Abstract
A catalyst-free [3 + 2] cycloaddition reaction of electron-deficient alkynes and o-hydroxyaryl azomethine ylides in water was developed, affording pyrroline derivatives in moderate to high yields (up to 90%).
Introduction
Nitrogen-containing heterocycles are widely present in various drugs, natural products, organic catalysts, and synthetic intermediates.1 Among these structural skeletons, 3-pyrroline has a unique application in that they not only can be further reduced to saturated pyrrolidines but also can be oxidized to pyrrolidones.2 As shown in Figure 1, 8-oxoerymelanthine (I) is a type of erythrina alkaloids and it has hypnotic activity and pharmacological effects such as sedation and antihypertensive effects.3 MK-0731(II), as a type of kinesin spindle protein inhibitors, can be used as a good cytotoxic agent for the treatment of refractory solid tumors.4 Spirodactylone (III), an alkaloid spirolactone isolated from marine sponge, showed activity in inhibitors of the carcinogenic PAX3-FOXO1 transcription factor.5 Considering the huge potential in drug discovery of the pyrrolidine, it is highly desirable and a great challenge to develop facile and efficient methodologies to access structural diversity and complexity of pyrrolidines.
Figure 1.
Selected nature products and biologically active molecules with the pyrroline unit.
To date, because of its significant biological activity, a number of methods have been reported to obtain 3-pyrroline derivatives. Krause’s group discovered in 2004 that when an amino group or a substituted amino group was present in the α-position of allene, under the catalysis of gold, intramolecular self-cyclization can occur to form an N-substituted pyrroline derivative (Scheme 1, eq 1).6 Subsequently, the Fan group, Soriano group, and Harmata group successively discovered that the substrate can also undergo intramolecular cyclization under the catalysis of different transition metals such as copper, platinum, and silver.7 In addition to metal catalytic systems, phosphine can be used to catalyze a series of unsaturated hydrocarbons to obtain pyrroline derivatives. Kwon’s group discovered that α-aminoalkylallenic esters can undergo intramolecular γ-umpolung addition under the catalysis of phosphine to obtain 3-carbethoxy-2-alkyl-3-pyrrolines.2 Compared to intramolecular addition, cycloaddition of two molecules was also a strategy for the synthesis of pyrrolines. In 2008, Lu’s group found that the modified allylic compounds and N-tosylimines can undergo [3 + 2] cycloaddition under the catalysis of phosphine to obtain N-protected pyrroline derivatives (eq 2).8 Subsequently, Marinetti’s group found that conjugated dienes which were activated by electron-withdrawing groups on both ends can undergo [3 + 2] cycloaddition with imines under phosphine catalysis to obtain functionalized 3-pyrrolines.9 Recently, Tong’s group found that δ-acetoxy allenoates can undergo [3 + 2] cycloaddition with 2-sulfonamidomalonate under the catalysis of phosphine to obtain highly substituted 3-pyrrolines.10 Besides, Zhang’s group found that under the catalysis of Lewis acid, alkynes and N-tosylaziridines can undergo [3 + 2] cycloaddition via a C–C bond cleavage to obtain highly substituted 3-pyrrolines (eq 3).11
Scheme 1. Different Methods for Synthesizing Pyrrolines.
In addition to the methods described above, the use of azomethine ylides and electron-deficient alkenes was also an effective approach to obtain 3-pyrroline derivatives since Grigg first reported it in 1978. They used a very active dimethyl acetylenedicarboxylate and N-phenylmaleimide refluxing in toluene to obtain the corresponding pyrroline derivative.12 It is significant to emphasize that Deng’s group successfully catalyzed the cyclization of azomethine ylides with electron-deficient alkynes using silver and copper (eq 4) and achieved asymmetric synthesis of pyrroline derivatives.13,14 However, under their catalytic system, only the terminal electron-deficient alkynes can react with azomethine ylides. When the end of alkyne was attached with substituents, the desired product cannot be obtained. In addition, our group also previously studied the synthesize of pyrroline derivatives by azomethine ylides and allenoates under phosphine catalysis or triethylamine.15,16
Nevertheless, these strategies have two key disadvantages. First, the use of transition-metal catalysis may result in the presence of residual metal ions which may lead to heavy metal contamination, while the organic phosphine is also toxic and environmentally unfriendly. In addition, organic solvents are also harmful to the environment. Herein, it is of great importance to develop a facile, environmentally friendly approach for preparing pyrrole derivatives without toxic catalysts and avoiding the use of organic solvents.
Compared to traditional transition-metal catalysis17 or phosphine-catalyzed reaction of azomethine ylide with electron-deficient alkynes, the highlight of our work is that no catalyst was used and no organic solvents were used. Using water as the solvent is completely nontoxic, environmentally friendly, and inexpensive. In addition, the reaction had a relatively high yield and no side reactions occurred during the process, and therefore, the atomic utilization rate can be recognized high. Last but not the least, the raw materials we used are easy to prepare.
Results and Discussion
According to our knowledge, the ynone 2a can undergo nucleophilic addition with Ph3P to generate zwitterions,18 and azomethine ylide can generate carbon anions under the action of zwitterions. We initiated our investigation with the cyclization of o-hydroxyaryl azomethine ylide 1a and 4-phenyl-3-butyn-2-one 2a under the phosphine-catalyzed condition. First, we used Ph3P as the catalyst and replaced different solvents such as methanol, toluene, acetonitrile, tetrahydrofuran (THF), diethyl ether, dimethylformamide (DMF), acetone, dichloromethane, and so on. Surprisingly, we found that 1a and 2a can only react in methanol. Then, we continued trying to replace different alcohol solvents and found that when ethanol is used as the solvent, the reaction yield was the highest. Next, we tried to replace the nucleophilic catalysts, such as tributylphosphine, trimethylamine, and 1,4-diazabicyclo [2.2.2] octane (DABCO). Unfortunately, the use of different organic nucleophilic catalysts cannot achieve satisfactory yield. We then tried to use inorganic bases such as potassium carbonate as the catalyst and found that the reaction yield was significantly improved (56%). Therefore, we speculated that the reaction can get higher yield under the catalysis of the inorganic base. Then, we tried other inorganic bases such as Cs2CO3, Na2CO3, and NaHCO3. We found that using NaHCO3 as the base can further increase the yield (up to 78%), while the reaction time reached 18 h. Based on the experimental results, we speculated that the reaction can be catalyzed by the weak base. Then, we made a new bold attempt: whether the reaction can continue to occur without adding any catalyst. In the beginning, we used ethanol as the solvent; when no catalyst was used, we found that the reaction could not occur at room temperature. Then, we tried to increase the reaction temperature and to our excitement, the reaction could be completed in 3 h when ethanol was refluxed and the yield did not decrease. Then, we had a new attempt to use water as the solvent. To our excitement, the reaction can be successfully carried out by using water as the solvent and no catalyst was added while the yield would drop slightly (70%) (Table 1). Considering that water is a solvent which is completely harmless to the environment and is cheaper than ethanol, we determined to use water as the solvent.
Table 1. Optimization of the Reaction Conditionsa.
| entry | solvent | cat (20 mol %) | time (h) | yieldb (%) |
|---|---|---|---|---|
| 1 | MeOH | Ph3P | 8 | 38 |
| 2 | toluene | Ph3P | trace | |
| 3 | MeCN | Ph3P | nr | |
| 4 | THF | Ph3P | nr | |
| 5 | Et2O | Ph3P | trace | |
| 6 | DMF | Ph3P | nr | |
| 7 | acetone | Ph3P | nr | |
| 8 | CH2Cl2 | Ph3P | nr | |
| 9 | 1,4-dioxane | Ph3P | nr | |
| 10 | EtOH | Ph3P | 14 | 50 |
| 11 | EtOH | Bu3P | 8 | 47 |
| 12 | EtOH | Et3N | 5 | 27 |
| 13 | EtOH | DABCO | 9 | 36 |
| 14 | EtOH | K2CO3 | 3 | 56 |
| 15 | EtOH | Cs2CO3 | 3 | 46 |
| 16 | EtOH | NaHCO3 | 18 | 78 |
| 17 | EtOH | nr | ||
| 18c | EtOH | 3 | 78 | |
| 19d | H2O | 18 | 70 | |
| 20e | H2O | 5 | 70 |
General conditions for the optimization: in the sequence, 1a (0.1 mmol), 1.0 mL of water, 2a (0.12 mmol), reflux 5 h.
Yield of the isolated product.
The reaction was performed at 78° C.
The reaction was performed at 80° C.
The reaction was performed at 100° C.
With the optimal reaction conditions secured, we tried to establish the scope of the synthesis of pyrrolines. In general, the reaction proceeded well to form the desired products 3 in good yields. When azomethine ylides reacted with alkynyl ketones (Scheme 2), the desired product can be obtained whether the alkynyl ketone was a terminal alkyne or a substituent. In addition, both ends of the alkynyl ketone can either be an alkane compound or an aromatic compound (3ai–3al). However, when both ends of the alkyne were alkane compounds, the yield of the resulting product (3ai) decreased (40%). It is worth noting that the substituent can only occur at the 5-position of the o-hydroxyaryl azomethine ylides (3aa–3ah).
Scheme 2. Scope of Alkynyl Ketones,
Reaction conditions: 1a (0.1 mmol), 2a (0.12 mmol), H2O (1 mL), 100° C (oil bath), 5 h.
Isolated yield.
When azomethine ylides reacted with alkynyl esters (Scheme 3), the yield of the desired target product was generally improved. Benzyl propynoate with various substituents can react with different azomethine ylides well, explaining whether the electron withdrawing group or the electron donating group can obtain the target product (3ba–3be and 3bl–3bq) in moderate to high yields (51–90%). Besides, azomethine ylide can also react with methyl propiolate, diethyl acetylenedicarboxylate, and 2-naphthyl propiolate to obtain the target product (3bf, 3bg, 3bh, 3bj, and 3bk) in high yields (63–75%). It is worth mentioning that the end group-substituted alkyne ester can react with azomethine ylide under our standard condition (3bi), while its yield became low (40%). Different from alkynyl ketones, acetylenic esters react with 3,5-disubstituted o-hydroxyaryl azomethine ylide (3br, 71%). More importantly, the reaction can be successfully scaled up in 61% yield (Scheme 6).
Scheme 3. Scope of Alkynyl Esters,
Reaction conditions: 1a (0.1 mmol), 2b (0.12 mmol), H2O (1 mL), 100 °C (oil bath), 5 h.
Isolated yield.
Scheme 6. Scale-Up and Synthetic Transformations.
In order to study the reaction mechanism, we synthesized diethyl (E)-2-(benzylideneamino)malonate 7 to react with alkynyl ketone; however, the expected target product cannot be obtained under our standard conditions (eq 1) (Scheme 4). In addition, we also synthesized ethyl (E)-2-((2-hydroxybenzylidene)amino)acetate 8; it still cannot react with alkynyl ketone to yield the target product (eq 2). At the same time, we also guessed whether it was because of the self-catalysis of phenolic hydroxyl groups. Therefore, we still used compound 7 and alkynyl ketone, under the same conditions; stoichiometric and catalytic amounts of phenol were added to the reaction system (eq 3), and it was found that no corresponding product was produced. Therefore, we believe that this reaction is not because of the self-catalysis of the phenolic hydroxyl group. In addition, according to previous reports of Grigg, some evidence for a tautomeric equilibrium was provided by heating the imines.12 We first dissolved compound 1a in a mixed solution of CDCl3 and CD3OD, heated it to 70 °C in a sealed tube, and observed whether there are 1,3-dipolar isomers 9. According to our previous work and related knowledge, the hydroxyl group at the 2-position of the azomethine ylide can form intramolecular hydrogen bonds with nitrogen to stabilize ylide.19 When the reaction is carried out using the substrate 8 from which an ester group is removed, transition-metal catalysis is required because of its insufficient activity.20
Scheme 4. Control Experiments.
Based on the results of our control experiments, we speculated the possible mechanism (Scheme 5): o-hydroxyaryl azomethine ylide in the polar protic solvent, heating will produce intramolecular proton transfer isomer 9,12 the carbon anion on the α-position of the two ethyl ester groups attacks one side of the alkynyl ketone, forming a double bond while negative charge transfer to form an intermediate 10. Then, intermediate 10 undergoes intramolecular Morita–Baylis–Hillman reaction to generate product 3aa.
Scheme 5. Proposed Mechanism.
To highlight the synthetic potential of the current method, the transformations of 3 were investigated (Scheme 6). The pyrrolidine derivatives can be readily transformed into other interesting compounds because of the presence of a free hydroxyl group. Treatment of 3aa with a formaldehyde aqueous solution in THF afforded the novel derivative 4 in 81% yield. The derivative 5 could be effectively formed when 3aa was treated with sodium borohydride in THF at 0 °C, while derivative 6 was given when 3aa was treated with triphosgene in CH2Cl2.
Conclusions
In conclusion, we have developed a catalyst-free, o-hydroxy-assisted [3 + 2] cycloaddition of azomethine ylides with electron-deficient alkyne. This reaction allows a wide range of o-hydroxyaryl azomethine ylides and alkynyl ketones or alkyne esters to provide useful and densely functionalized pyrroline derivatives. Notably, our discovery is not only the first example of the catalyst-free 1,3-dipolar cycloaddition reaction of azomethine to electron-deficient alkynes in the water phase but also greatly complementary to Deng’s metal catalyst system. However, it is regrettable that our scheme cannot achieve asymmetric synthesis of pyrroline; therefore, this is the direction our laboratory is working on.
Experimental Section
General Methods
All reactions were refluxed in water unless otherwise stated. Reactions were monitored through thin layer chromatography (TLC) on 0.30 mm SiliCycle silica gel plates and visualized under UV light. NMR spectra of the new products were recorded using Bruker AC-300 and Bruker AC-400 instruments, calibrated to CDCl3 as the internal reference (7.26 and 77.0 ppm for 1H and 13C NMR spectra, respectively). Chemical shifts (δ) and coupling constants (J) were expressed in ppm and Hz, respectively. The following abbreviations indicate the multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; and m, multiplet. High-resolution mass spectrometry (HRMS) was obtained on a Thermo Scientific LTQ Orbitrap XL Instrument equipped with an ESI source.
Synthesis of Diethyl (E)-2-((2-Hydroxybenzylidene) Amino) Malonate (1a)
To a stirred solution of salicylaldehyde (1.06 g, 10 mmol), diethyl aminomalonate hydrochloride (2.54 g, 12 mmol) and MeCN (20 mL) in a 50 mL round-bottomed flask was added Et3N (1.21 g, 12 mmol). After stirring for 5 h, the solution was concentrated by distillation under reduced pressure and then extracted with AcOEt three times. The combined organic layers were dried over Na2SO4 and concentrated under vacuum to afford o-hydroxyaryl azomethine ylide 1a, which was used without further purification. Yellow solid was purified by freezing from PE and then washed three times with PE. Yield: 56%. mp 45–46 °C. 1H NMR (300 MHz, chloroform-d): δ 12.60 (s, 1H), 8.41 (s, 1H), 7.33–7.18 (m, 2H), 6.95–6.88 (m, 1H), 6.83 (td, J = 7.5, 1.1 Hz, 1H), 4.79 (d, J = 0.7 Hz, 1H), 4.22 (qd, J = 7.1, 0.8 Hz, 4H), 1.24 (t, J = 7.1 Hz, 6H).
Synthesis of Propargyl Ketones
Method 1: Propargyl ketones were synthesized by the following literature.21 Phenylacetylene (8.0 mmol) was dissolved into THF (8 mL), and the solution was cooled to −78 °C. To the solution, n-BuLi (8.0 mmol) was added. After being stirred for 1 h at −78 °C, ethyl acetate (4.0 mmol) and BF3·OEt2 (9.6 mmol) were added successively. The reaction was quenched by sat. NH4Cl aq., and extracted three times with EtOAc. The combined organic layer was dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether/EtOAc = 30/1) to afford the desired 4-phenyl-3-butyn-2-one 2a. Pale yellow liquid. 1H NMR (400 MHz, chloroform-d): δ 2.46 (s, 3H), 7.35–7.42 (m, 2H), 7.43–7.49 (m, 1H), 7.54–7.61 (m, 2H). Method 2: An oven-dried 20 mL glass vial was charged with Pd(PPh3)2Cl2 (28.1 mg, 0.04 mmol), CuI (7.6 mg, 0.04 mmol), acid chloride (2.60 mmol), terminal alkyne (2.00 mmol) and anhydrous triethylamine (10 mL). The vial was flushed with nitrogen and sealed with a pressure relief cap. The reaction mixture was stirred at room temperature, overnight, until the disappearance of the starting material was observed, as monitored by TLC. The reaction mixture was diluted with diethyl ether (40 mL) and washed with brine (40 mL). The aqueous phase was then extracted with diethyl ether (2 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated using a rotary evaporator under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: petroleum ether/EtOAc).22
General Procedures for the Synthesis of 3
To a mixture of diethyl (E)-2-((2-hydroxybenzylidene) amino) malonate derivatives 1 (0.1 mmol) and H2O (1 mL) was added propargyl ketone or alkynyl ester 2 (0.12 mmol). The resulting solution was stirred at 100 °C for 1–10 h. The reaction solution was extracted with diethyl ether (2 × 1 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated using a rotary evaporator under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/EtOAc = 5/1) to give the desired products 3.
Diethyl 4-Acetyl-5-(2-hydroxyphenyl)-3-phenyl-1,5-dihydro-2H-pyrrole-2,2-dicarboxylate (3aa)
1H NMR (300 MHz, DMSO-d6): δ 9.74 (s, 1H), 7.45–7.36 (m, 3H), 7.33–7.25 (m, 2H), 7.18–7.03 (m, 2H), 6.83–6.73 (m, 2H), 5.77 (d, J = 6.2 Hz, 1H), 4.15–4.03 (m, 4H), 3.98 (d, J = 6.2 Hz, 1H), 1.69 (s, 3H), 1.02 (t, J = 7.2 Hz, 6H).·13C NMR (75 MHz, DMSO-d6): δ 197.96, 169.25, 169.21, 155.72, 146.61, 143.45, 133.70, 129.65, 129.05, 129.00, 128.47, 127.34, 119.52, 116.11, 82.33, 63.53, 62.16, 62.13, 30.65, 14.06, 14.02; HRMS (ESI): calcd for C24H26NO6+ (M + H)+ 424.4725; found, 424.4716.
Diethyl 4-Acetyl-5-(5-chloro-2-hydroxyphenyl)-3-phenyl-1,5-dihydro-2H-pyrrole-2,2-dicarboxylate (3ab)
It was obtained as colorless oil, 73% yield, 1H NMR (400 MHz, chloroform-d): δ 9.64 (d, J = 97.7 Hz, 1H), 7.44–7.34 (m, 3H), 7.30–7.26 (m, 2H), 7.16–7.09 (m, 2H), 6.79 (d, J = 8.5 Hz, 1H), 5.61 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 4.19 (q, J = 7.1 Hz, 2H), 1.61 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, chloroform-d): δ 198.89, 168.73, 168.54, 155.72, 144.26, 132.43, 130.15, 129.42, 129.32, 129.14, 128.37, 124.10, 123.59, 119.18, 80.74, 67.39, 63.10, 62.71, 30.51, 13.82, 13.76; HRMS (ESI): calcd for C24H25ClNO6+ (M + H)+ 458.9415; found, 458.9421.
Diethyl 4-Acetyl-5-(5-fluoro-2-hydroxyphenyl)-3-phenyl-1,5-dihydro-2H-pyrrole-2,2-dicarboxylate (3ac)
It was obtained as colorless oil, 72% yield, 1H NMR (400 MHz, chloroform-d): δ 9.47 (s, 1H), 7.43–7.35 (m, 3H), 7.31–7.26 (m, 2H), 6.92–6.83 (m, 2H), 6.79 (dd, J = 8.8, 4.9 Hz, 1H), 5.62 (s, 1H), 4.29 (q, J = 7.2 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 1.61 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H).·13C NMR (75 MHz, chloroform-d): δ 199.06, 168.73, 168.61, 152.92, 144.39, 142.30, 132.48, 129.30, 129.15, 128.37, 123.28, 118.65, 118.54, 116.82, 116.50, 116.14, 115.84, 80.82, 67.35, 63.05, 62.69, 30.51, 13.82, 13.75; HRMS (ESI): calcd for C24H25FNO6+ (M + H)+ 442.4629; found, 442.4626.
Diethyl 4-Acetyl-5-(5-bromo-2-hydroxyphenyl)-3-phenyl-1,5-dihydro-2H-pyrrole-2,2-dicarboxylate (3ad)
It was obtained as yellow oil, 60% yield, 1H NMR (400 MHz, chloroform-d): δ 9.77 (s, 1H), 7.44–7.34 (m, 3H), 7.30–7.26 (m, 3H), 6.74 (d, J = 8.6 Hz, 1H), 5.60 (s, 1H), 4.29 (q, J = 7.2 Hz, 2H), 4.19 (q, J = 7.1 Hz, 2H), 1.61 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.2 Hz, 3H).·13C NMR (101 MHz, chloroform-d): δ 198.86, 168.52, 156.24, 144.23, 142.20, 133.04, 132.41, 132.36, 129.33, 129.14, 128.38, 124.10, 119.71, 111.33, 67.34, 63.11, 62.72, 30.52, 13.84, 13.77; HRMS (ESI): calcd for C24H25BrNO6+ (M + H)+ 503.3685; found, 503.3685.
Diethyl 4-Acetyl-5-(2-hydroxy-5-nitrophenyl)-3-phenyl-1,5-dihydro-2H-pyrrole-2,2-dicarboxylate (3ae)
It was obtained as yellow oil, 68% yield, 1H NMR (400 MHz, chloroform-d): δ 10.98 (s, 1H), 8.16 (d, J = 2.8 Hz, 1H), 8.07 (dd, J = 9.0, 2.8 Hz, 1H), 7.46–7.37 (m, 3H), 7.31–7.27 (m, 2H), 6.91 (d, J = 9.0 Hz, 1H), 5.75 (s, 1H), 4.33–4.19 (m, 4H), 1.60 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H).·13C NMR (101 MHz, chloroform-d): δ 198.02, 168.58, 168.18, 163.27, 143.69, 143.22, 140.38, 132.15, 129.55, 129.05, 128.47, 127.24, 125.63, 122.04, 118.25, 80.75, 67.39, 63.34, 62.97, 30.41, 13.78; HRMS (ESI): calcd for C24H25N2O8+ (M + H)+ 469.4695; found, 469.4689.
Diethyl 4-Acetyl-5-(2,5-dihydroxyphenyl)-3-phenyl-1,5-dihydro-2H-pyrrole-2,2-dicarboxylate (3af)
It was obtained as yellow oil, 55% yield, 1H NMR (400 MHz, chloroform-d): δ 9.26 (s, 1H), 7.42–7.33 (m, 3H), 7.30–7.27 (m, 2H), 6.74 (d, J = 8.5 Hz, 1H), 6.70–6.64 (m, 2H), 5.57 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 4.19 (q, J = 7.1 Hz, 2H), 1.62 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H).·13C NMR (101 MHz, chloroform-d): δ 200.07, 168.82, 150.53, 148.65, 144.80, 141.66, 132.54, 129.22, 458129.18, 128.34, 122.68, 118.60, 116.88, 116.61, 80.76, 67.72, 63.03, 62.66, 30.63, 13.84, 13.76; HRMS (ESI): calcd for C24H26NO7+ (M + H)+ 440.4715; found, 440.4714.
Diethyl 4-Acetyl-5-(2-hydroxy-5-methylphenyl)-3-phenyl-1,5-dihydro-2H-pyrrole-2,2-dicarboxylate (3ag)
It was obtained as pale yellow oil, 61% yield, 1H NMR (400 MHz, chloroform-d): δ 9.51 (s, 1H), 7.43–7.33 (m, 3H), 7.31–7.25 (m, 2H), 7.00–6.88 (m, 2H), 6.76 (d, J = 8.1 Hz, 1H), 5.60 (s, 1H), 4.30 (q, J = 7.1 Hz, 2H), 4.18 (q, J = 7.2 Hz, 2H), 3.94 (s, J = 37.9 Hz, 1H), 2.24 (s, 3H), 1.60 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H).·13C NMR (101 MHz, chloroform-d): δ 199.65, 168.87, 168.77, 154.80, 145.13, 132.63, 130.83, 130.20, 129.20, 129.14, 128.50, 128.31, 121.48, 117.58, 80.58, 68.14, 62.98, 62.56, 30.67, 20.52, 13.86, 13.77; HRMS (ESI): calcd for C25H28NO6+ (M + H)+ 438.4995; found, 438.4987.
Diethyl 4-Acetyl-5-(2-hydroxy-5-methoxyphenyl)-3-phenyl-1,5-dihydro-2H-pyrrole-2,2-dicarboxylate (3ah)
It was obtained as yellow oil, 53% yield, 1H NMR (400 MHz, chloroform-d): δ 9.22 (s, 1H), 7.42–7.33 (m, 3H), 7.31–7.27 (m, 2H), 6.82–6.68 (m, 3H), 5.62 (s, 1H), 4.29 (q, J = 7.2 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 3.74 (s, 3H), 1.61 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H).·13C NMR (101 MHz, chloroform-d): δ 199.48, 168.84, 168.78, 152.63, 150.76, 144.96, 141.36, 132.62, 129.19, 129.17, 128.32, 122.75, 118.39, 115.36, 115.17, 80.77, 67.87, 62.96, 62.57, 55.70, 30.61, 13.84, 13.77; HRMS (ESI): calcd for C25H28NO7+ (M + H)+ 454.4985; found, 454.4969.
Diethyl 4-Acetyl-3-ethyl-5-(2-hydroxyphenyl)-1,5-Dihydro-2H-pyrrole-2,2-dicarboxylate (3ai)
It was obtained as yellow oil, 40% yield, 1H NMR (300 MHz, chloroform-d): δ 7.18 (m, J = 8.1, 7.3, 1.7 Hz, 1H), 7.04 (dd, J = 7.6, 1.7 Hz, 1H), 6.87–6.75 (m, 2H), 5.44 (d, J = 1.5 Hz, 1H), 4.39–4.26 (m, 4H), 2.68–2.50 (m, 2H), 2.02 (s, 3H), 1.35 (t, J = 7.1, 3.9 Hz, 6H), 1.10 (t, J = 7.5 Hz, 3H).·13C NMR (75 MHz, chloroform-d): δ 198.38, 169.01, 168.85, 157.36, 145.55, 140.89, 130.06, 129.86, 122.31, 119.36, 117.94, 67.72, 62.97, 62.82, 30.86, 20.71, 14.02, 13.95, 13.60; HRMS (ESI): calcd for C20H26NO6+ (M + H)+ 376.4285; found, 376.4282.
Diethyl 4-Benzoyl-5-(2-hydroxyphenyl)-1,5-dihydro-2H-pyrrole-2,2-dicarboxylate (3aj)
It was obtained as colorless oil, 65% yield, 1H NMR (300 MHz, chloroform-d): δ 9.90 (s, 1H), 7.85–7.77 (m, 2H), 7.59–7.50 (m, 1H), 7.46–7.37 (m, 2H), 7.22 (dd, J = 7.5, 1.7 Hz, 1H), 7.09 (m, J = 8.1, 7.3, 1.7 Hz, 1H), 6.82–6.72 (m, 2H), 6.41 (d, J = 2.5 Hz, 1H), 5.84 (d, J = 2.5 Hz, 1H), 4.43–4.18 (m, 4H), 1.38 (t, J = 7.1 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H).·13C NMR (75 MHz, chloroform-d): δ 191.45, 168.42, 157.15, 145.53, 136.79, 133.62, 132.79, 130.28, 129.55, 128.61, 121.39, 119.55, 117.70, 68.07, 63.17, 63.06, 14.03; HRMS (ESI): calcd for C23H24NO6+ (M + H)+ 410.4455; found, 410.4447.
Diethyl 4-Acetyl-5-(2-hydroxyphenyl)-1,5-dihydro-2H-pyrrole-2,2-dicarboxylate (3ak)
It was obtained as colorless oil, 73% yield, 1H NMR (300 MHz, chloroform-d): δ 9.40 (s, 1H), 7.30–7.20 (m, 1H), 7.15 (m, J = 7.8, 1.8 Hz, 1H), 6.83 (m, J = 11.0, 7.9, 2.7 Hz, 2H), 6.72 (d, J = 2.4 Hz, 1H), 5.60 (d, J = 2.6 Hz, 1H), 4.40–4.23 (m, 4H), 2.28 (s, J = 2.5 Hz, 3H), 1.34 (t, J = 6.9 Hz, 6H).·13C NMR (75 MHz, chloroform-d): δ 195.10, 168.50, 168.24, 156.61, 146.55, 134.14, 130.60, 129.43, 122.64, 119.57, 117.82, 66.26, 63.21, 63.07, 27.99, 14.06, 14.01; HRMS (ESI): calcd for C18H22NO6+ (M + H)+ 348.3745; found, 348.3747.
Diethyl 4-Benzoyl-5-(2-hydroxyphenyl)-3-phenyl-1,5-dihydro-2H-pyrrole-2,2-dicarboxylate (3al)
It was obtained as pale yellow oil, 69% yield, 1H NMR (300 MHz, chloroform-d): δ 10.33 (s, 1H), 7.66–7.56 (m, 2H), 7.28–7.19 (m, 1H), 7.15–6.96 (m, 9H), 6.78 (dd, J = 8.2, 1.3 Hz, 1H), 6.66 (m, J = 7.4, 1.2 Hz, 1H), 5.87 (s, 1H), 4.40 (q, J = 7.1 Hz, 2H), 4.15 (q, J = 7.1, 2.5 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H), 1.03 (t, J = 7.2 Hz, 3H).·13C NMR (75 MHz, chloroform-d): δ 194.50, 169.26, 168.74, 157.52, 143.22, 139.10, 136.16, 133.21, 132.20, 129.73, 129.68, 129.20, 129.14, 128.60, 128.01, 127.81, 120.72, 119.35, 117.67, 69.54, 63.14, 62.56, 13.92, 13.67; HRMS (ESI): calcd for C29H28NO6+ (M + H)+ 486.5435; found, 486.5418.
4-Benzyl 2,2-Diethyl 5-(2-Hydroxyphenyl)-1,5-dihydro-2H-pyrrole-2,2,4-tricarboxylate (3ba)
It was obtained as pale yellow oil, 89% yield, 1H NMR (300 MHz, chloroform-d): δ 9.52 (s, 1H), 7.39–7.28 (m, 3H), 7.25–7.11 (m, 4H), 6.93–6.71 (m, 3H), 5.55 (d, J = 2.5 Hz, 1H), 5.11 (d, J = 12.2 Hz, 1H), 4.99 (d, J = 12.3 Hz, 1H), 4.40–4.18 (m, 4H), 1.32 (t, J = 7.2, 4.8 Hz, 6H).·13C NMR (75 MHz, chloroform-d): δ 168.50, 168.14, 157.11, 138.68, 135.31, 135.03, 130.88, 129.58, 128.55, 128.47, 121.84, 119.30, 117.75, 66.94, 66.83, 63.18, 63.09, 14.05, 13.99; HRMS (ESI): calcd for C24H26NO7+ (M + H)+ 440.4715; found, 440.4717.
2,2-Diethyl 4-(4-(Trifluoromethyl)benzyl) 5-(2-Hydroxyphenyl)-1,5-dihydro-2H-pyrrole-2,2,4-tricarboxylate (3bb)
It was obtained as yellow oil, 76% yield, 1H NMR (300 MHz, chloroform-d): δ 9.44 (s, 1H), 7.58–7.52 (m, 2H), 7.28–7.10 (m, 4H), 6.92–6.72 (m, 3H), 5.55 (d, J = 2.6 Hz, 1H), 5.18 (d, J = 12.8 Hz, 1H), 5.02 (d, J = 12.8 Hz, 1H), 4.38–4.22 (m, 4H), 4.11–3.74 (s, 1H), 1.33 (t, J = 7.1, 4.2 Hz, 6H).·13C NMR (75 MHz, chloroform-d): δ 168.39, 168.06, 161.97, 157.11, 139.00, 138.39, 135.79, 130.80, 129.68, 128.24, 125.50, 125.45, 121.76, 119.30, 117.78, 66.85, 65.83, 63.22, 63.15, 14.04, 13.98; HRMS (ESI): calcd for C25H25F3NO7+ (M + H)+ 508.4697; found, 508.4693.
2,2-Diethyl 4-(4-Methylbenzyl) 5-(2-Hydroxyphenyl)-1,5-dihydro-2H-pyrrole-2,2,4-tricarboxylate (3bc)
It was obtained as yellow oil, 68% yield, 1H NMR (300 MHz, chloroform-d): δ 9.52 (s, 1H), 7.23–7.02 (m, 6H), 6.94–6.65 (m, 3H), 5.54 (d, J = 2.6 Hz, 1H), 5.06 (d, J = 12.1 Hz, 1H), 4.95 (d, J = 12.1 Hz, 1H), 4.38–4.18 (m, 4H), 2.34 (s, 3H), 1.31 (t, J = 7.1, 4.9 Hz, 6H).·13C NMR (75 MHz, chloroform-d): δ 168.51, 168.15, 162.28, 157.10, 138.75, 138.34, 135.18, 132.05, 130.88, 129.55, 129.23, 128.66, 121.88, 119.29, 117.75, 66.91, 66.81, 63.17, 63.07, 21.25, 13.99; HRMS (ESI): calcd for C25H28NO7+ (M + H)+ 454.4985; found, 454.4978.
2,2-Diethyl 4-(4-Fluorobenzyl) 5-(2-Hydroxyphenyl)-1,5-dihydro-2H-pyrrole-2,2,4-tricarboxylate (3bd)
It was obtained as yellow oil, 90% yield, 1H NMR (400 MHz, chloroform-d): δ 9.45 (s, 1H), 7.15 (m, J = 13.2, 7.3, 1.7 Hz, 4H), 7.02–6.94 (m, 2H), 6.87–6.72 (m, 3H), 5.54 (d, J = 2.6 Hz, 1H), 5.08 (d, J = 12.2 Hz, 1H), 4.94 (d, J = 12.2 Hz, 1H), 4.39–4.22 (m, 4H), 1.32 (t, J = 7.1, 5.8 Hz, 6H).·13C NMR (101 MHz, chloroform-d): δ 168.44, 168.11, 162.14, 157.10, 138.61, 135.44, 130.83, 130.47, 130.39, 129.60, 121.83, 119.27, 117.75, 115.57, 115.36, 77.05, 66.82, 66.17, 63.19, 63.11, 14.04, 13.98; HRMS (ESI): calcd for C24H25FNO7+ (M + H)+ 458.4619; found, 458.4613.
2,2-Diethyl 4-(4-Nitrobenzyl) 5-(2-Hydroxyphenyl)-1,5-dihydro-2H-pyrrole-2,2,4-tricarboxylate (3be)
It was obtained as yellow oil, 83% yield, 1H NMR (300 MHz, chloroform-d): δ 9.37 (s, 1H), 8.17–8.08 (m, 2H), 7.28–7.10 (m, 4H), 6.92 (d, J = 2.5 Hz, 1H), 6.87–6.73 (m, 2H), 5.56 (d, J = 2.6 Hz, 1H), 5.24 (d, J = 13.4 Hz, 1H), 5.06 (d, J = 13.4 Hz, 1H), 4.43–4.22 (m, 4H), 1.33 (t, J = 7.1, 3.1 Hz, 6H).·13C NMR (75 MHz, chloroform-d): δ 168.35, 168.05, 157.14, 147.68, 142.28, 138.23, 136.18, 130.78, 129.75, 128.37, 123.73, 121.85, 119.37, 117.82, 66.81, 65.24, 63.26, 63.20, 14.05, 13.98; HRMS (ESI): calcd for C24H25N2O9+ (M + H)+ 485.4685; found, 485.4689.
2,2-Diethyl 4-Methyl 5-(2-Hydroxyphenyl)-1,5-dihydro-2H-pyrrole-2,2,4-tricarboxylate (3bf)
It was obtained as yellow oil, 75% yield, 1H NMR (300 MHz, chloroform-d): δ 9.52 (s, 1H), 7.25–7.12 (m, 2H), 6.87–6.77 (m, 3H), 5.56 (d, J = 2.5 Hz, 1H), 4.42–4.23 (m, 4H), 3.65 (s, 3H), 1.33 (t, J = 7.1, 3.7 Hz, 6H).·13C NMR (75 MHz, chloroform-d): δ 168.51, 168.13, 162.80, 157.06, 138.59, 134.86, 130.71, 129.58, 121.81, 119.25, 117.77, 66.81, 63.18, 63.07, 51.98, 13.99; HRMS (ESI): calcd for C18H22NO7+ (M + H)+ 364.3735; found, 364.3727.
Triethyl 5-(2-Hydroxyphenyl)-1,5-dihydro-2H-pyrrole-2,2,4-tricarboxylate (3bg)
It was obtained as colorless oil, 72% yield, 1H NMR (300 MHz, chloroform-d): δ 9.53 (s, 1H), 7.24–7.12 (m, 2H), 6.87–6.76 (m, 3H), 5.55 (d, J = 2.5 Hz, 1H), 4.39–4.23 (m, 4H), 4.15–4.02 (m, 2H), 1.33 (t, J = 7.1, 3.9 Hz, 6H), 1.18 (t, J = 7.2 Hz, 3H).·13C NMR (75 MHz, chloroform-d): δ 168.57, 168.20, 162.44, 157.07, 138.99, 134.69, 130.83, 129.53, 121.95, 119.16, 117.71, 66.78, 63.15, 63.05, 61.16, 14.05, 13.99, 13.90; HRMS (ESI): calcd for C19H24NO7+ (M + H)+ 378.4005; found, 378.4002.
2,2-Diethyl 3,4-Dimethyl 5-(2-Hydroxyphenyl)-1,5-dihydro-2H-pyrrole-2,2,3,4-tetracarboxylate (3bh)
It was obtained as colorless oil, 51% yield, 1H NMR (300 MHz, chloroform-d): δ 9.57 (s, 1H), 7.19 (d, J = 11.6 Hz, 1H), 6.97 (s, 1H), 6.88–6.75 (m, 2H), 5.57 (s, 1H), 4.43–4.26 (m, 4H), 3.78 (s, 3H), 3.59 (s, 3H), 1.35 (dd, J = 17.1, 7.1 Hz, 6H).·13C NMR (75 MHz, chloroform-d): δ 168.47, 168.20, 163.15, 157.66, 145.22, 130.74, 130.34, 129.53, 119.35, 118.01, 69.04, 63.33, 63.18, 52.51, 52.48, 13.88, 13.85; HRMS (ESI): calcd for C20H24NO9+ (M + H)+ 422.4095; found, 422.4099.
Triethyl 5-(2-Hydroxyphenyl)-3-methyl-1,5-dihydro-2H-pyrrole-2,2,4-tricarboxylate (3bi)
It was obtained as yellow oil, 40% yield, 1H NMR (300 MHz, chloroform-d): δ 9.46 (s, 1H), 7.23–7.09 (m, 4H), 6.85–6.73 (m, 4H), 5.42 (d, J = 2.3 Hz, 2H), 4.40–4.26 (m, 8H), 4.15–3.93 (m, 4H), 2.25 (s, J = 2.3 Hz, 6H), 1.35 (t, J = 7.1, 1.8 Hz, 12H), 1.11 (t, J = 7.1 Hz, 6H).·13C NMR (75 MHz, chloroform-d): δ 168.62, 168.41, 157.29, 132.45, 131.13, 129.45, 122.41, 118.82, 117.57, 67.38, 62.95, 62.88, 60.63, 14.02, 13.88, 13.59; HRMS (ESI): calcd for C20H26NO7+ (M + H)+ 392.4275; found, 392.4275.
2,2-Diethyl 4-(Naphthalen-2-ylmethyl) 5-(2-Hydroxyphenyl)-1,5-dihydro-2H-pyrrole-2,2,4-tricarboxylate (3bj)
It was obtained as yellow oil, 63% yield, 1H NMR (300 MHz, chloroform-d): δ 9.52 (s, 1H), 7.84–7.77 (m, 3H), 7.66 (d, J = 1.7 Hz, 1H), 7.48 (m, J = 6.2, 3.1 Hz, 2H), 7.29 (m, J = 8.5, 1.7 Hz, 1H), 7.20–7.10 (m, 2H), 6.91–6.80 (m, 2H), 6.74 (m, J = 7.5, 1.3 Hz, 1H), 5.56 (d, J = 2.5 Hz, 1H), 5.28 (d, J = 12.3 Hz, 1H), 5.14 (d, J = 12.3 Hz, 1H), 4.37–4.19 (m, 4H), 1.31 (t, J = 7.1, 6.0 Hz, 6H).·13C NMR (75 MHz, chloroform-d): δ 157.13, 138.70, 135.42, 133.17, 133.10, 132.44, 130.91, 129.62, 128.38, 128.04, 127.72, 126.43, 126.36, 126.04, 121.84, 119.31, 117.78, 67.12, 66.86, 63.19, 63.10, 14.00; HRMS (ESI): calcd for C28H28NO7+ (M + H)+ 490.5315; found, 490.5313.
2,2-Diethyl 4-Phenyl 5-(2-Hydroxyphenyl)-1,5-dihydro-2H-pyrrole-2,2,4-tricarboxylate (3bk)
It was obtained as yellow oil, 64% yield, 1H NMR (300 MHz, chloroform-d): δ 9.56 (s, 1H), 7.32 (dd, J = 5.1, 1.3 Hz, 1H), 7.16 (t, J = 7.3 Hz, 2H), 7.04–6.94 (m, 2H), 6.85–6.74 (m, 3H), 5.54 (d, J = 2.5 Hz, 1H), 5.27 (d, J = 12.8 Hz, 1H), 5.14 (d, J = 12.8 Hz, 1H), 4.36–4.22 (m, 4H), 1.35–1.29 (m, 6H).·13C NMR (75 MHz, chloroform-d): δ 168.08, 161.98, 157.09, 138.43, 136.86, 135.42, 130.85, 129.58, 128.73, 127.17, 126.89, 121.63, 119.24, 117.73, 66.84, 63.20, 63.09, 61.01, 14.04, 13.99; HRMS (ESI): calcd for C23H24NO7+ (M + H)+ 426.4445; found, 426.4435.
4-Benzyl 2,2-Diethyl 5-(5-Fluoro-2-hydroxyphenyl)-1,5-dihydro-2H-pyrrole-2,2,4-tricarboxylate (3bl)
It was obtained as pale yellow oil, 72% yield, 1H NMR (400 MHz, chloroform-d): δ 9.17 (s, 1H), 7.38–7.29 (m, 3H), 7.26–7.20 (m, 2H), 6.94–6.81 (m, 3H), 6.76 (m, J = 8.9, 4.9 Hz, 1H), 5.50 (d, J = 2.5 Hz, 1H), 5.13 (d, J = 12.2 Hz, 1H), 5.02 (d, J = 12.2 Hz, 1H), 4.39–4.22 (m, 4H), 3.90 (s, 1H), 1.32 (t, J = 7.0 Hz, 6H).·13C NMR (101 MHz, chloroform-d): δ 168.42, 168.12, 162.28, 152.76, 138.34, 135.80, 134.82, 128.62, 128.55, 123.53, 118.68, 118.61, 116.97, 116.73, 116.05, 115.83, 67.19, 66.02, 66.00, 63.25, 63.13, 14.03, 13.98; HRMS (ESI): calcd for C24H25FNO7+ (M + H)+ 458.4619; found, 458.4616.
4-Benzyl 2,2-Diethyl 5-(5-Chloro-2-hydroxyphenyl)-1,5-dihydro-2H-pyrrole-2,2,4-tricarboxylate (3bm)
It was obtained as pale yellow oil, 78% yield, 1H NMR (400 MHz, chloroform-d): δ 9.49 (s, 1H), 7.38–7.31 (m, 3H), 7.27–7.21 (m, 2H), 7.16 (d, J = 2.6 Hz, 1H), 7.11 (dd, J = 8.6, 2.6 Hz, 1H), 6.87 (d, J = 2.5 Hz, 1H), 6.75 (d, J = 8.6 Hz, 1H), 5.49 (d, J = 2.5 Hz, 1H), 5.14–5.01 (m, 2H), 4.39–4.22 (m, 4H), 4.05–3.74 (s, 1H), 1.32 (t, J = 7.1 Hz, 6H).·13C NMR (101 MHz, chloroform-d): δ 168.33, 168.07, 162.16, 155.64, 138.27, 135.81, 134.83, 130.38, 129.36, 128.66, 128.56, 123.99, 123.63, 119.21, 77.19, 67.20, 66.13, 63.29, 63.20, 14.03, 13.98; HRMS (ESI): calcd for C24H25ClNO7+ (M + H)+ 474.9135; found, 474.9125.
4-Benzyl 2,2-Diethyl 5-(5-Bromo-2-hydroxyphenyl)-1,5-dihydro-2H-pyrrole-2,2,4-tricarboxylate (3bn)
It was obtained as yellow oil, 51% yield, 1H NMR (400 MHz, chloroform-d): δ 9.51 (s, 1H), 7.39–7.29 (m, 4H), 7.25 (dd, J = 7.9, 3.0 Hz, 3H), 6.86 (d, J = 2.5 Hz, 1H), 6.71 (d, J = 8.6 Hz, 1H), 5.48 (d, J = 2.5 Hz, 1H), 5.08 (q, J = 12.2 Hz, 2H), 4.37–4.22 (m, 4H), 1.32 (t, J = 7.1 Hz, 6H).·13C NMR (101 MHz, chloroform-d): δ 168.30, 168.05, 162.14, 156.18, 138.27, 135.79, 134.84, 133.27, 132.30, 128.68, 128.57, 128.55, 124.12, 119.74, 111.21, 67.20, 66.08, 63.30, 63.21, 14.03, 13.98; HRMS (ESI): calcd for C24H25BrNO7+ (M + H)+ 519.3675; found, 519.3679.
4-Benzyl 2,2-Diethyl 5-(2-Hydroxy-5-nitrophenyl)-1,5-dihydro-2H-pyrrole-2,2,4-tricarboxylate (3bo)
It was obtained as yellow oil, 53% yield, 1H NMR (400 MHz, chloroform-d): δ 10.86 (s, 1H), 8.12 (d, J = 2.8 Hz, 1H), 8.03 (m, J = 9.0, 2.0 Hz, 1H), 7.31 (m, J = 5.5, 3.1 Hz, 3H), 7.24–7.09 (m, 2H), 6.93 (t, J = 1.9 Hz, 1H), 6.84 (dd, J = 9.1, 1.4 Hz, 1H), 5.61 (d, J = 2.6 Hz, 1H), 5.13 (d, J = 12.0 Hz, 1H), 5.00 (d, J = 12.0 Hz, 1H), 4.44–4.24 (m, 4H), 1.34 (t, J = 7.1, 5.5, 1.4 Hz, 6H).·13C NMR (101 MHz, chloroform-d): δ 167.90, 167.81, 163.35, 161.71, 140.10, 137.50, 136.34, 134.51, 128.74, 128.65, 127.43, 125.59, 121.43, 118.18, 67.32, 66.43, 63.55, 63.49, 14.03, 13.96; HRMS (ESI): calcd for C24H25N2O9+ (M + H)+ 484.4685; found, 484.4685.
4-Benzyl 2,2-Diethyl 5-(2,5-Dihydroxyphenyl)-1,5-dihydro-2H-pyrrole-2,2,4-tricarboxylate (3bp)
It was obtained as yellow oil, 67% yield, 1H NMR (300 MHz, chloroform-d): δ 7.40–7.28 (m, 3H), 7.23 (dd, J = 6.7, 2.9 Hz, 2H), 6.85 (d, J = 2.4 Hz, 1H), 6.76–6.59 (m, 3H), 5.47 (d, J = 2.5 Hz, 1H), 5.12 (d, J = 12.2 Hz, 1H), 4.99 (d, J = 12.3 Hz, 1H), 4.40–4.20 (m, 4H), 1.31 (t, J = 7.1, 1.7 Hz, 6H).·13C NMR (101 MHz, chloroform-d): δ 168.62, 168.31, 162.51, 150.26, 148.56, 138.73, 135.55, 134.97, 128.60, 128.51, 128.48, 123.38, 118.60, 117.11, 116.52, 67.12, 66.07, 63.19, 63.09, 14.02, 13.97; HRMS (ESI): calcd for C24H26NO8+ (M + H)+ 456.4705; found, 456.4695.
4-Benzyl 2,2-Diethyl 5-(2-Hydroxy-5-methoxyphenyl)-1,5-dihydro-2H-pyrrole-2,2,4-tricarboxylate (3bq)
It was obtained as pale yellow oil, 76% yield, 1H NMR (400 MHz, chloroform-d): δ 8.75 (s, 1H), 7.37–7.28 (m, 3H), 7.20 (dd, J = 6.6, 2.9 Hz, 2H), 6.85 (dd, J = 2.6, 1.0 Hz, 1H), 6.80–6.70 (m, 3H), 5.53 (d, J = 2.5 Hz, 1H), 5.13 (d, J = 12.3 Hz, 1H), 5.01 (d, J = 12.3 Hz, 1H), 4.38–4.19 (m, 4H), 3.65 (s, J = 1.0 Hz, 3H), 1.31 (t, J = 7.1, 5.6, 1.0 Hz, 6H).·13C NMR (101 MHz, chloroform-d): δ 168.61, 168.29, 162.47, 152.68, 150.47, 138.82, 135.53, 135.00, 128.57, 128.41, 128.37, 123.41, 118.46, 115.52, 115.12, 67.01, 66.29, 63.13, 63.02, 55.61, 14.04, 13.99; HRMS (ESI): calcd for C25H28NO8+ (M + H)+ 470.4975; found, 470.4977.
4-Benzyl 2,2-Diethyl 5-(3,5-Dibromo-2-hydroxyphenyl)-1,5-dihydro-2H-pyrrole-2,2,4-tricarboxylate (3br)
It was obtained as yellow oil, 71% yield, 1H NMR (400 MHz, chloroform-d): δ 9.86 (s, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.39–7.31 (m, 3H), 7.29–7.20 (m, 3H), 6.90 (d, J = 2.5 Hz, 1H), 5.52 (d, J = 2.5 Hz, 1H), 5.16–5.00 (q, 2H), 4.37–4.21 (m, 4H), 3.95 (s, 1H), 1.36–1.28 (t, 6H).·13C NMR (101 MHz, chloroform-d): δ 168.16, 167.77, 161.89, 152.70, 137.82, 136.35, 134.78, 132.60, 128.70, 128.59, 128.54, 125.38, 112.42, 111.13, 67.22, 65.69, 63.37, 63.26, 14.03, 13.99; HRMS (ESI): calcd for C24H24Br2NO7+ (M + H)+ 598.2635; found, 598.2648.
Scale-Up Synthesis of 3aa
To a mixture of alminine esters 1a (3 mmol, 0.85 g) and H2O (6 mL) was added propargyl ketone 2a (3.6 mmol, 0.51 g). The resulting solution was stirred at 100 °C for 5 h. The reaction solution was extracted with diethyl ether (2 × 2 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated using a rotary evaporator under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/EtOAc = 5/1) to give the desired products 3aa in 61% yield.
General Procedure for the Synthesis of 4
A mixture of 3aa (0.1 mmol, 42.3 mg) and a formaldehyde solution (37%) (stabilized with methanol) (0.20 mmol, 16.7 mg) in THF (1.5 mL) was prepared. The resulting solution was stirred at room temperature under an argon atmosphere for 12 h. After removal of the solvent, the product was purified through silica gel chromatography (petroleum ether/AcOEt = 8/1) to give colorless oil 4 in 81% (35.3 mg) yield.
Diethyl 1-Acetyl-2-phenyl-5H-benzo[e]pyrrolo[1,2-c][1,3]oxazine-3,3(10bH)-dicarboxylate (4)
It was obtained as colorless oil, 1H NMR (300 MHz, chloroform-d): δ 7.41–7.29 (m, 3H), 7.23–7.16 (m, 2H), 7.13–7.03 (m, 2H), 6.88–6.74 (m, 2H), 6.15 (s, 1H), 5.21 (d, J = 11.3 Hz, 1H), 5.07 (d, J = 11.3 Hz, 1H), 4.30–4.20 (m, 1H), 4.17–4.07 (m, 1H), 4.00–3.82 (m, 2H), 1.79 (s, 3H), 1.12 (t, J = 7.2 Hz, 3H), 0.78 (t, J = 7.1 Hz, 3H).·13C NMR (75 MHz, chloroform-d): δ 199.62, 168.80, 167.48, 153.95, 144.31, 133.78, 129.00, 128.75, 128.34, 127.94, 126.05, 123.02, 121.46, 117.57, 63.63, 62.94, 61.79, 31.14, 13.47, 13.34; HRMS (ESI): calcd for C25H26NO6+ (M + H)+ 436.4835; found, 436.4828.
General Procedure for the Synthesis of 5
To a mixture of 3aa (0.1 mmol, 42.3 mg) and anhydrous THF (1.5 mL) was added NaBH4 (0.3 mmol, 11.3 mg) at 0 °C. Keep the temperature constant and stir the solution for 1 h. After removal of the solvent, the product was purified through silica gel chromatography (petroleum ether/AcOEt = 3/1) to give colorless oil 5 in 74% (31.6 mg) yield.
Diethyl 4-(1-Hydroxyethyl)-5-(2-hydroxyphenyl)-3-phenyl-1,5-dihydro-2H-pyrrole-2,2-dicarboxylate (5)
It was obtained as colorless oil, 1H NMR (300 MHz, chloroform-d): δ 9.85 (s, 1H), 7.38–7.27 (m, 5H), 7.25–7.10 (m, 2H), 6.95–6.81 (m, 2H), 5.48 (d, J = 34.9 Hz, 1H), 4.28 (m, J = 7.1, 5.2 Hz, 3H), 4.13 (m, J = 7.1, 3.0 Hz, 2H), 1.26 (m, J = 7.1, 4.0 Hz, 4H), 1.15–1.02 (m, 6H), 0.77 (d, J = 6.8 Hz, 1H).·13C NMR (75 MHz, chloroform-d): δ 169.65, 169.30, 157.81, 145.66, 135.15, 132.81, 130.15, 129.97, 129.54, 128.34, 127.97, 123.41, 119.62, 118.22, 117.95, 67.55, 64.76, 62.54, 62.37, 22.00, 13.99, 13.71; HRMS (ESI): calcd for C24H28NO6+ (M + H)+ 426.4885; found, 426.4887.
General Procedure for the Synthesis of 6
A mixture of 3aa (0.1 mmol, 42.3 mg) and bis(trichlormethyl) carbonate (0.20 mmol, 59.1 mg) in anhydrous CH2Cl2 (1.5 mL) was prepared. The resulting solution was stirred at room temperature for 12 h. After removal of the solvent, the product was purified through silica gel chromatography (petroleum ether/AcOEt 5:1) to give colorless oil 6 in 71% (32 mg) yield.
Diethyl 1-Acetyl-5-oxo-2-phenyl-5H-benzo[e]pyrrolo[1,2-c][1,3]oxazine-3,3(10bH)-dicarboxylate (6)
It was obtained as colorless oil, 1H NMR (400 MHz, chloroform-d): δ 7.47–7.28 (m, 4H), 7.15–7.02 (m, 4H), 6.95 (m, J = 7.8, 3.0, 1.6 Hz, 1H), 6.18 (d, J = 2.9 Hz, 1H), 4.15 (m, J = 13.7, 10.7, 7.1, 3.6 Hz, 4H), 1.88 (d, J = 3.0 Hz, 3H), 1.06 (m, J = 21.4, 7.1, 2.9 Hz, 6H). 13C NMR (101 MHz, chloroform-d): δ 198.95, 164.25, 163.91, 150.39, 149.09, 144.92, 141.49, 131.16, 129.97, 129.31, 128.76, 128.72, 124.81, 124.05, 122.14, 117.21, 63.30, 63.14, 62.78, 30.84, 13.87, 13.71; HRMS (ESI): calcd for C25H24NO7+ (M + H)+ 450.4665; found, 450.4653.
Acknowledgments
This work was financially supported by the National Natural Science Foundation of China (grant nos. 21102179 and 21572271), Qing Lan Project of Jiangsu Province, the “Double First-Class” University project (CPU2018GY35 and CPU2018GF02), and Postgraduate Scientific Research Innovation Projects of Jiangsu Province (KYCX19_0624).
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.0c01856.
Experimental procedures and spectroscopic data for the substrates and products (PDF)
The authors declare no competing financial interest.
Supplementary Material
References
- a Pyne S.; Davis A.; Gates N.; Hartley J.; Lindsay K.; Machan T.; Tang M. Asymmetric synthesis of polyfunctionalized pyrrolidines and related alkaloids. Synlett 2004, 2004, 2670–2680. 10.1055/s-2004-834801. [DOI] [Google Scholar]; b Bellina F.; Rossi R. Synthesis and biological activity of pyrrole, pyrroline and pyrrolidine derivatives with two aryl groups on adjacent positions. Tetrahedron 2006, 62, 7213–7256. 10.1016/j.tet.2006.05.024. [DOI] [Google Scholar]; c Hashimoto T.; Maruoka K. Recent advances of catalytic asymmetric 1,3-dipolar cycloadditions. Chem. Rev. 2015, 115, 5366–5412. 10.1021/cr5007182. [DOI] [PubMed] [Google Scholar]; d Michael J. P. Indolizidine and quinolizidine alkaloids. Nat. Prod. Rep. 2008, 25, 139–165. 10.1039/b612166g. [DOI] [PubMed] [Google Scholar]; e Narayan R.; Potowski M.; Jia Z.-J.; Antonchick A. P.; Waldmann H. Catalytic Enantioselective 1,3-Dipolar Cycloadditions of Azomethine Ylides for Biology-Oriented Synthesis. Acc. Chem. Res. 2014, 47, 1296–1310. 10.1021/ar400286b. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Andrews I. P.; Blank B. R.; Kwon O. Phosphine-catalyzed intramolecular γ-umpolung addition of α-aminoalkylallenic esters: facile synthesis of 3-carbethoxy-2-alkyl-3-pyrrolines. Chem. Commun. 2012, 48, 5373–5375. 10.1039/c2cc31347b. [DOI] [PMC free article] [PubMed] [Google Scholar]
- a Yoshida Y.; Mohri K.; Isobe K.; Itoh T.; Yamamoto K. Biomimetic Total Synthesis of (±)-8-Oxoerymelanthine. J. Org. Chem. 2009, 74, 6010–6015. 10.1021/jo9008645. [DOI] [PubMed] [Google Scholar]; b Padwa A.; Hennig R.; Kappe C. O.; Reger T. S. A triple cascade sequence as a strategy for the construction of the erythrinane skeleton. J. Org. Chem. 1998, 63, 1144–1155. 10.1021/jo9716183. [DOI] [Google Scholar]
- Cox C. D.; Coleman P. J.; Breslin M. J.; Whitman D. B.; Garbaccio R. M.; Fraley M. E.; Buser C. A.; Walsh E. S.; Hamilton K.; Schaber M. D.; Lobell R. B.; Tao W.; Davide J. P.; Diehl R. E.; Abrams M. T.; South V. J.; Huber H. E.; Torrent M.; Prueksaritanont T.; Li C.; Slaughter D. E.; Mahan E.; Fernandez-Metzler C.; Yan Y.; Kuo L. C.; Kohl N. E.; Hartman G. D. Kinesin Spindle Protein (KSP) inhibitors. 9. Discovery of (2S)-4-(2,5-difluorophenyl)-N-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the treatment of taxane-refractory cancer. J. Med. Chem. 2008, 51, 4239–4252. 10.1021/jm800386y. [DOI] [PubMed] [Google Scholar]
- a Pandey P. R.; Chatterjee B.; Olanich M. E.; Khan J.; Miettinen M. M.; Hewitt S. M.; Barr F. G. PAX3-FOXO1 is essential for tumour initiation and maintenance but not recurrence in a human myoblast model of rhabdomyosarcoma. J. Pathol. 2017, 241, 626–637. 10.1002/path.4867. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Kang U.; Caldwell D. R.; Cartner L. K.; Wang D.; Kim C.-K.; Tian X.; Bokesch H. R.; Henrich C. J.; Woldemichael G. M.; Schnermann M. J.; Gustafson K. R. Elucidation of spirodactylone, a polycyclic alkaloid from the sponge dactylia sp., and nonenzymatic generation from the co-metabolite Denigrin B. Org. Lett. 2019, 21, 4750–4753. 10.1021/acs.orglett.9b01636. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Hanna J. A.; Garcia M. R.; Lardennois A.; Leavey P. J.; Maglic D.; Fagnan A.; Go J. C.; Roach J.; Wang Y.-D.; Finkelstein D.; Hatley M. E. PAX3-FOXO1 drives miR-486-5p and represses miR-221 contributing to pathogenesis of alveolar rhabdomyosarcoma. Oncogene 2018, 37, 1991–2007. 10.1038/s41388-017-0081-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Morita N.; Krause N. Gold Catalysis in Organic Synthesis: Efficient Cycloisomerization of α-Aminoallenes to 3-Pyrrolines. Org. Lett. 2004, 6, 4121–4123. 10.1021/ol0481838. [DOI] [PubMed] [Google Scholar]
- a Zheng C.; Wang Y.; Fan R. Iodine(III)-mediated oxidative cross-coupling of enamines and propargylamines under metal-free conditions: An alternative way to prepare highly substituted 3-pyrrolines. Org. Lett. 2015, 17, 916–919. 10.1021/acs.orglett.5b00026. [DOI] [PubMed] [Google Scholar]; b Alcaide B.; Almendros P.; Aragoncillo C.; Gómez-Campillos G.; Quirós M. T.; Soriano E. Tunable metal-catalyzed heterocyclization reactions of allenic amino alcohols: An experimental and theoretical study. J. Org. Chem. 2016, 81, 7362–7372. 10.1021/acs.joc.6b00934. [DOI] [PubMed] [Google Scholar]; c Tata R. R.; Fu C.; Kelley S. P.; Harmata M. Synthesis of 3-(Arylsulfonyl)-3-pyrrolines from Allenyl Sulfonamides by Silver Ion Catalysis. Org. Lett. 2018, 20, 5723–5726. 10.1021/acs.orglett.8b02440. [DOI] [PubMed] [Google Scholar]
- Zheng S.; Lu X. A Phosphine-Catalyzed [3 + 2] Annulation Reaction of Modified Allylic Compounds andN-Tosylimines. Org. Lett. 2008, 10, 4481–4484. 10.1021/ol801661y. [DOI] [PubMed] [Google Scholar]
- Schuler M.; Duvvuru D.; Retailleau P.; Betzer J.-F.; Marinetti A. New access to trisubstituted 3-pyrrolines under phosphine catalysis. Org. Lett. 2009, 11, 4406–4409. 10.1021/ol901758k. [DOI] [PubMed] [Google Scholar]
- Wang D.; Liu W.; Hong Y.; Tong X. Phosphine-Catalyzed (3 + 2) Annulation of δ-Acetoxy Allenoates with 2-Sulfonamidomalonate: Synthesis of Highly Substituted 3-Pyrrolines and Mechanistic Insight. Org. Lett. 2018, 20, 5002–5005. 10.1021/acs.orglett.8b02156. [DOI] [PubMed] [Google Scholar]
- Li L.; Zhang J. Lewis Acid-catalyzed [3 + 2]Cyclo-addition of Alkynes withN-Tosyl-aziridines via Carbon-Carbon Bond Cleavage: Synthesis of Highly Substituted 3-Pyrrolines. Org. Lett. 2011, 13, 5940–5943. 10.1021/ol202603e. [DOI] [PubMed] [Google Scholar]
- Grigg R.; Kemp J.; Sheldrick G.; Trotter J. 1,3-Dipolar cycloaddition reactions of imines of α-amino-acid esters: X-ray crystal and molecular structure of methyl 4-(2-furyl)-2,7-diphenyl-6,8-dioxo-3,7-diazabicyclo[3.3.0]octane-2-carboxylate. J. Chem. Soc., Chem. Commun. 1978, 109–111. 10.1039/c39780000109. [DOI] [Google Scholar]
- Wang Z.; Shi Y.; Luo X.; Han D.-M.; Deng W.-P. Direct synthesis of pyrroles via 1,3-dipolar cycloaddition of azomethine ylides with ynones. New J. Chem. 2013, 37, 1742–1745. 10.1039/c3nj00067b. [DOI] [Google Scholar]
- Tang F.-F.; Yang W.-L.; Yu X.; Deng W.-P. Cu(OAc)2/FOXAP complex catalyzed construction of 2,5-dihydropyrrole derivatives via asymmetric 1,3-dipolar cycloaddition of azomethine ylides to ethynyl ketones. Catal. Sci. Technol. 2015, 5, 3568–3575. 10.1039/c5cy00422e. [DOI] [Google Scholar]
- Huang Z.; Bao Y.; Zhang Y.; Yang F.; Lu T.; Zhou Q. Hydroxy-assisted regio- and stereoselective synthesis of functionalized 4-methylenepyrrolidine derivatives via phosphine-catalyzed [3 + 2] cycloaddition of allenoates with o-hydroxyaryl azomethine ylides. J. Org. Chem. 2017, 82, 12726–12734. 10.1021/acs.joc.7b02560. [DOI] [PubMed] [Google Scholar]
- Huang Z.; Dai Z.; Zhu J.; Yang F.; Zhou Q. Synthesis of functionalized 2,5-dihydropyrrole derivatives via a convenient [3 + 2] annulation of azomethine ylides with allenoates. Org. Biomol. Chem. 2018, 16, 6638–6646. 10.1039/c8ob01946k. [DOI] [PubMed] [Google Scholar]
- Moura-Letts G.; Diblasi C. M.; Bauer R. A.; Tan D. S. Solid-phase synthesis and chemical space analysis of a 190-membered alkaloid/terpenoid-like library. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 6745–6750. 10.1073/pnas.1015268108. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhang K.; Cai L.; Hong S.; Kwon O. Phosphine-Catalyzed α-Umpolung-Aldol Reaction for the Synthesis of Benzo[b]azapin-3-ones. Org. Lett. 2019, 21, 5143–5146. 10.1021/acs.orglett.9b01749. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Esteban F.; Cieślik W.; Arpa E. M.; Guerrero-Corella A.; Díaz-Tendero S.; Perles J.; Fernández-Salas J. A.; Fraile A.; Alemán J. Intramolecular hydrogen bond activation: Thiourea-organocatalyzed enantioselective 1,3-dipolar cycloaddition of salicylaldehyde-derived azomethine ylides with nitroalkenes. ACS Catal. 2018, 8, 1884–1890. 10.1021/acscatal.7b03553. [DOI] [PMC free article] [PubMed] [Google Scholar]
- a Li Q.-H.; Wei L.; Wang C.-J. Catalytic asymmetric 1,3-dipolar [3 + 6] cycloaddition of azomethine ylides with 2-acyl cycloheptatrienes: Efficient construction of bridged heterocycles bearing piperidine moiety. J. Am. Chem. Soc. 2014, 136, 8685–8692. 10.1021/ja503309u. [DOI] [PubMed] [Google Scholar]; b Tong M.-C.; Chen X.; Li J.; Huang R.; Tao H.; Wang C.-J. Catalytic Asymmetric Synthesis of [2,3]-Fused Indoline Heterocycles through Inverse-Electron-Demand Aza-Diels-Alder Reaction of Indoles with Azoalkenes. Angew. Chem., Int. Ed. 2014, 53, 4680–4684. 10.1002/anie.201400109. [DOI] [PubMed] [Google Scholar]
- Sadamitsu Y.; Komatsuki K.; Saito K.; Yamada T. Access to tetronic acids via silver-catalyzed CO2 incorporation into conjugated ynones. Org. Lett. 2017, 19, 3191–3194. 10.1021/acs.orglett.7b01309. [DOI] [PubMed] [Google Scholar]
- Liu X.; Hong D.; She Z.; Hersh W. H.; Yoo B.; Chen Y. Complementary regioselective synthesis of 3,5-disubstituted isoxazoles from ynones. Tetrahedron 2018, 74, 6593–6606. 10.1016/j.tet.2018.09.043. [DOI] [Google Scholar]
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