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Article

Huisgen [3 + 2] Dipolar Cycloadditions of Phthalazinium Ylides to Activated Symmetric and Non-Symmetric Alkynes

by
Vasilichia Antoci
1,
Costel Moldoveanu
1,
Ramona Danac
1,
Violeta Mangalagiu
2,* and
Gheorghita Zbancioc
1,*
1
Faculty of Chemistry, Alexandru Ioan Cuza University of Iasi, 11 Carol 1st Bvd, 700506 Iasi, Romania
2
Institute of Interdisciplinary Research-CERNESIM Centre, Alexandru Ioan Cuza University of Iasi, 11 Carol I, 700506 Iasi, Romania
*
Authors to whom correspondence should be addressed.
Molecules 2020, 25(19), 4416; https://doi.org/10.3390/molecules25194416
Submission received: 2 September 2020 / Revised: 23 September 2020 / Accepted: 25 September 2020 / Published: 25 September 2020
(This article belongs to the Special Issue Huisgen 3+n Dipolar Cycloaddition Reactions: An Accessible and Useful Tool in Modern Organic and Heterocycle Synthesis)
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Abstract

:
We present herein a straightforward and efficient pathway for the synthesis of pyrrolophthalazine cycloadducts via Huisgen [3 + 2] dipolar cycloaddition reactions of phthalazinium ylides to methyl propiolate or dimethyl acetylenedicarboxylate (DMAD). A thoroughly comparative study concerning the efficiency of synthesis, conventional thermal heating (TH) versus microwave (MW) and ultrasound (US) irradiation, has been performed. The cycloaddition reactions of phthalazinium ylides to methyl propiolate occur regiospecific, with a single regioisomer being obtained. Under conventional TH, the cycloaddition reaction of phthalazinium ylides with DMAD occurs to a mixture of inseparable partial and fully aromatized pyrrolophthalazine cycloadducts, while MW or US irradiation are leading only to fully aromatized compounds, with the reactions becoming selective. A feasible mechanism for formation of fully aromatized compounds is presented. Besides selectivity, it has to be noticed that the reaction setup under MW or US irradiation offer a number of other certain advantages: higher yields, decreasing of the amount of used solvent comparative with TH, decreasing of the reaction time from hours to minutes and decreasing of the consumed energy; consequently, these reactions could be considered environmentally friendly.

Graphical Abstract

Academic Editor: Gianfranco Favi

1. Introduction

Azaheterocyclic compounds, especially 1,2-diazine derivatives, constantly raise interest in the scientific community because they have shown potential utilizations for optoelectronics (fluorescent materials, sensors and biosensors, etc.) [1,2,3], medicinal chemistry (including anticancer [4,5,6,7,8], antituberculosis [9,10], anti-Human Immunodeficiency Virus (HIV) [11], antioxidant [12] and antimicrobial activity [8]), etc.
The Huisgen [3 + 2] dipolar cycloaddition reactions of cycloimmonium ylides to variously symmetric and non-symmetric substituted dipolarophiles, represent a facile and convenient way to obtain fused azaheterocycles compounds, which are otherwise very difficult or even impossible to obtain [13,14]. These reactions are still widely discussed because of their theoretical and practical interest. Thus, the cycloaddition reactions of pyridazinium [15,16,17], pyrimidinium [18] and phthalazinium ylides [19,20,21] with symmetrical substituted dipolarophiles raise interesting problems of stereochemistry, while the reaction of ylides with non-symmetrical dipolarophiles raises supplementary issues regarding regiochemistry and chorochemistry, problems which are widely discussed and far away from being solved.
In recent years, microwave- and ultrasound-assisted reactions have proved to be a new trend in synthetic organic chemistry [22,23,24,25,26], offering a facile and useful alternative in a large variety of syntheses [2,22,27,28,29,30,31,32,33,34,35]. In comparison with conventional thermal heating (TH), both microwave and ultrasound irradiation have several important advantages: improved yields, high purity of the compounds, increased selectivity, decreases of reaction time, lower costs and simplicity in handling and processing. Considering all these advantages, reactions under MW and US irradiation could be considered environmentally friendly [36,37].
In continuation of our efforts for synthesis of new azaheterocycles via Huisgen [3 + 2] cycloadditions reactions [1,2,12,20,22,27,32], we decided to study the synthesis of fused pyrrolophthalazine derivatives under conventional TH, MW and US irradiation. In equal measure, we were interested in developing new environmentally friendly methods for preparation of these derivatives using MW and US technologies.

2. Results and Discussion

In previous research work, we studied the synthesis under conventional thermal heating and under US or MW irradiation of a series of new pyridazinium/phthalazinium derivatives with a dihydroxyacetophenone skeleton as well as their antimicrobial and/or anticancer activity [32,34,38]. Considering the good results obtained, we decided to broaden these studies to the pyrrolophthalazine derivatives with a dihydroxyacetophenone skeleton.
The general approach used for the synthesis of pyrrolophthalazine derivatives, 5 and 6, is straightforward and efficient and involves two steps: the in situ generation of the phthalazinium ylides with dihydroxyacetophenone skeleton 2a–e (from the corresponding phthalazinium salts 1a–e, in the presence of triehtylamine (TEA) as base), followed by a Huisgen [3 + 2] dipolar cycloaddition of phthalazinium ylides 2a–e to the corresponding dipolarophiles (methyl propiolate or DMAD), Scheme 1.
Initially, we performed these reactions under conventional TH, in refluxing chloroform, with TEA (diluted in chloroform) being added dropwise at the beginning of the reaction. After 6 h of reflux, the reaction was stopped, and the products were isolated from the reaction mixture. The reaction of phthalazinium ylides (2a–e) with methyl propiolate leads to the fully aromatized cycloadducts 5a–e, in moderate to good yields (48% to 76%, see Table 1).
Theoretically, the Huisgen [3 + 2] dipolar cycloadditions reactions of cycloimmonium ylides (dipole) to methyl propiolate (non-symmetrical substituted dipolarophile) raises problems of regiochemistry, because the double sense of addition of ylide to dipolarophile has often been found, with the formation of two regioisomers, A and B (Scheme 2), according to the orbital, steric and electronic factors [13,14,15,16,17,18,19,20].
As can be seen in Scheme 1, we find that in the case of the reaction of phthalazinium ylides 2a–e, the bond is formed between the ylide carbon and the non-substituted carbon atom of the methyl propiolate regioisomer A (Scheme 2). The assignment of the structure of the compounds 5a–e was made based on the spectral analysis (NMR-see Figures S1–S26 in the Supporting Information). In the HMBC long-range correlation spectra of the compound 5d (see Figure S11 in the Supporting Information), used as example, the signal of the proton from the second position gives correlation with the signal of the keto-carbonil from the eleventh position and with the quaternary carbon atom from the 10b position. Thus, the only possible structure of the compound 5d is the A regioisomer. With the structure being in accordance with the electronic effects exerted in the methyl propiolate molecule, a single regioisomer is obtained, which means that the reaction is regiospecific under a charge control.
The reaction of phthalazinium ylides (2a–e) with DMAD gives a mixture of inseparable partial and fully aromatized compounds (6a–e and 7a–e, respectively). Regardless of the separation methods we employed, we isolated in each case a mixture of compounds 6a–e and 7a–e. As to the mechanism, the formation of compounds 7a–e indicate that the reaction occurs as a normal Huisgen [3 + 2] dipolar cycloaddition, leading in a first step to the unsaturated dihydropyrrolophthalazine cycloadducts 7′a–e. In these cycloadducts, the hydrogen atom from the third position has an increased acidity due to the strong withdrawing effect of both the keto-carbonyl group from the eleventh position and of the highly electronegative nitrogen atom from the fourth position. Thus, under the influence of the base (triethylamine) which abstracts the acidic proton, the generated carbanion isomerizes, then the conjugated acid of the triethylamine transfers back the proton in the first position, leading to the dihydropyrrolophthalazine cycloadducts 7a–e. Finally, via an oxidative dehydrogenation, the presence of a hydrogen acceptor which is most often oxygen from the air [18,39] leads to the thermodynamically more stable aromatized pyrrolophthalazine derivatives 6a–e (Scheme 3). There are situations in which the aromatization can be accelerated by the use of oxidizing agents [40,41]. These experiments really showed that aromatization is delayed or even stopped in the nitrogen atmosphere and accelerated in the oxygen atmosphere. The oxidative dehydrogenation of the 7a–e to 6a–e cycloadducts occurs in the reaction mixture both before and after the workup of the reaction mixture during separation.
The major disadvantages of these reactions under conventional TH are the lack of selectivity for the DMAD cycloaddition, long reaction time (360 min in case of reaction with methyl propiolate and one week in case of reaction with DMAD) and the high energy consumption of the synthesis carried out under conventional conditions.
As an alternative route, we have performed the synthesis of the pyrrolophthalazine derivatives with dihydroxyacetophenone skeleton under MW and US irradiation. For MW irradiation reactions, we used a monomode reactor (Monowave 300; Anton Paar, Graz, Austria). This reactor allows stirring of the reaction mixture (0 to 1200 rpm) and can reach up to 300 °C with temperature control. The reactions take place in a closed vessel at 30 bars of maximum pressure. In our case, the optimal reaction conditions were found to be 130 °C and 5.5–6 bars, with the reactions being completed after 10 to 40 min of irradiation. For US irradiation reactions, we used a reactor Bandelin (Sonopuls GM 3200, Berlin, Germany), with a nominal power of 200 W. The instrumentation used allowed us to control the pulse sequence, as well as the amplitude (mean percent of the nominal power) and the irradiation time. All these parameters are expected to influence the reaction. The Huisgen [3 + 2] dipolar cycloaddition was performed using 80% of the instrument nominal power and was completed after 20 to 60 min of irradiation.
The best results obtained with optimized reaction conditions under MW and US irradiation are summarized in Table 1, compared to the optimized reaction conditions used in thermal heating (TH) conditions.
As indicated in Table 1, under MW and US irradiation, the cycloaddition reactions of phthalazinium ylides with DMAD became selective, with only fully aromatized compounds (6a–e) being obtained. We may also notice that the use of MW and US irradiation induced a remarkable acceleration for the Huisegen [3 + 2] dipolar cycloaddition reaction, with the reaction times decreasing from 6 h to 10 min (under MW irradiation) or 20 min (under US irradiation) in the case of the reaction with methyl propiolate, while in the case of the reaction with DMAD, the decreasing is even more accentuated from one week to 40 min (under MW irradiation) or 60 min (under US irradiation). This acceleration of the cycloaddition reactions under unconventional heating may be attributed to the fact that both MW and US irradiation make it possible to reach much higher temperatures (higher than the boiling point of the solvent) than in the case of the thermal heating. We also wish to point out that under MW and US irradiation, the yields were higher (by 30%) and the solvent amounts used in the former were at least three times lower than the corresponding quantities used under conventional conditions (see the Materials and Methods). Consequently, the cycloaddition reaction under MW and US irradiation could be considered environmentally friendly.
Based on our previous results [30], we presume that the MW heating approach is more effective in [3 + 2] dipolar cycloaddition reactions due to two factors: the mode of action under MW irradiation and the structure of the ylide intermediate. The MW theory [24,30,31] states that the dielectric heating effect of MW depends essentially on the dipole moment of the molecules: the greater the dipole moment is, the larger the effect of the MW energy will be. The ylides are excellent dipoles (they have a 1,2-dipolar structure) and, therefore, the efficiency of MW heating increases considerably when compared with TH.
Concerning the US irradiation efficiency in the Huisgen [3 + 2] dipolar cycloaddition reaction, we presume that this efficiency was due to the cavitations phenomena, with the energy being more efficiently transmitted to the substrates compared to the reactions performed under conventional conditions. Also, the collapse of bubbles induced mechanical stress that could be transmitted to a target single bond, with this phenomenon being specific to ultrasound action [25].

3. Materials and Methods

General Procedure

All the reagents and solvents were purchased from commercial sources and used without further purification. Melting points were recorded on an Electrothermal MEL-TEMP apparatus (Barnstead International, Dubuque, Iowa, USA) in open capillary tubes and are uncorrected. Analytical thin-layer chromatography was performed with commercial silica gel plates 60 F254 (Merck, Merck Darmstadt, Germany) and visualized with UV light. The NMR spectra were recorded on a Bruker Avance III 500 MHz spectrometer (Bruker, Vienna, Austria) operating at 500 MHz for 1H and 125 MHz for 13C. The following abbreviations were used to designate chemical shift multiplicities: s = singlet, d = doublet, t = triplet, m = multiplet. Chemical shifts were reported in delta (δ) units, part per million (ppm) and coupling constants (J) in Hz. Infrared (IR) data were recorded as films on potassium bromide (KBr) pellets on a Fourier-transform infrared spectroscopy (FT-IR) Shimadzu Prestige 8400 s spectrophotometer (Shimadzu, Kyoto, Japan). Ultrasound-assisted reactions were carried out using a Bandelin Ultrasound reactor (Sonopuls GM 3200, Bandelin electronic GmbH & Co. KG, Berlin, Germany), with a nominal power of 200 W and a frequency of 20 kHz. The booster horn SH 213 G (Bandelin electronic GmbH & Co. KG, Berlin, Germany) was fixed tightly to the ultrasonic converter. The titanium flat probe tip TT13 (diameter: 12.7 mm, length: 7 mm, Bandelin electronic GmbH & Co. KG, Berlin, Germany) was fixed tightly to the booster horn. The titanium probe tip was immersed in the used solvent. Microwave-assisted reactions were carried out using a monomode reactor Monowave 300 (Anton Paar, Graz, Austria). Some additional specifications of Monowave 300 (Graz, Austria) are as follows: microwave power 850 W, operation limits at 300 °C and 30 bars, reaction vial Borosilicat (Graz, Austria), operation volume between 0.5 and 20 mL, pressure control by hydraulic system, agitation with an integrated magnetic stirrer (0 to 1200 rpm) and cooling with compressed air.

General Procedure for Synthesis of Pyrrolophthalazine Derivatives, 5a–e and 6a–e under Conventional TH Conditions, MW and US Irradiation

A mixture of phthalazinium salts 1a–e (1 mmol, 0.505 g) and DMAD (0.17 mL, 1.4 mmol) or methyl propiolate (0.12 mL, 1.4 mmol) was suspended in 20 mL chloroform. Then, triethylamine (0.19 mL, 3.5 mmol) dissolved in 10 mL chloroform was added dropwise under stirring for one hour. The stirring and refluxing were continued for 6 h to 1 week. After the reaction was finished Thin-layer chromatography (TLC), the obtained solution was cooled down at room temperature and then the reaction mixtures were washed with water (3 × 30 mL), dried over magnesium sulfate and evaporated under reduced pressure to give the crude product. The purification of the crude product was done by column chromatography on silica gel (eluted with CH2Cl2 to 98/2 CH2Cl2/CH3OH).
Under MW irradiation, the mixture of reagents was dissolved in 10 mL chloroform, placed in the reaction vessel (borosilicate) and exposed to microwave irradiation (from 10 min to 40 min; see Table 1). Using MW irradiation, the best results were obtained using a “temperature control” method. The “temperature control” method ensures a constant temperature (in this case 130 °C) and varying the power and pressure. This method takes place in three stages. In the first step, the temperature is raised as quickly as possible (within less than 1 min) by applying the maximum power. In the second step, the reaction mixture is kept at a constant temperature with the control of the magnetron power. In the last step, the reaction tube is cooled to 55 °C by stopping the irradiation and blowing the reaction vial with compressed air. Once the heating cycle is completed, the reaction vial is removed from the reactor, and processed as indicated for TH.
Under US irradiation, the mixture of reagents (in 10 mL chloroform) was placed into the reaction vessel and exposed to irradiation (from 20 min to 60 min; see Table 1). Once the irradiation cycle was completed, the reaction tube was removed from the reactor, and processed as indicated above for TH.
Dimethyl 2,2′-((4-(1-(methoxycarbonyl)pyrrolo[2,1-a]phthalazine-3-carbonyl)-1,3-phenylene)bis(oxy)) diacetate (5a). 0.375 g, 74% (under classical heating), 0.471 g, 93% (under microwave) and 0.456 g, 90% (under ultrasounds) as white crystals, m.p. 135–136 °C; Rf (98/2 CH2Cl2/CH3OH) 0.36; IR (cm−1): 3111, 3057, 3026 (C-H arom.), 2951 (C-H aliph.), 1751, 1707 (C=O, ester), 1641 (C=O, keto), 1566, 1531, 1479, 1371 (aromatic and heteroaromatic ring), 1264, 1233, 1199, 1108 (C-O-C, ester); 1H-NMR (500 MHz, CDCl3): δ 9.82 (1H, d, J = 8.5 Hz, H-10); 8.67 (1H, s, H-6); 7.87 (2H, m, overlapped peaks, H-7, H-9), 7.77 (1H, s, H-2), 7.72 (1H, t, J = 7.5 Hz, H-8), 7.58 (1H, d, J = 8.5 Hz, H-17), 6.58 (1H, dd, J = 2.0, 8.5 Hz, H-16), 6.48 (1H, d, J = 2.0 Hz, H-14), 4.67 (2H: CH2 of methyl acetate group from 15 position, s), 4.44 (2H: CH2 of methyl acetate group from 13 position, s), 3.92 (3H, s, CH3 of methoxycarbonyl group from 1 position), 3.77 (3H: CH3 of methyl acetate group from 15 position, s), 3.70 (3H: CH3 of methyl acetate group from 13 position, s), 13C-NMR (125 MHz, CDCl3): δ 182.8 (CO keto), 168.3 (CO keto ester from 15 position), 168.0 (CO keto ester from 13 position), 164.9 (CO keto ester from 1 position), 161.2 (C-15), 157.8 (C-13), 146.0 (C-6), 132.9 (C-9), 132.1 (C-17), 129.7 (C-10b), 129.5 (C-8), 129.2 (C-3), 127.5 (C-7), 127.4 (C-10), 126.9 (C-12), 124.8 (C-10a), 124.7 (C-2); 122.0 (C-6a), 108.1 (C-1), 106.2 (C-16), 101.4 (C-14), 66.4 (CH2 of methyl acetate group from 15 position, -CH2-COOMe), 65.5 (CH2 of methyl acetate group from 13 position, -CH2-COOMe), 53.8 (CH3 of methyl acetate group from 15 position, -CH2-COOMe), 52.3 (CH3 of methyl acetate group from 13 position, -CH2-COOMe), 51.8 (CH3 of methoxycarbonyl group from 1 position). Anal. calc. for C26H22N2O9 (506.47): C 61.66, H 4.38, N 5.53; found: C 61.62, H 4.33, N 5.46.
Dimethyl 2,2′-((2-(1-(methoxycarbonyl)pyrrolo[2,1-a]phthalazine-3-carbonyl)-1,4-phenylene)bis(oxy)) diacetate (5b) 0.349 g, 69% (under classical heating), 0.451 g, 89% (under microwave) and 0.430 g, 85% (under ultrasounds) as yellowish crystals, m.p. 1′′24–125 °C; Rf (98/2 CH2Cl2/CH3OH) 0.37; IR (cm−1): 3106, 3066, 3001 (C-H arom.), 2955 (C-H aliph.), 1748, 1703 (C=O, ester), 1633 (C=O, keto), 1549, 1519, 1497, 1442, 1397 (aromatic and heteroaromatic ring), 1289, 1250, 1203, 1184, 1131 (C-O-C, ester); 1H-NMR (500 MHz, CDCl3): δ 9.83 (1H, d, J = 8 Hz, H-10); 8.75 (1H, s, H-6); 7.90 (2H, t, J = 8, 7.5 Hz, H-7, H-9), 7.76 (1H, t, J = 7.5 Hz, H-8), 7.74 (1H, s, H-2), 7.09 (1H, d, J = 2.5 Hz, H-17), 7.04 (1H, dd, J = 2.5, 9.0 Hz, H-15),6.88 (1H, d, J = 9.0 Hz, H-14), 4.64 (2H: CH2 of methyl acetate group from 16 position, s), 4.50 (2H: CH2 of methyl acetate group from 13 position, s), 3.92 (3H, s, CH3 of methoxycarbonyl group from 1 position), 3.80 (3H: CH3 of methyl acetate group from 16 position, s), 3.61 (3H: CH3 of methyl acetate group from 13 position, s), 13C-NMR (125 MHz, CDCl3): δ 183.0 (CO keto), 169.3 (CO keto ester from 16 position), 169.2 (CO keto ester from 13 position), 166.6 (CO keto ester from 1 position), 152.8 (C-16), 150.9 (C-13), 146.5 (C-6), 133.1 (C-9), 132.2 (C-10b), 130.5 (C-3), 130.0 (C-8), 128.2 (C-12), 127.7 (C-7), 127.6 (C-10), 126.9 (C-10a), 126.2 (C-2); 122.3 (C-6a), 118.6 (C-15), 116.0 (C-17), 115.8 (C-14), 108.6 (C-1), 67.7 (CH2 of methyl acetate group from 16 position, -CH2-COOMe), 66.2 (CH2 of methyl acetate group from 13 position, -CH2-COOMe), 52.4 (CH3 of methyl acetate group from 16 position, -CH2-COOMe), 52.2 (CH3 of methyl acetate group from 13 position, -CH2-COOMe), 52.0 (CH3 of methoxycarbonyl group from 1 position). Anal. calc. for C26H22N2O9 (506.47): C 61.66, H 4.38, N 5.53; found: C 61.61, H 4.34, N 5.47.
Dimethyl 2,2′-((2-(1-(methoxycarbonyl)pyrrolo[2,1-a]phthalazine-3-carbonyl)-1,3-phenylene)bis(oxy)) diacetate (5c). 0.334 g, 66% (under classical heating), 0.436 g, 86% (under microwave) and 0.430 g, 85% (under ultrasounds) as yellowish crystals, m.p. 145–146 °C; Rf (98/2 CH2Cl2/CH3OH) 0.36; IR (cm−1): 3100, 3064, 3001 (C-H arom.), 2957 (C-H aliph.), 1748, 1703 (C=O, ester), 1649 (C=O, keto), 1553, 1503, 1488, 1435, 1371 (aromatic and heteroaromatic ring), 1272, 1250, 1213, 1115 (C-O-C, ester); 1H-NMR (500 MHz, CDCl3): δ 9.73 (1H, d, J = 8.5 Hz, H-10); 8.79 (1H, s, H-6); 7.83 (2H, q, J = 7.5, 8.5, Hz, H-7, H-9), 7.74 (1H, s, H-2), 7.69 (1H, t, J = 7.5 Hz, H-8), 7.28 (1H, t, J = 8.5 Hz, H-15), 6.53 (2H, d, J = 8.5 Hz, H-14, H-16), 4.58 (4H: CH2 of methyl acetate groups from 13 and 17 positions, s), 3.87 (3H, s, CH3 of methoxycarbonyl group from 1 position), 3.64 (6H: CH3 of methyl acetate groups from 13 and 17 positions, s), 13C-NMR (125 MHz, CDCl3): δ 181.5 (CO keto), 169.1 (CO keto ester from 13 and 17 positions), 164.7 (CO keto ester from 1 position), 156.2 (C-13, C-17), 146.6 (C-6), 132.8 (C-9), 130.7 (C-15), 130.6 (C-10b), 129.8 (C-8), 128.1 (C-3), 127.5 (C-7), 127.4 (C-10), 126.8 (C-2), 126.6 (C-10a), 122.2 (C-6a), 120.8 (C-12), 108.4 (C-1), 106.1 (C-14, C-16), 66.0 (CH2 of methyl acetate groups from 13 and 17 positions, -CH2-COOMe), 52.1 (CH3 of methyl acetate groups from 13 and 17 positions, -CH2-COOMe), 51.8 (CH3 of methoxycarbonyl group from 1 position). Anal. calc. for C26H22N2O9 (506.47): C 61.66, H 4.38, N 5.53; found: C 61.59, H 4.35, N 5.45.
Dimethyl 2,2′-((4-(1-(methoxycarbonyl)pyrrolo[2,1-a]phthalazine-3-carbonyl)-1,2-phenylene)bis(oxy)) diacetate (5d). 0.355 g, 70% (under classical heating), 0.456 g, 90% (under microwave) and 0.456 g, 90% (under ultrasounds) as white crystals, m.p. 132–133 °C; Rf (98/2 CH2Cl2/CH3OH) 0.40; IR (cm−1): 3103, 3044, 3004 (C-H arom.), 2952 (C-H aliph.), 1751, 1705 (C=O, ester), 1638 (C=O, keto), 1554, 1535, 1498, 1453, 1378 (aromatic and heteroaromatic ring), 1277, 1210, 1198, 1153 (C-O-C, ester); 1H-NMR (500 MHz, CDCl3): δ 9.83 (1H, d, J = 8.5 Hz, H-10); 8.74 (1H, s, H-6); 7.90 (2H, q, J = 7.5, 8.5 Hz, H-7, H-9), 7.75 (1H, t, J = 7.5 Hz, H-8), 7.69 (1H, s, H-2), 7.61 (1H, dd, J = 1.5, 8.5 Hz, H-17), 7.55 (1H, d, J = 1.5 Hz, H-13), 6.92 (1H, d, J = 8.5 Hz, H-16), 4.84 (2H: CH2 of methyl acetate group from 15 position, s), 4.80 (2H: CH2 of methyl acetate group from 14 position, s), 3.94 (3H, s, CH3 of methoxycarbonyl group from 1 position), 3.83 (3H: CH3 of methyl acetate group from 15 position, s), 3.80 (3H: CH3 of methyl acetate group from 14 position, s), 13C-NMR (125 MHz, CDCl3): δ 183.1 (CO keto), 169.1 (CO keto ester from 15 position), 169.0 (CO keto ester from 14 position), 164.8 (CO keto ester from 1 position), 151.8 (C-15), 147.7 (C-14), 146.6 (C-6), 133.1 (C-9), 130.3 (C-10b), 129.9 (C-8), 127.7 (C-7), 127.6 (C-10), 127.1 (C-12), 127.0 (C-3), 126.9 (C-10a), 125.7 (C-17); 124.1 (C-2), 122.3 (C-6a), 115.9 (C-13), 113.5 (C-16), 107.8 (C-1), 66.4 (CH2 of methyl acetate group from 15 position, -CH2-COOMe), 66.3 (CH2 of methyl acetate group from 14 position, -CH2-COOMe), 52.5 (CH3 of methyl acetate group from 15 position, -CH2-COOMe), 52.4 (CH3 of methyl acetate group from 14 position, -CH2-COOMe), 52.0 (CH3 of methoxycarbonyl group from 1 position). Anal. calc. for C26H22N2O9 (506.47): C 61.66, H 4.38, N 5.53; found: C 61.58, H 4.34, N 5.46.
Dimethyl 2,2′-((5-(1-(methoxycarbonyl)pyrrolo[2,1-a]phthalazine-3-carbonyl)-1,3-phenylene)bis(oxy)) diacetate (5e). 0.375 g, 74% (under classical heating), 0.456 g, 90% (under microwave) and 0.451 g, 89% (under ultrasounds) as white crystals, m.p. 183–184 °C; Rf (98/2 CH2Cl2/CH3OH) 0.40; IR (cm−1): 3105, 3088, 3027 (C-H arom.), 2957 (C-H aliph.), 1742, 1706 (C=O, ester), 1647 (C=O, keto), 1539, 1519, 1470, 1389 (aromatic and heteroaromatic ring), 1287, 1251, 1989, 1115 (C-O-C, ester); 1H-NMR (500 MHz, CDCl3): δ 9.84 (1H, d, J = 8.5 Hz, H-10); 8.78 (1H, s, H-6); 7.91 (2H, m, overlapped peaks, H-7, H-9), 7.76 (1H, t, J = 7.5 Hz, H-8), 7.72 (1H, s, H-2), 7.10 (2H, d, J = 2.0 Hz, H-13, H-17), 6.76 (1H, t, J = 2.0, Hz, H-15), 4.68 (4H: CH2 of methyl acetate groups from 14 and 16 positions, s), 3.94 (3H, s, CH3 of methoxycarbonyl group from 1 position), 3.81 (6H: CH3 of methyl acetate groups from 14 and 16 positions, s), 13C-NMR (125 MHz, CDCl3): δ 183.5 (CO keto), 169.0 (CO keto ester from 14 and 16 positions), 164.7 (CO keto ester from 1 position), 159.0 (C-14, C-16), 146.7 (C-6), 141.4 (C-3), 133.2 (C-9), 130.8 (C-10b), 130.0 (C-8), 127.8 (C-7), 127.7 (C-10), 126.9 (C-12), 126.8 (C-10a), 125.2 (C-2); 122.4 (C-6a), 109.2 (C-13, C-17), 108.1 (C-1), 106.5 (C-15), 65.6 (CH2 of methyl acetate groups from 14 and 16 positions, -CH2-COOMe), 52.5 (CH3 of methyl acetate groups from 14 and 16 positions, -CH2-COOMe), 52.0 (CH3 of methoxycarbonyl group from 1 position). Anal. calc. for C26H22N2O9 (506.47): C 61.66, H 4.38, N 5.53; found: C 61.60, H 4.34, N 5.46.
Dimethyl 3-(2,4-bis(2-methoxy-2-oxoethoxy)benzoyl)pyrrolo[2,1-a]phthalazine-1,2-dicarboxylate (6a). 0.310 g, 55% (under classical heating), 0.463 g, 82% (under microwave) and 0.457 g, 81% (under ultrasounds) as yellow oil; Rf (98/2 CH2Cl2/CH3OH) 0.36; IR (cm−1): 3111, 3044, 3008 (C-H arom.), 2956 (C-H aliph.), 1738, 1706 (C=O, ester), 1629 (C=O, keto), 1546, 1522, 1501, 1455, 1387 (aromatic and heteroaromatic ring), 1279, 1239, 1209, 1162 (C-O-C, ester); 1H-NMR (500 MHz, CDCl3): δ 9.07 (1H, d, J = 8.0 Hz, H-10); 8.42 (1H, s, H-6); 7.76 (3H, m, H-17, H-7, H-9), 7.61 (1H, t, J = 7.5 Hz, H-8), 6.54 (1H, d, J = 9.0 Hz, H-16), 6.34 (1H, s, H-14), 4.63 (2H: CH2 of methyl acetate group from 15 position, s), 4.25 (2H: CH2 of methyl acetate group from 13 position, s), 3.91 (3H, s, CH3 of methoxycarbonyl group from 1 position), 3.80 (3H: CH3 of methyl acetate group from 15 position, s), 3.74 (3H: CH3 of methyl acetate group from 13 position, s), 3.69 (3H, s, CH3 of methoxycarbonyl group from 2 position), 13C-NMR (125 MHz, CDCl3): δ 183.2 (CO keto), 168.1 (CO keto ester from 15 position), 167.4 (CO keto ester from 13 position), 165.2 (CO keto ester from 2 position), 165.1 (CO keto ester from 1 position), 162.6 (C-15), 159.2 (C-13), 146.4 (C-6), 133.2 (C-9), 133.1 (C-17), 130.4 (C-10b), 129.1 (C-8), 128.6 (C-3), 128.0 (C-7), 126.8 (C-12), 125.5 (C-10), 125.2 (C-10a); 123.3 (C-2), 121.5 (C-6a), 106.8 (C-1), 106.5 (C-16), 101.0 (C-14), 66.4 (CH2 of methyl acetate group from 15 position, -CH2-COOMe), 65.4 (CH2 of methyl acetate group from 13 position, -CH2-COOMe), 53.7 (CH3 of methoxycarbonyl group from 1 position), 52.9 (CH3 of methyl acetate group from 15 position, -CH2-COOMe), 52.4 (CH3 of methyl acetate group from 13 position, -CH2-COOMe), 52.3 (CH3 of methoxycarbonyl group from 2 position). Anal. calc. for C28H24N2O11 (564.50): C 59.58, H 4.29, N 4.96; found: C 59.53, H 4.25, N 4.90.
Dimethyl 3-(2,5-bis(2-methoxy-2-oxoethoxy)benzoyl)pyrrolo[2,1-a]phthalazine-1,2-dicarboxylate (6b) 0.282 g, 50% (under classical heating), 0.435 g, 77% (under microwave) and 0.435 g, 77% (under ultrasounds) as yellow oil; Rf (98/2 CH2Cl2/CH3OH) 0.40; IR (cm−1): 3113, 3015, 2998 (C-H arom.), 2945, 2928 (C-H aliph.), 1739, 1708 (C=O, ester), 1618 (C=O, keto), 1540, 1497, 1448, 1429, 1387 (aromatic and heteroaromatic ring), 1299, 1285, 1222, 1176 (C-O-C, ester); 1H-NMR (500 MHz, CDCl3): δ 9.14 (1H, d, J = 8.0 Hz, H-10); 8.42 (1H, s, H-6); 7.79 (2H, q, J = 7.5, 8.0 Hz, H-7, H-9), 7.63 (1H, t, J = 7.5 Hz, H-8), 7.23 (1H, d, J = 3.0 Hz, H-17), 7.06 (1H, dd, J = 3.0, 8.0 Hz, H-15), 6.75 (1H, d, J = 8.0 Hz, H-14), 4.62 (2H: CH2 of methyl acetate group from 16 position, s), 4.25 (2H: CH2 of methyl acetate group from 13 position, s), 3.91 (3H, s, CH3 of methoxycarbonyl group from 1 position), 3.76 (3H: CH3 of methyl acetate group from 16 position, s), 3.71 (3H: CH3 of methyl acetate group from 13 position, s), 3.36 (3H, s, CH3 of methoxycarbonyl group from 2 position), 13C-NMR (125 MHz, CDCl3): δ 183.7 (CO keto), 169.1 (CO keto ester from 16 position), 168.3 (CO keto ester from 13 position), 165.1 (CO keto ester from 2 position), 164.9 (CO keto ester from 1 position), 152.7 (C-16), 152.1 (C-13), 146.4 (C-6), 133.1 (C-9), 130.1 (C-10b), 129.4 (C-8), 129.3 (C-3), 128.0 (C-7), 126.6 (C-12), 125.9 (C-10a), 125.8 (C-10); 122.8 (C-2), 121.6 (C-6a), 121.0 (C-15), 115.6 (C-17), 115.3 (C-14), 106.8 (C-1), 67.2 (CH2 of methyl acetate group from 16 position, -CH2-COOMe), 65.8 (CH2 of methyl acetate group from 13 position, -CH2-COOMe), 52.5 (CH3 of methoxycarbonyl group from 1 position), 52.4 (CH3 of methyl acetate group from 16 position, -CH2-COOMe), 52.3 (CH3 of methyl acetate group from 13 position, -CH2-COOMe), 51.9 (CH3 of methoxycarbonyl group from 2 position). Anal. calc. for C28H24N2O11 (564.50): C 59.58, H 4.29, N 4.96; found: C 59.52, H 4.24, N 4.89.
Dimethyl 3-(2,6-bis(2-methoxy-2-oxoethoxy)benzoyl)pyrrolo[2,1-a]phthalazine-1,2-dicarboxylate (6c). 0.271 g, 48% (under classical heating), 0.423 g, 75% (under microwave) and 0.423 g, 75% (under ultrasounds) as yellow oil; Rf (98/2 CH2Cl2/CH3OH) 0.36; IR (cm−1): 3099, 3051, 3011 (C-H arom.), 2955 (C-H aliph.), 1735, 1708 (C=O, ester), 1630 (C=O, keto), 1543, 1499, 1457, 1398, 1385 (aromatic and heteroaromatic ring), 1277, 1239, 1210, 1162 (C-O-C, ester); 1H-NMR (500 MHz, CDCl3): δ 9.44 (1H, d, J = 8.5 Hz, H-10); 8.53 (1H, s, H-6); 7.82 (2H, m, H-7, H-9), 7.69 (1H, t, J = 8.0 Hz, H-8), 7.28 (1H, t, J = 8.5 Hz, H-15), 6.50 (2H, d, J = 8.5 Hz, H-14, H-16), 4.52 (4H: CH2 of methyl acetate groups from 13 and 17 positions, s), 3.88 (3H, s, CH3 of methoxycarbonyl group from 1 position), 3.73 (3H, s, CH3 of methoxycarbonyl group from 2 position), 3.56 (6H: CH3 of methyl acetate groups from 13 and 17 positions, s), 13C-NMR (125 MHz, CDCl3): δ 181.3 (CO keto), 169.0 (CO keto ester from 13 and 17 positions), 166.1 (CO keto ester from 2 position), 164.2 (CO keto ester from 1 position), 157.1 (C-13, C-17), 146.5 (C-6), 133.1 (C-9), 131.6 (C-15), 131.5 (C-10b), 129.9 (C-8), 127.7 (C-7), 127.6 (C-3), 127.1 (C-2), 126.8 (C-10), 126.5 (C-10a), 122.1 (C-6a), 120.8 (C-12), 106.8 (C-14, C-16), 106.6 (C-1), 66.7 (CH2 of methyl acetate groups from 13 and 17 positions, -CH2-COOMe), 52.7 (CH3 of methoxycarbonyl group from 1 position), 52.3 (CH3 of methoxycarbonyl group from 2 position), 52.1 (CH3 of methyl acetate groups from 13 and 17 positions, -CH2-COOMe). Anal. calc. for C28H24N2O11 (564.50): C 59.58, H 4.29, N 4.96; found: C 59.50, H 4.25, N 4.91.
Dimethyl 3-(3,4-bis(2-methoxy-2-oxoethoxy)benzoyl)pyrrolo[2,1-a]phthalazine-1,2-dicarboxylate (6d). 0.294 g, 52% (under classical heating), 0.463 g, 82% (under microwave) and 0.452 g, 80% (under ultrasounds) as yellow oil; Rf (98/2 CH2Cl2/CH3OH) 0.40; IR (cm−1): 3101, 3049, 3005 (C-H arom.), 2952 (C-H aliph.), 1739, 1711 (C=O, ester), 1623 (C=O, keto), 1546, 1519, 1499, 1439, 1371 (aromatic and heteroaromatic ring), 1277, 1245, 1201, 1145 (C-O-C, ester); 1H-NMR (500 MHz, CDCl3): δ 8.70 (1H, d, J = 8.0 Hz, H-10); 8.45 (1H, s, H-6); 7.82 (2H, q, J = 7.5, 8.0 Hz, H-7, H-9), 7.63 (1H, t, J = 7.5 Hz, H-8), 7.50 (1H, s, H-13), 7.33 (1H, d, J = 8.5 Hz, H-17), 6.77 (1H, d, J = 8.5 Hz, H-16), 4.78 (2H: CH2 of methyl acetate group from 15 position, s), 4.76 (2H: CH2 of methyl acetate group from 14 position, s), 3.98 (3H, s, CH3 of methoxycarbonyl group from 1 position), 3.77 (3H: CH3 of methyl acetate group from 15 position, s), 3.76 (6H: CH3 of methyl acetate group from 14 position, s), 3.58 (3H, s, CH3 of methoxycarbonyl group from 2 position), 13C-NMR (125 MHz, CDCl3): δ 185.5 (CO keto), 168.8 (CO keto ester from 2 position), 168.7 (CO keto ester from 15 position), 168.6 (CO keto ester from 14 position), 168.1 (CO keto ester from 1 position), 166.0 (C-15), 163.8 (C-14), 147.2 (C-6), 133.5 (C-9), 132.0 (C-10b), 129.1 (C-8), 128.5 (C-12), 128.4 (C-7), 126.7 (C-3), 125.9 (C-2), 124.5 (C-10); 124.2 (C-10a), 121.2 (C-17), 118.8 (C-6a), 114.3 (C-13), 113.2 (C-16), 107.6 (C-1), 66.2 (CH2 of methyl acetate group from 15 position, -CH2-COOMe), 66.0 (CH2 of methyl acetate group from 14 position, -CH2-COOMe), 52.8 (CH3 of methoxycarbonyl group from 1 position), 52.5 (CH3 of methyl acetate group from 15 position, -CH2-COOMe), 52.3 (CH3 of methyl acetate group from 14 position, -CH2-COOMe), 52.2 (CH3 of methoxycarbonyl group from 2 position). Anal. calc. for C28H24N2O11 (564.50): C 59.58, H 4.29, N 4.96; found: C 59.52, H 4.24, N 4.89.
Dimethyl 3-(3,5-bis(2-methoxy-2-oxoethoxy)benzoyl)pyrrolo[2,1-a]phthalazine-1,2-dicarboxylate (6e). 0.294 g, 52% (under classical heating), 0.452 g, 80% (under microwave) and 0.440 g, 78% (under ultrasounds) as yellowish crystals, m.p. 138–139 °C; Rf (98/2 CH2Cl2/CH3OH) 0.40; IR (cm−1): 3098, 3044, 3001 (C-H arom.), 2953 (C-H aliph.), 1740, 1706 (C=O, ester), 1635 (C=O, keto), 1550, 1531, 1497, 1477, 1389 (aromatic and heteroaromatic ring), 1285, 1262, 1177, 1114 (C-O-C, ester); 1H-NMR (500 MHz, CDCl3): δ 8.64 (1H, d, J = 8.5 Hz, H-10); 8.41 (1H, s, H-6); 7.72 (2H, m, overlapped peaks, H-7, H-9), 7.57 (1H, t, J = 7.5 Hz, H-8), 6.95 (2H, d, J = 2.0 Hz, H-13, H-17), 6.70 (1H, t, J = 2.0 Hz, H-15), 4.57 (4H: CH2 of methyl acetate groups from 14 and 16 positions, s), 3.93 (3H, s, CH3 of methoxycarbonyl group from 1 position), 3.71 (6H: CH3 of methyl acetate groups from 14 and 16 positions, s), 3.55 (3H, s, CH3 of methoxycarbonyl group from 2 position), 13C-NMR (125 MHz, CDCl3): δ 185.9 (CO keto), 168.6 (CO keto ester from 14 and 16 positions), 165.5 (CO keto ester from 2 position), 163.7 (CO keto ester from 1 position), 158.9 (C-14, C-16), 147.1 (C-6), 139.7 (C-3), 133.3 (C-9), 129.1 (C-8), 128.3 (C-7), 127.8 (C-12), 126.3 (C-10b), 124.5 (C-2), 124.4 (C-10), 121.1 (C-10a); 119.6 (C-6a), 108.4 (C-13, C-17), 107.6 (C-15), 107.4 (C-1), 65.2 (CH2 of methyl acetate groups from 14 and 16 positions, -CH2-COOMe), 52.6 (CH3 of methoxycarbonyl group from 1 position), 52.2 (CH3 of methyl acetate groups from 14 and 16 positions, -CH2-COOMe), 52.1 (CH3 of methoxycarbonyl group from 2 position). Anal. calc. for C28H24N2O11 (564.50): C 59.58, H 4.29, N 4.96; found: C 59.51, H 4.24, N 4.90.

4. Conclusions

A thorough study concerning the Huisgen [3 + 2] dipolar cycloadditions of phthalazinium ylides to methyl propiolate or dimethyl acetylenedicarboxylate was presented here. The reaction pathway is straightforward and efficient and allows synthesis of pyrrolophthalazine derivatives, compounds which are difficult to be obtained otherwise. A comparative study concerning the efficiency of synthesis, conventional thermal heating (TH) versus microwave (MW) and ultrasound (US) irradiation, has been performed. The cycloaddition reactions of phthalazinium ylides to methyl propiolate occur regiospecific, with a single regioisomer being obtained, the one in which the bond is formed between the ylide carbon and the non-substituted carbon atom of the methyl propiolate, which means that the reaction is under a charge control. Under conventional TH, the cycloaddition reaction of phthalazinium ylides with DMAD occurred to a mixture of inseparable partial and fully aromatized pyrrolophthalazine derivatives. Under MW or US irradiation, the Huisgen [3 + 2] dipolar cycloaddition reactions of ylides to DMAD became selective, with only fully aromatized compounds being obtained. As for the mechanism, the formation of fully aromatized compounds could be explained by an oxidative dehydrogenation of the partial aromatized intermediaries, which are leading to the more thermodynamically stable compounds. Besides selectivity, it has to be noticed that the reaction setup under MW or US irradiation offers a number of certain other advantages: higher yields, decreasing of the amount of used solvent comparative with TH, decreasing of the reaction time from hours to minutes and decreasing of the consumed energy. Taking into consideration the above-mentioned advantages, the Huisgen [3 + 2] dipolar cycloaddition reactions of ylides to various dipolarophiles under MW or US irradiation could be considered environmentally friendly.

Supplementary Materials

The following are available online, Figure S1: 1H-NMR spectrum of the compound 5a, Figure S2: 13C-NMR spectrum of the compound 5a, Figure S3: 1H-NMR spectrum of the compound 5b, Figure S4: 13C-NMR spectrum of the compound 5b, Figure S5: 1H-NMR spectrum of the compound 5c, Figure S6: 13C-NMR spectrum of the compound 5c, Figure S7: 1H-NMR spectrum of the compound 5d, Figure S8: 13C-NMR spectrum of the compound 5d, Figure S9: 2D-COSY 45 spectrum of the compound 5d, Figure S10: 2D-HETCOR (HMQC) spectrum of the compound 5d, Figure S11: 2D-HETCOR (HMBC) spectrum of the compound 5d, Figure S12: 1H-NMR spectrum of the compound 5e, Figure S13: 13C-NMR spectrum of the compound 5e, Figure S14: 2D-COSY 45 spectrum of the compound 5e, Figure S15: 2D-HETCOR (HMQC) spectrum of the compound 5e, Figure S16: 2D-HETCOR (HMBC) spectrum of the compound 5e, Figure S17: 1H-NMR spectrum of the compound 6a, Figure S18: 13C-NMR spectrum of the compound 6a, Figure S19: 1H-NMR spectrum of the compound 6b, Figure S20: 13C-NMR spectrum of the compound 6b, Figure S21: 1H-NMR spectrum of the compound 6c, Figure S22: 13C-NMR spectrum of the compound 6c, Figure S23: 1H-NMR spectrum of the compound 6d, Figure S24: 13C-NMR spectrum of the compound 6d, Figure S25: 1H-NMR spectrum of the compound 6e, Figure S26: 13C-NMR spectrum of the compound 6e.

Author Contributions

Design, synthesis, and writing were performed by V.M., G.Z. and C.M. Experimental work and structure elucidation were performed by V.M., G.Z., C.M., V.A. and R.D. The final version was reviewed and approved by V.M., G.Z., C.M., V.A. and R.D. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Romanian Ministry of Research grant number PN-III-P1-1.1-TE-2016-1205 and Innovation Program 1–Development of the national RD system, Subprogram 1.2—Institutional Performance—RDI excellence funding projects, ContractGrant no. 34PFE/19.10.2018.

Acknowledgments

The authors are thankful to the Romanian Ministry of Research and Innovation, project PN-III-P1-1.1-TE-2016-1205 and Program 1–Development of the national RD system, Subprogram 1.2—Institutional Performance—RDI excellence funding projects, ContractGrant no. 34PFE/19.10.2018 for financial support and the POSCCE-O 2.2.1, SMIS-CSNR 13984-901, No. 257/28.09.2010 Project, CERNESIM, for NMR experiments.

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds are not available from the authors.
Molecules 25 04416 sch001 550
Scheme 1. The Huisgen [3 + 2] dipolar cycloadditions of phthalazinium ylides to methyl propiolate or DMAD. The structure of compounds was proven by elemental and spectral analysis (IR, 1H-NMR, 13C-NMR, 2D-COSY, 2D-HETCOR (HMQC), long-range 2D-HETCOR (HMBC)), and were in accordance with the proposed structure.
Scheme 1. The Huisgen [3 + 2] dipolar cycloadditions of phthalazinium ylides to methyl propiolate or DMAD. The structure of compounds was proven by elemental and spectral analysis (IR, 1H-NMR, 13C-NMR, 2D-COSY, 2D-HETCOR (HMQC), long-range 2D-HETCOR (HMBC)), and were in accordance with the proposed structure.
Molecules 25 04416 sch001
Molecules 25 04416 sch002 550
Scheme 2. Regiochemistry of addition of cycloimmonium ylides to methyl propiolate.
Scheme 2. Regiochemistry of addition of cycloimmonium ylides to methyl propiolate.
Molecules 25 04416 sch002
Molecules 25 04416 sch003 550
Scheme 3. The mechanism for formation of fully aromatized pyrrolophthalazine compounds 6a–e.
Scheme 3. The mechanism for formation of fully aromatized pyrrolophthalazine compounds 6a–e.
Molecules 25 04416 sch003
Table
Table 1. The best results obtained in the synthesis of pyrrolo[2,1-a]phthalazine derivatives with optimized reaction conditions under MW and US irradiation and conventional TH.
Table 1. The best results obtained in the synthesis of pyrrolo[2,1-a]phthalazine derivatives with optimized reaction conditions under MW and US irradiation and conventional TH.
CompoundMicrowaves (MW)Ultrasounds (US)Conventional (TH)
Reaction TimeYield, %Reaction TimeYield, %Reaction TimeYield, %
5a10 min9320 min90360 min74
5b10 min8920 min85360 min69
5c10 min8620 min85360 min66
5d10 min9020 min90360 min70
5e10 min9020 min89360 min74
6a40 min8260 min811 week55
6b40 min7760 min771 week50
6c40 min7560 min751 week48
6d40 min8260 min801 week52
6e40 min8060 min781 week52

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Antoci, V.; Moldoveanu, C.; Danac, R.; Mangalagiu, V.; Zbancioc, G. Huisgen [3 + 2] Dipolar Cycloadditions of Phthalazinium Ylides to Activated Symmetric and Non-Symmetric Alkynes. Molecules 2020, 25, 4416. https://doi.org/10.3390/molecules25194416

AMA Style

Antoci V, Moldoveanu C, Danac R, Mangalagiu V, Zbancioc G. Huisgen [3 + 2] Dipolar Cycloadditions of Phthalazinium Ylides to Activated Symmetric and Non-Symmetric Alkynes. Molecules. 2020; 25(19):4416. https://doi.org/10.3390/molecules25194416

Chicago/Turabian Style

Antoci, Vasilichia, Costel Moldoveanu, Ramona Danac, Violeta Mangalagiu, and Gheorghita Zbancioc. 2020. "Huisgen [3 + 2] Dipolar Cycloadditions of Phthalazinium Ylides to Activated Symmetric and Non-Symmetric Alkynes" Molecules 25, no. 19: 4416. https://doi.org/10.3390/molecules25194416

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