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

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.


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].
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.

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 It should be specially emphasized that the above-mentioned heterocycles and cyclopropanes (Scheme 1) have a lot of important practical applications. For instance, 1,2diazepines 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.

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 1 H-and 13 C-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. 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). 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). 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 carboncarbon 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  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 carboncarbon 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. 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 carboncarbon 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. 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 carboncarbon 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.
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 Ar 2 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 Ar 2 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 Ar 1 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 Ar 1 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 NCCH 2 COPh 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  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 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 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 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 Summarizing the date described in this paper and our previous results on reactions of enynones 1 with malononitrile CH 2 (CN) 2 [3,4], one may state that, depending on the used CH-acid (CH 2 (CN) 2 or NCCH 2 COPh) and nucleophilicity/basicity of the anionic reagent (RO − or i-Pr 2 N − ), 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-Pr 2 N − (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, CH 2 (CN) 2 and NCCH 2 COPh, give Michael addition product to the C=C bond of substrates 1 at first stages of these reaction. However, this reaction is stopped for NCCH 2 COPh at this step, and goes further for CH 2 (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 CH 2 (CN) 2 . See discussions on the reaction mechanisms in our works [3,4].  [3] 4 data from [4] this work

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 1 H-, 13 C-NMR spectra, respectively) at 25 °C. The solvent residual signals of CDCl3 (δ 7.26 ppm) for 1 H-NMR spectra, the carbon signal of CDCl3 (δ 77.0 ppm) for 13 C-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).

Experimental Section
The NMR spectra of solutions of compounds in CDCl 3 were recorded at Bruker AVANCE III 400 spectrometer (Karlsruhe, Germany) (at 400 and 100 MHz for 1 H-, 13 C-NMR spectra, respectively) at 25 • C. The solvent residual signals of CDCl 3 (δ 7.26 ppm) for 1 H-NMR spectra, the carbon signal of CDCl 3 (δ 77.0 ppm) for 13 C-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).