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cycloisomerization of ortho-alkynylbenzaldehydes: Regioselective synthesis of functionalized 1H-isochromene derivatives
Accepted Manuscript Silver-catalyzed tandem nucleophilic addition/cycloisomerization of orthoalkynylbenzaldehydes: Regioselective synthesis of functionalized 1H-isochromene derivatives Fang-Hui Li, Jian Li, Shun-Yi Wang, Shun-Jun Ji PII:
S0040-4020(17)30802-5
DOI:
10.1016/j.tet.2017.07.051
Reference:
TET 28883
To appear in:
Tetrahedron
Received Date: 14 June 2017 Revised Date:
21 July 2017
Accepted Date: 28 July 2017
Please cite this article as: Li F-H, Li J, Wang S-Y, Ji S-J, Silver-catalyzed tandem nucleophilic addition/ cycloisomerization of ortho-alkynylbenzaldehydes: Regioselective synthesis of functionalized 1Hisochromene derivatives, Tetrahedron (2017), doi: 10.1016/j.tet.2017.07.051. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Silver-Catalyzed Tandem Nucleophilic Addition/Cycloisomerization of orthoAlkynylbenzaldehydes: Regioselective Synthesis of Functionalized 1H-Isochromene Derivatives
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Fang-hui Li, Jian Li, Shun-Yi Wang* and Shun-Jun Ji* Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science & Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, 215123, P. R. China
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Tetrahedron journal homepage: www.elsevier.com
Fang-Hui Li, Jian Li, Shun-Yi Wang* and Shun-Jun Ji*
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Silver-Catalyzed Tandem Nucleophilic Addition/Cycloisomerization of orthoAlkynylbenzaldehydes: Regioselective Synthesis of Functionalized 1H-Isochromene Derivatives
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Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science & Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, 215123, P. R. China
ABSTRACT
Article history: Received Received in revised form Accepted Available online
An efficient silver-catalyzed domino cycloisomerization reaction for regioselective assembly of 1H-isochromene derivatives from o-alkynylaryl aldehydes with enaminones as the external nuclephiles is developed. This protocol affords isochromene derivatives in moderate to good yields under simple and mild reaction conditions.
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ARTICLE INFO
1. Introduction
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Keywords: Silver-Catalyzed cycloisomerization reaction 1H-isochromene derivatives
isochromene derivatives efficiently.6 Such domino reactions are believed to be powerful synthetic tools since they provide access to a variety of isochromenes in atom-economical and stepefficient manner.7 Since then, many transition metals , such as Pd, Cu, Fe, Ag, Au and In et al. are reported as efficient catalysts to construct isochromene derivatives in the presence of a wide variety of nucleophiles involving oxygen,8 nitrogen,9 phosphites,10 terminal alkynes,11 allyl trialkylsilane,12 activated methylenes,13 and hydride.14 Furthermore, aromatics and heteroaromatics also can be used as good external nucleophiles
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The 1H-isochromene unit has attracted synthetic chemists enormous attention for it represents a useful structural motif found in a vast array of natural products and pharmaceuticals.1 As shown in Scheme 1, Chloroquinocin (I, isolated from the culture broth of Streptomyces sp. LL-A9227)2 displayed a moderate inhibitory activity against Gram-positive bacteria.3 1Hisochromene derivative II was an anti-inflamatory agent.4 Alnumycin D, which was isolated from the deletion mutant Streptomyces albus strains, showed antimicrobial activity.5
2017 Elsevier Ltd. All rights reserved.
Scheme 1 Some biologically active 1H-isochromene derivatives In 2002, Yamamoto et al. developed a Pd(II)-catalyzed tandem nucleophilic addition/cycloisomerization reaction of ortho-alkynylbenzaldehydes with alcohols to build 1H-
Scheme 2 Transition-Metal-Catalyzed Domino Processes of ortho-Alkynylbenzaldehydes
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Tetrahedron
for such domino cycloisomerization.15 For example, recently,MANUSCRIPT Notably, the silver-catalyzed domino cycloisomerization reaction ACCEPTED Mariaule, Belmont and co-workers synthesized a series of shows a high regioselectivity and gnerates 6-endo-dig products only. functionalized isochromene derivatives utilizing electron-rich This is unambiguously confirmed by X-ray spectroscopy analysis aromatics as nucleophiles.16 As part of our ongoing research (Fig. 1).19 17 on ortho-alkynylbenzaldehydes, herein, we report a silvercatalyzed nucleophilic addition/cycloisomerization reaction of ortho-alkynylbenzaldehydes with enaminones18 as the external nuclephiles.
Table 1
Solv. (2 mL)b
1 2 3 4 5 6 7
AgF -Ag2CO3 AgOAc AgO AgSbF6 AgOTf
DMA DMA DMA DMA DMA DMA DMA
Temp (oC)
Yield (%)c
60 60 60 60 60 60 60
52 0 34 44 41 86 79
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Cat. (20 mol %)
Table 2
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To evaluate the scope of this reaction, diverse substituted ortho-alkynyl benzaldehydes were explored under the standard reaction conditions. As shown in Table 2, we first investigated the influence of substituents on the aryl aldehyde moiety. It was found that the reaction of the aromatic aldehyde bearing electrondonating groups (Me, OMe) on aryl ring proceeded smoothly to afford the corresponding products (3b-c), and of which methoxysubstituted substrate led to the desired product 3c in 94% yield.
Substrate scope of ortho-alkynyl benzaldehydesa
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Screening of reaction conditions.a
Entry
Fig. 1 The structure of 3k.
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Initially, the model reaction of 2-(phenylethynyl)benzaldehyde 1a and 5,5-dimethyl-3-(phenylamino)cyclohex-2-enone 2a was performed in DMA at 60 oC for 12 h catalyzed by 10 mol% AgF. The domino cycloisomerization product 3a was obtained in 52% isolated yield (Table 1, entry 1). Next, we further optimized this reaction conditions and found that this transformation did not occur without the silver catalyst (Table 1, entry 2). Catalyst screening showed that silver salts such as Ag2CO3, AgOAc or AgO led to decrease the yield of 3a comparing with AgF (Table 1, entries 2-5). The isochromene derivative 3a was also obtained in good yields in the presence of AgSbF6, AgOTf and AgNO3 (Table 1, entries 6-8), and AgNO3 gave the best result. Further screening of different solvents, such as DMF, DCM and THF, revealed that the yields were decreased (Table 1, entries 9-11). Other solvents such as CH3CN and DMSO performed less efficiency (Table 1, entries 12-13). It was found that the yield of isochromene derivative 3a decreased dramatically when the reaction was carried out in DMA without further purification (Table 1, entry 14). Meanwhile, a poor yield was observed when the reaction was carried out at room temperature (Table 1, entry 15). Therefore, the optimized conditions is following: 1a (0.5 mmol), 2a (2.0 equiv), AgNO3 (10 mol%) as the catalyst, and DMA (2 mL) as the solvent at 60 oC.
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2. Results and discussion
8 AgNO3 DMA 60 92 9 AgNO3 DMF 60 71 10 AgNO3 DCM 60 76 11 AgNO3 THF 60 79 12 AgNO3 CH3CN 60 59 13 AgNO3 DMSO 60 38 14d AgNO3 DMA 60 37 15 AgNO3 DMA rt 16 a Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), Cat. (10 mol%), DMA (2.0 mL) were stirred at corresponding temperature for 12 h. bExtra dry solvents with molecular sieves, Water≤50 ppm. cisolated yield. dDMA (AR, commercial sources without further purification, 2 mL) was used.
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Reaction conditions: aReaction conditions: 1a-l (0.5 mmol), 2a (1.0 mmol), DMA (2 mL) and the reaction was stirred at 60 °C with AgNO3 (10 mol%) for 12 h. b3h was carried out at 0.25 mmol scale.
Furthermore, halogen such as F and Cl substituted aromatic aldehydes resulted in the desired isochromenes 3d, 3e, and 3f in 83%, 64%, and 72% yields, respectively. Unfortunately, heteroaryl-containing substrate (3g) almost had no reactivity for
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endo-dig intermediate B with high regioselectivity. Next, this cycloisomerization transformation. Next,ACCEPTED the influence of MANUSCRIPT benzopyrylium intermediate B is attacked by nucleophile enaminone other substitutions on the aryl moiety of the alkyne were also 2a to give an iminium ion species C, then proton transfer would investigated. The results showed that the reaction was still yield product 3a and release the silver catalyst. compatible with both electron-donating and electron-withdrawing groups. An 68% yield (3h) was still achieved from methylsubstituted substrate. Moreover, halogen-containing products 3i3k could be isolated in good yields (80-91%), when the moderate electron-withdrawing substituents F, Cl, Br were deployed. However, a strong electron-deficient nitro group reduced the yield of product 3l to only 23%.
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Scheme 3 A plausible mechanism. 3. Conclusion
In conclusion, we have developed an efficient Ag-catalyzed tandem nucleophilic addition/cycloisomerization reaction of orthoalkynylbenzaldehydes with enaminones. The transformation could be finished under simple and mild conditions with a high regioselectivity and broad sustrate scopes. A series of 1Hisochromene derivatives are obtained in moderate to good yields. Further investigations of the reaction and its applications are ongoing in our laboratory.
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Next, we examined the reactions of orthoalkynylbenzaldehyde (1a) with substituted enaminones under the optimal reaction conditions and the results are summarized in Table 3. Methoxy- and halogen- substituted enaminones, afforded the desired functionalized isobenzopyran derivatives 3m-p in 54-75% yields. The reactions of substituted enaminones (2q-s) with 2-(phenylethynyl)benzaldehyde also proceed well to furnish the desired products 3q-s in moderate yields (42-69%). Only trace product 3t was detected when the enaminone with methyl substituted on N-atom was applied under the optimized codntions. The reactions of 3-((4-acetylphenyl)amino)-5,5dimethylcyclohex-2-enone (2u) and 5,5-dimethyl-3-(naphthalen2-ylamino)cyclohex-2-enone (2v) with 1a afforded the desired products 3u and 3v in 50% and 40% yields, respectively.
Substrate scope of enaminonea
4. Experimental Section
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4.1. General
a Reaction conditions: 1a (0.5 mmol), 2m-v (1.0 mmol), DMA (2 mL) and the reaction was stirred at 60 °C with AgNO3 (10 mol%) for 12 h.
According to the reported literatures6, 16 and our previous works,17, 18 a plausible mechanism for the silver-catalyzed domino cycloisomerization reaction is proposed in Scheme 3. First, the triple-bond of 1a coordinates with silver cation to enhance the electrophilicity of the alkyne and afford the intermediate A. Then the carbonyl group attacks the electron-deficient alkyne to afford 6-
Melting points were recorded on an Electrothermal digital melting point apparatus and were uncorrected. IR spectra were recorded on a BRUKER VERTEX 70 spectrophotometer. 1H NMR and 13C NMR spectra were recorded on a BRUKER 400 MHz (1H NMR) and 100 MHz (13C NMR) spectrumeter using CDCl3 as solvent and TMS as internal standard. High resolution mass spectra were obtained using BRUKER micrOTOF-Q III instrument with ESI source. 4.2. Typical procedure for the construction of 3a: The substrate 2-(phenylethynyl)benzaldehyde (1a, 0.5 mmol, 0.1030g), 5,5-dimethyl-3-(phenylamino)cyclohex-2-enone (2a, 1.0 mmol, 0.2151g, 2 equiv) and AgNO3 (0.05 mmol, 0.0085g, 10 mol %) were added to a 25 mL Schlenk tube, followed by addition of dry DMA (2.0 mL). The mixture was stirred at 60 oC for 12 h. The solution was then quenched by H2O and extracted with EtOAc, the combined organic layers were dried over Na2SO4, filtered, and evaporated under vaccum. The residue was purified by column chromatography on silica gel (eluent: light petroleum ether : ethyl acetate, V : V = 5 : 1) to afford the desired product 5,5-dimethyl-2-(3-phenyl-1H-isochromen-1-yl)-3(phenylamino)cyclohex-2-enone (3a). 4.2.1. 5,5-dimethyl-2-(3-phenyl-1H-isochromen-1-yl)-3(phenylamino)cyclohex-2-enone (3a): Yellow solid, mp: 161.7162.2 oC; IR (neat, ν, cm-1): 3348, 2955, 2865, 1636, 1024 cm-1; 1 H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 7.1 Hz, 2H), 7.66 (s, 1H), 7.41 – 7.31 (m, 3H), 7.24 (dd, J = 16.5, 8.5 Hz, 3H), 7.18 – 7.08 (m, 3H), 7.02 (d, J = 7.4 Hz, 1H), 6.87 (d, J = 7.7 Hz, 2H), 6.78 (s, 1H), 6.53 (s, 1H), 2.58 – 2.37 (m, 4H), 1.18 (s, 3H), 1.14
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(dd, J = 22.8, 7.4 Hz, 3H), 6.73 (s, 1H), 6.46 (s, 1H), 2.59 – 2.35 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.7, 160. 8, 154.1, MANUSCRIPT ACCEPTED (m, 4H), 1.17 (s, 3H), 1.13 (s, 3H); 13C NMR (101 MHz, CDCl3) 137.6, 133.6, 133.0, 129.7, 128.7, 128.5, 127.9, 127.8, 126.5, δ 193.7, 161.0, 155.4, 137.4, 134.8, 133.6, 133.1, 128.9, 128.8, 125.7, 125.1, 124.8, 123.5, 123.1, 106.1, 102.0, 73.7, 49.8, 40.5, 32.2, 28.3, 27.8; HRMS (ESI) m/z: Found: 444.1943. Calcd for 128.0, 127.9, 126.1, 125.9, 125.1, 124.9, 124.5, 123.3, 105.6, C29H27NO2: (M+Na)+ 444.1934. 101.0, 73.5, 49.8, 40.5, 32.2, 28.4, 27.7; HRMS (ESI) m/z: Found: 478.1556. Calcd for C29H26ClNO2: (M+Na)+ 478.1544. 4.2.2. 5,5-dimethyl-2-(6-methyl-3-phenyl-1H-isochromen-14.2.7. 5,5-dimethyl-3-(phenylamino)-2-(3-(p-tolyl)-1Hyl)-3-(phenylamino)cyclohex-2-enone (3b): Yellow Solid; mp: 84.0-84.8 oC; IR (neat, ν, cm-1): 3366, 2961, 2901, 1572, 1025 isochromen-1-yl)cyclohex-2-enone (3h): Yellow solid; mp: cm-1; 1H NMR (400 MHz, CDCl3) δ 7.72 (dd, J = 16.1, 9.1 Hz, 165.4-166.3 oC; IR (neat, ν, cm-1): 3344, 2970, 2901, 1570, 1038 3H), 7.36 (ddd, J = 8.3, 7.7, 3.6 Hz, 3H), 7.26 (dd, J = 8.9, 6.5 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.71 – 7.58 (m, 3H), 7.25 – Hz, 2H), 7.15 (t, J = 7.4 Hz, 1H), 6.92 (dt, J = 24.5, 7.6 Hz, 5H), 7.07 (m, 8H), 7.01 (d, J = 7.2 Hz, 1H), 6.86 (d, J = 7.5 Hz, 2H), 6.74 (s, 1H), 6.48 (s, 1H), 2.58 – 2.37 (m, 4H), 2.31 (s, 3H), 1.18 6.75 (s, 1H), 6.48 (s, 1H), 2.60 – 2.40 (m, 4H), 2.37 (s, 3H), 1.18 (s, 3H), 1.14 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.8, (s, 3H), 1.14 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.8, 160.8, 154.0, 137.6, 137.4, 133.7, 132.8, 128.7, 128.3, 127.9, 160.8, 154.2, 138.52, 137.60, 133.12, 130.81, 129.55, 128.72, 127.2, 126.8, 125.6, 125.0, 124.7, 124.3, 123.0, 106.3, 102.0, 128.60, 127.8, 126.3, 125.7, 125.1, 124.8, 123.3, 123.0, 106.2, 73.6, 49.8, 40.5, 32.2, 28.3, 27.8, 20.7; HRMS (ESI) m/z: Found: 101.2, 73.6, 49.8, 40.5, 32.2, 28.3, 27.8, 20.9; HRMS (ESI) m/z: 436.2270. Calcd for C30H29NO2: 436.2271 (M+H)+. Found: 436.2259. Calcd for C30H29NO2: 436.2271 (M+H)+. 4.2.8. 2-(3-(4-fluorophenyl)-1H-isochromen-1-yl)-5,5dimethyl-3-(phenylamino)cyclohex-2-enone (3i): Yellow solid, mp: 158.2-158.9 oC; IR (neat, ν, cm-1): 3351, 2958, 2853, 1636, 1038 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.78 – 7.67 (m, 2H), 7.59 (s, 1H), 7.25 (dt, J = 13.8, 7.4 Hz, 3H), 7.19 – 7.13 (m, 2H), 7.12 – 7.00 (m, 4H), 6.87 (d, J = 7.7 Hz, 2H), 6.77 (s, 1H), 6.45 (s, 1H), 2.60 – 2.36 (m, 4H), 1.19 (s, 3H), 1.15 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 194.2, 163.2 (JC-F = 247.2 Hz), 161.3, 153.8, 138.0, 133.3, 130.3 (JC-F = 3.2 Hz), 129.9, 129.2, 128.3, 127.2 (JC-F = 8.2 Hz), 127.0, 126.3, 125.6, 124.0, 123.6, 115.3 (JC-F = 21.6 Hz), 106.4, 102.1, 74.2, 50.3, 41.0, 32.6, 28.7, 28.4; 19 F NMR (376 MHz, CDCl3) δ -112.23; HRMS (ESI) m/z: Found: 462.1831. Calcd for C29H26FNO2: 462.1840 (M+Na)+.
4.2.4. 2-(7-fluoro-3-phenyl-1H-isochromen-1-yl)-5,5dimethyl-3-(phenylamino)cyclohex-2-enone (3d): Yellow Solid, mp: 179.9-180.8 oC; IR (neat, ν, cm-1): 3353, 2958, 2853, 1589, 1026 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.0 Hz, 3H), 7.42 – 7.32 (m, 3H), 7.27 (dd, J = 13.8, 6.0 Hz, 2H), 7.17 (t, J = 7.4 Hz, 1H), 7.07 (dd, J = 8.3, 5.4 Hz, 1H), 6.92 (dd, J = 13.6, 5.0 Hz, 3H), 6.78 – 6.70 (m, 2H), 6.51 (s, 1H), 2.47 (ddd, J = 31.5, 29.2, 15.0 Hz, 4H), 1.19 (s, 3H), 1.14 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.7, 161.8 (JC-F = 243.9 Hz), 161.0, 153.3 (JC-F = 2.4 Hz), 137.4, 133.3, 132.3 (JC-F = 6.6 Hz), 129.1 (JC-F = 3.0 Hz), 128.8, 128.5, 127.9, 125.9, 125.1, 124.9 (JC-F = 7.7 Hz), 124.6, 114.4 (JC-F = 21.8 Hz), 110.5 (JC-F = 23.4 Hz), 105.6, 101.2, 73.4 (JC-F = 1.9 Hz), 49.7, 40.5, 32.2, 28.6, 27.5; 19 F NMR (376 MHz, CDCl3) δ -114.65; HRMS (ESI) m/z: Found: 462.1848. Calcd for C29H26FNO2: (M+Na)+ 462.1840.
4.2.9. 2-(3-(4-chlorophenyl)-1H-isochromen-1-yl)-5,5dimethyl-3-(phenylamino)cyclohex-2-enone (3j): Yellow solid, mp: 91.6-92.3 oC; IR (neat, ν, cm-1): 3369, 2956, 2868, 1572, 1035 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.7 Hz, 2H), 7.58 (s, 1H), 7.34 (d, J = 8.7 Hz, 2H), 7.25 (dt, J = 12.5, 7.5 Hz, 3H), 7.16 (t, J = 7.4 Hz, 2H), 7.11 (d, J = 7.4 Hz, 1H), 7.02 (d, J = 7.4 Hz, 1H), 6.87 (d, J = 7.6 Hz, 2H), 6.77 (s, 1H), 6.50 (s, 1H), 2.58 – 2.37 (m, 4H), 1.19 (s, 3H), 1.14 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.8, 161.0, 153.0, 137.5, 134.2, 132.7, 132.1, 129.6, 128.8, 128.1, 127.9, 126.8, 126.0, 125.8, 125.1, 123.7, 123.1, 105.9, 102.3, 73.7, 49.8, 40.5, 32.1, 28.2, 27.9; HRMS (ESI) m/z: Found: 478.1554. Calcd for C29H26ClNO2: 478.1544 (M+Na)+.
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4.2.3. 2-(7-methoxy-3-phenyl-1H-isochromen-1-yl)-5,5dimethyl-3-(phenylamino)cyclohex-2-enone (3c): Yellow Solid, mp: 102.0-102.7 oC; IR (neat, ν, cm-1): 3352, 2958, 2902, 1570, 1036 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.71 (d, J = 7.4 Hz, 2H), 7.36 (t, J = 7.3 Hz, 2H), 7.32 – 7.23 (m, 3H), 7.15 (t, J = 7.3 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.88 (d, J = 7.7 Hz, 2H), 6.79 – 6.72 (m, 2H), 6.62 (s, 1H), 6.50 (s, 1H), 3.75 (s, 3H), 2.50 (dd, J = 50.7, 11.8 Hz, 4H), 1.19 (s, 3H), 1.14 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.8, 160.9, 158.8, 152.0, 137.5, 133.8, 131.7, 128.8, 128.0, 127.9, 125.8, 125.7, 125.0, 124.8, 124.4, 112.4, 109.7, 106.2, 101.7, 73.5, 54.9, 49.7, 40.5, 32.2, 28.2, 27.8; HRMS (ESI) m/z: Found: 474.2052. Calcd for C30H29NO3: 474.2040 (M+Na)+.
4.2.5. 2-(7-chloro-3-phenyl-1H-isochromen-1-yl)-5,5dimethyl-3-(phenylamino)cyclohex-2-enone (3e): Yellow solid, mp: 141.6-142.1 oC; IR (neat, ν, cm-1): 3371, 2954, 2872, 1620, 1041 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 6.9 Hz, 2H), 7.64 (s, 1H), 7.38 (d, J = 7.6 Hz, 3H), 7.28 (t, J = 7.3 Hz, 2H), 7.18 (d, J = 7.3 Hz, 2H), 7.06 – 6.95 (m, 2H), 6.91 (d, J = 7.5 Hz, 2H), 6.73 (s, 1H), 6.50 (s, 1H), 2.66 – 2.32 (m, 4H), 1.19 (s, 3H), 1.14 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.7, 161.1, 154.4, 137.4, 133.2, 131.8, 131.5, 128.9, 128.7, 128.0, 127.8, 125.9, 125.1, 124.8, 124.7, 123.4, 105.4, 101.2, 73.5, 49.7, 40.5, 32.3, 28.6, 27.5; HRMS (ESI) m/z: Found: 478.1547. Calcd for C29H26ClNO2: (M+Na)+ 478.1544. 4.2.6. 2-(6-chloro-3-phenyl-1H-isochromen-1-yl)-5,5dimethyl-3-(phenylamino)cyclohex-2-enone (3f): Yellow Solid, mp: 107.9-108.8 oC; IR (neat, ν, cm-1): 3356, 2957, 2867, 1562, 1024 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 6.4 Hz, 2H), 7.59 (s, 1H), 7.37 (d, J = 7.1 Hz, 3H), 7.26 (t, J = 7.2 Hz, 2H), 7.17 (d, J = 7.0 Hz, 1H), 7.10 (d, J = 8.1 Hz, 2H), 6.91
4.2.10. 2-(3-(4-bromophenyl)-1H-isochromen-1-yl)-5,5dimethyl-3-(phenylamino)cyclohex-2-enone (3k): Yellow solid; mp: 136.9-137.7 oC; IR (neat, ν, cm-1): 3364, 3061, 2955, 1573, 1036 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.4 Hz, 3H), 7.49 (d, J = 8.4 Hz, 2H), 7.28 (s, 1H), 7.25 – 7.20 (m, 2H), 7.17 (t, J = 6.9 Hz, 2H), 7.11 (d, J = 7.1 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.87 (d, J = 7.5 Hz, 2H), 6.77 (s, 1H), 6.51 (s, 1H), 2.57 – 2.40 (m, 4H), 1.18 (s, 3H), 1.14 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.8, 161.0, 153.1, 137.5, 132.7, 132.5, 131.0, 129.6, 128.8, 127.9, 126.8, 126.3, 125.9, 125.1, 123.7, 123.1, 122.5, 105.8, 102.4, 73.7, 49.8, 40.5, 32.1, 28.2, 27.9; HRMS (ESI) m/z: Found: 522.1033. Calcd for C29H26BrNO2: 522.1039 (M+Na)+. 4.2.11. 5,5-dimethyl-2-(3-(4-nitrophenyl)-1H-isochromen-1yl)-3-(phenylamino)cyclohex-2-enone (3l): Yellow solid; mp: 182.1-183.4 oC; IR (neat, ν, cm-1): 3367, 2962, 2902, 1590, 1040 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.9 Hz, 2H), 7.86 (d, J = 8.9 Hz, 2H), 7.51 (s, 1H), 7.30 (d, J = 7.4 Hz, 2H), 7.26 (d, J = 2.8 Hz, 1H), 7.24 – 7.16 (m, 3H), 7.06 (d, J = 7.2 Hz, 1H), 6.89 (d, J = 7.6 Hz, 2H), 6.83 (s, 1H), 6.71 (s, 1H), 2.50 (q,
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13 132.8, 129.9, 128.6, 128.4, 127.9, 127.7, 126.6, 125.5, 124.9, J = 16.9 Hz, 4H), 1.20 (s, 3H), 1.16 (s, 3H); C NMR (101 MANUSCRIPT ACCEPTED 124.8, 123.4, 123.0, 105.3, 102.1, 74.3, 39.0, 35.0, 24.9, 24.9, MHz, CDCl3) δ 193.9, 161.4, 151.8, 147.1, 139.7, 137.3, 132.0, 23.7; HRMS (ESI) m/z: Found: 444.1940. Calcd for C29H27NO2: 129.9, 128.9, 128.1, 127.8, 126.1, 125.2, 125.0, 124.4, 123.3, 444.1934 (M+H)+. 105.8, 105.4, 73.8, 49.6, 40.5, 32.1, 29.2, 28.1, 28.0; HRMS (ESI) m/z: Found: 467.1963. Calcd for C29H26N2O4: 467.1965 4.2.17. 2-(3-phenyl-1H-isochromen-1-yl)-3-(p(M+H)+. tolylamino)cyclohex-2-enone (3r): Yellow solid; mp: 117.94.2.12. 3-((4-methoxyphenyl)amino)-5,5-dimethyl-2-(3118.2 oC; IR (neat, ν, cm-1): 3364, 2988, 2901, 1561, 1044 cm-1; 1 phenyl-1H-isochromen-1-yl)cyclohex-2-enone (3m): Yellow H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.1 Hz, 2H), 7.60 (s, solid, mp: 64.6-65.2 oC; IR (neat, ν, cm-1): 3368, 2923, 2853, 1H), 7.42 – 7.33 (m, 3H), 7.22 (d, J = 7.2 Hz, 1H), 7.18 – 7.10 1572, 1024 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 6.8 (m, 2H), 7.02 (dd, J = 17.8, 7.7 Hz, 3H), 6.83 – 6.71 (m, 3H), Hz, 2H), 7.47 (s, 1H), 7.37 (d, J = 7.4 Hz, 3H), 7.22 – 7.01 (m, 6.53 (s, 1H), 2.69 – 2.48 (m, 4H), 2.28 (s, 3H), 2.07 (dd, J = 12.6, 5.8 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 194.2, 163.2, 154.1, 4H), 6.87 – 6.71 (m, 5H), 6.52 (s, 1H), 3.75 (s, 3H), 2.37 (dd, J = 135.8, 134.9, 133.7, 132.9, 129.6, 129.2, 128.4, 127.9, 127.8, 35.2, 13.2 Hz, 4H), 1.17 (s, 3H), 1.13 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 194.1, 162.3, 158.2, 154.7, 134.1, 133.5, 130.8, 126.5, 125.2, 124.8, 123.4, 123.0, 106.4, 102.1, 73.8, 36.2, 27.2, 130.2, 128.9, 128.3, 128.2, 127.6, 126.9, 125.2, 124.0, 123.6, 21.4, 20.4; HRMS (ESI) m/z: Found: 430.1779. Calcd for C28H25NO2: 430.1778 (M+Na)+. 114.3, 105.7, 102.3, 74.1, 55.5, 50.2, 40.9, 32.4, 28.6, 28.6; HRMS (ESI) m/z: Found: 474.2044. Calcd for C30H29NO3: 4.2.18. 3-((4-methoxybenzyl)amino)-5,5-dimethyl-2-(3474.2040 (M+Na)+. phenyl-1H-isochromen-1-yl)cyclohex-2-enone (3s): Yellow 4.2.13. 3-((4-chlorophenyl)amino)-5,5-dimethyl-2-(3-phenylsolid, mp: 118.0-118.8 oC; IR (neat, ν, cm-1): 3390, 2954, 1572, 1H-isochromen-1-yl)cyclohex-2-enone (3n): Yellow solid; mp: 1249, 1027 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 6.8 147.9-148.8 oC; IR (neat, ν, cm-1): 3381, 2928, 2869, 1589, 1025 Hz, 2H), 7.37 – 7.29 (m, 3H), 7.24 – 7.19 (m, 1H), 7.15 – 7.06 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.0 Hz, 2H), (m, 2H), 6.95 (d, J = 7.4 Hz, 1H), 6.85 (d, J = 8.5 Hz, 2H), 6.79 7.58 (s, 1H), 7.40 – 7.33 (m, 3H), 7.24 – 7.18 (m, 3H), 7.14 (dd, (s, 1H), 6.66 (d, J = 8.6 Hz, 2H), 6.44 (s, 1H), 6.26 (t, J = 6.0 Hz, 1H), 4.22 (qd, J = 15.9, 6.3 Hz, 2H), 3.70 (s, 3H), 2.38 (d, J = J = 15.1, 7.4 Hz, 2H), 6.99 (d, J = 7.4 Hz, 1H), 6.82 – 6.72 (m, 14.9 Hz, 4H), 1.14 (s, 3H), 1.12 (s, 3H); 13C NMR (101 MHz, 3H), 6.54 (s, 1H), 2.41 (dd, J = 44.1, 18.6 Hz, 4H), 1.18 (s, 3H), 13 CDCl3) δ 192.7, 163.0, 158.4, 154.0, 133.6, 132.8, 129.8, 129.4, 1.14 (s, 3H); C NMR (101 MHz, CDCl3) δ 193.9, 160.4, 154.0, 136.2, 133.5, 132.9, 131.3, 129.6, 128.9, 128.5, 127.9, 127.9, 128.4, 127.8, 127.7, 127.1, 126.4, 124.8, 123.5, 123.4, 113.6, 126.6, 126.3, 124.7, 123.6, 123.0, 106.8, 102.0, 73.6, 49.7, 40.5, 104.3, 101.4, 73.6, 54.8, 49.4, 45.8, 38.9, 31.5, 28.6, 28.1; 32.2, 28.3, 27.8; HRMS (ESI) m/z: Found: 478.1556. Calcd for HRMS (ESI) m/z: Found: 488.2203. Calcd for C31H31NO3: C29H26ClNO2: 478.1544 (M+Na)+. 488.2196 (M+Na)+.
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4.2.14. 3-((3-chlorophenyl)amino)-5,5-dimethyl-2-(3-phenyl1H-isochromen-1-yl)cyclohex-2-enone (3o): Yellow solid, mp: 129.7-130.2 oC; IR (neat, ν, cm-1): 3338, 3033, 2958, 1599, 1025 ℃; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 7.1 Hz, 2H), 7.64 (s, 1H), 7.37 (dd, J = 16.2, 8.8 Hz, 3H), 7.25 – 7.20 (m, 1H), 7.13 (dt, J = 14.9, 6.2 Hz, 4H), 6.98 (d, J = 7.1 Hz, 1H), 6.85 (s, 1H), 6.74 (s, 2H), 6.54 (s, 1H), 2.60 – 2.35 (m, 4H), 1.20 (s, 3H), 1.16 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 194.5, 160.5, 154.4, 139.3, 134.7, 133.9, 133.3, 130.2, 130.0, 129.0, 128.4, 127.1, 126.1, 125.3, 125.2, 124.1, 123.4, 107.7, 102.6, 74.1, 50.3, 41.0, 32.8, 28.9, 28.1; HRMS (ESI) m/z: Found: 456.1734. Calcd for C29H26ClNO2: 456.1725 (M+H)+.
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4.2.15. 3-((4-bromophenyl)amino)-5,5-dimethyl-2-(3-phenyl1H-isochromen-1-yl)cyclohex-2-enone (3p): Yellow Solid, mp: 136.9-137.7 oC; IR (neat, ν, cm-1): 3364, 3061, 2955, 1573, 1036 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.75 – 7.70 (m, 2H), 7.58 (s, 1H), 7.40 – 7.33 (m, 5H), 7.22 (d, J = 7.4 Hz, 1H), 7.14 (dd, J = 13.8, 7.4 Hz, 2H), 6.98 (d, J = 7.4 Hz, 1H), 6.73 (d, J = 8.9 Hz, 3H), 6.54 (s, 1H), 2.56 – 2.34 (m, 4H), 1.19 (s, 3H), 1.15 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 193.8, 161.0, 153.1, 137.5, 132.7, 132.5, 131.0, 129.6, 128.8, 127.9, 126.8, 126.3, 125.9, 125.1, 123.7, 123.1, 122.5, 105.8, 102.4, 73.7, 49.8, 40.5, 32.1, 28.2, 27.9; HRMS (ESI) m/z: Found: 522.1033. Calcd for C29H26BrNO2: 522.1039 (M+Na)+. 4.2.16. 6,6-dimethyl-2-(3-phenyl-1H-isochromen-1-yl)-3(phenylamino)cyclohex-2-enone (3q): Yellow solid, mp: 160.1160.8 oC; IR (neat, ν, cm-1): 3370, 2988, 2901, 1576, 1075 cm-1; 1 H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.3 Hz, 2H), 7.63 (s, 1H), 7.36 (dt, J = 19.7, 6.9 Hz, 3H), 7.22 (dd, J = 14.3, 6.9 Hz, 3H), 7.17 – 7.07 (m, 3H), 6.94 (d, J = 7.3 Hz, 1H), 6.88 (d, J = 7.7 Hz, 2H), 6.76 (s, 1H), 6.52 (s, 1H), 2.80 – 2.48 (m, 2H), 1.94 (tdd, J = 18.9, 12.9, 7.0 Hz, 2H), 1.30 (s, 3H), 1.26 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 199.1, 160.8, 154.0, 137.7, 133.7,
4.2.19. 3-((4-acetylphenyl)amino)-5,5-dimethyl-2-(3-phenyl1H-isochromen-1-yl)cyclohex-2-enone (3u): Yellow solid, mp: 100.1-100.9 oC; IR (neat, ν, cm-1): 3347, 2964, 2871, 1564, 1045 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 7.0 Hz, 2H), 7.37 (dt, J = 14.5, 5.5 Hz, 4H), 7.23 (dd, J = 14.0, 7.4 Hz, 2H), 6.96 (d, J = 7.3 Hz, 1H), 6.88 (d, J = 8.4 Hz, 2H), 6.75 (s, 1H), 6.56 (s, 1H), 2.74 (d, J = 16.5 Hz, 1H), 2.55 (s, 1H), 2.52 (s, 3H), 2.49 (s, 1H), 2.47 (s, 1H), 1.22 (s, 3H), 1.17 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 196.2, 194.2, 159.2, 153.7, 142.1, 133.3, 133.1, 132.6, 129.5, 129.2, 128.6, 128.0, 126.7, 126.2, 124.7, 123.6, 122.9, 122.8, 108.7, 102.1, 73.7, 49.8, 40.9, 32.6, 28.7, 27.3, 26.0; HRMS (ESI) m/z: Found: 486.2048. Calcd for C31H29NO3: 486.2040 (M+Na)+. 4.2.20. 5,5-dimethyl-3-(naphthalen-2-ylamino)-2-(3-phenyl1H-isochromen-1-yl)cyclohex-2-enone (3v): Yellow solid, mp: 190.1-190.9 oC; IR (neat, ν, cm-1): 3363, 2959, 2870, 1584, 1026 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.83 – 7.74 (m, 4H), 7.69 (d, J = 8.3 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.43 – 7.32 (m, 5H), 7.26 – 7.16 (m, 4H), 7.11 (dd, J = 6.1, 2.9 Hz, 2H), 6.91 (s, 1H), 6.53 (s, 1H), 2.47 – 2.23 (m, 4H), 1.12 (s, 3H), 1.07 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.7, 161.9, 153.8, 133.7, 133.6, 133.5, 132.9, 130.1, 129.8, 128.5, 127.9, 127.9, 127.8, 127.0, 126.6, 126.4, 126.1, 124.8, 124.7, 124.0, 123.7, 123.3, 121.9, 105.9, 101.8, 73.9, 49.8, 40.1, 31.9, 28.2, 27.8; HRMS (ESI) m/z: Found: 494.2083. Calcd for C33H29NO2: 494.2091 (M+Na)+.
Acknowledgements We gratefully acknowledge the National Natural Science Foundation of China (21672157, 21372174), PAPD, the Major Basic Research Project of the Natural Science Foundation of the Jiangsu Higher Education Institutions (No.16KJA150002), Soochow University, and State and Local Joint Engineering
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Cao, J.-J.; Wang, S.-Y.; Ji, S.-J. Chem. Sci., 2016, 7, 4067. (e) Yang, L.Laboratory for Novel Functional Polymeric Materials for MANUSCRIPT ACCEPTED F.; Liu, C.-G.; Xu, X.-P.; Ji, S.-J. Org. Biomol. Chem., 2016, 14, 2993. financial support.
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19. CCDC (1551699) (3k) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
S0040-4020(17)30802-5
DOI:
10.1016/j.tet.2017.07.051
Reference:
TET 28883
To appear in:
Tetrahedron
Received Date: 14 June 2017 Revised Date:
21 July 2017
Accepted Date: 28 July 2017
Please cite this article as: Li F-H, Li J, Wang S-Y, Ji S-J, Silver-catalyzed tandem nucleophilic addition/ cycloisomerization of ortho-alkynylbenzaldehydes: Regioselective synthesis of functionalized 1Hisochromene derivatives, Tetrahedron (2017), doi: 10.1016/j.tet.2017.07.051. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Silver-Catalyzed Tandem Nucleophilic Addition/Cycloisomerization of orthoAlkynylbenzaldehydes: Regioselective Synthesis of Functionalized 1H-Isochromene Derivatives
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Fang-hui Li, Jian Li, Shun-Yi Wang* and Shun-Jun Ji* Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science & Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, 215123, P. R. China
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Tetrahedron journal homepage: www.elsevier.com
Fang-Hui Li, Jian Li, Shun-Yi Wang* and Shun-Jun Ji*
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Silver-Catalyzed Tandem Nucleophilic Addition/Cycloisomerization of orthoAlkynylbenzaldehydes: Regioselective Synthesis of Functionalized 1H-Isochromene Derivatives
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Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science & Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, 215123, P. R. China
ABSTRACT
Article history: Received Received in revised form Accepted Available online
An efficient silver-catalyzed domino cycloisomerization reaction for regioselective assembly of 1H-isochromene derivatives from o-alkynylaryl aldehydes with enaminones as the external nuclephiles is developed. This protocol affords isochromene derivatives in moderate to good yields under simple and mild reaction conditions.
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1. Introduction
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Keywords: Silver-Catalyzed cycloisomerization reaction 1H-isochromene derivatives
isochromene derivatives efficiently.6 Such domino reactions are believed to be powerful synthetic tools since they provide access to a variety of isochromenes in atom-economical and stepefficient manner.7 Since then, many transition metals , such as Pd, Cu, Fe, Ag, Au and In et al. are reported as efficient catalysts to construct isochromene derivatives in the presence of a wide variety of nucleophiles involving oxygen,8 nitrogen,9 phosphites,10 terminal alkynes,11 allyl trialkylsilane,12 activated methylenes,13 and hydride.14 Furthermore, aromatics and heteroaromatics also can be used as good external nucleophiles
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The 1H-isochromene unit has attracted synthetic chemists enormous attention for it represents a useful structural motif found in a vast array of natural products and pharmaceuticals.1 As shown in Scheme 1, Chloroquinocin (I, isolated from the culture broth of Streptomyces sp. LL-A9227)2 displayed a moderate inhibitory activity against Gram-positive bacteria.3 1Hisochromene derivative II was an anti-inflamatory agent.4 Alnumycin D, which was isolated from the deletion mutant Streptomyces albus strains, showed antimicrobial activity.5
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Scheme 1 Some biologically active 1H-isochromene derivatives In 2002, Yamamoto et al. developed a Pd(II)-catalyzed tandem nucleophilic addition/cycloisomerization reaction of ortho-alkynylbenzaldehydes with alcohols to build 1H-
Scheme 2 Transition-Metal-Catalyzed Domino Processes of ortho-Alkynylbenzaldehydes
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for such domino cycloisomerization.15 For example, recently,MANUSCRIPT Notably, the silver-catalyzed domino cycloisomerization reaction ACCEPTED Mariaule, Belmont and co-workers synthesized a series of shows a high regioselectivity and gnerates 6-endo-dig products only. functionalized isochromene derivatives utilizing electron-rich This is unambiguously confirmed by X-ray spectroscopy analysis aromatics as nucleophiles.16 As part of our ongoing research (Fig. 1).19 17 on ortho-alkynylbenzaldehydes, herein, we report a silvercatalyzed nucleophilic addition/cycloisomerization reaction of ortho-alkynylbenzaldehydes with enaminones18 as the external nuclephiles.
Table 1
Solv. (2 mL)b
1 2 3 4 5 6 7
AgF -Ag2CO3 AgOAc AgO AgSbF6 AgOTf
DMA DMA DMA DMA DMA DMA DMA
Temp (oC)
Yield (%)c
60 60 60 60 60 60 60
52 0 34 44 41 86 79
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Cat. (20 mol %)
Table 2
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To evaluate the scope of this reaction, diverse substituted ortho-alkynyl benzaldehydes were explored under the standard reaction conditions. As shown in Table 2, we first investigated the influence of substituents on the aryl aldehyde moiety. It was found that the reaction of the aromatic aldehyde bearing electrondonating groups (Me, OMe) on aryl ring proceeded smoothly to afford the corresponding products (3b-c), and of which methoxysubstituted substrate led to the desired product 3c in 94% yield.
Substrate scope of ortho-alkynyl benzaldehydesa
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Screening of reaction conditions.a
Entry
Fig. 1 The structure of 3k.
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Initially, the model reaction of 2-(phenylethynyl)benzaldehyde 1a and 5,5-dimethyl-3-(phenylamino)cyclohex-2-enone 2a was performed in DMA at 60 oC for 12 h catalyzed by 10 mol% AgF. The domino cycloisomerization product 3a was obtained in 52% isolated yield (Table 1, entry 1). Next, we further optimized this reaction conditions and found that this transformation did not occur without the silver catalyst (Table 1, entry 2). Catalyst screening showed that silver salts such as Ag2CO3, AgOAc or AgO led to decrease the yield of 3a comparing with AgF (Table 1, entries 2-5). The isochromene derivative 3a was also obtained in good yields in the presence of AgSbF6, AgOTf and AgNO3 (Table 1, entries 6-8), and AgNO3 gave the best result. Further screening of different solvents, such as DMF, DCM and THF, revealed that the yields were decreased (Table 1, entries 9-11). Other solvents such as CH3CN and DMSO performed less efficiency (Table 1, entries 12-13). It was found that the yield of isochromene derivative 3a decreased dramatically when the reaction was carried out in DMA without further purification (Table 1, entry 14). Meanwhile, a poor yield was observed when the reaction was carried out at room temperature (Table 1, entry 15). Therefore, the optimized conditions is following: 1a (0.5 mmol), 2a (2.0 equiv), AgNO3 (10 mol%) as the catalyst, and DMA (2 mL) as the solvent at 60 oC.
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2. Results and discussion
8 AgNO3 DMA 60 92 9 AgNO3 DMF 60 71 10 AgNO3 DCM 60 76 11 AgNO3 THF 60 79 12 AgNO3 CH3CN 60 59 13 AgNO3 DMSO 60 38 14d AgNO3 DMA 60 37 15 AgNO3 DMA rt 16 a Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), Cat. (10 mol%), DMA (2.0 mL) were stirred at corresponding temperature for 12 h. bExtra dry solvents with molecular sieves, Water≤50 ppm. cisolated yield. dDMA (AR, commercial sources without further purification, 2 mL) was used.
a
Reaction conditions: aReaction conditions: 1a-l (0.5 mmol), 2a (1.0 mmol), DMA (2 mL) and the reaction was stirred at 60 °C with AgNO3 (10 mol%) for 12 h. b3h was carried out at 0.25 mmol scale.
Furthermore, halogen such as F and Cl substituted aromatic aldehydes resulted in the desired isochromenes 3d, 3e, and 3f in 83%, 64%, and 72% yields, respectively. Unfortunately, heteroaryl-containing substrate (3g) almost had no reactivity for
3
endo-dig intermediate B with high regioselectivity. Next, this cycloisomerization transformation. Next,ACCEPTED the influence of MANUSCRIPT benzopyrylium intermediate B is attacked by nucleophile enaminone other substitutions on the aryl moiety of the alkyne were also 2a to give an iminium ion species C, then proton transfer would investigated. The results showed that the reaction was still yield product 3a and release the silver catalyst. compatible with both electron-donating and electron-withdrawing groups. An 68% yield (3h) was still achieved from methylsubstituted substrate. Moreover, halogen-containing products 3i3k could be isolated in good yields (80-91%), when the moderate electron-withdrawing substituents F, Cl, Br were deployed. However, a strong electron-deficient nitro group reduced the yield of product 3l to only 23%.
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Scheme 3 A plausible mechanism. 3. Conclusion
In conclusion, we have developed an efficient Ag-catalyzed tandem nucleophilic addition/cycloisomerization reaction of orthoalkynylbenzaldehydes with enaminones. The transformation could be finished under simple and mild conditions with a high regioselectivity and broad sustrate scopes. A series of 1Hisochromene derivatives are obtained in moderate to good yields. Further investigations of the reaction and its applications are ongoing in our laboratory.
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Table 3
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Next, we examined the reactions of orthoalkynylbenzaldehyde (1a) with substituted enaminones under the optimal reaction conditions and the results are summarized in Table 3. Methoxy- and halogen- substituted enaminones, afforded the desired functionalized isobenzopyran derivatives 3m-p in 54-75% yields. The reactions of substituted enaminones (2q-s) with 2-(phenylethynyl)benzaldehyde also proceed well to furnish the desired products 3q-s in moderate yields (42-69%). Only trace product 3t was detected when the enaminone with methyl substituted on N-atom was applied under the optimized codntions. The reactions of 3-((4-acetylphenyl)amino)-5,5dimethylcyclohex-2-enone (2u) and 5,5-dimethyl-3-(naphthalen2-ylamino)cyclohex-2-enone (2v) with 1a afforded the desired products 3u and 3v in 50% and 40% yields, respectively.
Substrate scope of enaminonea
4. Experimental Section
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4.1. General
a Reaction conditions: 1a (0.5 mmol), 2m-v (1.0 mmol), DMA (2 mL) and the reaction was stirred at 60 °C with AgNO3 (10 mol%) for 12 h.
According to the reported literatures6, 16 and our previous works,17, 18 a plausible mechanism for the silver-catalyzed domino cycloisomerization reaction is proposed in Scheme 3. First, the triple-bond of 1a coordinates with silver cation to enhance the electrophilicity of the alkyne and afford the intermediate A. Then the carbonyl group attacks the electron-deficient alkyne to afford 6-
Melting points were recorded on an Electrothermal digital melting point apparatus and were uncorrected. IR spectra were recorded on a BRUKER VERTEX 70 spectrophotometer. 1H NMR and 13C NMR spectra were recorded on a BRUKER 400 MHz (1H NMR) and 100 MHz (13C NMR) spectrumeter using CDCl3 as solvent and TMS as internal standard. High resolution mass spectra were obtained using BRUKER micrOTOF-Q III instrument with ESI source. 4.2. Typical procedure for the construction of 3a: The substrate 2-(phenylethynyl)benzaldehyde (1a, 0.5 mmol, 0.1030g), 5,5-dimethyl-3-(phenylamino)cyclohex-2-enone (2a, 1.0 mmol, 0.2151g, 2 equiv) and AgNO3 (0.05 mmol, 0.0085g, 10 mol %) were added to a 25 mL Schlenk tube, followed by addition of dry DMA (2.0 mL). The mixture was stirred at 60 oC for 12 h. The solution was then quenched by H2O and extracted with EtOAc, the combined organic layers were dried over Na2SO4, filtered, and evaporated under vaccum. The residue was purified by column chromatography on silica gel (eluent: light petroleum ether : ethyl acetate, V : V = 5 : 1) to afford the desired product 5,5-dimethyl-2-(3-phenyl-1H-isochromen-1-yl)-3(phenylamino)cyclohex-2-enone (3a). 4.2.1. 5,5-dimethyl-2-(3-phenyl-1H-isochromen-1-yl)-3(phenylamino)cyclohex-2-enone (3a): Yellow solid, mp: 161.7162.2 oC; IR (neat, ν, cm-1): 3348, 2955, 2865, 1636, 1024 cm-1; 1 H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 7.1 Hz, 2H), 7.66 (s, 1H), 7.41 – 7.31 (m, 3H), 7.24 (dd, J = 16.5, 8.5 Hz, 3H), 7.18 – 7.08 (m, 3H), 7.02 (d, J = 7.4 Hz, 1H), 6.87 (d, J = 7.7 Hz, 2H), 6.78 (s, 1H), 6.53 (s, 1H), 2.58 – 2.37 (m, 4H), 1.18 (s, 3H), 1.14
4
Tetrahedron
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(dd, J = 22.8, 7.4 Hz, 3H), 6.73 (s, 1H), 6.46 (s, 1H), 2.59 – 2.35 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.7, 160. 8, 154.1, MANUSCRIPT ACCEPTED (m, 4H), 1.17 (s, 3H), 1.13 (s, 3H); 13C NMR (101 MHz, CDCl3) 137.6, 133.6, 133.0, 129.7, 128.7, 128.5, 127.9, 127.8, 126.5, δ 193.7, 161.0, 155.4, 137.4, 134.8, 133.6, 133.1, 128.9, 128.8, 125.7, 125.1, 124.8, 123.5, 123.1, 106.1, 102.0, 73.7, 49.8, 40.5, 32.2, 28.3, 27.8; HRMS (ESI) m/z: Found: 444.1943. Calcd for 128.0, 127.9, 126.1, 125.9, 125.1, 124.9, 124.5, 123.3, 105.6, C29H27NO2: (M+Na)+ 444.1934. 101.0, 73.5, 49.8, 40.5, 32.2, 28.4, 27.7; HRMS (ESI) m/z: Found: 478.1556. Calcd for C29H26ClNO2: (M+Na)+ 478.1544. 4.2.2. 5,5-dimethyl-2-(6-methyl-3-phenyl-1H-isochromen-14.2.7. 5,5-dimethyl-3-(phenylamino)-2-(3-(p-tolyl)-1Hyl)-3-(phenylamino)cyclohex-2-enone (3b): Yellow Solid; mp: 84.0-84.8 oC; IR (neat, ν, cm-1): 3366, 2961, 2901, 1572, 1025 isochromen-1-yl)cyclohex-2-enone (3h): Yellow solid; mp: cm-1; 1H NMR (400 MHz, CDCl3) δ 7.72 (dd, J = 16.1, 9.1 Hz, 165.4-166.3 oC; IR (neat, ν, cm-1): 3344, 2970, 2901, 1570, 1038 3H), 7.36 (ddd, J = 8.3, 7.7, 3.6 Hz, 3H), 7.26 (dd, J = 8.9, 6.5 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.71 – 7.58 (m, 3H), 7.25 – Hz, 2H), 7.15 (t, J = 7.4 Hz, 1H), 6.92 (dt, J = 24.5, 7.6 Hz, 5H), 7.07 (m, 8H), 7.01 (d, J = 7.2 Hz, 1H), 6.86 (d, J = 7.5 Hz, 2H), 6.74 (s, 1H), 6.48 (s, 1H), 2.58 – 2.37 (m, 4H), 2.31 (s, 3H), 1.18 6.75 (s, 1H), 6.48 (s, 1H), 2.60 – 2.40 (m, 4H), 2.37 (s, 3H), 1.18 (s, 3H), 1.14 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.8, (s, 3H), 1.14 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.8, 160.8, 154.0, 137.6, 137.4, 133.7, 132.8, 128.7, 128.3, 127.9, 160.8, 154.2, 138.52, 137.60, 133.12, 130.81, 129.55, 128.72, 127.2, 126.8, 125.6, 125.0, 124.7, 124.3, 123.0, 106.3, 102.0, 128.60, 127.8, 126.3, 125.7, 125.1, 124.8, 123.3, 123.0, 106.2, 73.6, 49.8, 40.5, 32.2, 28.3, 27.8, 20.7; HRMS (ESI) m/z: Found: 101.2, 73.6, 49.8, 40.5, 32.2, 28.3, 27.8, 20.9; HRMS (ESI) m/z: 436.2270. Calcd for C30H29NO2: 436.2271 (M+H)+. Found: 436.2259. Calcd for C30H29NO2: 436.2271 (M+H)+. 4.2.8. 2-(3-(4-fluorophenyl)-1H-isochromen-1-yl)-5,5dimethyl-3-(phenylamino)cyclohex-2-enone (3i): Yellow solid, mp: 158.2-158.9 oC; IR (neat, ν, cm-1): 3351, 2958, 2853, 1636, 1038 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.78 – 7.67 (m, 2H), 7.59 (s, 1H), 7.25 (dt, J = 13.8, 7.4 Hz, 3H), 7.19 – 7.13 (m, 2H), 7.12 – 7.00 (m, 4H), 6.87 (d, J = 7.7 Hz, 2H), 6.77 (s, 1H), 6.45 (s, 1H), 2.60 – 2.36 (m, 4H), 1.19 (s, 3H), 1.15 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 194.2, 163.2 (JC-F = 247.2 Hz), 161.3, 153.8, 138.0, 133.3, 130.3 (JC-F = 3.2 Hz), 129.9, 129.2, 128.3, 127.2 (JC-F = 8.2 Hz), 127.0, 126.3, 125.6, 124.0, 123.6, 115.3 (JC-F = 21.6 Hz), 106.4, 102.1, 74.2, 50.3, 41.0, 32.6, 28.7, 28.4; 19 F NMR (376 MHz, CDCl3) δ -112.23; HRMS (ESI) m/z: Found: 462.1831. Calcd for C29H26FNO2: 462.1840 (M+Na)+.
4.2.4. 2-(7-fluoro-3-phenyl-1H-isochromen-1-yl)-5,5dimethyl-3-(phenylamino)cyclohex-2-enone (3d): Yellow Solid, mp: 179.9-180.8 oC; IR (neat, ν, cm-1): 3353, 2958, 2853, 1589, 1026 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.0 Hz, 3H), 7.42 – 7.32 (m, 3H), 7.27 (dd, J = 13.8, 6.0 Hz, 2H), 7.17 (t, J = 7.4 Hz, 1H), 7.07 (dd, J = 8.3, 5.4 Hz, 1H), 6.92 (dd, J = 13.6, 5.0 Hz, 3H), 6.78 – 6.70 (m, 2H), 6.51 (s, 1H), 2.47 (ddd, J = 31.5, 29.2, 15.0 Hz, 4H), 1.19 (s, 3H), 1.14 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.7, 161.8 (JC-F = 243.9 Hz), 161.0, 153.3 (JC-F = 2.4 Hz), 137.4, 133.3, 132.3 (JC-F = 6.6 Hz), 129.1 (JC-F = 3.0 Hz), 128.8, 128.5, 127.9, 125.9, 125.1, 124.9 (JC-F = 7.7 Hz), 124.6, 114.4 (JC-F = 21.8 Hz), 110.5 (JC-F = 23.4 Hz), 105.6, 101.2, 73.4 (JC-F = 1.9 Hz), 49.7, 40.5, 32.2, 28.6, 27.5; 19 F NMR (376 MHz, CDCl3) δ -114.65; HRMS (ESI) m/z: Found: 462.1848. Calcd for C29H26FNO2: (M+Na)+ 462.1840.
4.2.9. 2-(3-(4-chlorophenyl)-1H-isochromen-1-yl)-5,5dimethyl-3-(phenylamino)cyclohex-2-enone (3j): Yellow solid, mp: 91.6-92.3 oC; IR (neat, ν, cm-1): 3369, 2956, 2868, 1572, 1035 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.7 Hz, 2H), 7.58 (s, 1H), 7.34 (d, J = 8.7 Hz, 2H), 7.25 (dt, J = 12.5, 7.5 Hz, 3H), 7.16 (t, J = 7.4 Hz, 2H), 7.11 (d, J = 7.4 Hz, 1H), 7.02 (d, J = 7.4 Hz, 1H), 6.87 (d, J = 7.6 Hz, 2H), 6.77 (s, 1H), 6.50 (s, 1H), 2.58 – 2.37 (m, 4H), 1.19 (s, 3H), 1.14 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.8, 161.0, 153.0, 137.5, 134.2, 132.7, 132.1, 129.6, 128.8, 128.1, 127.9, 126.8, 126.0, 125.8, 125.1, 123.7, 123.1, 105.9, 102.3, 73.7, 49.8, 40.5, 32.1, 28.2, 27.9; HRMS (ESI) m/z: Found: 478.1554. Calcd for C29H26ClNO2: 478.1544 (M+Na)+.
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4.2.3. 2-(7-methoxy-3-phenyl-1H-isochromen-1-yl)-5,5dimethyl-3-(phenylamino)cyclohex-2-enone (3c): Yellow Solid, mp: 102.0-102.7 oC; IR (neat, ν, cm-1): 3352, 2958, 2902, 1570, 1036 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.71 (d, J = 7.4 Hz, 2H), 7.36 (t, J = 7.3 Hz, 2H), 7.32 – 7.23 (m, 3H), 7.15 (t, J = 7.3 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.88 (d, J = 7.7 Hz, 2H), 6.79 – 6.72 (m, 2H), 6.62 (s, 1H), 6.50 (s, 1H), 3.75 (s, 3H), 2.50 (dd, J = 50.7, 11.8 Hz, 4H), 1.19 (s, 3H), 1.14 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.8, 160.9, 158.8, 152.0, 137.5, 133.8, 131.7, 128.8, 128.0, 127.9, 125.8, 125.7, 125.0, 124.8, 124.4, 112.4, 109.7, 106.2, 101.7, 73.5, 54.9, 49.7, 40.5, 32.2, 28.2, 27.8; HRMS (ESI) m/z: Found: 474.2052. Calcd for C30H29NO3: 474.2040 (M+Na)+.
4.2.5. 2-(7-chloro-3-phenyl-1H-isochromen-1-yl)-5,5dimethyl-3-(phenylamino)cyclohex-2-enone (3e): Yellow solid, mp: 141.6-142.1 oC; IR (neat, ν, cm-1): 3371, 2954, 2872, 1620, 1041 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 6.9 Hz, 2H), 7.64 (s, 1H), 7.38 (d, J = 7.6 Hz, 3H), 7.28 (t, J = 7.3 Hz, 2H), 7.18 (d, J = 7.3 Hz, 2H), 7.06 – 6.95 (m, 2H), 6.91 (d, J = 7.5 Hz, 2H), 6.73 (s, 1H), 6.50 (s, 1H), 2.66 – 2.32 (m, 4H), 1.19 (s, 3H), 1.14 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.7, 161.1, 154.4, 137.4, 133.2, 131.8, 131.5, 128.9, 128.7, 128.0, 127.8, 125.9, 125.1, 124.8, 124.7, 123.4, 105.4, 101.2, 73.5, 49.7, 40.5, 32.3, 28.6, 27.5; HRMS (ESI) m/z: Found: 478.1547. Calcd for C29H26ClNO2: (M+Na)+ 478.1544. 4.2.6. 2-(6-chloro-3-phenyl-1H-isochromen-1-yl)-5,5dimethyl-3-(phenylamino)cyclohex-2-enone (3f): Yellow Solid, mp: 107.9-108.8 oC; IR (neat, ν, cm-1): 3356, 2957, 2867, 1562, 1024 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 6.4 Hz, 2H), 7.59 (s, 1H), 7.37 (d, J = 7.1 Hz, 3H), 7.26 (t, J = 7.2 Hz, 2H), 7.17 (d, J = 7.0 Hz, 1H), 7.10 (d, J = 8.1 Hz, 2H), 6.91
4.2.10. 2-(3-(4-bromophenyl)-1H-isochromen-1-yl)-5,5dimethyl-3-(phenylamino)cyclohex-2-enone (3k): Yellow solid; mp: 136.9-137.7 oC; IR (neat, ν, cm-1): 3364, 3061, 2955, 1573, 1036 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.4 Hz, 3H), 7.49 (d, J = 8.4 Hz, 2H), 7.28 (s, 1H), 7.25 – 7.20 (m, 2H), 7.17 (t, J = 6.9 Hz, 2H), 7.11 (d, J = 7.1 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.87 (d, J = 7.5 Hz, 2H), 6.77 (s, 1H), 6.51 (s, 1H), 2.57 – 2.40 (m, 4H), 1.18 (s, 3H), 1.14 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.8, 161.0, 153.1, 137.5, 132.7, 132.5, 131.0, 129.6, 128.8, 127.9, 126.8, 126.3, 125.9, 125.1, 123.7, 123.1, 122.5, 105.8, 102.4, 73.7, 49.8, 40.5, 32.1, 28.2, 27.9; HRMS (ESI) m/z: Found: 522.1033. Calcd for C29H26BrNO2: 522.1039 (M+Na)+. 4.2.11. 5,5-dimethyl-2-(3-(4-nitrophenyl)-1H-isochromen-1yl)-3-(phenylamino)cyclohex-2-enone (3l): Yellow solid; mp: 182.1-183.4 oC; IR (neat, ν, cm-1): 3367, 2962, 2902, 1590, 1040 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.9 Hz, 2H), 7.86 (d, J = 8.9 Hz, 2H), 7.51 (s, 1H), 7.30 (d, J = 7.4 Hz, 2H), 7.26 (d, J = 2.8 Hz, 1H), 7.24 – 7.16 (m, 3H), 7.06 (d, J = 7.2 Hz, 1H), 6.89 (d, J = 7.6 Hz, 2H), 6.83 (s, 1H), 6.71 (s, 1H), 2.50 (q,
5
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13 132.8, 129.9, 128.6, 128.4, 127.9, 127.7, 126.6, 125.5, 124.9, J = 16.9 Hz, 4H), 1.20 (s, 3H), 1.16 (s, 3H); C NMR (101 MANUSCRIPT ACCEPTED 124.8, 123.4, 123.0, 105.3, 102.1, 74.3, 39.0, 35.0, 24.9, 24.9, MHz, CDCl3) δ 193.9, 161.4, 151.8, 147.1, 139.7, 137.3, 132.0, 23.7; HRMS (ESI) m/z: Found: 444.1940. Calcd for C29H27NO2: 129.9, 128.9, 128.1, 127.8, 126.1, 125.2, 125.0, 124.4, 123.3, 444.1934 (M+H)+. 105.8, 105.4, 73.8, 49.6, 40.5, 32.1, 29.2, 28.1, 28.0; HRMS (ESI) m/z: Found: 467.1963. Calcd for C29H26N2O4: 467.1965 4.2.17. 2-(3-phenyl-1H-isochromen-1-yl)-3-(p(M+H)+. tolylamino)cyclohex-2-enone (3r): Yellow solid; mp: 117.94.2.12. 3-((4-methoxyphenyl)amino)-5,5-dimethyl-2-(3118.2 oC; IR (neat, ν, cm-1): 3364, 2988, 2901, 1561, 1044 cm-1; 1 phenyl-1H-isochromen-1-yl)cyclohex-2-enone (3m): Yellow H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.1 Hz, 2H), 7.60 (s, solid, mp: 64.6-65.2 oC; IR (neat, ν, cm-1): 3368, 2923, 2853, 1H), 7.42 – 7.33 (m, 3H), 7.22 (d, J = 7.2 Hz, 1H), 7.18 – 7.10 1572, 1024 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 6.8 (m, 2H), 7.02 (dd, J = 17.8, 7.7 Hz, 3H), 6.83 – 6.71 (m, 3H), Hz, 2H), 7.47 (s, 1H), 7.37 (d, J = 7.4 Hz, 3H), 7.22 – 7.01 (m, 6.53 (s, 1H), 2.69 – 2.48 (m, 4H), 2.28 (s, 3H), 2.07 (dd, J = 12.6, 5.8 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 194.2, 163.2, 154.1, 4H), 6.87 – 6.71 (m, 5H), 6.52 (s, 1H), 3.75 (s, 3H), 2.37 (dd, J = 135.8, 134.9, 133.7, 132.9, 129.6, 129.2, 128.4, 127.9, 127.8, 35.2, 13.2 Hz, 4H), 1.17 (s, 3H), 1.13 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 194.1, 162.3, 158.2, 154.7, 134.1, 133.5, 130.8, 126.5, 125.2, 124.8, 123.4, 123.0, 106.4, 102.1, 73.8, 36.2, 27.2, 130.2, 128.9, 128.3, 128.2, 127.6, 126.9, 125.2, 124.0, 123.6, 21.4, 20.4; HRMS (ESI) m/z: Found: 430.1779. Calcd for C28H25NO2: 430.1778 (M+Na)+. 114.3, 105.7, 102.3, 74.1, 55.5, 50.2, 40.9, 32.4, 28.6, 28.6; HRMS (ESI) m/z: Found: 474.2044. Calcd for C30H29NO3: 4.2.18. 3-((4-methoxybenzyl)amino)-5,5-dimethyl-2-(3474.2040 (M+Na)+. phenyl-1H-isochromen-1-yl)cyclohex-2-enone (3s): Yellow 4.2.13. 3-((4-chlorophenyl)amino)-5,5-dimethyl-2-(3-phenylsolid, mp: 118.0-118.8 oC; IR (neat, ν, cm-1): 3390, 2954, 1572, 1H-isochromen-1-yl)cyclohex-2-enone (3n): Yellow solid; mp: 1249, 1027 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 6.8 147.9-148.8 oC; IR (neat, ν, cm-1): 3381, 2928, 2869, 1589, 1025 Hz, 2H), 7.37 – 7.29 (m, 3H), 7.24 – 7.19 (m, 1H), 7.15 – 7.06 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.0 Hz, 2H), (m, 2H), 6.95 (d, J = 7.4 Hz, 1H), 6.85 (d, J = 8.5 Hz, 2H), 6.79 7.58 (s, 1H), 7.40 – 7.33 (m, 3H), 7.24 – 7.18 (m, 3H), 7.14 (dd, (s, 1H), 6.66 (d, J = 8.6 Hz, 2H), 6.44 (s, 1H), 6.26 (t, J = 6.0 Hz, 1H), 4.22 (qd, J = 15.9, 6.3 Hz, 2H), 3.70 (s, 3H), 2.38 (d, J = J = 15.1, 7.4 Hz, 2H), 6.99 (d, J = 7.4 Hz, 1H), 6.82 – 6.72 (m, 14.9 Hz, 4H), 1.14 (s, 3H), 1.12 (s, 3H); 13C NMR (101 MHz, 3H), 6.54 (s, 1H), 2.41 (dd, J = 44.1, 18.6 Hz, 4H), 1.18 (s, 3H), 13 CDCl3) δ 192.7, 163.0, 158.4, 154.0, 133.6, 132.8, 129.8, 129.4, 1.14 (s, 3H); C NMR (101 MHz, CDCl3) δ 193.9, 160.4, 154.0, 136.2, 133.5, 132.9, 131.3, 129.6, 128.9, 128.5, 127.9, 127.9, 128.4, 127.8, 127.7, 127.1, 126.4, 124.8, 123.5, 123.4, 113.6, 126.6, 126.3, 124.7, 123.6, 123.0, 106.8, 102.0, 73.6, 49.7, 40.5, 104.3, 101.4, 73.6, 54.8, 49.4, 45.8, 38.9, 31.5, 28.6, 28.1; 32.2, 28.3, 27.8; HRMS (ESI) m/z: Found: 478.1556. Calcd for HRMS (ESI) m/z: Found: 488.2203. Calcd for C31H31NO3: C29H26ClNO2: 478.1544 (M+Na)+. 488.2196 (M+Na)+.
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4.2.14. 3-((3-chlorophenyl)amino)-5,5-dimethyl-2-(3-phenyl1H-isochromen-1-yl)cyclohex-2-enone (3o): Yellow solid, mp: 129.7-130.2 oC; IR (neat, ν, cm-1): 3338, 3033, 2958, 1599, 1025 ℃; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 7.1 Hz, 2H), 7.64 (s, 1H), 7.37 (dd, J = 16.2, 8.8 Hz, 3H), 7.25 – 7.20 (m, 1H), 7.13 (dt, J = 14.9, 6.2 Hz, 4H), 6.98 (d, J = 7.1 Hz, 1H), 6.85 (s, 1H), 6.74 (s, 2H), 6.54 (s, 1H), 2.60 – 2.35 (m, 4H), 1.20 (s, 3H), 1.16 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 194.5, 160.5, 154.4, 139.3, 134.7, 133.9, 133.3, 130.2, 130.0, 129.0, 128.4, 127.1, 126.1, 125.3, 125.2, 124.1, 123.4, 107.7, 102.6, 74.1, 50.3, 41.0, 32.8, 28.9, 28.1; HRMS (ESI) m/z: Found: 456.1734. Calcd for C29H26ClNO2: 456.1725 (M+H)+.
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4.2.15. 3-((4-bromophenyl)amino)-5,5-dimethyl-2-(3-phenyl1H-isochromen-1-yl)cyclohex-2-enone (3p): Yellow Solid, mp: 136.9-137.7 oC; IR (neat, ν, cm-1): 3364, 3061, 2955, 1573, 1036 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.75 – 7.70 (m, 2H), 7.58 (s, 1H), 7.40 – 7.33 (m, 5H), 7.22 (d, J = 7.4 Hz, 1H), 7.14 (dd, J = 13.8, 7.4 Hz, 2H), 6.98 (d, J = 7.4 Hz, 1H), 6.73 (d, J = 8.9 Hz, 3H), 6.54 (s, 1H), 2.56 – 2.34 (m, 4H), 1.19 (s, 3H), 1.15 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 193.8, 161.0, 153.1, 137.5, 132.7, 132.5, 131.0, 129.6, 128.8, 127.9, 126.8, 126.3, 125.9, 125.1, 123.7, 123.1, 122.5, 105.8, 102.4, 73.7, 49.8, 40.5, 32.1, 28.2, 27.9; HRMS (ESI) m/z: Found: 522.1033. Calcd for C29H26BrNO2: 522.1039 (M+Na)+. 4.2.16. 6,6-dimethyl-2-(3-phenyl-1H-isochromen-1-yl)-3(phenylamino)cyclohex-2-enone (3q): Yellow solid, mp: 160.1160.8 oC; IR (neat, ν, cm-1): 3370, 2988, 2901, 1576, 1075 cm-1; 1 H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.3 Hz, 2H), 7.63 (s, 1H), 7.36 (dt, J = 19.7, 6.9 Hz, 3H), 7.22 (dd, J = 14.3, 6.9 Hz, 3H), 7.17 – 7.07 (m, 3H), 6.94 (d, J = 7.3 Hz, 1H), 6.88 (d, J = 7.7 Hz, 2H), 6.76 (s, 1H), 6.52 (s, 1H), 2.80 – 2.48 (m, 2H), 1.94 (tdd, J = 18.9, 12.9, 7.0 Hz, 2H), 1.30 (s, 3H), 1.26 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 199.1, 160.8, 154.0, 137.7, 133.7,
4.2.19. 3-((4-acetylphenyl)amino)-5,5-dimethyl-2-(3-phenyl1H-isochromen-1-yl)cyclohex-2-enone (3u): Yellow solid, mp: 100.1-100.9 oC; IR (neat, ν, cm-1): 3347, 2964, 2871, 1564, 1045 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 7.0 Hz, 2H), 7.37 (dt, J = 14.5, 5.5 Hz, 4H), 7.23 (dd, J = 14.0, 7.4 Hz, 2H), 6.96 (d, J = 7.3 Hz, 1H), 6.88 (d, J = 8.4 Hz, 2H), 6.75 (s, 1H), 6.56 (s, 1H), 2.74 (d, J = 16.5 Hz, 1H), 2.55 (s, 1H), 2.52 (s, 3H), 2.49 (s, 1H), 2.47 (s, 1H), 1.22 (s, 3H), 1.17 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 196.2, 194.2, 159.2, 153.7, 142.1, 133.3, 133.1, 132.6, 129.5, 129.2, 128.6, 128.0, 126.7, 126.2, 124.7, 123.6, 122.9, 122.8, 108.7, 102.1, 73.7, 49.8, 40.9, 32.6, 28.7, 27.3, 26.0; HRMS (ESI) m/z: Found: 486.2048. Calcd for C31H29NO3: 486.2040 (M+Na)+. 4.2.20. 5,5-dimethyl-3-(naphthalen-2-ylamino)-2-(3-phenyl1H-isochromen-1-yl)cyclohex-2-enone (3v): Yellow solid, mp: 190.1-190.9 oC; IR (neat, ν, cm-1): 3363, 2959, 2870, 1584, 1026 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.83 – 7.74 (m, 4H), 7.69 (d, J = 8.3 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.43 – 7.32 (m, 5H), 7.26 – 7.16 (m, 4H), 7.11 (dd, J = 6.1, 2.9 Hz, 2H), 6.91 (s, 1H), 6.53 (s, 1H), 2.47 – 2.23 (m, 4H), 1.12 (s, 3H), 1.07 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.7, 161.9, 153.8, 133.7, 133.6, 133.5, 132.9, 130.1, 129.8, 128.5, 127.9, 127.9, 127.8, 127.0, 126.6, 126.4, 126.1, 124.8, 124.7, 124.0, 123.7, 123.3, 121.9, 105.9, 101.8, 73.9, 49.8, 40.1, 31.9, 28.2, 27.8; HRMS (ESI) m/z: Found: 494.2083. Calcd for C33H29NO2: 494.2091 (M+Na)+.
Acknowledgements We gratefully acknowledge the National Natural Science Foundation of China (21672157, 21372174), PAPD, the Major Basic Research Project of the Natural Science Foundation of the Jiangsu Higher Education Institutions (No.16KJA150002), Soochow University, and State and Local Joint Engineering
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Cao, J.-J.; Wang, S.-Y.; Ji, S.-J. Chem. Sci., 2016, 7, 4067. (e) Yang, L.Laboratory for Novel Functional Polymeric Materials for MANUSCRIPT ACCEPTED F.; Liu, C.-G.; Xu, X.-P.; Ji, S.-J. Org. Biomol. Chem., 2016, 14, 2993. financial support.
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19. CCDC (1551699) (3k) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.