1H NMR (400 MHz, CDCl3) δ 8.23 (dd, J = 8.0, 1.5 Hz, 1H), 7.69 (d, J = 7.4 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.41−7.28 (m, 5H), 6.84 (d, J = 7.7 Hz, 1H), 6.45 (d, J = 7.4 Hz, 1H), 5.90 (dd, J = 9.7, 5.9 Hz, 1H), 5.61−5.64 (m, 1H), 5.03 (s, 1H), 4.70 (t, J = 6.6 Hz, 1H), 4.36 (d, J = 5.0 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 175.9, 169.3, 155.0, 135.4, 134.5, 131.7, 131.1 (q, JCF = 28.8 Hz), 130.8, 129.0, 128.1, 126.6, 126.5 (q, JCF = 5.8 Hz), 125.5, 124.4 (q, JCF = 275.0 Hz), 122.8, 121.5, 118.5 (q, JCF = 1.4 Hz), 118.0, 117.3, 117.2, 116.3, 110.3, 101.1, 59.1, 56.6; HRMS (ESI) m/z [M − H]− calcd for C25H14F3N2O2 431.1013; found 431.1011. 14-Oxo-6-(4-(trifluoromethyl)phenyl)-6,6a-dihydro-14Hchromeno[2,3-d]pyrido[1,2-α]azepine-12-carbonitrile (3f): yellow solid, 64 mg, 74% yield, eluent ratio (petroleum ether/ethyl acetate = 10:1), mp 160.1−162.3 °C; 1H NMR (400 MHz, CDCl3) δ 8.28 (dd, J = 8.0, 1.6 Hz, 1H), 7.67 (ddd, J = 8.6, 7.2, 1.7 Hz, 1H), 7.47− 7.39 (m, 3H), 7.35 (dd, J = 8.5, 0.6 Hz, 1H), 7.29 (s, 1H), 7.07 (d, J = 8.3 Hz, 2H), 6.31 (dd, J = 7.5, 0.7 Hz, 1H), 6.14 (dd, J = 9.6, 5.9 Hz, 1H), 5.77−5.70 (m, 1H), 4.66 (t, J = 6.2 Hz, 1H), 4.54 (s, 1H), 4.08 (d, J = 4.9 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 175.8, 168.1, 155.2, 138.4, 134.5, 130.5 (q, JCF = 32.6 Hz), 129.3, 126.8, 125.6, 125.1 (q, JCF = 3.7 Hz), 124.2, 124.1 (q, JCF = 270.0 Hz), 121.6, 117.93, 117.89, 117.6, 116.6, 116.1, 109.1, 100.6, 62.0, 59.1; HRMS (ESI) m/z [M − H]− calcd for C25H14F3N2O2 431.1013; found 431.1006. 6-(4-Nitrophenyl)-14-oxo-6,6a-dihydro-14H-chromeno[2,3-d]pyrido[1,2-α]azepine-12-carbonitrile (3g): yellow solid, 75 mg, 92% yield, eluent ratio (petroleum ether/ethyl acetate = 5:1), mp 191.2− 193.2 °C; 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 8.7 Hz, 2H), 7.68 (ddd, J = 8.6, 7.2, 1.7 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.30 (s, 1H), 7.14 (d, J = 8.7 Hz, 2H), 6.32 (d, J = 7.5 Hz, 1H), 6.17 (dd, J = 9.6, 6.0 Hz, 1H), 5.77 (dd, J = 9.6, 5.1 Hz, 1H), 4.67 (t, J = 6.6 Hz, 1H), 4.61 (s, 1H), 4.12 (d, J = 5.0 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 175.6, 167.3, 155.2, 147.9, 141.6, 134.7, 129.9, 129.4, 126.8, 125.7, 124.4, 123.2, 121.5, 118.0, 117.9, 117.4, 116.6, 115.9, 109.3, 100.9, 62.0, 59.2; HRMS (ESI) m/z [M + H]+ calcd for C24H16N3O4 410.1135; found 410.1143. D

DOI: 10.1021/acs.joc.8b03210 J. Org. Chem. XXXX, XXX, XXX−XXX

Note

The Journal of Organic Chemistry (d, J = 5.0 Hz, 1H), 3.91 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 175.8, 169.0, 157.2, 150.1, 134.7, 129.4, 129.0, 128.2, 128.1, 124.5, 123.9, 122.2, 119.4, 117.9, 117.1, 116.4, 116.3, 109.3, 105.6, 100.2, 62.2, 59.2, 56.2; HRMS (ESI) m/z [M − H]− calcd for C25H17N2O3 393.1245; found 393.1245. 3-Bromo-14-oxo-6-phenyl-6,6a-dihydro-14H-chromeno[2,3-d]pyrido[1,2-α]azepine-12-carbonitrile (3n): yellow solid, 63 mg, 71% yield, eluent ratio (petroleum ether/ethyl acetate = 10:1), mp 181.1− 182.4 °C; 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.51 (dd, J = 8.5, 1.8 Hz, 1H), 7.29−7.23 (m, 1H), 7.21 (s, 1H), 7.17 (t, J = 7.5 Hz, 2H), 6.90 (d, J = 7.2 Hz, 2H), 6.32 (d, J = 7.5 Hz, 1H), 6.10 (dd, J = 9.6, 5.9 Hz, 1H), 5.70 (dd, J = 9.6, 5.1 Hz, 1H), 4.66 (t, J = 6.7 Hz, 1H), 4.43 (s, 1H), 4.01 (d, J = 5.0 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 175.3, 169.1, 155.1, 134.4, 129.2, 129.1, 128.9, 128.7, 128.22, 128.19, 128.06, 123.9, 121.1, 120.4, 118.03, 117.99, 116.9, 116.2, 108.4, 100.5, 62.1, 59.2; HRMS (ESI) m/z [M − H]− calcd for C24H14BrN2O2 441.0244; found 441.0255. 2,4-Dichloro-14-oxo-6-phenyl-6,6a-dihydro-14H-chromeno[2,3d]pyrido[1,2-α]azepine-12-carbonitrile (3o): yellow solid, 70 mg, 81% yield, eluent ratio (petroleum ether/ethyl acetate = 10:1), mp >350 °C; 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 2.5 Hz, 1H), 7.68 (d, J = 2.5 Hz, 1H), 7.27 (t, J = 7.3 Hz, 1H), 7.18 (dd, J = 9.6, 5.4 Hz, 3H), 6.91 (d, J = 7.5 Hz, 2H), 6.34 (d, J = 7.5 Hz, 1H), 6.13 (dd, J = 9.6, 5.9 Hz, 1H), 5.75 (dd, J = 9.6, 5.0 Hz, 1H), 4.70 (t, J = 6.8 Hz, 1H), 4.55 (s, 1H), 3.98 (d, J = 4.9 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 174.4, 168.7, 149.5, 134.3, 134.2, 131.0, 129.1, 128.8, 128.3, 124.7, 124.1, 123.9, 123.3, 118.3, 118.0, 117.3, 116.0, 107.6, 100.8, 62.1, 59.4; HRMS (ESI) m/z [M − H]− calcd for C24H13Cl2N2O2 431.036; found 431.0353. Ethyl 14-Oxo-6-phenyl-6,6a-dihydro-14H-chromeno[2,3-d]pyrido[1,2-α]azepine-12-carboxylate (3ab): yellow solid, 67 mg, 81% yield, eluent ratio (petroleum ether/ethyl acetate = 5:1), mp 201.3−203.2 °C; 1H NMR (400 MHz, CDCl3) δ 8.28 (dd, J = 8.0, 1.6 Hz, 1H), 7.79 (s, 1H), 7.62 (ddd, J = 8.6, 7.2, 1.7 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.23 (t, J = 7.3 Hz, 1H), 7.13 (t, J = 7.6 Hz, 2H), 7.02 (d, J = 7.4 Hz, 2H), 6.05 (dd, J = 9.5, 5.8 Hz, 1H), 6.00 (d, J = 7.6 Hz, 1H), 5.65 (dd, J = 9.5, 5.5 Hz, 1H), 4.44−4.30 (m, 4H), 3.90 (d, J = 5.6 Hz, 1H), 1.42 (t, J = 7.1 Hz, 3H); 13 C{1H} NMR (125 MHz, CDCl3) δ 176.8, 169.8, 165.2, 155.3, 135.7, 134.0, 133.1, 133.0, 129. 6, 127.8, 127.7, 126.6, 125.1, 124.4, 121.8, 117.9, 117.4, 116.5, 107.5, 98.0, 62.0, 61.8, 58.2, 14.4; HRMS (ESI) m/z [M − H]− calcd for C26H20NO4 410.1398; found 410.1391. N,N-Dimethyl-14-oxo-6-phenyl-6,6a-dihydro-14H-chromeno[2,3-d]pyrido[1,2-α]azepine-12-carboxamide (3ac): yellow solid, 46 mg, 56% yield, eluent ratio (petroleum ether/ethyl acetate = 10:1), mp 146.7−149.0 °C; 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 8.0 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 7.3 Hz, 1H), 7.17 (t, J = 7.4 Hz, 2H), 7.07 (d, J = 7.5 Hz, 2H), 6.69 (s, 1H), 6.04 (dd, J = 9.6, 5.9 Hz, 1H), 5.84 (d, J = 7.4 Hz, 1H), 5.67 (dd, J = 9.6, 5.1 Hz, 1H), 4.49 (t, J = 6.6 Hz, 1H), 4.43 (s, 1H), 4.11 (d, J = 5.1 Hz, 1H), 3.05 (s, 3H), 3.02 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 176.7, 167.8, 166.7, 155.1, 138.0, 135.3, 133.6, 129.4, 129.2, 127.8, 127.6, 126.3, 124.7, 123.5, 121.6, 118.0, 117.73, 117.70, 99.1, 97.9, 61.8, 58.4, 38.1, 35.3; HRMS (ESI) m/z [M − H]− calcd for C26H21N2O3 409.1558; found 409.1552. (2Z,4E)-5-(2-Hydroxybenzoyl)-7-phenyl-3-(pyridin-1-ium-1-yl)hepta-2,4-dien-6-yn-2-olate (4a): salmon solid, 65 mg, 85% yield, eluent ratio (dichloromethane/methanol = 20:1), mp 198.4−200.0 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.82 (d, J = 5.7 Hz, 2H), 8.46 (t, J = 7.6 Hz, 1H), 8.29 (s, 1H), 8.05 (t, J = 7.0 Hz, 2H), 7.85 (d, J = 7.3 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.22−7.12 (m, 3H), 6.85 (d, J = 8.0 Hz, 1H), 6.78 (t, J = 7.5 Hz, 1H), 6.60 (d, J = 6.8 Hz, 2H), 2.30 (s, 3H); 13C{1H} NMR (125 MHz, DMSO-d6) δ 190.4, 185.3, 158.2, 148.4, 144.6, 138.1, 131.5, 129.7, 129.6, 128.1, 126.6, 126.5, 124.7, 124.0, 123.8, 117.4, 116.4, 95.5, 90.0, 89.5, 24.0; HRMS (ESI) m/z [M − H]− calcd for C25H18NO3 380.1292; found 380.1284.

(1Z,3E)-4-(2-Hydroxybenzoyl)-1,6-diphenyl-2-(pyridin-1-ium-1yl)hexa-1,3-dien-5-yn-1-olate (4b): salmon solid, 78 mg, 88% yield, eluent ratio (dichloromethane/methanol = 20:1), mp 223.8−225.0 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.99 (d, J = 5.5 Hz, 2H), 8.49 (t, J = 7.8 Hz, 1H), 8.13−8.07 (m, 2H), 7.96 (s, 1H), 7.57−7.61 (m, 3H), 7.46−7.49 (m, 3H), 7.17−7.23 (m, 4H), 6.81 (d, J = 8.1 Hz, 1H), 6.73 (t, J = 7.2 Hz, 1H), 6.65 (dd, J = 7.8, 1.3 Hz, 2H); 13C{1H} NMR (125 MHz, DMSO-d6) δ 191.3, 184.2, 157.0, 148.7, 144.7, 141.4, 139.6, 131.0, 130.0, 129.9, 129.2, 128.3, 128.2, 128.1, 126.8, 126.7, 125.6, 123.9, 122.8, 117.6, 116.3, 95.7, 92.1, 89.5; HRMS (ESI) m/z [M − H]− calcd for C30H20NO3 442.1449; found 442.1450.

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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.8b03210.

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X-ray crystal structure data for 3a(CIF) X-ray crystal structure data for 4a (CIF) Spectroscopic data for all new compounds (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Youhong Hu: 0000-0003-1770-6272 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This study was financially supported by the State Key Laboratory of Drug Research (SIMM1803ZZ-01) and Science and Technology Commission of Shanghai Municipality (18431907100).

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REFERENCES

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DOI: 10.1021/acs.joc.8b03210 J. Org. Chem. XXXX, XXX, XXX−XXX