DOI:
10.1039/C5RA25691G
(Paper)
RSC Adv., 2016,
6, 10943-10948
AlCl3-catalyzed [3 + 3] cycloaddition of chalcones and β-enamine ketones (esters): a highly efficient access to multisubstituted cyclohexa-1,3-dienamines†
Received
2nd December 2015
, Accepted 15th January 2016
First published on 19th January 2016
Abstract
AlCl3-catalyzed [3 + 3] intermolecular cycloaddition of enones with enamines is described. This efficient protocol was successfully achieved to give 1,3-cyclohexadiene derivatives in good to excellent yields.
Introduction
[3 + 3] cycloaddition reactions have attracted burgeoning interest in convergent synthesis because of their special electronic characteristics, which contribute to the efficient and highly selective construction of six-membered compounds, such as oxindoles,1,2 arenes,3,4 pyranones5–7 and cyclohexenes.8,9 Enamines have proven to be one of the most effective participants in this transformation, which is widely used in nucleophilic addition reactions offering significant advantages over conventional single-step syntheses.10–13
1,3-Cyclohexadiene is the key structural motif in numerous biologically active compounds,14–18 such as oxindole alkaloids19 and antimicrobially active agents,20 which exhibit significant biological and pharmacological properties (Fig. 1). In addition, 1,3-cyclohexadiene has also been used successfully as a versatile synthetic intermediate in the preparation of polysubstituted diphenylamines,21 dihydroquinazolinones22 and other various compounds.23–26 As a consequence, considerable effort has been devoted to the synthesis of these six-membered compounds. However, the development of an efficient and practical strategy for the synthesis of substituted 1,3-cyclohexadienes from readily accessible starting materials is still highly sought after.
 |
| Fig. 1 Representative examples of biologically active products. | |
Very recently, we have developed a simple and novel approach for the synthesis of a variety of polysubstituted anti-2,3-dihydropyrroles via iodine-promoted tandem Michael/cyclization of chalcones and β-enamine ketones (esters).27 In this context, we envisioned that diverse products could be obtained through a new pathway, and developed a direct and efficient synthetic methodology for the formation of substituted 1,3-cyclohexadienes which is constituted of Lewis acid-promoted [3 + 3]-cycloaddition of chalcones and β-enamine ketones (Scheme 1).
 |
| Scheme 1 Strategies via chalcones and β-enamine ketones. | |
Results and discussion
As part of our continuing interest in developing methods for the preparation of biologically active and new organic compounds, we herein developed an efficient approach for the synthesis of multisubstituted cyclohexa-1,3-dienamine derivatives via AlCl3 promoted cascade addition/cyclization of chalcones and β-enamines (Scheme 2).
 |
| Scheme 2 Tandem Michael/cyclization reaction of chalcones/benzalacetone and β-enamine ketones (esters). | |
Our investigation commenced with the cycloaddition of chalcone (1a, 0.5 mmol) and β-enamino ester (2a, 0.6 mmol) as the model reaction, with the aim of optimizing the reaction conditions to the extent that they could subsequently be applied to a variety of different chalcones and enaminoesters (Table 1). An initial experiment revealed that acid-catalyzing was an important mediator in this reaction because no target product was detected without acid (entry 1) or in the presence of base (entry 2). To our delight, when the reaction was performed in toluene at 80 °C catalyzed by TsOH, the expected product 3a was isolated in 21% yield (Table 1, entry 3). Screening of various acids including TsOH, H2SO4, CF3COOH, FeCl3·6H2O, CH3COOH and AlCl3 revealed that AlCl3 was the most efficient acid, which increased the yield up to 93% (entries 4–8). Then different solvents and reaction temperature were also evaluated for their effect on the production of compound 3a, and the highest yield (93%) was obtained in toluene at 80 °C (entries 9–14). The yield decreased to 73% when the temperature was lowered to 60 °C in toluene with 1 equiv. of AlCl3 (entry 13). The yield was lessen along with the decrease of the amount of AlCl3 for this reaction (entries 15–16). Finally, the optimal reaction conditions of the cycloaddition of chalcone and β-enamino ester were obtained by using 1 equiv. of AlCl3 in dry toluene at 80 °C for 8 h (Table 1, entry 8).
Table 1 Optimization of [3 + 3] cycloaddition reaction conditionsa

|
Entry |
Additive (equiv.) |
Temp. (°C) |
Solvent |
Time (h) |
Yieldb (%) |
Reaction conditions: a mixture of 1a (0.5 mmol), 2a (0.6 mmol) and AlCl3 (0.5 mmol) in dry solvent (3 mL) was stirred at 80 °C for 8 h. Isolated yield based on 1a. ND = not detected. |
1 |
— |
80 |
Toluene |
8 |
NDc |
2 |
K2CO3 (1.0) |
80 |
Toluene |
8 |
NDc |
3 |
TsOH (1.0) |
80 |
Toluene |
8 |
21 |
4 |
H2SO4 (1.0) |
80 |
Toluene |
8 |
31 |
5 |
CF3COOH (1.0) |
80 |
Toluene |
8 |
29 |
6 |
FeCl3·6H2O (1.0) |
80 |
Toluene |
8 |
13 |
7 |
CH3COOH (1.0) |
80 |
Toluene |
8 |
Trace |
8 |
AlCl3 (1.0) |
80 |
Toluene |
8 |
93 |
9 |
AlCl3 (1.0) |
Reflux |
DCE |
8 |
83 |
10 |
AlCl3 (1.0) |
Reflux |
THF |
8 |
82 |
11 |
AlCl3 (1.0) |
Reflux |
MeCN |
8 |
45 |
12 |
AlCl3 (1.0) |
Reflux |
EtOH |
8 |
Trace |
13 |
AlCl3 (1.0) |
60 |
Toluene |
8 |
73 |
14 |
AlCl3 (1.0) |
100 |
Toluene |
8 |
92 |
15 |
AlCl3 (0.5) |
80 |
Toluene |
8 |
36 |
16 |
AlCl3 (0.2) |
80 |
Toluene |
8 |
24 |
With the optimized reaction conditions in hand, we further investigated the substrate scope of our methodology by employing various β-enamino esters and chalcones to construct multisubstituted 1,3-cyclohexadienes 3 (Schemes 3 and 4). The different substituted chalcones were employed in the reaction and the corresponding multisubstituted 1,3-cyclohexadienes 3 were formed successfully in good to excellent yields in all cases (3a–5c).
 |
| Scheme 3 Synthesis of substituted 1,3-cyclohexadienes from substituted chalcones/benzalacetone and substituted β-enamine ketones (esters) (2)a,b. aReaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), AlCl3 (0.5 mmol) in dry toluene (3 mL) at 80 °C for 8 h. bIsolated yields based on 1. | |
 |
| Scheme 4 Synthesis of substituted 1,3-cyclohexadienes from chalcones and methyl 3-(phenylamino)pent-2-enoatea,b. aReaction conditions: 1 (0.5 mmol), 4 (0.6 mmol), AlCl3 (0.5 mmol) in dry toluene (3 mL) at 80 °C for 8 h. bIsolated yields based on 1. | |
To our delight, a series of chalcones with different substituents reacted smoothly with the N-phenyl ethyl β-enamino ester (2a) to generate the desired products in good yields (Scheme 3, 3a–3l). Generally, chalcones bearing electron donating substituents adjacent to carbonyl groups afforded desire products 3 in higher yields as compared with the chalcones bearing electron withdrawing groups (Scheme 3, 3a–3e) due to the electronic effects of substituent group which influence the activity of chalcone. Moreover, heteroaryl chalcone species such as furanyl also underwent the desired reaction to give the corresponding product 3k in 76% yield (Scheme 3, 3k). Further investigations demonstrated that the steric hindrance of the substitutes on the benzene rings, the methyl substrates 1f, 1g and 1h reacted with 2a to form the products 3f, 3g and 3h in 78%, 86% and 81%, respectively (Scheme 3, 3f–3h). In addition, the yield of product 3 indicated good tolerance for chalcones bearing either electron-withdrawing or electron-releasing groups connected to C–C double bond, (Scheme 3, 3i, 3j). When benzalacetone was used in this reaction, the expected product 3l was also afforded but the yield was slight low (3l in 48% and 3m in 44%), together with a significant amount of unreacted starting material (Scheme 3, 3l, 3m).
To explore the substrate scope further, different N-substituted β-enamino esters were investigated (Scheme 3, 3m–3r). When the derivatives of N-alkyl β-enamino esters were examined, the corresponding products were obtained in moderate yields (3n in 73% and 3o in 61%) (Scheme 3, 3n, 3o). N-Phenyl enaminones were also suitable for this reaction, 4-(phenylamino)pent-3-en-2-one reacted with chalcones to give moderate yields of the desired products in 56%, 60% and 65% respectively (Scheme 3, 3p–3r).
To expand the applicability of the present method, we used readily available ethyl 3-(phenylamino) pent-2-enoate 4 as starting materials and satisfactorily, desired products could be obtained. This method has easily been applied to the synthesis of ethyl 6′-methyl-5′-(phenylamino)-2′,3′-dihydro-[1,1′:3′,1′′-terphenyl]-4′-carboxylate and its derivates could be obtained smoothly with good results (Scheme 4, 5a–5c).
On the basis of the above experimental results and literature presents,28 we proposed a reasonable mechanism for this reaction (Scheme 5). The catalyst AlCl3 activated chalcone 1a via coordination with the carbonyl groups to form an intermediate A. Then this reaction would be considered to proceed with a Michael addition of enamine 2a to intermediate B. Yielding C as the intermediate. Under acid condition, the in situ generated intermediate D undergoes a series of tautomerism. Then the ensuing nucleophilic attack would proceed an intramolecular cyclization reaction to facilitate the key intermediate E. Subsequent dehydration and tautomerization gives the target product 3a.
 |
| Scheme 5 Proposed mechanism. | |
Conclusions
In summary, we have developed a novel protocol for the synthesis of multisubstituted 1,3-cyclohexadienes via a one-pot direct cyclization reaction between chalcones and β-enamines promoted by AlCl3 in dry toluene at 80 °C. This reaction provides a novel, rapid and efficient route for the preparation of a variety of multisubstituted 1,3-cyclohexadienes derivatives in moderate to excellent yields from readily accessible starting materials. These results will be important for developing new reactions for the synthesis of 1,3-cyclohexadienes, which have potential application in constructing building blocks for natural products.
Experimental
General information
All reagents and solvents were of commercial quality and were used as received. Reactions were monitored by TLC analysis. Melting points were measured on an X-4 hot stage microscope, and are uncorrected. 1H NMR spectra were recorded on an NMR instrument operated at 500 MHz. Chemical shifts are reported in ppm with the solvent resonance as the internal standard (CDCl3: δ 7.26 ppm). 13C NMR spectra were recorded on an NMR instrument operated at 126 MHz with complete proton decoupling. Chemical shifts are reported in ppm with the solvent resonance as the internal standard (CDCl3: δ 77.1 ppm). Topspin (Bruker) or Mestrenova (Mestrelab) software packages were used throughout for data processing.
Representative procedure for the synthesis of 3 and 5
Chalcone 1a (0.104 g, 0.5 mmol), β-enamine ester 2a (0.123 g, 0.6 mmol), AlCl3 (0.066 g, 0.5 mmol) were added to dry toluene (5 mL) under N2 and stirring was continued for 8 h at 80 °C. After completion of the reaction, as indicated by TLC, the mixture was dissolved in CH2Cl2 (30 mL) and then washed with aqueous ammonia (10%) (15 mL × 2). The separated organic layer was concentrated under vacuum and the solvent was evaporated under reduced pressure. Pure products 3a were obtained by silica gel column chromatography as a yellow solid (0.184 g, 93%), eluting with a petroleum ether–ethyl acetate mixture (20
:
1, v/v).
Ethyl 5′-(phenylamino)-2′,3′-dihydro-[1,1′:3′,1′′-terphenyl]-4′-carboxylate (3a). Yellow solid, 3a (0.184 g, 93%); mp 113–115 °C; 1H NMR (500 MHz, CDCl3) δ 10.80 (s, 1H), 7.38 (t, J = 7.9 Hz, 2H), 7.34–7.28 (m, 7H), 7.25 (t, J = 7.6 Hz, 2H), 7.20–7.13 (m, 4H), 6.70 (d, J = 2.9 Hz, 1H), 4.39 (d, J = 7.7 Hz, 1H), 4.24–4.05 (m, 2H), 3.27 (ddd, J = 16.6, 8.7, 2.9 Hz, 1H), 3.04 (dd, J = 16.7, 1.5 Hz, 1H), 1.21 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 170.1, 151.2, 145.1, 144.0, 139.9, 139.9, 129.1 (2C), 128.5 (2C), 128.4; 128.0 (2C), 127.2 (2C), 126.0, 125.8 (2C), 123.8, 123.2 (2C), 118.0, 95.3, 59.3, 36.9, 34.6, 14.3; HRMS (ESI-TOF) m/z calcd for C27H25NO2 [M + H]+ 396.1964, found 396.1963.
Ethyl 4-methoxy-5′-(phenylamino)-2′,3′-dihydro-[1,1′:3′,1′′-terphenyl]-4′-carboxylate (3b). Yellow oil, 3b (0.202 g, 95%); 1H NMR (500 MHz, CDCl3) δ 10.76 (s, 1H), 7.36 (t, J = 7.9 Hz, 2H), 7.28 (t, J = 7.5 Hz, 5H), 7.21 (t, J = 7.6 Hz, 2H), 7.13 (dd, J = 11.6, 7.5 Hz, 4H), 6.84–6.79 (m, 2H), 6.60 (d, J = 2.8 Hz, 1H), 4.34 (d, J = 7.5 Hz, 1H), 4.20–4.04 (m, 2H), 3.79 (s, 3H), 3.19 (ddd, J = 16.6, 8.6, 2.8 Hz, 1H), 3.00 (dd, J = 16.6, 1.6 Hz, 1H), 1.19 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 170.2, 160.1, 151.6, 145.3, 143.7, 140.1, 132.4, 129.2 (2C), 128.1 (2C), 127.3 (2C), 127.2 (2C), 126.0, 123.8, 123.3 (2C), 116.3, 114.1 (2C), 94.8, 59.3, 55.4, 36.9, 34.5, 14.4; HRMS (ESI-TOF) m/z calcd for C28H27NO3 [M + H]+ 426.2069, found 426.2071.
Ethyl 4-methoxy-4′′-methyl-5′-(phenylamino)-2′,3′-dihydro-[1,1′:3′,1′′-terphenyl]-4′-carboxylate (3c). Yellow solid, 3c (0.204 g, 93%), mp 110–112 °C; 1H NMR (500 MHz, CDCl3) δ 10.87 (s, 1H), 7.41 (t, J = 7.9 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 7.2 Hz, 2H), 7.22 (d, J = 7.7 Hz, 2H), 7.17 (t, J = 7.4 Hz, 1H), 7.09 (d, J = 7.9 Hz, 2H), 6.87 (d, J = 8.9 Hz, 2H), 6.70 (d, J = 2.7 Hz, 1H), 4.41 (d, J = 7.9 Hz, 1H), 4.28–4.14 (m, 2H), 3.80 (s, 3H), 3.25 (ddd, J = 16.5, 8.5, 2.8 Hz, 1H), 3.07 (dd, J = 16.6, 1.4 Hz, 1H), 2.34 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 170.1, 160.0, 151.3, 143.6, 142.1, 140.0, 135.2, 132.2, 129.0 (2C), 128.7 (2C), 127.1 (2C), 128.1 (2C), 123.6, 123.1 (2C), 116.1, 113.9 (2C), 95.0, 59.2, 55.1, 36.3, 34.4, 20.9, 14.4; HRMS (ESI-TOF) m/z calcd for C29H29NO3 [M + H]+ 440.2226, found 440.2227.
Ethyl 4-nitro-5′-(phenylamino)-2′,3′-dihydro-[1,1′:3′,1′′-terphenyl]-4′-carboxylate (3d). Orange solid, 3d (0.110 g, 50%), mp 109–111 °C; 1H NMR (500 MHz, CDCl3) δ 10.71 (s, 1H), 8.14–8.10 (m, 2H), 7.41–7.34 (m, 4H), 7.27–7.21 (m, 4H), 7.18–7.13 (m, 2H), 7.11 (d, J = 7.6 Hz, 2H), 6.75 (d, J = 3.0 Hz, 1H), 4.39 (dd, J = 8.5, 1.2 Hz, 1H), 4.20–4.06 (m, 2H), 3.28 (ddd, J = 16.5, 8.6, 3.0 Hz, 1H), 2.96 (dd, J = 16.5, 1.6 Hz, 1H), 1.18 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 169.9, 150.1, 147.3, 146.2, 144.2, 141.2, 139.6, 129.3 (2C), 128.2 (2C), 127.2 (2C), 126.5 (2C), 126.4, 124.1, 123.9 (2C), 123.1 (2C), 121.4, 96.5, 59.6, 36.7, 34.6, 14.3; HRMS (ESI-TOF) m/z calcd for C27H24N2O4 [M + H]+ 441.1814, found 441.1814.
Ethyl 4-bromo-5′-(phenylamino)-2′,3′-dihydro-[1,1′:3′,1′′-terphenyl]-4′-carboxylate (3e). Yellow solid, 3e (0.142 g, 60%), mp 120–122 °C; 1H NMR (500 MHz, CDCl3) δ 10.75 (s, 1H), 7.42–7.34 (m, 4H), 7.28–7.21 (m, 4H), 7.17–7.12 (m, 6H), 6.65 (d, J = 2.9 Hz, 1H), 4.36 (d, J = 7.4 Hz, 1H), 4.20–4.08 (m, 2H), 3.23 (ddd, J = 16.6, 8.6, 2.9 Hz, 1H), 2.94 (dd, J = 16.6, 1.6 Hz, 1H), 1.19 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 170.1, 150.8, 144.7, 142.6, 139.8, 138.7, 131.7 (2C), 129.2 (2C), 128.1 (2C), 127.3 (2C), 127.2 (2C), 126.1, 123.9, 123.1 (2C), 122.5, 118.5, 95.5, 59.4, 36.7, 34.4, 14.4; HRMS (ESI-TOF) m/z calcd for C27H24BrNO2 [M + H]+ 474.1069, found 474.1040.
Ethyl 4′′-methyl-5′-(phenylamino)-2′,3′-dihydro-[1,1′:3′,1′′-terphenyl]-4′-carboxylate (3f). Yellow solid, 3f (0.159 g, 78%), mp 116–118 °C; 1H NMR (500 MHz, CDCl3) δ 10.76 (s, 1H), 7.38–7.27 (m, 7H), 7.20–7.13 (m, 5H), 7.03 (d, J = 7.9 Hz, 2H), 6.68 (d, J = 2.9 Hz, 1H), 4.35 (t, J = 7.0 Hz, 1H), 4.23–4.07 (m, 2H), 3.23 (ddd, J = 16.6, 8.6, 2.9 Hz, 1H), 3.01 (dd, J = 16.7, 1.6 Hz, 1H), 2.29 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 170.2, 151.0, 144.0, 141.9, 139.9, 139.9, 135.4, 129.1 (2C), 128.8 (2C), 128.5 (2C), 128.4, 127.1 (2C), 125.8 (2C), 123.7, 123.1 (2C), 118.0, 95.5, 59.4, 36.3, 34.5, 21.0, 14.4; HRMS (ESI-TOF) m/z calcd for C28H27NO2 [M + H]+ 410.2120, found 410.2119.
Ethyl 3′′-methyl-5′-(phenylamino)-2′,3′-dihydro-[1,1′:3′,1′′-terphenyl]-4′-carboxylate (3g). Yellow solid, 3g (0.176 g, 86%), mp 108–110 °C; 1H NMR (500 MHz, CDCl3) δ 10.77 (s, 1H), 7.39–7.27 (m, 7H), 7.17–7.09 (m, 6H), 6.98–6.96 (m, 1H), 6.68 (d, J = 2.9 Hz, 1H), 4.34 (dd, J = 8.6, 1.4 Hz, 1H), 4.23–4.07 (m, 2H), 3.25 (ddd, J = 16.7, 8.7, 2.9 Hz, 1H), 3.02 (dd, J = 16.7, 1.6 Hz, 1H), 2.30 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 170.2, 151.1, 145.0, 144.0, 139.9, 139.9, 137.4, 129.1 (2C), 128.5 (2C), 128.4, 128.1, 127.9, 126.8, 125.8 (2C), 124.3, 123.7, 123.1 (2C), 118.0, 95.3, 59.3, 36.7, 34.5, 21.6, 14.4; HRMS (ESI-TOF) m/z calcd for C28H27NO2 [M + H]+ 410.2120, found 410.2122.
Ethyl 2′′-methyl-5′-(phenylamino)-2′,3′-dihydro-[1,1′:3′,1′′-terphenyl]-4′-carboxylate (3h). Yellow solid, 3h (0.166 g, 81%), mp 115–117 °C; 1H NMR (500 MHz, CDCl3) δ 10.76 (s, 1H), 7.37 (t, J = 7.9 Hz, 2H), 7.28–7.25 (m, 5H), 7.19–7.13 (m, 5H), 7.06–7.01 (m, 2H), 6.71 (d, J = 2.9 Hz, 1H), 4.61 (dd, J = 9.4, 1.2 Hz, 1H), 4.16–3.96 (m, 2H), 3.25 (ddd, J = 16.5, 9.5, 2.9 Hz, 1H), 2.78 (dd, J = 16.6, 1.4 Hz, 1H), 2.53 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 170.0, 151.3, 143.6, 142.6, 140.1, 139.9, 134.6, 130.1, 129.1 (2C), 128.5 (2C), 128.4, 127.0, 125.9, 125.8 (2C), 128.7, 123.6, 123.0 (2C), 118.2, 95.6, 59.3, 33.0, 32.4, 19.5, 14.2; HRMS (ESI-TOF) m/z calcd for C28H27NO2 [M + H]+ 410.2120, found 410.2123.
Ethyl 4′′-methoxy-5′-(phenylamino)-2′,3′-dihydro-[1,1′:3′,1′′-terphenyl]-4′-carboxylate (3i). Yellow solid, 3i (0.155 g, 73%), mp 104–106 °C; 1H NMR (500 MHz, CDCl3) δ 10.75 (s, 1H), 7.38–7.35 (m, 2H), 7.32–7.27 (m, 5H), 7.23–7.21 (m, 2H), 7.16–7.14 (m 3H), 6.78 (d, J = 8.7 Hz, 2H), 6.68 (d, J = 2.9 Hz, 1H), 4.33 (d, J = 7.4 Hz, 1H), 4.22–4.08 (m, 2H), 3.76 (s, 3H), 3.22 (ddd, J = 16.6, 8.5, 2.9 Hz, 1H), 2.99 (dd, J = 16.6, 1.6 Hz, 1H), 1.22 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 170.2, 157.9, 150.9, 144.0, 139.9, 137.1, 129.1 (2C), 128.7 (2C), 128.5, 128.4, 128.2 (2C), 125.8 (2C), 123.7, 123.1 (2C), 118.0, 113.4 (2C), 95.6, 59.3, 55.1, 35.9, 34.7, 14.4; HRMS (ESI-TOF) m/z calcd for C28H27NO3 [M + H]+ 426.2069, found 426.2070.
Ethyl 4′′-nitro-5′-(phenylamino)-2′,3′-dihydro-[1,1′:3′,1′′-terphenyl]-4′-carboxylate (3j). Yellow oil, 3j (0.158 g, 72%); 1H NMR (500 MHz, CDCl3) δ 10.79 (s, 1H), 8.07 (d, J = 8.8 Hz, 2H), 7.44–7.40 (m, 2H), 7.38–7.33 (m, 2H), 7.28–7.23 (m, 5H), 7.16–7.12 (m, 3H), 6.66 (d, J = 2.9 Hz, 1H), 4.46–4.39 (m, 1H), 4.17–4.02 (m, 2H), 3.28 (ddd, J = 16.7, 8.8, 2.9 Hz, 1H), 2.95 (dd, J = 16.8, 1.6 Hz, 1H), 1.15 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 169.7, 153.2, 151.7, 146.6, 143.8, 139.4, 139.3, 129.2 (2C), 128.9, 128.7 (2C), 128.1 (2C), 125.7 (2C), 124.3, 123.5 (2C), 123.5 (2C), 117.9, 93.3, 59.5, 37.1, 34.1, 14.4; HRMS (ESI-TOF) m/z calcd for C27H24N2O4 [M + H]+ 441.1814, found 441.1819.
Ethyl 5-(furan-2-yl)-3-(phenylamino)-1,6-dihydro-[1,1′-biphenyl]-2-carboxylate (3k). Yellow solid, 3k (0.146 g, 76%), mp 147–149 °C; 1H NMR (500 MHz, CDCl3) δ 10.77 (s, 1H), 7.38–7.34 (m, 3H), 7.26–7.20 (m, 4H), 7.15–7.122 (m, 4H), 6.80 (d, J = 2.8 Hz, 1H), 6.42 (d, J = 3.4 Hz, 1H), 6.37 (dd, J = 3.4, 1.8 Hz, 1H), 4.32 (d, J = 7.4 Hz, 1H), 4.18–4.04 (m, 2H), 3.10 (ddd, J = 16.5, 8.6, 2.8 Hz, 1H), 2.85 (dd, J = 16.5, 1.6 Hz, 1H), 1.18 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 170.0, 153.3, 151.2, 145.0, 143.6, 139.9, 132.4, 129.1 (2C), 128.1 (2C), 127.3 (2C), 126.0, 123.8, 123.3 (2C), 114.2, 111.8, 109.8, 94.9, 59.3, 36.3, 31.9, 14.4; HRMS (ESI-TOF) m/z calcd for C25H23NO3 [M + H]+ 386.1756, found 386.1757.
Ethyl 5-methyl-3-(phenylamino)-1,6-dihydro-[1,1′-biphenyl]-2-carboxylate (3l). Yellow solid, 3l (0.080 g, 48%), mp 102–104 °C; 1H NMR (500 MHz, CDCl3) δ 10.75 (s, 1H), 7.46–7.30 (m, 3H), 7.27–7.23 (m, 3H), 7.22–7.05 (m, 4H), 6.11 (dd, J = 2.6, 1.4 Hz, 1H), 4.18 (d, J = 7.8 Hz, 1H), 4.15–4.03 (m, 2H), 3.08–2.77 (m, 1H), 2.33 (dd, J = 17.0, 1.3 Hz, 1H), 1.77 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 170.3, 151.8, 145.9, 145.4, 139.8, 129.0 (2C), 128.0 (2C), 127.2 (2C), 125.9, 123.8, 123.6 (2C), 117.0, 93.2, 59.1, 37.2, 36.7, 24.4, 14.4; HRMS (ESI-TOF) m/z calcd for C22H23NO2 [M + H]+ 334.1807, found 334.1813.
Ethyl 3-((4-methoxyphenyl)amino)-5-methyl-1,6-dihydro-[1,1′-biphenyl]-2-carboxylate (3m). Yellow oil, 3m (0.080 g, 44%); 1H NMR (500 MHz, CDCl3) δ 10.61 (s, 1H), 7.27–7.20 (m, 4H), 7.19–7.13 (m, 1H), 7.09–7.00 (m, 2H), 6.93–6.85 (m, 2H), 5.98 (dd, J = 2.6, 1.4 Hz, 1H), 4.16 (d, J = 7.9 Hz, 1H), 4.12–4.02 (m, 2H), 3.83 (s, 3H), 2.93–2.82 (m, 1H), 2.31 (dd, J = 17.0, 1.3 Hz, 1H), 1.15 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 170.4, 156.8, 152.8, 146.3, 145.7, 132.6, 127.9 (2C), 127.2 (2C), 126.0 (2C), 125.8, 116.8, 114.2 (2C), 91.5, 59.0, 55.5, 37.4, 36.8, 24.4, 14.4; HRMS (ESI-TOF) m/z calcd for C23H25NO3 [M + H]+ 364.1913, found 364.1913.
Ethyl 5′-(cyclohexylamino)-2′,3′-dihydro-[1,1′:3′,1′′-terphenyl]-4′-carboxylate (3n). Yellow oil, 3n (0.146 g, 73%); 1H NMR (500 MHz, CDCl3) δ 9.17 (d, J = 8.0 Hz, 1H), 7.39–7.28 (m, 7H), 7.24–7.13 (m, 3H), 6.66 (d, J = 2.8 Hz, 1H), 4.31 (d, J = 7.4 Hz, 1H), 4.18–4.01 (m, 2H), 3.67–3.57 (m, 1H), 3.19 (ddd, J = 16.8, 8.5, 2.9 Hz, 1H), 2.95 (dd, J = 16.8, 1.6 Hz, 1H), 2.11–1.63 (m, 5H), 1.53–1.30 (m, 5H), 1.18 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 170.3, 154.2, 146.0, 145.9, 140.5, 128.5 (2C), 128.4, 127.8 (2C), 127.2 (2C), 125.8 (2C), 125.7, 116.5, 89.4, 58.6, 51.0, 36.7, 35.2, 34.6, 34.2, 25.5, 24.7, 24.6, 14.5; HRMS (ESI-TOF) m/z calcd for C27H31NO2 [M + H]+ 402.2433, found 402.2433.
Ethyl 5′-(butylamino)-2′,3′-dihydro-[1,1′:3′,1′′-terphenyl]-4′-carboxylate (3o). Yellow oil, 3o (0.090 g, 48%); 1H NMR (500 MHz, CDCl3) δ 9.06 (s, 1H), 7.45–7.30 (m, 6H), 7.27–7.10 (m, 4H), 6.64 (d, J = 2.9 Hz, 1H), 4.28 (d, J = 7.8 Hz, 1H), 4.14–4.03 (m, 2H), 3.48–3.33 (m, 2H), 3.17 (ddd, J = 16.8, 8.4, 2.9 Hz, 1H), 2.95 (dd, J = 16.8, 1.5 Hz, 1H), 1.71–1.63 (m, 2H), 1.54–1.45 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H), 1.00 (t, J = 7.3 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 170.4, 155.1, 146.3, 145.9, 140.4, 128.5 (2C), 128.5, 127.9 (2C), 127.2 (2C), 125.8 (2C), 125.7, 116.3, 89.4, 58.7, 42.7, 36.8, 35.2, 32.8, 20.2, 14.5, 13.9; HRMS (ESI-TOF) m/z calcd for C25H29NO2 [M + H]+ 376.2277, found 376.2278.
1-(5′-(Phenylamino)-2′,3′-dihydro-[1,1′:3′,1′′-terphenyl]-4′-yl)ethanone (3p). Yellow solid, 3p (0.102 g, 56%), mp 94–96 °C; 1H NMR (500 MHz, CDCl3) δ 13.20 (s, 1H), 7.42–7.38 (m, 2H), 7.29–7.17 (m, 13H), 6.71 (d, J = 2.9 Hz, 1H), 4.26 (dd, J = 7.9, 1.3 Hz, 1H), 3.31 (ddd, J = 16.4, 8.1, 2.9 Hz, 1H), 3.07 (dd, J = 16.4, 1.7 Hz, 1H), 2.12 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 197.1, 153.0, 145.4, 143.8, 139.6, 139.0, 129.1 (2C), 128.7, 128.5 (2C), 128.3 (2C), 127.5 (2C), 126.4, 125.8 (2C), 124.8, 124.2 (2C), 117.6, 103.0, 39.1, 35.7, 27.7; HRMS (ESI-TOF) m/z calcd for C26H23NO [M + H]+ 366.1858, found 366.1862.
1-(3′′-Methyl-5′-(phenylamino)-2′,3′-dihydro-[1,1′:3′,1′′-terphenyl]-4′-yl)ethanone (3q). Yellow oil, 3q (0.114 g, 60%); 1H NMR (500 MHz, CDCl3) δ 13.19 (s, 1H), 7.42–7.38 (m, 2H), 7.28–7.07 (m, 12H), 6.71 (d, J = 2.8 Hz, 1H), 4.22 (d, J = 7.2 Hz, 1H), 3.29 (ddd, J = 16.4, 8.2, 2.8 Hz, 1H), 3.06 (dd, J = 16.4, 1.6 Hz, 1H), 2.31 (s, 3H), 2.11 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 197.2, 153.0, 145.4, 143.8, 139.6, 139.06, 137.8, 129.1 (2C), 128.6, 128.5 (2C), 128.2 (2C), 127.2, 125.8 (2C), 124.7, 124.6, 124.2 (2C), 117.6, 103.0, 39.0, 35.7, 27.7, 21.5; HRMS (ESI-TOF) m/z calcd for C27H25NO [M + H]+ 380.2014, found 380.2012.
1-(5-(Furan-2-yl)-3-(phenylamino)-1,6-dihydro-[1,1′-biphenyl]-2-yl)ethanone (3r). Yellow oil, 3r (0.115 g, 65%); 1H NMR (500 MHz, CDCl3) δ 13.25 (s, 1H), 7.42–7.38 (m, 2H), 7.33 (d, J = 1.6 Hz, 1H), 7.27–7.15 (m, 8H), 6.84 (d, J = 2.7 Hz, 1H), 6.42 (d, J = 3.4 Hz, 1H), 6.35 (dd, J = 3.4, 1.8 Hz, 1H), 4.22 (dd, J = 8.0, 1.4 Hz, 1H), 3.16 (ddd, J = 16.3, 8.0, 2.7 Hz, 1H), 2.90 (dd, J = 16.3, 1.6 Hz, 1H), 2.09 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 196.6, 153.2, 153.0, 143.9, 143.8, 139.0, 133.5, 129.1 (2C), 128.4 (2C), 127.5 (2C), 126.4, 124.8, 124.3 (2C), 113.6, 111.9, 110.5, 102.8, 38.6, 33.1, 27.6; HRMS (ESI-TOF) m/z calcd for C24H21NO2 [M + H]+ 356.1651, found 356.1651.
Ethyl 6′-methyl-5′-(phenylamino)-2′,3′-dihydro-[1,1′:3′,1′′-terphenyl]-4′-carboxylate (5a). Yellow oil, 5a (0.160 g, 81%); 1H NMR (500 MHz, CDCl3) δ 10.53 (s, 1H), 7.39–7.30 (m, 7H), 7.24–7.20 (m, 3H), 7.15–7.09 (m, 3H), 6.75 (dd, J = 8.1, 1.4 Hz, 2H), 4.33 (dd, J = 7.1, 1.4 Hz, 1H), 3.70 (s, 3H), 3.20 (ddd, J = 16.3, 7.2, 2.7 Hz, 1H), 2.80 (dd, J = 16.3, 1.6 Hz, 1H), 1.62 (d, J = 2.4 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 170.3, 155.8, 143.0, 142.7, 141.6, 141.6, 129.1 (2C), 128.1 (2C), 127.9 (3C), 127.5 (2C), 127.1, 127.0, 126.2, 122.8, 120.9 (2C), 118.7, 102.4, 51.2, 39.4, 36.8, 16.8; HRMS (ESI-TOF) m/z calcd for C27H25NO2 [M + H]+ 396.1964, found 396.1964.
Ethyl 4-methoxy-6′-methyl-5′-(phenylamino)-2′,3′-dihydro-[1,1′:3′,1′′-terphenyl]-4′-carboxylate (5b). Yellow oil, 5b (0.181 g, 85%); 1H NMR (500 MHz, CDCl3) δ 10.51 (s, 1H), 7.37–7.29 (m, 6H), 7.27–7.24 (m, 1H), 7.13–7.06 (m, 3H), 6.78–6.69 (m, 4H), 4.30 (d, J = 5.8 Hz, 1H), 3.77 (s, 3H), 3.69 (s, 3H), 3.19–3.11 (m, 1H), 2.78 (dd, J = 16.3, 1.5 Hz, 1H), 1.62 (d, J = 2.4 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 170.3, 158.7, 156.1, 143.1, 142.9, 141.4, 133.8, 129.4 (2C), 129.1 (2C), 128.1 (2C), 127.5 (2C), 126.4, 126.2, 122.8, 121.0 (2C), 113.4 (2C), 102.1, 55.2, 51.2, 39.5, 36.8, 17.0; HRMS (ESI-TOF) m/z calcd for C28H27NO3 [M + H]+ 426.2069, found 426.2095.
Ethyl 6′-methyl-4-nitro-5′-(phenylamino)-2′,3′-dihydro-[1,1′:3′,1′′-terphenyl]-4′-carboxylate (5c). Yellow solid, 5c (0.161 g, 73%), mp 128–130 °C; 1H NMR (500 MHz, CDCl3) δ 10.35 (s, 1H), 7.95 (d, J = 8.8 Hz, 2H), 7.27–7.21 (m, 4H), 7.18–7.13 (m, 3H), 7.02–6.94 (m, 3H), 6.67 (d, J = 8.8 Hz, 2H), 4.22 (d, J = 5.6 Hz, 1H), 3.58 (s, 3H), 3.17–3.02 (m, 1H), 2.59 (dd, J = 16.1, 1.6 Hz, 1H), 1.45 (d, J = 2.4 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 170.1, 155.0, 148.5, 146.7, 142.8, 142.1, 139.0, 129.4, 129.3 (2C), 128.8 (2C), 128.4 (2C), 127.5 (2C), 126.6, 123.4 (2C), 123.2, 121.0 (2C), 103.1, 51.4, 39.2, 36.8, 16.9; HRMS (ESI-TOF) m/z calcd for C28H26N2O4 [M + H]+ 441.1814, found 441.1807.
Acknowledgements
This work was supported by the Natural Science Foundation of China (Grant no. 21176223), the National Natural Science Foundation of Zhejiang (Grant no. LY13B020016), and the Key Innovation Team of Science and Technology in Zhejiang Province (Grant no. 2010R50018).
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Footnote |
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra25691g |
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