Next Article in Journal
Sustainable and Green Synthesis of Waste-Biomass-Derived Carbon Dots for Parallel and Semi-Quantitative Visual Detection of Cr(VI) and Fe3+
Previous Article in Journal
Anion-Responsive Fluorescent Supramolecular Gels
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 27
Issue 4
10.3390/molecules27041256
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Michael Addition of 3-Oxo-3-phenylpropanenitrile to Linear Conjugated Enynones: Approach to Polyfunctional δ-Diketones as Precursors for Heterocycle Synthesis

by
Anastasiya V. Igushkina
1,
Alexander A. Golovanov
2 and
Aleksander V. Vasilyev
1,3,*
1
Department of Organic Chemistry, Institute of Chemistry, Saint Petersburg State University, Universitetskaya nab., 7/9, 199034 Saint Petersburg, Russia
2
S.P. Korshunov Research Laboratory No. 13, Department Chemical Technology and Resource Conservation, Togliatti State University, Belorusskaya ul., 14, 445667 Togliatti, Russia
3
Department of Chemistry, Saint Petersburg State Forest Technical University, Institutsky per., 5, 194021 Saint Petersburg, Russia
*
Author to whom correspondence should be addressed.
Molecules 2022, 27(4), 1256; https://doi.org/10.3390/molecules27041256
Submission received: 25 January 2022 / Revised: 10 February 2022 / Accepted: 11 February 2022 / Published: 13 February 2022
(This article belongs to the Section Organic Chemistry)
Browse Figures
Versions Notes

Abstract

:
Reaction of linear conjugated enynones, 1,5-diarylpent-2-en-4-yn-1-ones [Ar1C≡CCH=CHC(=O)Ar2], with 3-oxo-3-phenylpropanenitrile (NCCH2COPh) in the presence of sodium methoxide MeONa as a base in MeOH at room temperature for 4–26 h affords polyfunctional δ-diketones as a product of regioselective Michael addition to the double carbon–carbon bond of starting enynones. The δ-diketones have been formed as mixtures of two diastereomers in a ratio of 2.5:1 in good general yields of 53–98%. A synthetic potential of the obtained δ-diketones has been demonstrated by heterocyclization with hydrazine into substututed 5,6-dihydro-4H-1,2-diazepine.

Graphical Abstract

1. Introduction

Linear conjugated enynones, pent-2-en-4-yn-1-ones, are widely used as versatile building blocks in organic synthesis. The presence of three important functional groups, such as a carbonyl one, and double carbon–carbon and triple bonds, in their structure makes these compounds valuable precursors for synthesis of various polyfunctional compounds, and carbocycles, and, especially, heterocycles (see recent reviews on this issue [1,2]).
In our previous works [3,4], we studied multicomponent reactions of linear conjugated enynones, 1,5-diarylpent-2-en-4-yn-1-ones, with malononitrile as a CH-acid in the presence of different bases. Depending on the base used, these reactions gave rise to various products. In the case of using sodium alkoxide, as a strong nucleophilic base, substituted pyridines were obtained [3]. Contrary to that, a use of less nucleophilic base, lithium diisopropylamide (LDA), resulted in the formation of substituted cyclohexane as a major reaction product and Michael addition product to the double carbon–carbon bond as a minor one [4].
To continue this study, in the current work, we present reactions of 1,5-diarylpent-2-en-4-yn-1-ones with another CH-acid, 3-oxo-3-phenylpropanenitrile (NCCH2COPh), that leads to products of Michael addition to the double carbon–carbon bond of starting enynones. The obtained reaction products contain δ-diketones structural fragment. In general, terminally arylated δ-diketones have been widely applied for synthesis of various heterocyclic compounds (Scheme 1) [5,6,7,8,9,10]. Substituted 1,2-diazepines were obtained by interaction of such diketones with hydrazine [5]. These diketones were cyclized into tetrahydropyrans in the reaction with indium chloride (III) and triethylsilane [6]. Cyclization of δ-diketones under the action of boron trifluoride furnished pyrylium salts [7,8]. Reaction of δ-diketones with iodine and sodium hydroxide led to substituted cyclopropanes [9]. There is an interesting example of Ni-catalyzed synthesis of substituted pyridines from 2-benzoyl-5-oxopentanenitriles (δ-dioxonitriles) and arylboronic acids [10]. In this case, the cyano group took part in the pyridine ring formation.
It should be specially emphasized that the above-mentioned heterocycles and cyclopropanes (Scheme 1) have a lot of important practical applications. For instance, 1,2-diazepines exhibit antimicrobial [11], immunomodulatory [12] and antioxidant [13] properties. The tetrahydropyran motif is included in structures of many natural bioactive alkaloids that show toxicity in human tumor cells [14], and have anti-inflammatory properties [15]. A new natural compound, tetrahydropyran containing galiumic acid, reveals antimicrobial activity [16]. Pyrylium salts are widely used as luminescent biolabels for imaging of proteins, nucleic acids, biogenic amines and surface amino groups [17,18,19]. Pyrylium derivatives allow improving mass spectrometry-based detection of peptides [20]. Cyclopropanes are applied as pesticides [21], antiproliferatives [22], drugs for the treatment of osteoporosis [23], and anti-inflammatory agents [24]. 3-Benzoylpyridines show anticonvulsant activity [25]. Apart from that, 3-benzoylpyridines are components of activated delayed fluorescence organic light-emitting diodes [26]. Besides, using 3-benzoylpyridines as an on-tissue cycloaddition reagent for mass spectrometry makes it possible to distinguish a position of the C=C bond in structural isomers of lipids in biological tissues [27].
Thus, a development of methods of synthesis of such δ-diketones and further preparation of various carbo- and hetero-cycles from them are important goals for organic chemistry, biology, medicine, and material science.

2. Results and Discussion

Results of reactions of enynones 1a–l with 3-oxo-3-phenylpropanenitrile under the action of bases (sodium methoxide MeONa or LDA) are presented in Table 1. The diastereomeric pairs of polysubstituted δ-diketones 2.1/2.2 have been isolated. Structures of the obtained compounds have been determined by means of NMR, IR spectroscopy and HRMS (see Experimental Section and Supplementary Materials). There are two sets of signals in 1H- and 13C-NMR spectra corresponding to diastereomers 2.1 and 2.2 formed in a constant ratio of 2.5:1. Unfortunately, based on NMR data, we have not been able to identify the exact structure of each stereoisomer.
In most of the cases, the formation of diketones 2.1/2.2 takes place at room temperature for 4 h at a ratio of starting enynone 1 and 3-oxo-3-phenylpropanenitrile as 1:1 with MeONa in MeOH (Table 1, entries 1,4–9,12,13). In general, higher yields of the target diketones have been observed for starting enynones 1d,e,j bearing electron-withdrawing substituents in aromatic rings Ar2 adjacent to the carbonyl group (entries 6,7,12). That is caused by an electron density pulling away from the C=C bond, that makes it more attractive for anion attack. The presence of electron-donating substituents in the ring Ar2 at the carbonyl group in enynones 1a,c,i,l does not significantly decrease the yields of the target diketones 2.1a,c,i,l/2.2a,c,i,l (entries 4,5,11,14). However, it may take a longer reaction time (entries 11,14). On the other hand, enynones 1f,g,h bearing electron-donating substituents in aromatic ring Ar1 conjugated with acetylene bond give usually lower yields of the corresponding compounds 2.1/2.2 (entries 8,9,13). Thus, one may state that the greater influence on electronic structure and reactivity of enynones 1 in these reactions, as well as on the yields of diketones 2.1/2.2, have substituents in aromatic rings Ar1 at the triple carbon–carbon bond.
Changing ratio of enynone 1 and 3-oxo-3-phenylpropanenitrile from 1:1 to 2:1 has no effect on the structure of the reaction product (compare entries 1 and 2). It is in contrast with our previous work [4] on the synthesis of multisubstituted cyclohexanes from enynones 1 and malononitrile in the presence of LDA with their ratio of 2:1. The use of LDA as a base in the reaction of enynone 1a with NCCH2COPh results in the same diketones 2.1a/2.2a similarly to the reaction with MeONa (compare entries 1 and 3).
A plausible reaction mechanism is given in Scheme 2. The reaction starts from regioselective Michael addition of 3-oxo-3-phenylpropanenitrile anion to the double carbon–carbon bond of starting enynone 1. At this stage, the anion may attack from both sides of the C=C bond plane, that gives rise to diastereomeric anions A1/A2. Protonation of the latter affords finally diastereomers of δ-diketones 2.1 and 2.2.
To demonstrate a synthetic potential of the obtained polyfunctional δ-diketones 2.1/2.2 we carried out the reaction of compounds 2.1a/2.2a with hydrazine leading to substituted 5,6-dihydro-4H-1,2-diazepine 3 solely as a diastereomer in a good yield of 83% (Scheme 3). According to NMR data, there is no NOESY correlation between protons H4 (4.23–4.26 ppm) and H5 (1.26–1.29 ppm) (see Supplementary Materials), that points out trans-configuration of substituents at the carbons C4 and C5.
Summarizing the date described in this paper and our previous results on reactions of enynones 1 with malononitrile CH2(CN)2 [3,4], one may state that, depending on the used CH-acid (CH2(CN)2 or NCCH2COPh) and nucleophilicity/basicity of the anionic reagent (RO− or i-Pr2N−), various reaction products may be obtained 2, 4 or 5 (Scheme 4). The use of strong basic and high nucleophilic alkoxide anions RO− lead to an involvement of this species in the structure of reaction products, pyridines 4 [3]. On the other hand, the use of less nucleophilic anion i-Pr2N− (due to its large spatial volume), directs the reaction into another pathway with a formation of cyclohexanes 5 [4]. It should be noted that both CH-acids, CH2(CN)2 and NCCH2COPh, give Michael addition product to the C=C bond of substrates 1 at first stages of these reaction. However, this reaction is stopped for NCCH2COPh at this step, and goes further for CH2(CN)2. That is caused by stronger electron acceptor properties of the CN group compared to COPh one. Due to that, there is a possibility of generating of secondary carbanionic species in reactions with CH2(CN)2. See discussions on the reaction mechanisms in our works [3,4].

3. Experimental Section

The NMR spectra of solutions of compounds in CDCl3 were recorded at Bruker AVANCE III 400 spectrometer (Karlsruhe, Germany) (at 400 and 100 MHz for 1H-, 13C-NMR spectra, respectively) at 25 °C. The solvent residual signals of CDCl3 (δ 7.26 ppm) for 1H-NMR spectra, the carbon signal of CDCl3 (δ 77.0 ppm) for 13C-NMR spectra were used as references. IR spectra of compounds were taken with Bruker spectrometer (Karlsruhe, Germany). HRMS was carried out at instrument Bruker maXis HRMS-ESI-QTOF (Karlsruhe, Germany). Preparative TLC was performed on silica gel Chemapol L 5/40 (Chemapol, Praga, Zcech Republic).
Preparation and characterization of starting enynones 1 was previously described [28,29].

3.1. General Procedure for the Synthesis of 3-(2-Aryl-2-oxoethyl)-5-aryl-2-benzoylpent-4-ynenitriles (2a–l)

3-oxo-3-phenylpropannitrile (1 equiv.) was added to sodium methoxide (1 equiv.) solution (1.08 mmol/mL) in methanol with stirring. The enynone 1 (1 equiv.) was added to the obtained solution. The reaction mixture was stirred at room temperature for 1–26 h (see Table 1). Then the mixture was poured into water (30 mL), and was extracted with CH2Cl2 (3 × 30 mL). The combined organic layers were dried with Na2SO4. Solvent was evaporated under the reduced pressure. A residue was subjected to purification by preparative thin layer chromatography on silica gel using hexane-ethyl acetate mixtures as an eluent. That gave two diastereomers 2.1 and 2.2 in a ratio of 2.5:1.

3.1.1. 2-Benzoyl-3-(2-oxo-2-phenylethyl)-5-phenylpent-4-ynenitrile (2.1a/2.2a)

Mixture of diastereomers. Obtained from 1a (50 mg, 0.22 mmol) in a yield of 75 mg (90%). Obtained from 1a (50 mg, 0.22 mmol) and 3-oxo-3-phenylpropanenitrile 79.8 mg (0.55 mmol) in a yield of 70 mg (84%). Obtained from 1a (50 mg, 0.22 mmol) and 3-oxo-3-phenylpropanenitrile (31.0 mg, 0.22 mmol) in presence of LDA (0.22 mmol) in a yield of 66 mg (79%). Oilish compound. 1H-NMR, 2.1a (selected signals of major isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 3.81 dd (1H, CH2, J = 9.9, 18.7 Hz), 5.20 (1H, CH-CN, J = 4.3 Hz), 8.08 t (2H, Ph, J = 7.2 Hz), 8.23 d (2H, Ph, J = 7.4 Hz). 1H-NMR, 2.2a (selected signals of minor isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 5.13 d (1H, CH-CN, J = 6.3 Hz), 8.02 d (2H, Ph, J = 7.3 Hz). 1H-NMR, (signals of mixture of isomers) δ, ppm: 3.61–3.35 m (3H, CH2), 4.09–4.15 m (2H, CH-CC), 7.23–7.26, 7.30–7.33, 7.41–7.43, 7.49–7.72 m. 13C-NMR, 2.1a (selected signals of major isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 29.3, 41.7, 45.7, 84.87 (C≡), 86.4 (C≡), 115.5 (CN), 122.18, 189.4 (CO), 197.3 (CO). 13C-NMR, 2.2a (selected signals of minor isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 29.0, 40.6, 43.5, 84.89 (C≡), 86.7 (C≡), 115.8 (CN), 122.15, 189.5 (CO), 196.2 (CO). 13C-NMR, (signals of mixture of isomers) δ, ppm: 128.14, 125.22, 128.23, 128.47, 128.58, 128.8, 128.9, 129.0, 129.1, 129.2, 131.7, 131.9, 133.7, 133.95, 134.14, 134.38, 134.43, 134.8, 135.9, 136.4. IR (KBr): 1684 cm−1 (CO), 2249 cm−1 (CN, C≡C). HRMS (ESI) [M + Na]+: Calcd for C26H19NO2Na 400.1313, Found 400.1308.

3.1.2. 2-Benzoyl-3-(2-(4-methylphenyl)-2-oxo-ethyl)-5-phenylpent-4-ynenitrile (2.1b/2.2b)

Mixture of diastereomers. Obtained from 1b (50 mg, 0.20 mmol) in a yield of 72 mg (92%). Oilish compound. 1H-NMR, 2.1b (selected signals of major isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 2.47 s (3H, CH3), 3.78 dd (1H, CH2, J = 10.0, 18.7 Hz), 5.20 d (1H, CH-CN, J = 4.3 Hz), 7.97 d (2H, Ar, J = 8.2 Hz), 8.24 d (2H, Ar, J = 7.2 Hz). 1H-NMR, 2.2b (selected signals of minor isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 2.44 s (3H, CH3), 5.14 d (1H, CH-CN, J = 6.4 Hz), 7.92 d (2H, Ar, J = 8.3 Hz), 8.09 d (2H, Ar, J = 7.2 Hz). 1H-NMR, (signals of mixture of isomers) δ, ppm: 3.57–3.62 m (3H, CH2), 4.07–4.14 m (2H, CH-CC), 7.22–7.35, 7.41–7.44, 7.54–7.62, 7.67–7.71 m. 13C-NMR, 2.1b (selected signals of major isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 21.8 (CH3), 29.4, 41.6, 45.8, 85.0 (C≡), 86.4 (C≡), 115.6 (CN), 122.23, 145.2, 189.5 (CO), 196.9 (CO). 13C-NMR, 2.2b (selected signals of minor isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 21.8 (CH3), 29.4, 41.6, 45.8, 85.0 (C≡), 86.4 (C≡), 115.6 (CN), 122.23, 145.2, 189.5 (CO), 196.9 (CO). 13C-NMR, (signals of mixture of isomers) δ, ppm:128.1, 128.2, 128.35, 128.44, 128.48, 128.55, 129.0, 129.1, 129.2, 129.4, 129.6, 131.7, 131.9, 133.4, 133.94, 133.97, 134.4, 134.7. IR (KBr): 1681 cm−1 (CO), 2250 cm−1 (CN, C≡C). HRMS (ESI) [M + Na]+: Calcd for C27H21NO2Na 414.1470, Found 414.1465.

3.1.3. 2-Benzoyl-3-(2-(4-methoxyphenyl)-2-oxo-ethyl)-5-phenylpent-4-ynenitrile (2.1c/2.2c)

Mixture of diastereomers. Obtained from 1c (50 mg, 0.19 mmol) in a yield of 72 mg (94%). Oilish compound. 1H-NMR, 2.1c (selected signals of major isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 3.92 s (3H, OCH3), 3.76 dd (1H, CH2, J = 10.1, 18.5 Hz),5.21 d (1H, CH-CN, J = 4.2 Hz), 7.01 d (2H, Ar, J = 8.9 Hz), 8.05 d (2H, Ar, J = 8.9 Hz), 8.24 d (2H, Ar, J = 7.2 Hz). 1H-NMR, 2.2c (selected signals of minor isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 3.90 s (3H, OCH3), 5.14 d (1H, CH-CN, J = 6.3 Hz), 6.98 d (2H, Ar, J = 8.9 Hz), 8.00 d (2H, Ar, J = 8.9 Hz), 8.08 d (2H, Ar, J = 7.3 Hz). 1H-NMR, (signals of mixture of isomers) δ, ppm: 3.53–3.59 m (3H, CH2), 3.90–4.13 m (2H, CH-CC), 7.22–7.33, 7.41–7.43, 7.54–7.62, 7.61–7.71 m. 13C-NMR, 2.1c (selected signals of major isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 29.5, 41.3, 45.9, 55.62 (OCH3), 85.0 (C≡), 86.4 (C≡), 114.1, 115.6 (CN), 122.23, 130.61, 131.9, 133.9, 134.41, 164.3 (C-O, Ar), 189.57 (CO), 195.7 (CO). 13C-NMR, 2.2c (selected signals of minor isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 29.1, 40.1, 43.6, 55.56 (OCH3), 84.8 (C≡), 86.9 (C≡), 113.9, 115.9 (CN), 122.22, 130.56, 131.7, 134.39, 134.7, 164.0 (C-O, Ar), 189.62 (CO), 194.6 (CO). 13C-NMR, (signals of mixture of isomers) δ, ppm: 128.1, 128.2, 128.4, 1528.5, 128.6, 128.9, 129.06, 129.09, 129.2, 129.5. IR (KBr): 1673 cm−1, 1689 cm−1 (CO), 2250 cm−1 (CN, C≡C). HRMS (ESI) [M + Na]+: Calcd for C27H21NO3Na 430.1419, Found 430.1414.

3.1.4. 2-Benzoyl-3-(2-(4-fluorophenyl)-2-oxoethyl)-5-phenylpent-4-ynenitrile (2.1d/2.2d)

Mixture of diastereomers. Obtained from 1d (30 mg, 0.12 mmol) in a yield of 46 mg (98%). Oilish compound. 1H-NMR, 2.1d (selected signals of major isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 3.76 dd (1H, CH2, J = 9.7, 18.6 Hz), 5.18 d (1H, CH-CN, J = 4.4 Hz), 7.69 t (1H, Ar, J = 7.4 Hz), 8.22 (2H, Ar, J = 7.3 Hz). 1H-NMR, 2.2d (selected signals of minor isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 5.11 d (1H, CH-CN, J = 6.1 Hz). 1H-NMR, (signals of mixture of isomers) δ, ppm: 3.57–3.62 m (3H, CH2), 4.08–4.14 m (2H, CH-CC), 7.13–7.25 m, 7.30–7.33 m, 7.40–7.42 m, 7.55–7.62 m, 8.04–8.12 m. 13C-NMR, 2.1d (selected signals of major isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 29.3, 41.6, 45.6, 84.8 (C≡), 86.5 (C≡), 115.5 (CN), 116.2 d (Ar, p-C-F, J = 22.0 Hz), 122.12, 189.4 (CO), 195.7 (CO). 13C-NMR, 2.2d (selected signals of minor isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 28.9, 40.5, 43.6, 84.9 (C≡), 86.7 (C≡), 115.76 (CN), 115.9 d (Ar, p-C-F, J = 22.0 Hz), 122.10, 189.5 (CO), 194.6 (CO). 13CNMR, (signals of mixture of isomers) δ, ppm:128.2, 128.3, 128.55, 128.56, 128.63, 129.0, 129.1, 129.2, 130.9, 130.96, 131.03, 131.7, 131.9, 132.1, 133.9, 134.3, 134.5, 134.8, 165.2 d (Ar, i-C-F, J = 32.9 Hz), 167.2 d (Ar, i-C-F, J = 33.8 Hz). IR (KBr): 1674 cm−1 (CO), 1690 cm−1 (CO), 2249 cm−1 (CN, C≡C). HRMS (ESI) [M + Na]+: Calcd for C26H18NO2FNa 419.1219, Found 418.1214.

3.1.5. 2-Benzoyl-3-(2-(4-chlorophenyl)-2-oxoethyl)-5-phenylpent-4-ynenitrile (2.1e/2.2e)

Mixture of diastereomers. Obtained from 1e (30 mg, 0.11 mmol) in a yield of 43 mg (96%). Oilish compound. 1H-NMR, 2.1e (selected signals of major isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 3.75 dd (1H, CH2, J = 9.6, 18.7 Hz), 5.16 d (1H, CH-CN, J = 4.4 Hz), 7.41 dd (2H, Ar, J = 1.9, 7.6 Hz), 7.52 d (2H, Ar, J = 8.5 Hz), 7.61 d (2H, Ar, J = 7.9 Hz), 7.70 t (1H, Ar, J = 7.4 Hz), 8.01 d (2H, Ar, J = 8.5 Hz), 8.21 (2H, Ar, J = 7.2 Hz). 1H-NMR, 2.2e (selected signals of minor isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 5.09 d (1H, CH-CN, J = 6.1 Hz), 7.49 d (2H, Ar, J = 8.5 Hz), 7.96 d (2H, Ar, J = 8.6 Hz), 8.08 d (2H, Ar, 7.3 Hz). 1H-NMR, (signals of mixture of isomers) δ, ppm: 3.57–3.62 m (3H, CH2), 4.08–4.14 m (2H, CH-CC), 7.24–7.33, 7.57–7.59 m. 13C-NMR, 2.1e (selected signals of major isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 29.3, 41.7, 45.6, 84.7 (C≡), 86.5 (C≡), 115.5 (CN), 122.08, 140.7 (Ar, C-Cl), 189.3 (CO), 196.1 (CO). 13C-NMR, 2.2e (selected signals of minor isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 28.8, 40.6, 43.6, 85.0 (C≡), 86.6 (C≡), 115.7 (CN), 122.05, 140.2 (Ar, C-Cl), 189.4 (CO), 195.0 (CO). 13C-NMR, (signals of mixture of isomers) δ, ppm: 128.19, 128.24, 128.56, 128.64, 129.0, 129.07, 129.11, 129.2, 129.3, 129.6, 131.7, 131.9, 133.9, 134.2, 134.3, 134.5, 134.7, 134.8. IR (KBr): 1689 cm−1 (CO), 2252 cm−1 (CN, C≡C). HRMS (ESI) [M + Na]+: Calcd for C26H18NO2ClNa 434.0924, Found 434.0918.

3.1.6. 2-Benzoyl-3-(2-oxo-2-phenylethyl)-5-(p-tolyl)pent-4-ynenitrile (2.1f/2.2f)

Mixture of diastereomers. Obtained from 1f (50 mg, 0.20 mmol) in a yield of 61 mg (78%). Oilish compound. 1H-NMR, 2.1f (selected signals of major isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 2.35 s (3H, CH3), 3.79 dd (1H, CH2, J = 9.8, 18.7 Hz), 5.19 d (1H, CH-CN, J = 4.3 Hz), 7.31 d (2H, Ar, J = 8.0 Hz), 8.23 d (2H, Ar, J = 7.4 Hz). 1H-NMR, 2.2f (selected signals of minor isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 2.32 s (3H, CH3), 5.12 d (1H, CH-CN, J = 6.3 Hz), 7.04 d (2H, Ar, J = 7.8 Hz), 8.02 d (2H, Ar, J = 7.4 Hz).). 1H-NMR, (signals of mixture of isomers) δ, ppm: 3.59–3.64 m (3H, CH2), 4.08–4.14 m (2H, CH-CC), 7.10–7.14 m, 7.51–7.69 m, 8.06–8.09 m. 13C-NMR, 2.1f (selected signals of major isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 21.5 (CH3), 29.4, 41.8, 45.8, 84.2 (C≡), 86.6 (C≡), 115.6 (CN), 119.12, 135.9, 138.7, 189.5 (CO), 197.4 (CO). 13C-NMR, 2.2f (selected signals of minor isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 21.4 (CH3), 29.0, 40.7, 43.7, 85.1 (C≡), 86.0 (C≡), 115.9 (CN), 119.08, 136.4, 138.6, 189.6 (CO), 196.2 (CO). 13C-NMR, (signals of mixture of isomers) δ, ppm: 128.2, 128.8, 128.91, 128.93, 128.98, 129.03, 129.1, 129.2, 131.6, 131.8, 133.6, 134.0, 134.1, 134.4, 134.7. IR (KBr): 1686 cm−1 (CO), 2252 cm−1 (CN, C≡C). HRMS (ESI) [M + Na]+: Calcd for C27H21NO2Na 414.1470, Found 414.1465.

3.1.7. 2-Benzoyl-5-(4-methoxyphenyl)-3-(2-oxo-2-phenylethyl)pent-4-ynenitrile (2.1g/2.2g)

Mixture of diastereomers. Obtained from 1g (30 mg, 0.11 mmol) in a yield of 24 mg (53%). Oilish compound. 1H-NMR, 2.1g (selected signals of major isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 3.82 s (3H, OCH3), 5.19 d (1H, CH-CN, J = 4.3 Hz), 6.83 d (2H, Ar, J = 8.8 Hz), 7.34 d (2H, Ar, J = 8.8 Hz), 7.95 d (2H, Ar, J = 7.8 Hz), 8.23 d (2H, Ar, J = 7.3 Hz). 1H-NMR, 2.2g (selected signals of minor isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 3.79 s (3H, OCH3), 5.11 d (1H, CH-CN, J = 6.3 Hz), 6.76 d (2H, Ar, J = 8.8 Hz), 7.16 d (2H, Ar, J = 8.8 Hz), 8.02 d (2H, Ar, J = 7.5 Hz). 1H-NMR, (signals of mixture of isomers) δ, ppm: 3.58–3.64 m (3H, CH2), 3.75–3.84 m (1H, CH2), 4.07–4.10 m (2H, CH-CC), 7.51–7.69 m, 8.06–8.09 m. 13C-NMR, 2.1g (selected signals of major isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 29.4, 41.9, 45.9, 55.30 (OCH3), 85.4 (C≡), 86.4 (C≡), 115.6 (CN), 159.8 (Ar, C-O), 189.5 (CO), 197.4 (CO). 13C-NMR, 2.2g (selected signals of minor isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 29.1, 40.7, 43.7, 55.25 (OCH3), 84.9 (C≡), 85.3 (C≡), 115.9 (CN), 159.7 (Ar, C-O), 189.7 (CO), 196.3 (CO). 13C-NMR, (signals of mixture of isomers) δ, ppm: 113.8, 113.9, 114.2, 114.3, 128.2, 128.5, 128.8, 128.9, 129.0, 129.1, 129.2, 133.1, 133.3, 133.6, 134.0, 134.1, 134.3, 134.4, 134.7, 135.9, 136.4. IR (KBr): 1691 cm−1 (CO), 2252 cm−1 (CN, C≡C). HRMS (ESI) [M + Na]+: Calcd fo rC27H21NO3Na 430.1419, Found 430.1414.

3.1.8. 2-Benzoyl-5-(4-chlorophenyl)-3-(2-oxo-2-phenylethyl)pent-4-ynenitrile (2.1h/2.2h)

Mixture of diastereomers. Obtained from 1h (30 mg, 0.11 mmol) in a yield of 37 mg (82%). Oilish compound. 1H-NMR, 2.1h (selected signals of major isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 3.79 dd (1H, CH2, J = 9.8, 18.7 Hz), 5.18 d (1H, CH-CN, J = 4.3 Hz), 7.28 d (2H, Ar, J = 8.4 Hz), 7.34 d (2H, Ar, J = 8.6 Hz), 8.23 d (2H, Ar, J = 7.2 Hz). 1H-NMR, 2.2h (selected signals of minor isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 5.12 d (1H, CH-CN, J = 6.4 Hz), 7.15 d (2H, Ar, J = 8.6 Hz), 7.21 d (2H, Ar, J = 8.5 Hz), 8.02 d (2H, Ar, J = 7.2 Hz). 1H-NMR, (signals of mixture of isomers) δ, ppm: 3.59–3.64 m (3H, CH2), 4.08–4.13 m (2H, CH-CC), 7.50–7.72 m, 8.06–8.09 m. 13C-NMR, 2.1h (selected signals of major isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 29.3, 41.6, 45.6, 85.3 (C≡), 86.0 (C≡), 115.5 (CN), 120.66, 135.8, 189.3 (CO), 197.2 (CO). 13C-NMR, 2.2h (selected signals of minor isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 28.9, 40.5, 43.3, 83.8 (C≡), 87.8 (C≡), 115.7 (CN), 120.64, 136.3, 189.4 (CO), 196.1 (CO). 13C-NMR, (signals of mixture of isomers) δ, ppm: 128.20, 128.23, 128.5, 128.6, 128.8, 128.96, 129.04, 129.1, 129.21, 129.23, 132.9, 133.1, 133.7, 133.8, 134.2, 134.3, 134.6, 134.7, 134.8. IR (KBr): 1685 cm−1 (CO), 2250 cm−1 (CN, C≡C). HRMS (ESI) [M + Na]+: Calcd for C26H18NO2ClNa 434.0924, Found 434.0918.

3.1.9. 2-Benzoyl-3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-5-phenylpent-4-ynenitrile (2.1i/2.2i)

Mixture of diastereomers. Obtained from 1i (30 mg, 0.10 mmol) in a yield of 27 mg (63%). Oilish compound. 1H-NMR, 2.1i (selected signals of major isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 3.77 dd (1H, CH2, J = 10.1, 18.5 Hz), 4.00 s (6H, OCH3), 5.19 d (1H, CH-CN, J = 4.2 Hz), 6.96 d (2H, Ar, J = 8.5 Hz), 8.23 d (2H, Ar, J = 7.4 Hz). 1H-NMR, 2.2i (selected signals of minor isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 3.96 s (3H, OCH3), 3.98 s (3H, OCH3), 5.14 d (1H, CH-CN, J = 6.4 Hz), 6.93 d (2H, Ar, J = 8.4 Hz), 7.94 d (2H, Ar, J = 8.1 Hz), 8.09 d (2H, Ar, J = 7.6 Hz). 1H-NMR, (signals of mixture of isomers) δ, ppm: 3.54–3.59 m (3H, CH2), 4.08–4.13 m (2H, CH-CC), 7.22–7.23, 7.30–7.33, 7.41–7.43, 7.54–7.7.62, 7.65–7.73 m. 13C-NMR, 2.1i (selected signals of major isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 29.5, 41.2, 45.9, 56.1 (OCH3), 56.21 (OCH3), 85.0 (C≡), 86.4 (C≡),110.0, 110.3, 115.6 (CN), 149.3, 154.2, 189.5 (CO), 195.7 (CO). 13C-NMR, 2.2i (selected signals of minor isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 29.2, 40.0, 43.6, 56.0 (OCH3), 56.15 (OCH3), 84.9 (C≡), 86.9 (C≡), 110.1, 110.2, 115.9 (CN), 149.2, 153.8, 189.6 (CO), 194.7 (CO). 13C-NMR, (signals of mixture of isomers) δ, ppm: 122.2, 123.1, 123.3, 128.1, 128.2, 128.45, 125.47, 128.6, 129.0, 129.07, 129.08, 129.2, 129.6, 131.7, 131.9, 132.1, 132.2, 133.9, 134.4, 134.72, 134.74. IR (KBr): 1695 cm−1 (CO), 2252 cm−1 (CN, C≡C). HRMS (ESI) [M + Na]+: Calcd for C28H23NO4Na 460.1525, Found 460.1519.

3.1.10. 2-Benzoyl-3-(2-(4-chlorophenyl)-2-oxoethyl)-5-(p-tolyl)pent-4-ynenitrile (2.1j/2.2j)

Mixture of diastereomers. Obtained from 1j (50 mg, 0.18 mmol) in a yield of 75 mg (97%). Oilish compound. 1H-NMR, 2.1j (selected signals of major isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 2.36 s (3H, CH3), 3.74 dd (1H, CH2, J = 9.6, 18.6 Hz), 5.15 d (1H, CH-CN, J = 4.4 Hz), 7.29 d (2H, Ar, J = 8.0 Hz), 7.52 d (2H, Ar, J = 8.6 Hz), 8.01 d (2H, Ar, J = 8.6 Hz), 8.21 d (2H, Ar, J = 7.4 Hz). 1H-NMR, 2.2j (selected signals of minor isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 2.32 s (3H, CH3), 5.08 d (1H, CH-CN, J = 6.1 Hz), 7.05 d (2H, Ar, J = 8.0 Hz), 7.48 d (2H, Ar, J = 8.6 Hz), 8.57 d (2H, Ar, J = 8.6 Hz), 8.07 d (2H, Ar, J = 7.5 Hz). 1H-NMR, (signals of mixture of isomers) δ, ppm: 3.55–3.61 m (3H, CH2), 4.07–4.11 m (2H, CH-CC), 7.10–7.14, 7.57–7.61, 7.68–7.71 m. 13C-NMR, 2.1j (selected signals of major isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 21.51 (CH3), 29.3, 41.8, 45.7, 83.9 (C≡), 86.7 (C≡), 115.5 (CN), 118.99, 138.8, 140.7, 189.4 (CO), 196.2 (CO). 13C-NMR, 2.2j (selected signals of minor isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 21.46 (CH3), 29.9, 40.7, 43.7, 85.1 (C≡), 85.8 (C≡), 115.8 (CN), 118.95, 138.7, 140.2, 189.5 (CO), 195.1 (CO). 13C-NMR, (signals of mixture of isomers) δ, ppm: 128.5, 128.9, 128.99, 129.02, 129.08, 129.10, 129.17, 129.20, 129.3, 129.6, 131.6, 131.8, 133.9, 134.2, 134.5, 134.7, 134.75, 134.82. IR (KBr): 1687 cm−1 (CO), 2250 cm−1 (CN, C≡C). HRMS (ESI) [M + Na]+: Calcd for C27H20ClNO2Na 448.1080, Found 448.1075.

3.1.11. 2-Benzoyl-3-(2-(4-bromphenyl)-2-oxoethyl)-5-(p-tolyl)pent-4-ynenitrile (2.1k/2.2k)

Mixture of diastereomers. Obtained from 1k (50 mg, 0.15 mmol) in a yield of 54 mg (77%). Oilish compound. 1H-NMR, 2.1k (selected signals of major isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 2.35 s (3H, CH3), 3.73 dd (1H, CH2, J = 9.6, 18.6 Hz), 5.15 d (1H, CH-CN, J = 4.4 Hz), 7.29 d (2H, Ar, J = 8.0 Hz), 7.92 d (2H, Ar, J = 8.5 Hz), 8.20 d (2H, Ar, J = 7.4 Hz). 1H-NMR, 2.2k (selected signals of minor isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 2.32 s (3H, CH3), 5.08 d (1H, CH-CN, J 6.1 Hz), 7.05 d (2H, Ar, J = 8.0 Hz), 7.87 d (2H, Ar, J = 8.5 Hz), 8.07 d (2H, Ar, J = 7.4 Hz). 1H-NMR, (signals of mixture of isomers) δ, ppm:3.54–3.60 m (3H, CH2), 4.06–4.12 m (2H, CH-CC), 7.09–7.14 m, 7.56–7.69 m. 13C-NMR, 2.1k (selected signals of major isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 21.49 (CH3), 29.3, 41.7, 45.7, 84.0 (C≡), 86.7 (C≡), 115.5 (CN), 118.96, 131.8, 132.3, 134.0, 134.5, 134.6, 138.8, 189.4 (CO), 196.4 (CO). 13C-NMR, 2.2j (selected signals of minor isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 21.45 (CH3), 28.8, 40.6, 43.7, 85.2 (C≡), 85.8 (C≡), 115.8 (CN), 119.00, 131.6, 132.1, 134.3, 134.8, 135.1, 138.7, 189.5 (CO), 195.3 (CO). 13C-NMR, (signals of mixture of isomers) δ, ppm:128.91, 128.94, 128.99, 129.00, 129.1, 129.2, 129.5, 129.70, 129.73. IR (KBr): 1687 cm−1 (CO), 2250 cm−1 (CN, C≡C). HRMS (ESI) [M + Na]+: Calcd for C27H20BrNO2Na 492.0575, Found 492.0570.

3.1.12. 2-Benzoyl-3-(2-oxo-2-(thiophen-2-yl)ethyl)-5-(p-tolyl)pent-4-ynenitrile (2.1l/2.2l)

Mixture of diastereomers. Obtained from 1l (30 mg, 0.12 mmol) in a yield of 46 mg (96%). Oilish compound. 1H-NMR, 2.1l (selected signals of major isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 2.35 s (3H, CH3), 3.73 dd (1H, CH2, J = 9.9, 18.2 Hz), 5.17 d (1H, CH-CN, J = 4.4 Hz), 7.30 d (2H, Ar, J = 8.1 Hz), 7.76 d (1H, thio, J = 4.9 Hz), 7.88 d (1H, thio, J = 3.8 Hz), 8.19 d (2H, Ar, J = 7.5 Hz). 1H-NMR, 2.2l (selected signals of minor isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 2.31 s (3H, CH3), 5.13 d (1H, CH-CN, J = 6.5 Hz), 7.83 d (1H, thio, J = 3.4 Hz), 8.08 d (2H, Ar, J = 7.6 Hz). 1H-NMR, (signals of mixture of isomers) δ, ppm: 3.52–3.58 m (3H, CH2), 4.05–4.10 m (2H, CH-CC), 7.02–7.12, 7.19–7.23, 7.54–7.60, 7.67–7.71 m. 13C-NMR, 2.1l (selected signals of major isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 21.5 (CH3), 29.5, 41.0, 45.8, 83.9 (C≡), 86.7 (C≡), 115.5 (CN), 119.04, 138.8, 143.0, 189.4 (CO), 190.1 (CO). 13C-NMR, 2.2l (selected signals of minor isomer, obtained from spectrum of mixture of stereoisomers) δ, ppm: 21.4 (CH3), 29.3, 41.0, 43.5, 85.4 (C≡), 85.6 (C≡), 115.8 (CN), 119.00, 138.6, 143.6, 189.1 (CO), 189.6 (CO). 13C-NMR, (signals of mixture of isomers) δ, ppm: 128.3, 128.6, 128.88, 128.97, 129.01, 129.16, 129.18, 131.6, 131.8, 132.7, 133.2, 133.9, 134.4, 134.5, 134.7, 135.0. IR (KBr): 1660 cm−1 (CO), 1693 cm−1 (CO), 2250 cm−1 (CN, C≡C). HRMS (ESI) [M + Na]+: Calcd for C25H19NO2SNa 420.1034, Found 420.1029.

3.2. Procedure for the Synthesis of 5,6-Dihydro-4H-1,2-diazepine (3)

A total of 0.23 mL of hydrazine hydrochloride (3.4 mg, 0.8 mmol) solution (15 mg/mL) in ethanol was added to mixture of diastereomers 2.1a/2.2a (30 mg, 0.8 mmol). The mixture was diluted with 2 mL of ethanol. Three drops of concentrated hydrochloric acid were added. The mixture was refluxed for 5 h. The reaction was monitored by TLC. Then, the mixture was poured into water (30 mL), and was extracted with CH2Cl2 (3 × 30 mL). The combined organic layers were washed with water (30 mL) and were dried with Na2SO4. Solvent was evaporated under the reduced pressure, that gave compound 3 in the yield of 25 mg (83%).

4,5-trans-4-Cyano-3,7-diphenyl-5-(phenylethynyl)-5,6-dihydro-4H-1,2-diazepine (3)

Oilish compound. 1H-NMR, ppm: 1.26–1.29 m (1H, CH-C≡), 3.39 dd (1H, CH2, J = 2.16, 13.5 Hz), 3.63 dd (1H, CH2, J = 6.7, 13.5 Hz), 4.24 dd (1H, CH-CN, J = 2.1, 6.6 Hz), 7.19–7.27 m (5H, Ph), 7.41–7.46 m (3H, Ph), 7.50–7.51 m (3H, Ph), 7.63–7.66 m (2H, Ph), 7.84–7.88 m (2H, Ph). 13C-NMR, ppm: 29.7 (CH-C≡), 33.9 (CH2), 36.1 (CH-CN), 83.7 (C≡), 85.3 (C≡), 119.1 (C≡N), 120.7, 122.6, 126.7, 128.1, 128.6, 128.7, 129.1, 129.8, 130.7, 131.7, 134.0, 137.7, 153.2 (C=N), 128.8 (C=N). HRMS (ESI) [M + Na]+: Calcd for C26H19N3Na 396.1477, Found 396.1471.

4. Conclusions

We have developed a synthesis of novel polyfunctional δ-diketones by Michael addition of 3-oxo-3-phenylpropanenitrile to conjugated 1,5-diarylpent-1-en-4-yn-1-ones under the action of sodium methoxide in methanol. The obtained δ-diketones are promising precursors for synthesis of various heterocycles.

Supplementary Materials

The following are available online, 1H-, 13C-NMR, IR spectra of the obtained compounds 2.1/2.2 and 3.

Author Contributions

Conceptualization, A.V.I., A.A.G. and A.V.V.; methodology, A.V.I.; validation, A.V.I., A.A.G. and A.V.V.; investigation, A.V.I.; resources, A.V.V.; data curation, A.V.I.; writing—original draft preparation, A.V.I.; writing—review and editing, A.V.V.; visualization, A.V.V.; supervision, A.V.V.; project administration, A.V.V.; funding acquisition, A.V.V. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Russian Scientific Foundation, grant number 21-13-00006.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All the data of the present study are presented in the manuscript. https://www.mdpi.com/ethics.

Acknowledgments

Spectral studies were performed at Center for Magnetic Resonance, Center for Chemical Analysis and Materials Research of Saint Petersburg State University, Saint Petersburg, Russia.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds 2 are available from the authors.

References

  1. Golovanov, A.A.; Odin, I.S.; Zlotskii, S.S. Conjugated enynones: Preparation, properties and applications in organic synthesis. Russ. Chem. Rev. 2019, 88, 280–318. [Google Scholar] [CrossRef]
  2. Golovanov, A.A.; Gusev, D.M.; Odin, I.S.; Zlotskii, S.S. Conjugated 2,4,1- and 1,4,3-enynones as polycentric electrophiles in synthesis of heterocyclic compounds. Chem. Heterocycl. Compd. 2019, 55, 333–348. [Google Scholar] [CrossRef]
  3. Kuznetcova, A.V.; Odin, I.S.; Golovanov, A.A.; Grigorev, I.M.; Vasilyev, A.V. Multicomponent reaction of conjugated enynones with malononitrile and sodium alkoxides: Complex reaction mechanism of the formation of pyridine derivatives. Tetrahedron 2019, 75, 4516–4530. [Google Scholar] [CrossRef]
  4. Igushkina, A.V.; Golovanov, A.A.; Boyarskaya, I.A.; Kolesnikov, I.E.; Vasilyev, A.V. Stereoselective synthesis of multisubstituted cyclohexanes by reaction of conjugated enynones with malononitrile in the presence of LDA. Molecules 2020, 25, 5920. [Google Scholar] [CrossRef] [PubMed]
  5. Kharchenko, V.G.; Markova, L.I.; Fedotova, O.V.; Pchelintseva, N.V. Reactions of 1,5-diketones with ammonia and its derivatives. Chem. Heterocycl. Compd. 2003, 39, 1121–1142. [Google Scholar] [CrossRef]
  6. Jia, W.; Xi, Q.; Liu, T.; Yang, M.; Chen, Y.; Yin, D.; Wang, X. One-pot synthesis of O-heterocycles or aryl ketones using an InCl3/Et3SiH system by switching the solvent. J. Org. Chem. 2019, 84, 5141–5149. [Google Scholar] [CrossRef]
  7. Zhu, X.; Liu, Y.; Liu, C.; Yang, H.; Fu, H. Light and oxygen-enabled sodium trifluoromethane sulfinate-mediated selective oxidation of C–H bonds. Green Chem. 2020, 22, 4357–4363. [Google Scholar] [CrossRef]
  8. Court, M.; Alaaeddine, M.; Barth, V.; Tortech, L.; Fichou, D. Structural and electronic properties of 2,20,6,60-tetraphenyldipyranylidene and its use as a hole-collecting interfacial layer in organic solar cells. Dyes Pigm. 2017, 141, 487–492. [Google Scholar] [CrossRef]
  9. Colon, I.; Griffin, G.W.; O’Connell, E.J. 1,2-diaroylcyclopropanes: Trans-1,2-dibenzoylcyclopropane. Org. Synth. 1972, 52, 33. [Google Scholar]
  10. Zhen, Q.; Li, R.; Qi, L.; Hu, K.; Yao, X.; Shao, Y.; Chen, J. Nickel(II)-catalyzed C–C, N–C cascade coupling of ketonitriles into substituted pyrroles and pyridines. Org. Chem. Front. 2020, 7, 286–291. [Google Scholar] [CrossRef]
  11. Mahmoud, N.F.H.; Elsayed, G.A.; Ismail, M.F. Synthesis of various fused heterocyclic rings from oxoindenyl esters and their pharmacological and antimicrobial evaluations. J. Heterocyclic Chem. 2018, 55, 465–474. [Google Scholar] [CrossRef]
  12. Velcicky, J.; Bodendorf, U.; Rigollier, P.; Epple, R.; Beisner, D.R.; Guerini, D.; Smith, P.; Liu, B.; Feifel, R.; Wipfli, P.; et al. Discovery of the first potent, selective, and orally bioavailable signal peptide peptidase-like 2a (SPPL2a) inhibitor displaying pronounced immunomodulatory effects in vivo. J. Med. Chem. 2018, 61, 865–880. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Mohammed, K.S.; Elbeily, E.E.; El-Taweel, F.M.; Faddac, A.A. Synthesis, characterization, and antioxidant evaluation of some novel pyrazolo[3,4-c][1,2]diazepine and pyrazolo[3,4-c]pyrazole derivatives. J. Heterocyclic Chem. 2019, 56, 493–500. [Google Scholar] [CrossRef]
  14. Go, E.B.; Kim, L.J.; Nelson, H.M.; Ohashi, M.; Tang, Y. Biosynthesis of the fusarium mycotoxin (−)-sambutoxin. Org. Lett. 2021, 23, 7819–7823. [Google Scholar] [CrossRef]
  15. Song, M.; Ying, Z.; Ying, X.; Jia, L.; Yang, G. Three novel alkaloids from Portulaca oleracea L. and their anti-inflammatory bioactivities. Fitoterapia 2022, 156, 105087. [Google Scholar] [CrossRef]
  16. Toktas, U.; Sarikahya, N.B.; Parlak, C.; Ozturk, I.; Kayalar, H. A new iridoid skeleton from Galium asparagi folium and biological activity studies. J. Mol. Str. 2022, 1250, 131693. [Google Scholar] [CrossRef]
  17. Wolfbeis, O.S. Fluorescent chameleon labels for bioconjugation and imaging of proteins, nucleic acids, biogenic amines and surface amino groups. Methods Appl. Fluoresc. 2021, 9, 042001. [Google Scholar] [CrossRef]
  18. Wang, G.; Li, X.; Wang, X.; Zhang, K. Efficient cascade reactions for luminescent pyrylium biolabels catalysed by light rare-earth elements. New J. Chem. 2021, 45, 12305–12310. [Google Scholar] [CrossRef]
  19. Resta, I.M.; Lucantoni, F.; Apostolova, N.; Galindo, F. Fluorescent styrylpyrylium probes for the imaging of mitochondria in live cells. Org. Biomol. Chem. 2021, 19, 9043–9057. [Google Scholar] [CrossRef]
  20. Huang, S.; Palanisamy, S.; Yu, X.; Wang, Y.; Liu, D.; Gong, W.; Zhang, X. α-Active pyrylium salt 2,4,5-triphenylpyrylium for improved mass spectrometry-based detection of peptides. Anal. Chem. 2021, 93, 11072–11080. [Google Scholar] [CrossRef]
  21. Wang, A.; Zhang, K.; Gao, Y.; Weng, A.; Wang, L.; Zhang, Y.; Zhang, Z.; She, D.; Ning, J.; Mei, X. Synthesis and bioactivity studies of sex pheromone analogs of the diamond back moth Plutella xylostella. Pest. Manag. Sci. 2019, 75, 1045–1055. [Google Scholar] [CrossRef] [PubMed]
  22. Lu, J.F.; Zhao, J.; Sun, M.; Ji, X.H.; Huang, P.; Ge, H.G. Synthesis and crystal structure of 1-(3-amino-4-morpholino-1H-indazole-1-carbonyl)-N-(4-methoxyphenyl)cyclopropane-1-carboxamide, a molecule with antiproliferative activity. Crystallogr. Rep. 2021, 66, 455–460. [Google Scholar] [CrossRef]
  23. Zhou, S.; Huang, G.; Chen, G. Synthesis and biological activities of drugs for the treatment of osteoporosis. Eur. J. Med. Chem. 2020, 197, 112313. [Google Scholar] [CrossRef] [PubMed]
  24. Xiao, H.; Yan, Q.; He, Z.; Zou, Z.; Le, Q.; Chen, T.; Cai, B.; Yang, X.; Luo, S. Total synthesis and anti-inflammatory bioactivity of (−)-majusculoic acid and its derivatives. Mar. Drugs 2021, 19, 288. [Google Scholar] [CrossRef] [PubMed]
  25. Gaydukov, I.O.; Voronina, T.A.; Litvinova, S.A.; Kutepova, I.S. Anticonvulsant activity of new 3- and 4-benzoilpiridines oxime derivatives in comparison with valproic acid. Med. Chem. Res. 2020, 29, 783. [Google Scholar] [CrossRef]
  26. Wang, L.; Cai, X.; Li, B.; Li, M.; Wang, Z.; Gan, L.; Qiao, Z.; Xie, W.; Liang, Q.; Zheng, N.; et al. Achieving enhanced thermally activated delayed fluorescence rates and shortened exciton lifetimes by constructing intramolecular hydrogen bonding channels. ACS Appl. Mater. Interfaces 2019, 11, 45999–46007. [Google Scholar] [CrossRef] [PubMed]
  27. Sun, C.; Ma, C.; Li, L.; Han, Y.; Wang, D.; Wan, X. A novel on-tissue cycloaddition reagent for mass spectrometry imaging of lipid C=C position isomers in biological tissues. Chin. Chem. Lett. 2021; in press. [Google Scholar] [CrossRef]
  28. Golovanov, A.A.; Latypova, D.R.; Bekin, V.V.; Pisareva, V.S.; Vologzhanina, A.V.; Dokichev, V.A. Synthesis of 1,5-disubstituted (E)-pent-2-en-4-yn-1-ones. Russ. J. Org. Chem. 2013, 49, 1264–1269. [Google Scholar] [CrossRef]
  29. Saulnier, S.; Golovanov, A.A.; Vasilyev, A.V. A controlled tandem transformation of conjugated enynones with arenes under superelectrophilic activation leading to aryl substituted dienones and indenes. RSC Adv. 2016, 6, 103546–103555. [Google Scholar] [CrossRef]
Molecules 27 01256 sch001 550
Scheme 1. Reactions of δ-diketones leading to various heterocycles and cyclopropanes: a—N2H4, HCl, EtOH, reflux [5]; b—InCl3 or Al(OTf)3, Et3SiH,CH3CN, r.t. [6]; c—BF3×Et2O, PhMe, 130 °C [7,8]; d—NaOH, I2, 25–40 °C [9]; e—Ni(dppe)Cl2, ZnCl2, B(OH)2Ar, THF, 100 °C [10].
Scheme 1. Reactions of δ-diketones leading to various heterocycles and cyclopropanes: a—N2H4, HCl, EtOH, reflux [5]; b—InCl3 or Al(OTf)3, Et3SiH,CH3CN, r.t. [6]; c—BF3×Et2O, PhMe, 130 °C [7,8]; d—NaOH, I2, 25–40 °C [9]; e—Ni(dppe)Cl2, ZnCl2, B(OH)2Ar, THF, 100 °C [10].
Molecules 27 01256 sch001
Molecules 27 01256 sch002 550
Scheme 2. Plausible mechanism of the reaction of enynones 1 with 3-oxo-3-phenylpropanenitrile under basic conditions leading to diastereomeric δ-diketones 2.1/2.2.
Scheme 2. Plausible mechanism of the reaction of enynones 1 with 3-oxo-3-phenylpropanenitrile under basic conditions leading to diastereomeric δ-diketones 2.1/2.2.
Molecules 27 01256 sch002
Molecules 27 01256 sch003 550
Scheme 3. Reaction of δ-diketones 2.1a/2.2a with hydrazine leading to diazepine 3.
Scheme 3. Reaction of δ-diketones 2.1a/2.2a with hydrazine leading to diazepine 3.
Molecules 27 01256 sch003
Molecules 27 01256 sch004 550
Scheme 4. Reactions of enynones 1 with malononitrile [CH2(CN)2] and 3-oxo-3-phenylpropanenitrile (NCCH2COPh) under the basic conditions leading to compounds 2, 4 and 5.
Scheme 4. Reactions of enynones 1 with malononitrile [CH2(CN)2] and 3-oxo-3-phenylpropanenitrile (NCCH2COPh) under the basic conditions leading to compounds 2, 4 and 5.
Molecules 27 01256 sch004
Table
Table 1. Reactions of enynones 1 with 3-oxo-3-phenylpropanenitrile and sodium methoxide in methanol leading to δ-diketones 2.1/2.2.
Table 1. Reactions of enynones 1 with 3-oxo-3-phenylpropanenitrile and sodium methoxide in methanol leading to δ-diketones 2.1/2.2.
Molecules 27 01256 i001
EntryStarting EnynoneReaction Conditions: Base–Solvent, Temperature, Time, R—Ratio of Enynone 1 and NCCH2COPhReaction Products, Ratio of Diastereomers, Yield
1 Molecules 27 01256 i002MeONa, MeOH,
r.t., 4 h,
R = 1:1		 Molecules 27 01256 i003
21aMeONa, MeOH,
r.t., 3 h,
R = 2:1		 Molecules 27 01256 i004
31aLDA, THF,
r.t., 1 h,
R = 2:1		 Molecules 27 01256 i005
4 Molecules 27 01256 i006MeONa, MeOH,
r.t., 4 h,
R = 1:1		 Molecules 27 01256 i007
5 Molecules 27 01256 i008MeONa, MeOH,
r.t., 4 h,
R = 1:1		 Molecules 27 01256 i009
6 Molecules 27 01256 i010MeONa, MeOH,
r.t., 5 h,
R = 1:1		 Molecules 27 01256 i011
7 Molecules 27 01256 i012MeONa, MeOH,
r.t., 4 h,
R = 1:1		 Molecules 27 01256 i013
8 Molecules 27 01256 i014MeONa, MeOH,
r.t., 4 h,
R = 1:1		 Molecules 27 01256 i015
9 Molecules 27 01256 i016MeONa, MeOH,
r.t., 4 h,
R = 1:1		 Molecules 27 01256 i017
10 Molecules 27 01256 i018MeONa, MeOH,
r.t., 23 h,
R = 1:1		 Molecules 27 01256 i019
11 Molecules 27 01256 i020MeONa, MeOH,
r.t., 26 h,
R=1:1		 Molecules 27 01256 i021
12 Molecules 27 01256 i022MeONa, MeOH,
r.t., 4 h,
R= 1:1		 Molecules 27 01256 i023
13 Molecules 27 01256 i024MeONa, MeOH,
r.t., 4 h,
R = 1:1		 Molecules 27 01256 i025
14 Molecules 27 01256 i026MeONa, MeOH,
r.t., 23 h,
R = 1:1		 Molecules 27 01256 i027
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Igushkina, A.V.; Golovanov, A.A.; Vasilyev, A.V. Michael Addition of 3-Oxo-3-phenylpropanenitrile to Linear Conjugated Enynones: Approach to Polyfunctional δ-Diketones as Precursors for Heterocycle Synthesis. Molecules 2022, 27, 1256. https://doi.org/10.3390/molecules27041256

AMA Style

Igushkina AV, Golovanov AA, Vasilyev AV. Michael Addition of 3-Oxo-3-phenylpropanenitrile to Linear Conjugated Enynones: Approach to Polyfunctional δ-Diketones as Precursors for Heterocycle Synthesis. Molecules. 2022; 27(4):1256. https://doi.org/10.3390/molecules27041256

Chicago/Turabian Style

Igushkina, Anastasiya V., Alexander A. Golovanov, and Aleksander V. Vasilyev. 2022. "Michael Addition of 3-Oxo-3-phenylpropanenitrile to Linear Conjugated Enynones: Approach to Polyfunctional δ-Diketones as Precursors for Heterocycle Synthesis" Molecules 27, no. 4: 1256. https://doi.org/10.3390/molecules27041256

Article Metrics

Back to TopTop