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DOI: 10.1055/a-2371-3579
One-Pot, Two-Step Synthesis of Highly Functionalized 4-Indolyl/Pyrrolyl-Chromanes via a para-Quinone Methide Formation–1,8-Addition Sequence
Financial support from the Science and Engineering Research Board, SERB (No. CRG/2021/000760) and the JK Science Technology & Innovation Council, JKST&IC (JKST&IC/J/14/2022/463-67) is gratefully acknowledged. R.K. thanks Central University of Jammu for a research fellowship and A.G. thanks the Council of Scientific and Industrial Research (CSIR), New Delhi for the award of a Senior Research Fellowship.
Abstract
An efficient one-pot, two-step synthesis of structurally diverse 4-indolyl-/pyrrolyl-chromanes was developed starting from o-propargylated salicylaldehydes, 2,6-dialkylphenols and indoles/pyrrole. This process begins with a sequential secondary amine-catalyzed formation of p-quinone methides followed by Brønsted acid catalyzed 1,8-addition with indoles/pyrrole to access the functionalized chromanes in high yields (up to 91%). This sequential reaction generates three new C–C bonds, shows high step- and atom-economy with only one molecule of water as the side product and gives access to complex molecular frameworks without the need for the isolation of the intermediates.
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Key words
heterocycles - 4-indolyl-chromanes - 4-pyrrolyl-chromanes - p-quinone methide - 1,8-additionQuinone methides, also known as methylenequinones or quinone methines, are derived from quinones by substituting one of the carbonyl oxygens with a methylene or a substituted methylene group. In recent years, para-quinone methides (p-QMs) have gained prominence as essential building blocks for synthesizing a wide range of functionalized organic compounds.[1] Beyond their role as intermediates in numerous biological and biosynthetic pathways, certain derivatives of quinone methides occur naturally and exhibit significant biological properties.[2] A notable example is pristimerin I, isolated from Celastraceae, which is known for the treatment of tumour-related processes such as apoptosis and autophagy (Figure [1]).[3] Brazilein II, isolated from Caesalpinia sappan Linn, is known to exhibit anti-inflammatory and anticancer activities.[4] UPA0043 III and UPA0044 IV are recognized for their notable cytotoxic and antifungal properties.[5] Additionally, p-QMs represent a class that is gaining importance for the synthesis of diverse heterocycles.[6]
Oxygen-containing heterocyclic compounds including chromanes are prevalent in a wide array of biologically relevant molecules and pharmaceutical agents.[7] For instance, vitamin E (V) has proven to be highly effective in preventing and reversing various disease complications. This is due to its antioxidant properties, its role in anti-inflammatory processes, its ability to inhibit platelet aggregation, and its immune-boosting activities (Figure [2]).[8] Fuscinarin VI, isolated from the soil fungus Oidiodendron griseum, effectively competes with macrophage inflammatory protein (MIP)-1 for binding to human CCR5, a crucial target in preventing HIV-1 entry into cells,[9] and rhododaurichromanic acid A (VII) is also known to possess anti-HIV properties.[10] Further, troglitazone VIII is utilized in the treatment of patients with non-insulin-dependent diabetes mellitus (NIDDM).[11]
Owing to the importance of p-quinone methides and chromanes, it was envisioned that a one-pot approach could be developed for the synthesis of 4-indolyl-chromanes 5 and 4-pyrrolyl-chromanes 7 starting from O-propargyl salicylaldehyde derivatives 1, 2,6-dialkylphenols 2 and indoles 4/pyrrole 6 (Scheme [1]). The proposed approach involves the combination of our recently developed secondary amine-catalyzed p-quinone methide formation[12] and Brønsted or Lewis acid catalyzed 1,8-addition of indoles 4 or pyrrole 6 to the in situ generated p-QMs 3. The cascade/domino reactions enable the transformation of simple starting materials into highly functionalized, complex structures through sequential reactions in one pot.[13] In particular, the incorporation of p-quinone methides in cascade reactions has become increasingly popular, as it provides a swift and efficient route to valuable heterocycles.[14] [15]
To identify suitable reaction conditions for the proposed one-pot, two-step synthesis, the reaction was initiated by testing the model substrates 1a and 2a under various conditions as shown in Table [1]. At the outset, we tested the reaction under our previously established reaction conditions involving toluene as the solvent in the presence of 10 mol% of piperidine as catalyst at 110 °C, where p-quinone methide 3a was obtained in 83% yield in 4 h (entry 1).[12] When the reaction was performed in MeCN at 80 °C, an enhanced yield of 87% was obtained in 5 h (entry 2) and the use of polar protic solvent EtOH was also fruitful in giving the desired product 3a in 79% at 80 °C (entry 3). However, the reaction was sluggish in ethereal solvent DME, delivering the product in a moderate yield of 72% in 24 h (entry 4). The use of polar aprotic solvents DMF and DMSO was also efficient in yielding the desired product 3a in 74% and 71% yields, respectively, in 20 h (entries 5 and 6).
a Step 1: Unless otherwise noted, all reactions were performed using 1a (0.5 mmol), 2a (0.5 mmol), piperidine (10 mol%) in solvent (6 mL). Step 2: After completion of the Step 1, solvent and base were evaporated and the residue was dissolved in solvent (6 mL). To this solution, 4a (0.5 mmol) and catalyst (10 mol%) were added and the reaction was continued at r.t.
b Optimized reaction condition for Step 1.
c Step 2 was performed without evaporation of the base; after completion of Step 1, 4a (0.5 mmol) and p-TsOH (10 mol%) were added and the reaction was continued at r.t.
d Unreacted p-quinone methide 3a was recovered.
e Reaction was performed without evaporating piperidine after completion of the first step.
With the established optimal conditions for the first step (10 mol% of piperidine, MeCN, 80 °C, entry 2), the study then focused on obtaining high-yielding reaction conditions for the subsequent 1,8-addition step, which involves the use of indole 4a as the nucleophile. After completion of the first step, the reaction mixture was cooled, 10 mol% p-TsOH was added, and the reaction was continued at room temperature. Under all the six tested conditions involving toluene, MeCN, EtOH, DME, DMF and DMSO as solvents, the envisioned 1,8-addition failed to proceed even after 48 h and the unreacted p-quinone methide 3a was recovered (entries 7–12). Owing to the lack of initial success, we presumed that the removal of piperidine is essential upon completion of the p-quinone methide formation. After the first step was completed in MeCN, the solvent and base were evaporated and the crude product was dissolved in toluene. To this mixture, indole 4a and 10 mol% of p-TsOH were added and the reaction was continued at room temperature. As expected, the 1,8-addition of indole 4a proceed smoothly at room temperature to deliver the desired compound 5a in 75% overall yield in 4 h (entry 13). Further, the second step of the reaction was performed in MeCN and EtOH in the presence of 10 mol% of p-TsOH, and the reaction was completed in 2–3 h in both the cases, giving the desired product 5a in 76–79% yield (entries 14 and 15).
The use of 10 mol% TFA catalyst in toluene and MeCN furnished the desired product in 78% and 82% yields, respectively, in just 2 h (entries 16 and 17). The combination of EtOH and TFA also delivered compound 5a in 80% yield; however, the reaction required 7 h for completion (entry 18). Further, the role of Lewis acid catalysts was tested for the 1,8-addition step in most promising solvents MeCN and EtOH. The use of 10 mol% Sc(OTf)3 in MeCN and EtOH delivered the desired product 5a in 81% and 76% yields, respectively, in 2–5 h at room temperature (entries 19 and 20). Similarly, Yb(OTf)3 was also effective in MeCN and EtOH, where 73–78% of the desired product was obtained in 1–5 h (entries 21 and 22). Finally, the activity of AcOH (10 mol%) was tested in MeCN and EtOH, where only 43-46% yields were obtained after allowing the reaction for 48 h and the remaining starting material 3a was recovered (entries 23 and 24). Addition of TFA (20 mol% or 1.0 equiv) without evaporating piperidine after completion of the first step furnished inferior results (entries 25 and 26). After the detailed and systematic evaluation of various catalysts and solvents, the conditions given in entry 17 were established as the optimal conditions for the one-pot, two-step sequence (step 1: 10 mol% piperidine, MeCN, 80 °C; Step 2: 10 mol% TFA, MeCN, r.t.).
After establishing the optimized reaction conditions (entry 17), we proceeded to investigate the scope and limitations of the one-pot, two-step synthesis of 4-indolyl-chromanes 5 involving a variety of substituted O-propargylated salicylaldehydes 1, 2,6-disubstituted phenols 2 and indoles 4 (Scheme [2]). Initially, various substituents including electron-releasing and electron-withdrawing groups were introduced at the R2 position. The incorporation of electron-releasing Me and OMe substituents at the R2 position delivered the desired products 5b (E/Z = 1.0:0.43) and 5c (E/Z = 1.0:0.08) in 84% and 76% yields, respectively. The moderately electron-withdrawing substituents including chloro and bromo groups at the R2 position did not affect the outcome of the reaction sequence, where 72% (E/Z = 1:0.51) and 79% (E/Z = 1:0.30) yield of the desired compounds 5d and 5e, respectively, were obtained.
The introduction of a OMe substituent at the R1 position delivered the corresponding 4-indolyl-chromane 5f in 67% yield and compound 5g, bearing a bromo substituent at the R2 position and a OMe group at the R1 position, was obtained in 71% yield. Additionally, a strongly electron-releasing N,N-diethylamino group was introduced at the R1 position to access the corresponding 4-indolyl-chromanes 5h (R1 = NEt2; R2 = H) and 5i (R1 = NEt2; R2 = Cl, E/Z = 1.0:0.30) in 62–75% yields. Furthermore, the compatibility of the reaction was tested with 2-hydroxy-1-naphthaldehyde-derived alkyne, where the desired product 5j was obtained in 79% yield as a 1:1 mixture of E and Z isomers.
Subsequently, the effect of substituents on the indole moiety was explored. The reaction between 5-bromoindole and in situ generated p-quinone methides bearing various substituents at the R2 position delivered the corresponding 4-indolyl-chromanes 5k–m in good yields (5k, R2 = H, 83%; 5l, R2 = Me, 87%; 5m, R2 = Cl, 80%). However, the introduction of a strong electron-withdrawing substituent at R2 delivered the nitro-substituted 4-indolyl-chromane 5n in a moderate yield of 57% (E/Z = 1.0:0.19). The use of 6-bromoindole as a nucleophile also allowed successful access to 5o in 78% yield. Introducing a chloro substituent at the R1 position in the O-propargylated salicylaldehyde along with a bromo substituent in the 5-position of the indole significantly increased the yield, delivering the corresponding 4-indolyl-chromane 5p in 91% yield.
Further, the reaction between 2-hydroxy-1-naphthaldehyde-derived p-quinone methide and 5-bromoindole furnished the corresponding 4-indolyl-chromane 5q in 82% yield (E/Z = 1:0.43). N-Methyl-1H-indole was also used as a nucleophile, where the desired products 5r and 5s (E/Z = 1.0:0.28) were obtained in 69–77% yield. Finally, the reaction was tested with 2,6-diisopropylphenol-derived p-quinone methides and indoles. A couple of 4-indolyl-chromane derivatives 5t and 5u (E/Z = 1.0:0.11) were obtained involving 5-bromoindole and N-methyl-1H-indole as nucleophiles in 51–65% yields. The reported structures of 5 were confirmed from spectral studies and single-crystal X-ray analysis of compound 5b (CCDC: 2359276).
In order to further extend the applicability of the proposed reaction sequence, pyrrole 6 was used as the nucleophile to access the corresponding 4-pyrrolyl-chromanes 7 (Scheme [3]). The in situ generated parent p-quinone methide reacted smoothly with pyrrole to furnish compound 7a in 85% yield. Similarly, the bromo-substituted analogue 7b was also accessed in 67% yield under the standard conditions.
The proposed mechanistic pathway for the one-pot, two-step process is depicted in Scheme [4]. The reaction starts with the formation of iminium ion A via condensation of secondary amine catalyst and O-propargyl salicylaldehydes 1. Next, intermolecular attack of 2,6-dialkylphenol 2 to the alkyne followed by intramolecular cyclization delivers intermediate B, which eliminates the catalyst to generate the p-quinone methide scaffold 3.[12] The Brønsted acid TFA activates compound 3 and triggers the 1,8-addition with the nucleophilic indole 4 to furnish intermediate D via species C. Final deprotonation completes the reaction cycle to deliver the desired 4-indolyl-chromanes 5. The formation of minor isomer 5′ could be visualized via intermediate D′.
In summary, we have developed a one-pot, two-step sequence for the synthesis of 4-indolyl- and 4-pyrrolyl-chromanes from readily available starting materials in high yields (up to 91%). This strategy involves the secondary amine catalyzed formation of p-quinone methides starting from O-propargylated salicylaldehydes and 1,6-disubstituted phenols followed by Brønsted acid catalyzed 1,8-addition with indoles and pyrrole. The reaction shows high atom economy (–H2O) and generates three new C–C bonds in a single synthetic operation without isolation of the intermediates.
All reagents and solvents were purchased from commercial suppliers (Alfa Aesar, Sigma Aldrich, Merck, SRL, SDFine) and used without further purification. All reactions were carried out in oven-dried glassware. The reactions were monitored by thin-layer chromatography using Merck silica gel 60 F254 and visualized by UV detection or by using molecular iodine or p-anisaldehyde stain. Silica gel (230–400 mesh) was used for flash column chromatography. Melting points were recorded with a melting-point apparatus in capillaries and are reported uncorrected. 1H and 13C{1H} NMR spectra were recorded in CDCl3 at r.t. with a Brucker AC-400 spectrometer operating at 400 MHz for 1H and 101 MHz or 126 MHz for 13C{1H}. Chemical shifts (δ) are expressed in ppm using TMS as an internal standard and coupling constants (J) are given in Hz. Infrared (IR) spectra were recorded neat with a Perkin–Elmer FTIR spectrophotometer. Elemental analyses were determined at the CAI de Microanálisis Elemental, Universidad Complutense, with a Leco 932 CHNS combustion microanalyzer.
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Synthesis of Compounds 1; General Procedure[12]
Compounds 1 were synthesized on a 5 mmol scale starting from salicylaldehyde derivatives involving base-mediated O-propargylation followed by Sonogashira coupling with iodoarenes using a reported procedure.[12] Two-step overall yields are reported.
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2-((3-Phenylprop-2-yn-1-yl)oxy)benzaldehyde (1a)[12]
Yield: 0.967 g (82%); colourless solid; mp 75–77 °C.
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2-((3-(p-Tolyl)prop-2-yn-1-yl)oxy)benzaldehyde (1b)[12]
Yield: 0.975 g (78%); colourless solid; mp 95–97 °C.
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2-((3-(4-Methoxyphenyl)prop-2-yn-1-yl)oxy)benzaldehyde (1c)[12]
Yield: 0.944 g (71%); colourless solid; mp 87–89 °C.
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2-((3-(4-Chlorophenyl)prop-2-yn-1-yl)oxy)benzaldehyde (1d)[12]
Yield: 0.918 g (68%); colourless solid; mp 92–94 °C.
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2-((3-(4-Bromophenyl)prop-2-yn-1-yl)oxy)benzaldehyde (1e)[12]
Yield: 1.26 g (80%); colourless solid; mp 108–110 °C.
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2-((3-(4-Nitrophenyl)prop-2-yn-1-yl)oxy)benzaldehyde (1f)[12]
Yield: 1.025 g (73%); colourless solid; mp 107–109 °C.
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2-((3-Phenylprop-2-yn-1-yl)oxy)-1-naphthaldehyde (1g)[16]
Yield: 0.8 g (56%); colourless solid; mp 109–111 °C.
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2-((3-(p-Tolyl)prop-2-yn-1-yl)oxy)-1-naphthaldehyde (1h)
Yield: 0.765 g (51%); colourless solid; mp 115–117 °C.
IR (neat): 2889.4, 2216.2, 1662.6, 1587.4, 1460.1, 1365.1, 1212.3, 1064.7 cm–1.
1H NMR (400 MHz, CDCl3): δ = 10.88 (s, 1 H), 9.22 (d, J = 8.7 Hz, 1 H), 8.02 (d, J = 9.1 Hz, 1 H), 7.72 (d, J = 8.1 Hz, 1 H), 7.56 (td, J = 6.9, 1.3 Hz, 1 H), 7.42–7.35 (m, 2 H), 7.24–7.19 (m, 2 H), 7.03 (d, J = 7.9 Hz, 2 H), 5.09 (s, 2 H), 2.26 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 192.20, 162.33, 139.25, 137.29, 131.70, 131.52, 129.86, 129.15, 129.04, 128.24, 125.12, 118.67, 117.95, 114.34, 88.62, 82.24, 58.39, 21.54.
Anal. Calcd. for C21H16O2: C, 83.98; H, 5.37. Found: C, 83.66; H, 5.31.
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4-Methoxy-2-((3-phenylprop-2-yn-1-yl)oxy)benzaldehyde (1i)[12]
Yield: 0.997 g (75%); orange viscous liquid.
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2-((3-(4-Bromophenyl)prop-2-yn-1-yl)oxy)-4-methoxybenzaldehyde (1j)[12]
Yield: 1.38 g (81%); pale-yellow solid; mp 99–101 °C.
IR (neat): 2932.1, 2231.1, 1672.5, 1469.5, 1334.6, 1232.9, 1055.1 cm–1.
1H NMR (400 MHz, CDCl3): δ = 10.36 (s, 1 H), 7.88 (d, J = 8.6 Hz, 1 H), 7.48 (d, J = 8.2 Hz, 2 H), 7.32 (d, J = 8.2 Hz, 2 H), 6.69–6.62 (m, 2 H), 5.03 (s, 2 H), 3.91 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 188.2, 165.9, 161.7, 133.2, 131.7, 130.7, 123.4, 120.8, 119.6, 106.7, 99.6, 87.1, 83.9, 57.2, 55.7.
Anal. Calcd. for C17H13BrO3: C, 59.15; H, 3.80. Found: C, 58.83; H, 3.73.
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4-(Diethylamino)-2-((3-phenylprop-2-yn-1-yl)oxy)benzaldehyde (1k)[16]
Yield: 1.004 g (65%); purple solid; mp 112–114 °C.
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2-((3-(4-Chlorophenyl)prop-2-yn-1-yl)oxy)-4-(diethylamino)benzaldehyde (1l)
Yield: 1159 mg (68%); purple solid; mp 100–102 °C.
IR (neat): 2974.2, 2931.8, 2848.4, 2349.4, 1716.6, 1651.7, 1552.7, 1489.0, 1300.0, 1234.4 cm–1.
1H NMR (400 MHz, CDCl3): δ = 10.16 (s, 1 H), 7.73 (d, J = 8.9 Hz, 1 H), 7.36–7.33 (m, 2 H), 7.29–7.26 (m, 2 H), 6.34 (dd, J = 8.9, 2.1 Hz, 1 H), 6.28 (d, J = 2.2 Hz, 1 H), 5.00 (s, 2 H), 3.43 (q, J = 7.1 Hz, 4 H), 1.23 (t, J = 7.0 Hz, 6 H).
13C NMR (101 MHz, CDCl3): δ = 186.89, 162.21, 153.66, 134.82, 132.90, 130.58, 128.67, 120.48, 114.51, 105.02, 94.43, 86.59, 84.58, 56.90, 44.86, 12.58.
Anal. Calcd. for C20H20ClNO2: C, 70.27; H, 5.90. Found: C, 70.02; H, 5.96.
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5-Chloro-2-((3-phenylprop-2-yn-1-yl)oxy)benzaldehyde (1m)[12]
Yield: 1.201 g (89%); colourless solid; mp 104–106 °C.
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Synthesis of 4-Indolyl- and 4-Pyrrolyl-chromanes 5 and 7; General Procedure
A mixture of aldehyde 1 (0.5 mmol, 1.0 equiv), 2,6-dialkylphenol 2 (0.5 mmol, 1.0 equiv), and piperidine (0.05 mmol, 0.1 equiv) in MeCN (6 mL) was heated at 80 °C for 5 h. After completion of the reaction, as indicated by TLC, the reaction mixture was cooled to r.t. The catalyst and solvent were evaporated under reduced pressure and the crude product 3 obtained was dissolved in MeCN (6 mL). To this mixture, TFA (0.05 mmol, 0.1 equiv) and indole/pyrrole 4/6 (0.5 mmol, 1.0 equiv) were added and the mixture was stirred at r.t. for 2–4 h. After the reaction was completed, the mixture was diluted with water and extracted with EtOAc (2 × 15 mL). The organic layer was washed with water followed by brine and dried over anhydrous Na2SO4. The solvent was removed by rotary evaporation, and the crude residue was purified by column chromatography on silica gel (petroleum ether/EtOAc, 90:10 to 85:15, v/v) to obtain the desired products 5/7.
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(E)-4-((4-(1H-Indol-3-yl)chroman-3-ylidene)(phenyl)methyl)-2,6-di-tert-butylphenol (5a)
Yield: 221 mg (82%); colourless solid; mp 231–233 °C.
IR (neat): 3562.2, 3460.3, 2951.2, 2866.6, 1653.4, 1488.5, 1233.2, 1124.2 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.97 (s, 1 H), 7.42–7.32 (m, 6 H), 7.23–7.14 (m, 3 H), 7.07 (d, J = 6.5 Hz, 1 H), 7.00 (d, J = 7.4 Hz, 1 H), 6.92 (d, J = 7.2 Hz, 2 H), 6.80 (s, 2 H), 6.57 (d, J = 1.7 Hz, 1 H), 5.34 (s, 1 H), 5.19 (s, 1 H), 4.93 (d, J = 11.8 Hz, 1 H), 4.80 (d, J = 11.8 Hz, 1 H), 1.35 (s, 18 H).
13C NMR (101 MHz, CDCl3): δ = 154.5, 153.1, 142.04, 141.0, 136.0, 135.1, 132.3, 130.1, 130.0, 129.4, 128.1, 128.0, 127.8, 127.1, 127.0, 126.6, 121.8, 120.7, 120.4, 119.3, 119.0, 118.7, 116.3, 110.9, 65.8, 37.9, 34.2, 30.2.
Anal. Calcd for C38H39NO2: C, 84.25; H, 7.26; N, 2.59. Found: C, 83.93; H, 7.21; N, 2.48.
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(E/Z)-4-((4-(1H-Indol-3-yl)chroman-3-ylidene)(p-tolyl)methyl)-2,6-di-tert-butylphenol (5b)
Yield: 233 mg (84%); E/Z = 1.0:0.43; colourless solid.
IR (neat): 3628.1, 3446.8, 3414.0, 2690.7, 1580.6, 1486.1, 1312.5, 1233.5, 1112.9 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.95 (s, 2 H, E & Z), 7.35–7.26 (m, 6 H, E & Z), 7.24–7.15 (m, 6 H, E & Z), 7.08–7.00 (m, 10 H, E & Z), 6.96–6.90 (m, 5 H, E & Z), 6.80 (s, 1 H, Z), 6.55 (s, 1 H, Z), 6.50 (s, 1 H, E), 5.37 (s, 2 H, E & Z), 5.27 (s, 1 H, E), 5.19 (s, 1 H, Z), 4.92 (d, J = 11.7 Hz, 1 H, Z), 4.79 (d, J = 11.7 Hz, 1 H, Z), 4.75 (s, 2 H, E), 2.43 (s, 3 H, Z), 2.35 (s, 3 H, E), 1.43 (s, 18 H, E), 1.36 (s, 18 H, Z).
13C NMR (101 MHz, CDCl3): δ = 154.6, 154.5, 153.1, 153.0, 141.1, 141.1, 139.0, 138.5, 136.7, 136.4, 136.4, 135.4, 135.0, 132.7, 132.4, 130.0, 129.8, 129.5, 129.6, 129.3, 128.8, 128.5, 127.9, 127.8, 126.8, 126.7, 126.6, 126.2, 126.3, 126.2, 123.6, 123.4, 121.9, 121.8, 121.1, 120.8, 120.3, 120.2, 120.1, 119.9, 119.2, 119.1, 116.4, 116.3, 111.0, 110.9, 65.8, 65.7, 38.1, 38.0, 34.3, 34.2, 30.4, 30.3, 21.3, 21.2. * Two aromatic carbons are merged with others.
Anal. Calcd for C39H41NO2: C, 84.29; H, 7.44; N, 2.52. Found: C, 83.95; H, 7.35; N, 2.44.
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(E)-4-((4-(1H-Indol-3-yl)chroman-3-ylidene)(4-methoxyphenyl)methyl)-2,6-di-tert-butylphenol (5c)
Yield: 216 mg (76%); E/Z = 1.0:0.08; colourless solid; mp 210–212 °C.
IR (neat): 3628.3, 3417.8, 2945.9, 1697.3, 1581.7, 1435.0, 1317.3, 1265.3, 1122.5 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.96 (s, 2 H, E & Z), 7.34 (d, J = 8.1 Hz, 1 H, E), 7.31 (s, 1 H, Z), 7.24 (d, J = 8.0 Hz, 2 H, E & Z), 7.22–7.19 (m, 6 H, E & Z), 7.17 (t, J = 7.4 Hz, 2 H, E & Z), 7.09 (t, J = 7.9 Hz, 2 H, E & Z), 7.01 (t, J = 7.6 Hz, 2 H, E & Z), 6.95–6.90 (m, 8 H, E & Z), 6.81 (s, 2 H, Z), 6.79 (s, 2 H, E), 6.56 (d, J = 1.9 Hz, 1 H, E), 6.49 (d, J = 1.8 Hz, 1 H, Z), 5.36 (s, 1 H, Z), 5.38 (s, 1 H, E), 5.27 (s, 1 H, Z), 5.19 (s, 1 H, E), 4.90 (dd, J = 11.8, 1.5 Hz, 2 H, E & Z), 4.78 (d, J = 11.8 Hz, 2 H, E & Z), 3.88 (s, 3 H, E), 3.81 (s, 3 H, Z), 1.36 (s, 18 H, Z), 1.36 (s, 18 H, E).
13C NMR (101 MHz, CDCl3): δ (E only) = 158.6, 154.5, 153.1, 140.7, 136.4, 135.0, 134.5, 132.4, 131.4, 129.4, 129.3, 127.8, 126.8, 126.7, 126.3, 123.3, 121.9, 120.8, 120.4, 119.9, 119.3, 116.3, 113.5, 110.9, 65.9, 55.3, 38.1, 34.2, 30.3.
Anal. Calcd for C39H41NO3: C, 81.93; H, 7.23; N, 2.45. Found: C, 81.66; H, 7.19; N, 2.48.
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(E/Z)-4-((4-(1H-Indol-3-yl)chroman-3-ylidene)(4-chlorophenyl)methyl)-2,6-di-tert-butylphenol (5d)
Yield: 207 mg (72%); E/Z = 1.0:0.51; colourless solid.
IR (neat): 3656.1, 3427.1, 2988.1, 1691.3, 1577.2, 1441.5, 1366.9, 1260.1, 1119.2 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.96 (s, 2 H, E & Z), 7.38 (d, J = 7.7 Hz, 2 H, Z), 7.34 (d, J = 7.9 Hz, 2 H, E), 7.28–7.17 (m, 12 H, E & Z), 7.08–7.00 (m, 8 H, E & Z), 6.96–6.91 (m, 4 H, E & Z), 6.58 (d, J = 7.9 Hz, 1 H, Z), 6.50 (d, J = 8.1 Hz, 1 H, E), 5.39 (s, 1 H, E), 5.30 (s, 1 H, E), 5.28 (s, 1 H, Z), 5.23 (s, 1 H, Z), 4.92 (dd, J = 11.7, 1.3 Hz, 1 H, Z), 4.80 (d, J = 11.7 Hz, 1 H, Z), 4.75 (d, J = 11.8 Hz, 1 H, E), 4.67 (dd, J = 11.8, 1.3 Hz, 1 H, E), 1.43 (s, 18 H, E), 1.36 (s, 18 H, Z).
13C NMR (101 MHz, CDCl3): δ = 154.5, 154.4, 153.4, 153.3, 140.4, 139.9, 139.8, 136.4, 136.3, 135.7, 135.2, 133.0, 133.1, 132.1, 131.7, 131.4, 131.3, 131.0, 130.8, 130.7, 129.4, 128.4, 128.1, 128.0, 127.9, 126.9, 126.6, 126.5, 126.2, 126.1, 125.9, 123.7, 123.4, 122.1, 122.0, 121.0, 120.5, 120.4, 119.8, 119.6, 119.4, 119.3, 116.4, 116.3, 111.1, 111.0, 65.8, 65.4, 38.1, 38.4, 34.3, 34.2, 30.4, 30.2.
Anal. Calcd for C38H38ClNO2: C, 79.21; H, 6.65; N, 2.43. Found: C, 78.85; H, 6.64; N, 2.48.
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(E)-4-((4-(1H-Indol-3-yl)chroman-3-ylidene)(4-bromophenyl)methyl)-2,6-di-tert-butylphenol (5e)
Yield: 244 mg (79%); E/Z = 1.0:0.30; pale-yellow solid; mp 238–240 °C.
IR (neat): 3616.5, 3456.4, 2960.7, 2870.0, 1583.5, 1390.6, 1236.3, 1180.4 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.99 (s, 2 H, E & Z), 7.54 (d, J = 8.4 Hz, 2 H, E), 7.44 (dd, J = 8.4, 2.4 Hz, 1 H, Z), 7.40 (dd, J = 8.3, 2.2 Hz, 2 H, Z), 7.38 (d, J = 7.2 Hz, 1 H, Z), 7.34 (d, J = 8.1 Hz, 2 H, E & Z), 7.26–7.20 (m, 4 H, E & Z), 7.18–7.15 (m, 4 H, E & Z), 7.09–6.95 (m, 6 H, E & Z), 6.95–6.90 (m, 3 H, E), 6.87 (t, J = 7.2 Hz, 1 H, Z), 6.77 (s, 2 H, E & Z), 6.58 (d, J = 2.0 Hz, 1 H, E), 6.49 (d, J = 2.0 Hz, 1 H, Z), 5.38 (s, 1 H, Z), 5.31 (s, 1 H, Z), 5.27 (s, 1 H, E), 5.23 (s, 1 H, E), 4.91 (dd, J = 11.9, 1.6 Hz, 1 H, E), 4.79 (d, J = 11.9 Hz, 1 H, E), 4.75 (d, J = 11.6 Hz, 1 H, Z), 4.91 (dd, J = 11.6, 1.5 Hz, 1 H, Z), 1.42 (s, 18 H, Z), 1.36 (s, 18 H, E).
13C NMR (101 MHz, CDCl3): δ = 154.5, 154.4, 153.4, 153.3, 140.9, 140.4, 140.0, 139.8, 136.4, 136.3, 135.7, 135.2, 132.1, 131.8, 131.6, 131.3, 131.1, 130.7, 130.6, 129.4, 128.0, 127.9, 126.9, 126.6, 126.4, 126.1, 126.0, 125.8, 123.7, 123.4, 122.1, 122.0, 121.3, 121.2, 120.9, 120.5, 120.4, 120.4, 119.8, 119.6, 119.4, 119.2, 116.4, 116.3, 111.1, 111.0, 65.8, 65.4, 38.1, 38.0, 34.3, 34.2, 30.4, 30.2.
Anal. Calcd for C38H38BrNO2: C, 73.54; H, 6.17; N, 2.26. Found: C, 73.33; H, 6.12; N, 2.24.
#
(E)-4-((4-(1H-Indol-3-yl)-7-methoxychroman-3-ylidene)(phenyl)methyl)-2,6-di-tert-butylphenol (5f)
Yield: 191 mg (67%); colourless solid; mp 180–182 °C.
IR (neat): 3647.3, 3402.4, 2958.8, 2868.1, 1616.3, 1577.9, 1487.1, 1340.5, 1236.3, 1124.5, 1097.1 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.96 (s, 1 H), 7.42–7.39 (m, 6 H), 7.21 (d, J = 8.0 Hz, 1 H), 7.16 (td, J = 7.1, 1.6 Hz, 1 H), 7.01–6.96 (m, 2 H), 6.80 (s, 2 H), 6.58 (d, J = 2.2 Hz, 1 H), 6.52 (dd, J = 8.2, 1.9 Hz, 1 H), 6.48 (d, J = 2.5 Hz, 1 H), 5.30 (s, 1 H), 5.19 (s, 1 H), 4.90 (dd, J = 11.7, 1.7 Hz, 1 H), 4.77 (d, J = 11.7 Hz, 1 H), 3.83 (s, 3 H), 1.36 (s, 18 H).
13C NMR (101 MHz, CDCl3): δ = 159.5, 155.2, 153.1, 142.1, 140.9, 136.4, 135.1, 132.2, 130.2, 130.1, 129.9, 128.2, 127.1, 126.6, 126.3, 123.4, 121.8, 121.1, 119.9, 119.3, 119.0, 110.9, 107.2, 101.2, 65.7, 55.3, 37.3, 34.2, 30.3.
Anal. Calcd for C39H41NO3: C, 81.93; H, 7.23; N, 2.45. Found: C, 81.81; H, 7.15; N, 2.41.
#
(E)-4-((4-(1H-Indol-3-yl)-7-methoxychroman-3-ylidene)(4-bromophenyl)methyl)-2,6-di-tert-butylphenol (5g)
Yield: 230 mg (71%); pale-brown solid; mp 165–167 °C.
IR (neat): 3675.4, 3450.1, 2975.2, 1653.0, 1486.1, 1458.2, 1201.6, 1111.9 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.92 (s, 1 H), 7.46 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.2 Hz, 1 H), 7.24–7.28 (m, 3 H), 7.15 (t, J = 7.7 Hz, 1 H), 7.11 (s, 2 H), 6.98 (d, J = 8.5 Hz, 1 H), 6.93 (t, J = 7.5 Hz, 1 H), 6.68–6.64 (m, 2 H), 6.43 (dd, J = 8.5, 2.3 Hz, 1 H), 5.94 (s, 1 H), 5.04 (s, 1 H), 4.82 (d, J = 15.8 Hz, 1 H), 4.77 (d, J = 15.8 Hz, 1 H), 3.79 (s, 3 H), 1.37 (s, 18 H).
13C NMR (101 MHz, CDCl3): δ = 158.7, 156.0, 151.7, 136.7, 135.1, 134.2, 133.3, 131.5, 130.2, 127.2, 126.7, 125.5, 123.8, 122.8, 121.7, 121.4, 120.8, 120.2, 119.1, 110.8, 105.5, 100.6, 85.7, 85.6, 57.4, 55.3, 40.7, 34.3, 30.4.
Anal. Calcd for C39H40 Br NO3: C, 71.99; H, 6.20; N, 2.15. Found: C, 71.67; H, 6.29; N, 2.18.
#
(E)-2,6-Di-tert-butyl-4-((7-(diethylamino)-4-(1H-indol-3-yl)chroman-3-ylidene)(phenyl)methyl)phenol (5h)
Yield: 189 mg (62%); purple solid; mp 203–205 °C.
IR (neat): 3618.4, 3417.8, 2961.9, 1653.5, 1581.6, 1471.6, 1301.9, 1290.3, 1159.3 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.85 (s, 1 H), 7.31–7.27 (m, 2 H), 7.25–7.22 (m, 3 H), 7.20–7.18 (m, 2 H), 7.10–7.03 (m, 2 H), 6.88 (t, J = 7.2 Hz, 1 H), 6.79 (d, J = 8.5 Hz, 1 H), 6.70 (s, 1 H), 6.56 (d, J = 1.9 Hz, 1 H), 6.21 (dd, J = 8.5, 2.4 Hz, 1 H), 6.13 (d, J = 2.3 Hz, 1 H), 5.20 (s, 1 H), 5.07 (s, 1 H), 4.78 (dd, J = 11.7, 1.5 Hz, 1 H), 4.67 (d, J = 11.7 Hz, 1 H), 3.26 (q, J = 7.0 Hz, 4 H), 1.25 (s, 18 H), 1.09 (t, J = 7.0 Hz, 6 H).
13C NMR (101 MHz, CDCl3): δ = 155.31, 152.94, 142.20, 140.26, 136.35, 134.99, 132.43, 130.95, 130.21, 129.95, 128.89, 128.22, 128.07, 126.95, 126.66, 126.42, 123.48, 121.69, 121.56, 120.05, 119.12, 110.83, 65.59, 44.45, 36.96, 34.21, 30.31, 12.71. *Two aromatic carbons are merged with others.
Anal. Calcd for C42H48N2O2: C, 82.31; H, 7.89; N, 4.57. Found: C, 82.05; H, 7.86; N, 4.51.
#
(E)-2,6-Di-tert-butyl-4-((4-chlorophenyl)(7-(diethylamino)-4-(1H-indol-3-yl)chroman-3-ylidene)methyl)phenol (5i)
Yield: 242 mg (75%); E/Z = 1.0:0.30; purple solid; mp 167–169 °C.
IR (neat): 3587.9, 3380.2, 2955.5, 2878.1, 1617.1, 1558.8, 1456.9, 1233.7, 1114.5 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.96 (s, 2 H, E & Z), 7.37–7.32 (m, 7 H, E & Z), 7.25–7.14 (m, 9 H, E & Z), 7.06 (s, 2 H, Z), 7.02–6.98 (m, 2 H, E), 6.90 (d, J = 8.4 Hz, 2 H, E & Z), 6.77 (s, 2 H, E), 6.67 (s, 1 H, E), 6.62 (s, 1 H, Z), 6.34–6.29 (m, 2 H, E & Z), 6.22 (s, 2 H, E & Z), 5.28 (s, 1 H, Z), 5.20 (s, 1 H, E), 4.85 (d, J = 11.2 Hz, 1 H, E), 4.75 (d, J = 11.2 Hz, 1 H, E), 4.71 (d, J = 11.8 Hz, 1 H, Z), 4.61 (d, J = 12.0 Hz, 1 H, Z), 3.35 (q, J = 6.8 Hz, 8 H, E & Z), 1.41 (s, 18 H, Z), 1.35 (s, 18 H, E), 1.19 (t, J = 6.9 Hz, 12 H, E & Z).
13C NMR (101 MHz, CDCl3): δ (E only) = 155.3, 153.1, 148.1, 140.6, 139.0, 136.4, 135.2, 132.8, 131.9, 131.7, 131.6, 131.3, 126.9, 126.6, 126.2, 123.4, 121.8, 121.3, 119.7, 119.2, 113.5, 110.9, 105.2, 98.7, 65.6, 44.3, 37.1, 34.2, 30.3, 12.7.
Anal. Calcd for C42H47ClN2O2: C, 77.93; H, 7.32; N, 4.33. Found: C, 77.79; H, 7.33; N, 4.25.
#
(E/Z)-4-((1-(1H-Indol-3-yl)-1H-benzo[f]chromen-2(3H)-ylidene)(phenyl)methyl)-2,6-di-tert-butylphenol (5j)
Yield: 233 mg (79%); E/Z = 1:1; colourless solid.
IR (neat): 3650.2, 3443.1, 3479.5, 2956.3, 1623.1, 1598.0, 1470.5, 1319.4, 1154.3, 1085.3 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.82–7.80 (m, 3 H, E & Z), 7.75 (d, J = 8.8 Hz, 2 H, E), 7.57 (d, J = 8.8 Hz, 2 H, Z), 7.39–7.14 (m, 21 H, E & Z), 7.10–7.02 (m, 6 H, E & Z), 6.81 (s, 2 H, E & Z), 6.48 (s, 1 H, E), 6.43 (s, 1 H, Z), 6.06 (s, 2 H, E & Z), 5.29 (s, 1 H, E), 5.22 (s, 1 H, Z), 5.03 (d, J = 11.6 Hz, 1 H, E), 4.95 (d, J = 11.6 Hz, 1 H, E), 4.90 (d, J = 11.3 Hz, 1 H, Z), 4.80 (d, J = 11.3 Hz, 1 H, Z), 1.37 (s, 18 H, E), 1.32 (s, 18 H, Z).
13C NMR (101 MHz, CDCl3): δ = 153.4, 153.1, 152.0, 151.9, 142.2, 141.5, 141.4, 141.1, 136.5, 136.3, 135.6, 135.1, 132.8, 132.4, 132.2, 132.2, 130.5, 130.1, 129.5, 129.3, 129.2, 129.1, 128.4, 128.4, 128.3, 128.2, 127.8, 127.3, 127.1, 126.9, 126.8, 126.5, 126.4, 126.3, 124.3, 123.8, 123.0, 122.5, 122.3, 121.9, 121.8, 120.1, 120.0, 119.9, 119.8, 119.3, 119.2, 119.1, 118.7, 118.6, 117.4, 116.7, 111.1, 110.9, 65.3, 65.2, 34.3, 34.3, 34.2, 34.1, 30.3, 30.2. * Two aromatic carbons are merged with others.
Anal. Calcd for C42H41NO2: C, 85.24; H, 6.98; N, 2.37. Found: C, 85.91; H, 6.89; N, 2.28.
#
(Z)-4-((4-(5-Bromo-1H-indol-3-yl)chroman-3-ylidene)(phenyl)methyl)-2,6-di-tert-butylphenol (5k)
Yield: 257 mg (83%); colourless solid; mp 180–182 °C.
IR (neat): 3629.1, 3462.1, 2950.5, 1683.0, 1559.4, 1485.2, 1111.9, 1089.8 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.00 (s, 1 H), 7.47–7.38 (m, 2 H), 7.40 (d, J = 7.1 Hz, 1 H), 7.33–7.28 (m, 3 H), 7.26–7.18 (m, 3 H), 7.07 (d, J = 7.3 Hz, 1 H), 6.93 (t, J = 7.2 Hz, 2 H), 6.80 (s, 2 H), 6.56 (d, J = 1.6 Hz, 1 H), 5.30 (s, 1 H), 5.21 (s, 1 H), 4.92 (d, J = 11.9 Hz, 1 H), 4.73 (d, J = 11.9 Hz, 1 H), 1.37 (s, 18 H).
13C NMR (101 MHz, CDCl3): δ = 154.4, 153.2, 141.7, 141.4, 135.2, 134.9, 132.1, 130.1, 129.4, 129.3, 128.4, 128.0, 127.9, 127.4, 126.6, 126.2, 124.8, 124.5, 122.5, 120.6, 120.5, 116.4, 112.7, 112.3, 65.6, 37.6, 34.3, 30.3.
Anal. Calcd. for C38H38BrNO2: C, 73.54; H, 6.17; N, 2.26. Found: C, 73.22; H, 6.11; N, 2.22.
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(E)-4-((4-(5-Bromo-1H-indol-3-yl)chroman-3-ylidene)(p-tolyl)methyl)-2,6-di-tert-butylphenol (5l)
Yield: 275 mg (87%); colourless solid, mp: 235–237 °C.
IR (neat): 3665.5, 3423.6, 2960.7, 2866.2, 1581.6, 1485.1, 1435.0, 1390.6, 1111.7, 1091.4 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.97 (s, 1 H), 7.26–7.17 (m, 8 H), 7.05 (d, J = 7.36, 1 H), 6.92 (t, J = 8.28, 2 H), 6.79 (s, 2 H), 6.56 (d, J = 1.92, 1 H), 5.33 (s, 1 H), 5.19 (s, 1 H), 4.89 (d, J = 11.8, 1 H), 4.71 (d, J = 11.8, 1 H), 2.44 (s, 3 H), 1.36 (s, 18 H).
13C NMR (101 MHz, CDCl3): δ = 154.5, 153.1, 141.4, 138.7, 137.0, 135.1, 134.8, 132.3, 129.9, 129.5, 129.1, 129.0, 127.9, 127.9, 126.5, 126.2, 124.7, 124.4, 122.5, 120.9, 120.4, 116.4, 112.7, 112.3, 65.6, 37.5, 34.2, 30.2, 21.3.
Anal. Calcd for C39H40NBrO2: C, 73.81; H, 6.35; N, 2.21. Found: C, 73.46; H, 6.31; N, 2.27.
#
(E)-4-((4-(5-Bromo-1H-indol-3-yl)chroman-3-ylidene)(4-chlorophenyl)methyl)-2,6-di-tert-butylphenol (5m)
Yield: 262 mg (80%); colourless solid; mp 230–232 °C.
IR (neat): 3629.1, 3456.2, 2959.8, 2917.3, 1730.1, 1581.6, 1486.5, 1390.7, 1223.8, 1112.9, 1060.5 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.02 (s, 1 H), 7.42 (d, J = 8.3 Hz, 2 H), 7.31 (s, 1 H), 7.27–7.19 (m, 5 H), 7.06 (d, J = 7.4 Hz, 1 H), 6.95–6.89 (m, 2 H), 6.77 (s, 2 H), 6.56 (d, J = 2.0 Hz, 1 H), 5.23 (s, 2 H), 4.88 (d, J = 11.9 Hz, 1 H), 4.71 (d, J = 11.9 Hz, 1 H), 1.37 (s, 18 H).
13C NMR (101 MHz, CDCl3): δ = 154.4, 153.3, 140.2, 135.3, 134.9, 133.3, 131.6, 131.4, 130.1, 129.3, 128.6, 128.1, 127.8, 126.6, 125.8, 124.8, 124.5, 122.3, 120.6, 120.4, 116.5, 112.7, 112.4, 65.6, 37.7, 34.2, 30.2. * One aromatic carbon is merged with others.
Anal. Calcd for C38H37BrClNO2: C, 69.67; H, 5.69; N, 2.14. Found: C, 69.53; H, 5.73; N, 2.19.
#
(E)-4-((4-(5-Bromo-1H-indol-3-yl)chroman-3-ylidene)(4-nitrophenyl)methyl)-2,6-di-tert-butylphenol (5n)
Yield: 189 mg (57%); E/Z = 1.0:0.19; pale-yellow solid; mp 197–198 °C.
IR (neat): 3649.3, 3421.6, 2958.8, 2864.2, 1635.6, 1583.5, 1487.2, 1307.6, 1224.8, 1159.1 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.32 (d, J = 8.7 Hz, 2 H, E), 8.18 (d, J = 8.6 Hz, 2 H, Z), 8.08 (s, 1 H, E), 7.52 (d, J = 1.3 Hz, 1 H, Z), 7.46 (d, J = 8.7 Hz, 2 H, E), 7.25–7.26 (m, 4 H, Z), 7.28–7.21 (m, 3 H, E), 7.16 (s, 1 H, E), 7.12 (dd, J = 7.6, 1.5 Hz, 1 H, Z), 7.06–7.03 (m, 3 H, E & Z), 7.02–6.99 (m, 2 H, Z), 6.97–6.92 (m, 3 H, E & Z), 6.90 (s, 1 H, Z), 6.77 (s, 2 H, E), 6.61 (d, J = 2.1 Hz, 1 H, E), 6.50 (d, J = 2.0 Hz, 1 H, Z), 5.43 (s, 1 H, Z), 5.37 (s, 1 H, Z), 5.30 (s, 1 H, E), 5.18 (s, 1 H, E), 4.92 (dd, J = 12.1, 1.5 Hz, 1 H, E), 4.75 (d, J = 12.1 Hz, 1 H, E), 4.68 (d, J = 11.7 Hz, 1 H, Z), 4.52 (dd, J = 11.7, 1.6 Hz, 1 H, Z), 1.42 (s, 18 H, Z), 1.37 (s, 18 H, E).
13C NMR (101 MHz, CDCl3): δ = 154.4, 154.3, 153.9, 153.6, 148.6, 148.4, 147.0, 146.9, 139.7, 139.3, 136.1, 135.7, 135.2, 134.8, 132.2, 132.0, 131.0, 130.8, 130.7, 129.4, 129.3, 128.4, 128.3, 128.2, 127.7, 127.6, 126.9, 126.5, 125.5, 125.1, 125.0, 124.9, 124.6, 123.8, 123.4, 123.3, 122.2, 121.8, 120.9, 120.7, 120.2, 119.9, 116.6, 116.5, 112.9, 112.8, 112.7, 112.6, 65.5, 65.4, 38.2, 37.7, 34.4, 34.2, 30.2, 30.2.
Anal. Calcd for C38H37BrN2O4: C, 68.57; H, 5.60; N, 4.21. Found: C, 68.32; H, 5.55; N, 4.13.
#
(E)-4-((4-(6-Bromo-1H-indol-3-yl)chroman-3-ylidene)(phenyl)methyl)-2,6-di-tert-butylphenol (5o)
Yield: 241 mg (78%); colourless solid; mp 185–187 °C.
IR (neat): 3566.3, 3410.1, 2951.0, 2870.0, 1587.4, 1487.1, 1435.0, 1330.8, 1228.6, 1112.9 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.95 (s, 1 H), 7.48 (s, 1 H), 7.42–7.35 (m, 3 H), 7.28–7.20 (m, 3 H), 7.10–7.00 (m, 3 H), 6.92–6.89 (m, 2 H), 6.77 (s, 2 H), 6.54 (d, J = 1.6, 1 H), 5.31 (s, 1 H), 5.20 (s, 1 H), 4.93 (d, J = 11.9, 1 H), 4.74 (d, J = 11.9, 1 H), 1.35 (s, 18 H).
13C NMR (400 MHz, CDCl3): δ = 154.4, 153.2, 141.9, 141.2, 137.1, 135.1, 132.1, 130.1, 129.6, 129.4, 128.2, 127.9, 127.2, 126.5, 126.3, 125.2, 123.8, 122.6, 121.1, 120.9, 120.5, 116.5, 115.5, 113.8, 65.7, 37.6, 34.2, 30.2.
Anal. Calcd for C38H38BrNO2: C, 73.54; H, 6.17; N, 2.26. Found: C, 73.21; H, 6.18; N, 2.29.
#
(E)-4-((4-(5-Bromo-1H-indol-3-yl)-6-chlorochroman-3-ylidene)(phenyl)methyl)-2,6-di-tert-butylphenol (5p)
Yield: 298 mg (91%); colourless solid; mp 250–252 °C.
IR (neat): 3630.9, 3328.4, 2942.6, 1653.4, 1481.3, 1230.4, 1181.6 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.03 (s, 1 H), 7.49–7.42 (m, 3 H), 7.30–7.24 (m, 4 H), 7.20 (d, J = 8.1 Hz, 1 H), 7.16 (dd, J = 8.6, 2.5 Hz, 1 H), 7.02 (d, J = 2.5 Hz, 1 H), 6.85 (d, J = 8.7 Hz, 1 H), 6.78 (s, 2 H), 6.57 (d, J = 2.0 Hz, 1 H), 5.26 (s, 1 H), 5.22 (s, 1 H), 4.91 (dd, J = 11.9, 1.7 Hz, 1 H), 4.71 (d, J = 11.9 Hz, 1 H), 1.36 (s, 18 H).
13C NMR (101 MHz, CDCl3): δ = 153.3, 153.1, 142.2, 141.5, 135.2, 134.8, 131.9, 129.9, 128.9, 128.5, 128.3, 128.0, 127.7, 127.6, 127.5, 126.5, 125.0, 124.9, 124.5, 122.3, 120.1, 117.9, 112.8, 112.4, 65.7, 37.5, 34.2, 30.2.
Anal. Calcd for C38H37BrClNO2; C, 69.67; H, 5.69; N, 2.14. Found: C, 69.41; H, 5.62; N, 2.10.
#
(E/Z)-4-((1-(6-Bromo-1H-indol-3-yl)-1H-benzo[f]chromen-2(3H)-ylidene)(p-tolyl)methyl)-2,6-di-tert-butylphenol (5q)
Yield: 280 mg (82%); E/Z = 1:0.43; colourless solid.
IR (neat): 3658.9, 3455.1, 2953.0, 1599.0, 1435.5, 1319.4, 1153.4, 1044.4 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.43 (s, 2 H, E & Z), 7.70–7.62 (m, 4 H, E & Z), 7.42–7.38 (m, 4 H, E & Z), 7.17–6.90 (m, 19 H, E & Z), 6.82 (d, J = 8.2 Hz, 2 H, E), 6.65 (s, 1 H, E), 6.37 (s, 1 H, Z), 6.32 (s, 1 H, E), 5.93 (s, 1 H, Z), 5.89 (s, 1 H, E), 5.17 (s, 1 H, E), 5.09 (s, 1 H, Z), 4.85 (d, J = 11.2 Hz, 1 H, Z), 4.75 (d, J = 11.2 Hz, 1 H, Z), 4.71 (s, 2 H, E), 2.33 (s, 3 H, Z), 2.25 (s, 3 H, E), 1.25 (s, 18 H, Z), 1.19 (s, 18 H, E).
13C NMR (101 MHz, CDCl3): δ = 153.4, 153.1, 152.0, 151.9, 141.7, 141.3, 138.3, 137.2, 137.1, 137.0, 136.9, 135.6, 135.0, 132.8, 132.3, 132.1, 132.0, 130.3, 129.9, 129.2, 129.1, 128.9, 128.7, 128.5, 128.6, 128.4, 128.5, 127.1, 127.6, 126.8, 126.5, 125.1, 125.2, 124.6, 124.2, 123.0, 122.5, 122.4, 122.3, 122.2, 122.1, 121.3, 121.2, 120.5, 120.4, 118.7, 118.6, 116.9, 116.9, 116.3, 115.5, 115.5, 113.9, 113.8, 65.2, 65.2, 34.2, 34.1, 34.0, 33.8, 30.3, 30.1, 21.3, 21.2. * Two aromatic carbons are merged with others.
Anal. Calcd for C43H42BrNO2: C, 75.43; H, 6.18; N, 2.05. Found: C, 75.09; H, 6.15; N, 2.00.
#
(E)-2,6-Di-tert-butyl-4-((4-(1-methyl-1H-indol-3-yl)chroman-3-ylidene)(phenyl)methyl)phenol (5r)
Yield: 213 mg (77%); colourless solid; mp 218–220 °C.
IR (neat): 3650.2, 2916.4, 2895.2, 1632.2, 1586.4, 1487.1, 1433.1, 1233.5, 1219.0, 1119.7 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.43–7.34 (m, 4 H), 7.27–7.18 (m, 5 H), 7.07 (d, J = 7.1 Hz, 1 H), 6.99 (t, J = 7.4 Hz, 1 H), 6.93 (d, J = 7.6 Hz, 2 H), 6.81 (s, 2 H), 6.42 (s, 1 H), 5.33 (s, 1 H), 5.19 (s, 1 H), 4.93 (d, J = 11.8 Hz, 1 H), 4.83 (d, J = 11.8 Hz, 1 H), 3.68 (s, 3 H), 1.36 (s, 18 H).
13C NMR (101 MHz, CDCl3): δ = 154.4, 153.0, 142.0, 140.8, 137.0, 135.1, 132.2, 130.1, 130.1, 129.4, 128.1, 128.1, 127.7, 127.1, 127.0, 126.6, 121.4, 120.4, 119.9, 119.0, 118.7, 116.4, 108.9, 65.8, 37.9, 34.2, 32.6, 30.3. * One aromatic carbon is merged with others.
Anal. Calcd for C39H41NO2: C, 84.29; H, 7.44; N, 2.52. Found: C, 83.92; H, 7.32; N, 2.44.
#
(E)-2,6-Di-tert-butyl-4-((4-(1-methyl-1H-indol-3-yl)chroman-3-ylidene)(p-tolyl)methyl)phenol (5s)
Yield: 196 mg (69%); E/Z = 1.0:0.28; colourless solid; mp 211–213 °C.
IR (neat): 3629.5, 2996.5, 2856.7, 1612.5, 1558.5, 1487.1, 1363.7, 1231.5, 1155.3, 1058.2 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.25 (s, 2 H, E & Z), 7.23–7.18 (m, 8 H, E & Z), 7.10–7.07 (m, 4 H, E & Z), 7.00–6.90 (m, 10 H, E & Z), 6.80 (s, 2 H, E), 6.59 (s, 2 H, Z), 6.40 (s, 1 H, E), 6.35 (s, 1 H, Z), 6.18 (s, 1 H, Z), 5.35 (s, 1 H, E), 5.25 (s, 1 H, Z), 5.17 (s, 1 H, E), 4.89 (d, J = 11.7, 1 H, E), 4.79 (d, J = 11.7, 1 H, E), 4.75 (brs, 1 H, Z), 4.53 (brs, 1 H, Z), 3.71 (s, 3 H, Z), 3.68 (s, 3 H, E), 2.42 (s, 3 H, E), 2.34 (s, 3 H, Z), 1.42 (s, 18 H, Z), 1.35 (s, 18 H, E).
13C NMR (101 MHz, CDCl3): δ (E only) = 154.5, 153.0, 140.8, 139.0, 137.1, 136.6, 135.0, 132.4, 130.1, 129.6, 129.4, 128.8, 128.1, 127.7, 127.0, 126.6, 121.4, 120.3, 120.1, 119.1, 118.6, 116.3, 108.9, 65.8, 38.0, 34.2, 30.4, 30.3, 21.3. * One aromatic carbon is merged with others.
Anal. Calcd for C40H43NO2: C, 84.32; H, 7.61; N, 2.46. Found: C, 84.03; H, 7.55; N, 2.42.
#
(E/Z)-4-((4-(5-Bromo-1H-indol-3-yl)chroman-3-ylidene)(4-methoxyphenyl)methyl)-2,6-diisopropylphenol (5t)
Yield: 202 mg (65%); E/Z = 1:0.75; colourless solid.
IR (neat): 3646.1, 3432.3, 2922.2, 1582.2, 1422.5, 1166.4, 1043.2 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.06 (s, 1 H, E), 7.98 (s, 1 H, Z), 7.50 (d, J = 2.2 Hz, 1 H, Z), 7.34 (d, J = 2.2 Hz, 1 H, E), 7.28–7.17 (m, 10 H, E & Z), 7.09–7.07 (m, 2 H, E & Z), 6.99–6.90 (m, 10 H, E & Z), 6.83–6.81 (m, 2 H, E & Z), 6.67 (s, 2 H, E), 6.56 (d, J = 1.8 Hz,1 H, E), 6.46 (d, J = 1.9 Hz,1 H, Z), 5.38 (s, 1 H, Z), 5.37 (s, 1 H, E), 4.90 (s, 1 H, Z), 4.84 (dd, J = 11.2, 2.2 Hz, 1 H, E), 4.81 (s, 1 H, E), 4.75 (dd, J = 11.2, 2.2 Hz, 1 H, Z), 4.70 (d, J = 11.4 Hz, 1 H, E), 4.67 (d, J = 11.7 Hz, 1 H, Z), 3.90 (s, 3 H, E), 3.83 (s, 3 H, Z), 3.19 (sep, J = 6.8 Hz, 2 H, Z), 3.10 (sep, J = 6.8 Hz, 2 H, E), 1.26 (s, 12 H, Z), 1.21 (d, J = 6.8 Hz, 6 H, E), 1.16 (d, J = 6.8 Hz, 6 H, E).
13C NMR (101 MHz, CDCl3): δ = 158.8, 158.7, 155.3, 154.5, 154.5, 149.6, 149.3, 140.9, 140.7, 135.1, 134.9, 134.1, 133.9, 133.7, 133.6, 133.5, 133.2, 131.3, 131.2, 129.5, 129.2, 128.8, 128.7, 128.1, 128.0, 127.9, 126.1, 125.8, 125.6, 125.3, 124.8, 124.7, 124.6, 124.5, 122.5, 120.9, 120.7, 120.4, 120.3, 116.4, 116.5, 113.8, 113.3, 112.7, 112.4, 112.3, 66.0, 65.6, 55.3, 55.2, 38.0, 37.5, 27.3, 27.2, 22.7, 22.6. * Two aromatic carbons are merged with others.
Anal. Calcd for C37H36BrNO3: 71.38; H, 5.83; N, 2.25. Found: 71.02; H, 5.75; N, 2.16.
#
(E)-2,6-Diisopropyl-4-((4-(1-methyl-1H-indol-3-yl)chroman-3-ylidene)(phenyl)methyl)phenol (5u)
Yield: 134 mg (51%); E/Z = 1.0:0.11; colourless solid; mp 187–189 °C.
IR (neat): 3649.5, 2960.7, 1581.6, 1487.1, 1363.6, 1251.8, 1153.3 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.42–7.37 (m, 3 H, E), 7.35–7.33 (m, 4 H, Z), 7.29–7.26 (m, 3 H, E), 7.24 (d, J = 1.6 Hz, 2 H, Z), 7.23–7.20 (m, 2 H, E), 7.18 (d, J = 7.3 Hz, 2 H, Z), 7.15 (d, J = 8.0 Hz, 2 H, E & Z), 7.11 (d, J = 8.1 Hz, 1 H, Z), 7.08 (dd, J = 8.0, 1.4 Hz, 1 H, E), 6.99 (dd, J = 8.4, 2.5 Hz, 1 H, E), 6.96 (d, J = 1.8 Hz, 1 H, Z), 6.93 (d, J = 7.8 Hz, 2 H, E), 6.90–6.89 (m, 2 H, Z), 6.68 (s, 2 H, E), 6.59 (s, 1 H, Z), 6.47 (s, 1 H, Z), 6.42 (s, 1 H, E), 6.07 (s, 1 H, Z), 5.38 (s, 1 H, E), 4.93 (s, 1 H, Z), 4.91 (dd, J = 11.8, 1.6 Hz, 1 H, E), 4.82 (d, J = 11.8 Hz, 3 H, E & Z), 4.78 (s, 1 H, E), 4.66 (s, 1 H, Z), 3.70 (s, 3 H, Z), 3.69 (s, 3 H, E), 3.09 (sep, J = 6.8 Hz, 4 H, E & Z), 1.19 (d, J = 6.8 Hz, 12 H, E & Z), 1.15 (d, J = 6.8 Hz, 12 H, E & Z).
13C NMR (101 MHz, CDCl3): δ (E only) = 154.6, 149.3, 141.5, 140.5, 137.1, 133.8, 133.4, 130.2, 129.9, 129.3, 128.2, 127.9, 127.8, 127.1, 126.7, 126.3, 125.5, 121.4, 120.3, 120.0, 119.4, 118.6, 116.3, 109.1, 65.6, 38.1, 32.6, 29.7, 27.2, 22.9, 22.7.
Anal. Calcd for C37H37NO2: C, 84.21; H, 7.07; N, 2.65. Found: C, 83.85; H, 7.01; N, 2.68.
#
(E)-4-((4-(1H-Pyrrol-2-yl)chroman-3-ylidene)(phenyl)methyl)-2,6-di-tert-butylphenol (7a)
Yield: 208 mg (85%); pale-brown solid; mp 238–240 °C.
IR (neat): 3668.3, 3356.2, 2954.9, 2826.5, 1602.8, 1558.4, 1456.2, 1390.6, 1361, 1151.5 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.83 (s, 1 H), 7.38–7.20 (m, 6 H), 7.07 (d, J = 6.8 Hz, 1 H), 6.95–6.91 (m, 4 H), 6.68 (s, 1 H), 6.15 (s, 1 H), 5.84 (s, 1 H), 5.23 (s, 1 H), 4.95 (s, 1 H), 4.89 (d, J = 11.7 Hz, 1 H), 4.62 (d, J = 11.7 Hz, 1 H), 1.40 (s, 18 H).
13C NMR (101 MHz, CDCl3): δ = 154.7, 153.2, 141.7, 135.2, 134.4, 131.5, 130.0, 129.2, 129.0, 128.5, 128.3, 127.2, 126.3, 123.5, 120.5, 116.9, 116.8, 108.6, 106.3, 64.9, 39.4, 34.3, 30.3. * One aromatic carbon is merged with others.
Anal. Calcd for C34H37NO2: C, 83.06; H, 7.59; N, 2.85. Found: C, 82.77; H, 7.52; N, 2.77.
#
(E)-4-((4-(1H-Pyrrol-2-yl)chroman-3-ylidene)(4-bromophenyl)methyl)-2,6-di-tert-butylphenol (7b)
Yield: 190 mg (67%); pale-brown solid; mp 238–240 °C.
IR (neat): 3653.5, 3325.2, 2952.8, 1613.5, 1513.2, 1422.5, 1392.1, 1130.2 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.82 (s, 1 H), 7.50 (d, J = 8.1 Hz, 2 H), 7.23 (t, J = 7.6 Hz, 1 H), 7.17 (d, J = 8.0 Hz, 2 H), 7.08 (d, J = 7.7 Hz, 1 H), 6.96–6.89 (m, 4 H), 6.68 (s, 1 H), 6.17 (s, 1 H), 5.88 (s, 1 H), 5.26 (s, 1 H), 4.87 (d, J = 11.8 Hz, 1 H), 4.88 (s, 1 H), 4.62 (d, J = 11.8 Hz, 1 H), 1.41 (s, 18 H).
13C NMR (101 MHz, CDCl3): δ = 154.7, 153.4, 140.6, 140.5, 135.5, 133.9, 131.5, 131.3, 131.0, 129.8, 129.5, 129.3, 128.5, 126.4, 123.4, 120.6, 117.1, 116.9, 108.8, 106.1, 65.2, 39.6, 34.2, 30.2.
Anal. Calcd for C34H36BrNO2: C, 71.57; H, 6.36; N, 2.45. Found: C, 71.41; H, 6.31; N, 2.48.
#
Crystal Data
CCDC 2359276 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.
Compound 5b was dissolved in EtOAc/hexane (1:1) and kept undisturbed for three days to obtain transparent crystals. The mother liquor was filtered and the crystals were taken out carefully for characterization.
C39H41NO2; colour: yellow; molecular weight = 555.73; shape: block-shaped; D calc = 1.167 g/cm3; orthorhombic crystal; space group = Pbca; a = 17.86050(10) Å, b = 16.59980(10) Å, c = 21.3441(2) Å, α = 90°, β = 90°, γ = 90°; V = 6328.11(8) Å3; Z = 8, Z′ = 1; wavelength = 1.54184 Å; radiation type = Cu Kα, Qmin = 4.185/°, Qmax = 80.017/°; measured refls = 60003, indep. refls = 6810; refls I ≥ 2 s(I) = 6415; R int = 0.0321; parameters = 390; restraints = 0; largest peak = 0.234; deepest hole = –0.201; GooF = 1.031; wR2 (all data) = 0.1080, wR2 = 0.1063, R 1 (all data) = 0.0428, R 1 = 0.0410.
#
#
Conflict of Interest
The authors declare no conflict of interest.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2371-3579.
- Supporting Information
-
References
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- 15a Debnath B, Sarkar T, Karjee P, Purkayastha SK, Guha AK, Punniyamurthy T. J. Org. Chem. 2023; 88: 9704
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- 16 Saini MK, Korawat HS, Verma SK, Basak AK. Tetrahedron Lett. 2020; 61: 152657
For reviews on p-QMs see:
For reviews on chromanes see:
For reviews on domino reactions, see:
For recent examples see:
Corresponding Author
Publication History
Received: 04 June 2024
Accepted after revision: 23 July 2024
Accepted Manuscript online:
23 July 2024
Article published online:
20 August 2024
© 2024. Thieme. All rights reserved
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-
References
- 1a Liu X, Ren Y, Zhu L, Li T, Xu W, Liu Y, Tang K.-W, Xiong B. Tetrahedron 2023; 148: 133655
- 1b Gan YF, Li YY, Chen XQ, Guo YY, Wang R. Synthesis 2023; 55: 1172
- 1c Singh G, Pandey R, Pankhade YA, Fatma S, Anand RV. Chem. Rec. 2021; 21: 4150
- 1d Wang J.-Y, Hao W.-J, Tu S.-J, Jiang B. Org. Chem. Front. 2020; 7: 1743
- 2a Toteva MM, Richard JP. Adv. Phys. Org. Chem. 2011; 45: 39
- 2b Yang B, Gao S. Chem. Soc. Rev. 2018; 47: 7926
- 3 Li JJ, Yan YY, Sun HM, Liu Y, Su CY, Chen HB, Zhang JY. Front. Pharmacol. 2019; 10: 746
- 4 Zhao YN, Pan Y, Tao JL, Xing DM, Du LJ. Pharmacology 2006; 76: 76
- 5 Takao KI, Sasaki T, Kozaki T, Yanagisawa Y, Tadano KI, Kawashima A, Shinonaga H. Org. Lett. 2001; 3: 4291
- 6a Osipov DV, Osyanin VA, Klimochkin YN. Russ. Chem. Rev. 2017; 86: 625
- 6b Szatmári I, Belasri K, Heydenreich M, Koch A, Kleinpeter E, Fülöp F. ChemistryOpen 2019; 8: 961
- 7a Pratap R, Ram VJ. Chem. Rev. 2014; 114: 10476
- 7b Pini E, Poli G, Tuccinardi T, Chiarelli LR, Mori M, Gelain A, Costantino L, Villa S, Meneghetti F, Barlocco D. Molecules 2018; 23: 1506
- 7c Netscher T. Angew. Chem. Int. Ed. 2014; 53: 14313
- 8 Vatassery GT, Smith WE, Quach HT. Lipids 1989; 24: 1043
- 9 Yoganathan K, Rossant C, Ng S, Huang Y, Butler MS, Buss AD. J. Nat. Prod. 2003; 66: 1116
- 10 Kashiwada Y, Yamazaki K, Ikeshiro Y, Yamagishi T, Fujioka T, Mihashi K, Mizuki K, Cosentino LM, Fowke K, Morris-Natschke SL, Lee KH. Tetrahedron 2001; 57: 1559
- 11 Spencer CM, Markham A. Drugs 1997; 54: 89
- 12 Rajput D, Jan G, Karuppasamy M, Bhuvanesh N, Nagarajan S, Maheswari CU, Sridharan V. J. Org. Chem. 2023; 88: 11778
- 13a Tietze LF. Chem. Rev. 1996; 96: 115
- 13b Tietze LF, Rackelmann N. Pure Appl. Chem. 2004; 76: 1967
- 14a Kanchupalli V, Shukla RK, Singh A, Volla CM. Eur. J. Org. Chem. 2020; 29: 4494
- 14b Shirsath SR, Ghotekar GS, Bahadur V, Gonnade RG, Muthukrishnan M. J. Org. Chem. 2020; 85: 15038
- 15a Debnath B, Sarkar T, Karjee P, Purkayastha SK, Guha AK, Punniyamurthy T. J. Org. Chem. 2023; 88: 9704
- 15b Ali A, Jajoria R, Harit HK, Singh RP. J. Org. Chem. 2022; 87: 5213
- 16 Saini MK, Korawat HS, Verma SK, Basak AK. Tetrahedron Lett. 2020; 61: 152657
For reviews on p-QMs see:
For reviews on chromanes see:
For reviews on domino reactions, see:
For recent examples see:
