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Article

The Reactions of N,N′-Diphenyldithiomalondiamide with Arylmethylidene Meldrum’s Acids

by
Victor V. Dotsenko
1,2,*,
Alexander V. Aksenov
2,*,
Anna E. Sinotsko
1,
Ekaterina A. Varzieva
1,
Alena A. Russkikh
1,
Arina G. Levchenko
1,
Nicolai A. Aksenov
2 and
Inna V. Aksenova
2
1
Department of Organic Chemistry and Technologies, Kuban State University, 149 Stavropolskaya St., 350040 Krasnodar, Russia
2
Department of Organic Chemistry, North Caucasus Federal University, 1a Pushkin St., 355017 Stavropol, Russia
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(24), 15997; https://doi.org/10.3390/ijms232415997
Submission received: 9 November 2022 / Revised: 8 December 2022 / Accepted: 11 December 2022 / Published: 15 December 2022
(This article belongs to the Section Macromolecules)
Browse Figures
Versions Notes

Abstract

:
The Michael addition reaction between dithiomalondianilide (N,N′-diphenyldithiomalondiamide) and arylmethylidene Meldrum’s acids, accompanied by subsequent heterocyclization, was investigated along with factors affecting the mixture composition of the obtained products. The plausible mechanism includes the formation of stable Michael adducts which, under the studied conditions, undergo further transformations to yield corresponding N-methylmorpholinium 4-aryl-6-oxo-3-(N-phenylthio-carbamoyl)-1,4,5,6-tetrahydropyridin-2-thiolates and their oxidation derivatives, 4,5-dihydro-3H-[1,2]dithiolo[3,4-b]pyridin-6(7H)-ones. The structure of one such product, N-methylmorpholinium 2,2-dimethyl-5-(1-(2-nitrophenyl)-3-(phenylamino)-2-(N-phenylthiocarbamoyl)-3-thioxopropyl)-4-oxo-4H-1,3-dioxin-6-olate, was confirmed via X-ray crystallography.

1. Introduction

Active methylene compounds bearing a thioamide group are routinely used for the synthesis of various functionalized N,S-heterocycles such as 2-mercapto(2-thioxo)-pyridines [1,2,3,4,5,6], 4H-thiopyrans [7,8] and thiochromones [9], thiazolines [10], isothiazoles [11,12], 1,2,4-dithiazoles [13], 1,2,3-thiadiazoles and 1,2,3-triazoles [14,15], thieno[2,3-b]pyridines [16,17,18,19,20,21], and 1,3,5-thiadiazines [22,23], many of which are shown to be promising organic semi-conductors, fluorescent dyes, drugs, agrochemicals, etc.
It is worth noting that while cyanothioacetamide NCCH2C(S)NH2 [24,25,26,27] and β-ketothioamides [27,28] are among the most common reagents in such types of heterocyclization reactions, the use of active methylene thio- and dithiomalonamides is far less studied [28], despite the fact that the latter often show quite different behavior, resulting in unique products.
Thus, for example, an application scope of the readily available N,N′-diphenyldithiomalondiamide (dithiomalondianilide) 1 [29,30] (Scheme 1) includes the synthesis of S,S- or S,N-bidentate ligands capable of heavy metal binding [31,32,33,34,35,36,37,38,39], or its use as a lubricant additive [40,41] or steel corrosion inhibitor [42]. In heterocyclic synthesis, dithioamide 1 was used to prepare 1,2-dithiolium salts [43,44], 1,3-dithiinium perchlorates [45,46,47,48], functionalized thiazolidines [49,50], 3,5-bis(phenylamino)pyrazole [51,52], and 2,3-dihydrothiophenes [51] (Scheme 1).
Nevertheless, despite its rather high CH-acidity (pKa = 10.3) [30], there are only few articles reporting use of malondithiodianilide 1 as an active methylene reagent. Thus, the Knoevenagel condensation of compound 1 with 4-nitro benzaldehyde leads to the corresponding unsaturated thioanilide 2, albeit in a very low yield (14%) [51]. The diazo-transfer reaction with phenylsulfonyl azide gives 1,2,3-thiadiazole 3 [53], while the tandem Michael addition–oxidation process with arylmethylidene malononitriles in the presence of morpholine results in [1,2]dithiolo[3,4-b]pyridines 4 [54].
The preparation of labile (though isolable) Michael adducts 6 via the reaction of another active methylene compound, cyanothioacetamide 5, with arylmethylidene Meldrum’s acids (or with Meldrum’s acid and aldehydes) is well documented [55,56,57,58,59,60,61,62,63,64,65,66,67,68] (Scheme 2). The adducts 6 (Scheme 2) are widely used as convenient precursors for further transformations into partially saturated nicotinonitriles 7,8 [56,57,58,59,60,62,63,67,68], (2-thiazolyl)acrylonitriles 9 [55], thioglutarimides 10 [69], functionalized 4H-thiopyrans 11 [55], pyrido[2,1-b][1,3,5]thiadiazines 12 [64,65,66,67,68,70], or polycyclic thienopyridine ensembles 13 [61]. Many of these compounds show promising biological activity [65,66,67,68,71,72,73,74,75]. However, no successful attempts to isolate similar Michael adducts derived from Meldrum’s acid and other active methylene thioamide-based reagents are known today [76,77].
Therefore, here, we would like to present the results of our study on the Michael addition reaction between N,N′-diphenyldithiomalondiamide 1 and various arylmethylidene Meldrum’s acids.

2. Results and Discussion

Initially, we choose 4-nitrobenzylidene Meldrum’s acid (2,2-dimethyl-5-(4-nitrobenzylidene)-1,3-dioxane-4,6-dione, 14a) as a model substrate, only to find out that its reaction with N,N′-diphenyldithiomalondiamide 1 proceeds smoothly in refluxing acetone in the presence of excess Et3N, yielding 34% of the stable Michael adduct 15a′ (Scheme 3) (Table 1, Entry 1):
At this point, some efforts to optimize the reaction conditions have been made. Thus, acetone was found to be the solvent of choice because it easily dissolves the starting reagents 1 and 14, whereas the salt-like Michael adducts 15 are insoluble and precipitate during the reaction. The reaction in EtOH gives lower yields and the products are often contaminated with the starting N,N′-diphenyldithiomalondiamide 1, which is poorly soluble in alcohols (Table 1, entry 2). In the same way, we checked some other solvents. MeCN, EtOAc, pyridine, and THF are not suitable solvents due to the bad solubility of dithiomalondianilide 1. Halogenated hydrocarbons such as CH2Cl2 and ClCH2CH2Cl partially dissolve 1, but cannot be used because of their alkylating effects.
The presence of somewhat weaker base N-methylmorpholine instead of triethylamine improved the yield significantly, probably due to the lower solubility of the N-methylmorpholinium salts (Table 1, entry 3) and from further on, N-methylmorpholine was used as the preferable base. To evaluate the substrate scope, we introduced the Michael acceptors 14b,c (R = 2-NO2C6H4 (b), 2-ClC6H4 (c)) as the model ones, in addition to the original 14a (R = 4-NO2C6H4). As was found, the reaction time plays a significant role here as with its increase, the yields of Michael adducts 15 also increased. However, along with this, the formation of two side products—1,4,5,6-tetrahydropyridine-2-thiolates 16 originating from the cyclization of adducts 15 and the oxidation products of pyridine-2-thiolates 16, 4,5-dihydro-3H-[1,2]dithiolo[3,4-b]pyridin-6(7H)-ones 17 (Scheme 4)—was also observed. Empirically, the best yields of the Michael adducts 15 can be achieved upon 40–80 min of gentle reflux in acetone, while further heating leads to noticeable subsequent heterocyclization of Michael adducts 15 into tetrahydropyridin-2-thiolates 16. Still, the complete conversion of 15 → 16 does not happen under prolonged heating due to the ease of oxidation of thiolates 16 to[1,2]dithiolo[3,4-b]pyridines 17. It should be pointed out that the mild oxidation of 2-mercaptopyridin-3-thiocarboxamides (or related-thiones or -thiolates) into[1,2]dithiolo[3,4-b]pyridine or isothiazolo[5,4-b]pyridine derivatives is well known and documented in the literature [54,78,79,80,81,82,83,84,85].
Notably, partially saturated [1,2]dithiolo[3,4-b]pyridines are a rather rare class of heterocyclic compounds and very little work has been conducted on their chemistry and preparation [54,86,87]. Preliminary experiments under an inert atmosphere (nitrogen) show that dithiolopyridines 17 do not form under these conditions. However, the mechanism of oxidation 16 → 17 is unclear and requires further study.
The cyclization ability of Michael adducts 15 seems to be determined by their solubility, which depends largely on the structure of an aromatic substituent. Thus, the refluxing of dithiomalondianilide 1 and arylmethylidene compound 14a in acetone for 2.5 h results in the formation of a mixture of Michael adduct 15a and dithiolopyridine 17a in a ~54:46 ratio (Table 1, entry 5); meanwhile, pure 15a, although with a low yield (9%), can be isolated upon running the reaction at room temperature (Table 1, entry 4). On the other hand, the brief heating of an acetone solution of dithiodianilide 1, N-methylmorpholine, and the Michael acceptor 14b (Ar = 2-NO2C6H4) gives the adduct 15b alone, while extended 2.5 h refluxing leads to a mixture of adduct 15b and its cyclization product, thiolate 16b, in a ~3:1 ratio (Table 1, entries 6,7) (Scheme 4).
Meanwhile, the NMR spectra of Michael adduct 15c prepared by heating 1 with 2,2-dimethyl-5-(2-chlorobenzylidene)-1,3-dioxane-4,6-dione 14c in acetone for 3h reveals only traces of the corresponding thiolate 16c (Table 1, entry 10). Similar results are observed in the case of some other arylmethylidene compounds 14d–j, likely as a consequence of the better reactivity of Michael acceptors 14 bearing strong electron-withdrawing groups compared to those with strong electron-donor ones. Thus, according to the TLC, 40 min of reaction time is enough for the full conversion of the starting materials 14d (Ar = 4-ClC6H4) and 14e (Ar = 2,4-Cl2C6H3) to the corresponding adducts 15 and cyclization products 16 (Table 1, entries 11, 12). At the same time, according to the TLC and NMR data, the reaction of compound 14f with dithiomalondianilide 1 occurs only with ~50% conversion after 80 min, giving ~33% of adduct 15f and ~2% of 16f (NMR yield) (Table 1, entry 13). Complete conversion of the starting reagents 14f and 1 was achieved in only ~3 h and the oxidation product 17f was detected via NMR among the compounds 15f and 16f (Table 1, entry 14).
Table
Table 1. The products, conditions and yields in the reactions between 1 and Michael acceptors 14.
Table 1. The products, conditions and yields in the reactions between 1 and Michael acceptors 14.
EntriesStarting
Reagents 14		Reaction
Conditions		Products (Yields) 1
Michael Adducts 15Pyridine-2-Thiolates 16Dithiolo-Pyridines 17
entry 114a Ijms 23 15997 i0011.5 eq. Et3N, acetone,
reflux 2 h		15a′ (34%)ND 2ND
entry 214aIjms 23 15997 i0021.5 eq. NMM, EtOH,
reflux 2 h		15a (42%)tracesND
entry 314aIjms 23 15997 i0031.5 eq. NMM, acetone,
reflux 1 h		15a (56%)tracesND
entry 414aIjms 23 15997 i0041.5 eq. NMM, acetone,
25 °C		15a (9%)NDND
entry 514aIjms 23 15997 i0051.5 eq. NMM, acetone,
reflux 2.5 h		15a (24%)ND17a (21%)
entry 614bIjms 23 15997 i0061.5 eq. NMM, acetone,
reflux 1 h		15b (57%)tracesND
entry 714bIjms 23 15997 i0071.5 eq. NMM, acetone,
reflux 2.5 h		15b (36%)16b (13%)ND
entry 814cIjms 23 15997 i0081.5 eq. NMM, acetone,
reflux 20 min		15c (43%)NDND
entry 914cIjms 23 15997 i0091.5 eq. NMM, acetone,
reflux 40 min		15c (60%)tracesND
entry 1014cIjms 23 15997 i0101.5 eq. NMM, acetone,
reflux 3 h		15c (58%)16b (<5%)ND
entry 1114dIjms 23 15997 i0111.5 eq. NMM, acetone,
reflux 40 min		15d (19%)16d (19%)ND
entry 1214eIjms 23 15997 i0121.5 eq. NMM, acetone,
reflux 35 min		15e (44%)16e (22%)ND
entry 1314fIjms 23 15997 i0131.5 eq. NMM, acetone,
reflux 80 min		15f (33%)16f (2%)ND
entry 1414fIjms 23 15997 i0141.5 eq. NMM, acetone,
reflux 3 h		15f (35%)16f (20%)17f (8%)
entry 1514gIjms 23 15997 i0151.5 eq. NMM, acetone,
reflux 80 min		15g (18%)16g (14%)17g (12%)
entry 1614hIjms 23 15997 i0161.5 eq. NMM, acetone,
reflux 1 h 		15h (27%)16h (7%)traces
entry 1714hIjms 23 15997 i0171.5 eq. NMM, acetone,
reflux 4 h 		15h (19%)16h (4%)17h (13%)
entry 1814iIjms 23 15997 i0181.5 eq. NMM, acetone,
reflux 1.5 h		15i (20%)16h (~2%)ND
entry 1914jIjms 23 15997 i0191.5 eq. NMM, acetone,
reflux 80 min		NDND17j (29%)
1 In entries 5,7,11–18, NMR yields are given; the products were not isolated in individual state. 2 ND—not detected.
Interestingly, unlike 2-nitro and 4-nitro, Michael acceptors 14a,b, and 2,2-dimethyl-5-(3-nitrobenzylidene)-1,3-dioxane-4,6-dione 14g under the same conditions (gentle heating for 80 min) give a complex mixture of the Michael addition/heterocyclization products 15g, 16g, and 17g (in a molar ratio of ~42:32:26) along with detectable amounts of starting thioamide 1 (Table 1, entry 15).
In the case of 4-methoxybenzylidene Meldrum’s acid 14h, the reaction does not proceed to completion after 1 h, resulting in a mixture of Michael adduct 15h (27%), small amounts (~7%) of pyridine-2-thiolate 16h, and plenty of unreacted starting material (Table 1, entry 16). According to the NMR, starting dithiomalondianilide 1 (about 7%) is still present in the reaction mixture even after 4 h along with adduct 15h (~19%), thiolate 16h (~4%), and dithiolopyridine 17h (~13%) (Table 1, entry 17).
Similarly, only ~25% conversion is observed in the reaction with 4-hydroxybenzylidene Meldrum’s acid 14i after 1.5 h. The NMR spectra reveal signals of the Michael adduct 15i with a small admixture of thiolate 16i (Table 1, entry 18). Moreover, even after 6 h of heating, the starting materials remain in the reaction mixture and full conversion does not occur due to, presumably, the reduced reactivity of compound 14i caused by the strong donor effect of a substituent (OH or O−) at the para-position of the benzene ring.
In this regard, it is somewhat surprising that 5-[4-(dimethylamino)benzylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione 14j reacts smoothly with thioamide 1 to give a sole isolated product, 4-(4-(dimethylamino)phenyl)-7-phenyl-3-(phenylimino)-4,5-dihydro-3H-[1,2]dithiolo[3,4-b]pyridin-6(7H)-one 17j, albeit in a modest yield (Table 1, entry 19).
The structure of all the prepared compounds was confirmed via FT-IR and NMR spectroscopy (including DEPTQ 13C, 2D NMR 1H-13C HSQC and 1H-13C HMBC experiments) (See Electronic Supplementary Materials File). 1,4,5,6-Tetrahydropyridine-2-thiolates 16 and 4,5-dihydro-3H-[1,2]dithiolo[3,4-b]pyridin-6(7H)-ones 17 can be clearly identified through characteristic [56,57,58,59,60,62,63,67,68] ABX-patterns of C(O)-CH2-CHR protons in the 1H NMR spectra. In addition, the 1H NMR spectra of 1,4,5,6-tetrahydropyridine-2-thiolates 16 exhibit the signals of an N-methylmorpholinium cation and a broadened singlet of a C(S)NH proton, strongly shifted downfield to δ 15.81–15.92 ppm due to the intramolecular hydrogen bond S−…H-N(C=S). In the FTIR spectra of [1,2]dithiolo[3,4-b]pyridines 17, absorption bands corresponding to C=N vibrations are detected, and the 13C DEPTQ spectra reveal no C=S signals; however, only C=N carbon signals appear at δ = 163–164 ppm.
In turn, the 1H and 13C NMR spectra of the Michael adducts 15 show non-equivalence of the signals of two different C(S)NHPh fragments. Thus, the difference in the 1H chemical shifts between C(S)NH peaks reaches Δ 1.05–1.07 ppm (e.g., adducts 15a,d) and could be explained by hydrogen bonding between the negatively charged oxygen atom of the anionic part of the molecule and the proton of one of the C(S)NH groups (–O−…H-N(C=S) (Figure 1). The difference in chemical shifts between two C(S)NHPh protons decreases to Δ 0.3–0.5 ppm (e.g., adducts 15b,c,e) when an aromatic ring bears a substituent capable of hydrogen bond formation at ortho-position (e.g., Cl, NO2).
Another characteristic feature of the 1H NMR spectra of the Michael adducts 15 is that the signals of CH–CH protons appear as a pair of doublets with coupling constants, 3J = 12.0–12.1 Hz. An approximate estimate of the CH–CH dihedral angle (ϕ) by the Haasnoot–DeLeeuw–Altona [88] and Altona–Donders [89] equations gives a range of 169°…177°, indicating the anti-periplanar orientation of CH–CH protons (Figure 1). These values are in a good agreement with the results of X-ray diffraction studies of a single crystal of the Michael adduct 15b, according to which the CH–CH dihedral angle ϕ is 179.8° (Figure 2).
Next, we decided to study the reactivity of the studied Michael adducts 15 towards alkylating agents. The structurally similar thioamide-based Michael adducts 6 are known [55,60,62,69] to react with alkylating agents, with the formation of a variety heterocyclization products (Scheme 2). We speculated (Scheme 5) that the alkylation of adducts 15 would lead to pyridines 18, which could be cyclized further into thieno[2,3-b]pyridines 19, known for their pharmacological importance [16,17,18,19,20,21].
Therefore, we examined the reactions of the Michael adduct 15c with certain α-chloroacetamides 20a–c (Scheme 5) in DMF solution in the presence of 1 eq. KOH at 25 °C. To our surprise, no alkylation products were formed and the dithiolopyridine 17c was the only isolated product in all cases. The most plausible mechanism involves intramolecular cyclization of the Michael adduct 15c to form 3-(N-phenylthiocarbamoyl)-1,4,5,6-tetrahydropyridin-2-thiolate, which is then rapidly oxidized (most likely, by air).
Considering all of the above, we envision two main directions for our future studies. First is the finding of direct and selective oxidation-free cyclization of the Michael adducts 15 to the corresponding 3-(N-phenylthiocarbamoyl)tetrahydropyridin-2-thiolates 16, which are valuable reagents with great synthetic potential. Secondly, the mechanism of oxidation 16 → 17 and the development a new preparative transformation of adducts 15 into dithiolopyridines 17 will also be subjects of our further research efforts.

3. Materials and Methods

1H and 13C DEPTQ NMR spectra were recorded and 2D NMR experiments conducted in solutions of DMSO-d6 using a Bruker AVANCE-III HD instrument (at 400.40 or 100.61 MHz, respectively). Residual solvent signals were used as internal standards, in DMSO-d6 (2.49 ppm for 1H, and 39.50 ppm for 13C nuclei). Single-crystal X-ray diffraction analysis of compound 15b was performed using an automatic four-circle diffractometer (Agilent Super Nova, Dual, Cu at zero, Atlas S2). High-resolution mass spectra (HRMS) were registered using a Bruker MaXis Impact spectrometer (electrospray ionization, using HCO2Na–HCO2H for calibration). The samples were dissolved in MeOH under moderate heating (37–38 °C) and ultrasonication. See the Supplementary Materials File for NMR, FTIR, HRMS spectral charts, and X-ray analysis data.
FT-IR spectra were measured using a Bruker Vertex 70 instrument equipped with an ATR sampling module. Elemental analyses were carried out using a Carlo Erba 1106 Elemental Analyzer. The reaction progress and purity of isolated compounds were controlled via TLC on Sorbfil-A plates, eluent—acetone:hexane 1:1 or ethyl acetate, and the spots were visualized using UV-light or iodine vapors. Starting arylmethylidene Meldrum’s acids 14 were synthesized according to known procedures [90,91,92] and were identical to those described. N,N′-Diphenyldithiomalondiamide (dithiomalondianilide) 1 was prepared from acetylacetone and phenyl isothiocyanate as described earlier [29,30]. All other reagents and solvents were purchased from commercial vendors and used as received. A preliminary report on the reaction of 1 with arylmethylidene Meldrum’s acids was published as a proceeding paper [93].
Triethylammonium 2,2-dimethyl-5-(1-(4-nitrophenyl)-3-(phenylamino)-2-(N-phenylthio-carbamoyl)-3-thioxopropyl)-4-oxo-4H-1,3-dioxin-6-olate (15a′). A round-bottom flask was charged with anhydrous acetone (50 mL), 500 mg (1.80 mmol) of 4-nitrobenzylidene Meldrum’s acid (2,2-dimethyl-5-(4-nitrobenzylidene)-1,3-dioxane-4,6-dione, 14a), 480 mg (1.80 mmol) of dithiomalondianilide 1, and triethylamine (0.4 mL, 2.9 mmol). The solution was refluxed under vigorous stirring, and the crystals of adduct 15a′ started to precipitate. The mixture was refluxed for 2 h and monitored via TLC until the starting reagents were consumed. The mixture was left overnight and the crystals were filtered off and washed with acetone and light petroleum. The yield was 400 mg (34%), bright yellow crystals. 1H NMR (400 MHz, DMSO-d6): 1.15 (t, 3J = 7.3 Hz, 9H, 3 CH3CH2), 1.27–1.31 (m, 6H, 2 Me), 3.07 (q, 3J = 7.3 Hz, 6H, 3 CH3CH2), 5.27 (d, 3J = 12.1 Hz, 1H, CH), 5.95 (d, 3J = 12.1 Hz, 1H, CH), 7.15 (AB2-t, 3J = 7.3 Hz, 1H, H-4 Ph), 7.21 (AB2-t, 3J = 7.3 Hz, 1H, H-4 Ph), 7.26–7.31 (m, 2H, H-Ph), 7.36–7.40 (m, 2H, H-Ph), 7.55 (d, 3J = 7.8 Hz, 2H, H-Ph), 7.80–7.84 (m, 4H, H-Ar), 7.98 (d, 3J = 8.7 Hz, 2H, H-Ar), 8.86 (br s, 1H, HN+), 10.89 (s, 1H, C(S)NH), 11.96 (s, 1H, C(S)NH). 13C DEPTQ NMR (101 MHz, DMSO-d6): 8.7* (3 CH3), 25.8* (2 CH3), 45.2* (CH–Ar), 45.7 (3 CH2N), 71.5* (CH–CSNHPh), 74.8 (C–C=O), 99.7 (O–CMe2–O), 122.1* (2 CH Ar), 123.1* (2 CH Ph), 123.3* (2 CH Ph), 125.9* (C4H Ph), 126.0* (C4H Ph), 128.3* (2 CH Ph), 128.4* (2 CH Ph), 129.6* (2 CH Ar), 139.4 (C1 Ph), 139.6 (C1 Ph), 144.9 (C Ar), 152.5 (C Ar), 197.0 (C=S), 198.8 (C=S). *Signals with a negative phase. The signal of C-O− carbons was not observed, probably due to its low intensity. FTIR, νmax, cm−1: 3256, 3196, 3142, 2991, 2941, 2636 (N-H, C-H); 1516 (NO2asym); 1342 (NO2sym). HRMS (ESI) m/z: calculated for C34H41N4O6S2 [M + H]+: 665.2468; found: 665.2466 (Δ 0.3 ppm). Elemental Analysis (C34H40N4O6S2, M 664.83): calculated (%): C, 61.42; H, 6.06; N, 8.43; found (%): C, 61.41; H, 6.15; N, 8.40.
N-Methylmorpholinium 2,2-dimethyl-5-(1-(4-nitrophenyl)-3-(phenylamino)-2-(N-phenyl-thiocarbamoyl)-3-thioxopropyl)-4-oxo-4H-1,3-dioxin-6-olate (15a) (Table 1, entry 3). To a clear solution of 2,2-dimethyl-5-(4-nitrobenzylidene)-1,3-dioxane-4,6-dione 14a (369 mg, 1.33 mmol) and dithiomalondianilide 1 (381 mg, 1.33 mmol) in anhydrous acetone (15 mL), an excess (0.6 mL, 5.45 mmol) of N-methylmorpholine was added. The mixture was refluxed under vigorous stirring and bright yellow crystals of adduct 15a started to precipitate within 5 min. The mixture was refluxed for 1 h and monitored via TLC until the starting reagents were consumed. The crystals were filtered off and washed with acetone and light petroleum. The yield was 491 mg (56%), bright yellow crystals. 1H NMR (400 MHz, DMSO-d6): 1.28 (br s, 3H, Me), 1.33 (br s, 3H, Me), 2.78 (s, 3H, NMe), 3.15–3.19 (m, 4H, CH2NCH2), 3.73–3.78 (m, 4H, CH2OCH2), 5.27 (d, 3J = 12.1 Hz, 1H, CH), 5.97 (d, 3J = 12.1 Hz, 1H, CH), 7.13–7.16 (m, 1H, H-4 Ph), 7.19–7.23 (m, 1H, H-4 Ph), 7.26–7.30 (m, 2H, H-3, H-5 Ph), 7.36–7.40 (m, 2H, H-3, H-5 Ph), 7.54 (d, 3J = 7.8 Hz, 2H, H-2, H-6 Ph), 7.82–7.85 (m, 4H, H-2, H-6 Ph and H-2, H-6 4-NO2C6H4 overlapped), 7.98 (d, 3J = 8.6 Hz, 2H, H-3, H-5 4-NO2C6H4), 9.68 (br s, 1H, HN+), 10.92 (s, 1H, C(S)NH), 11.97 (s, 1H, C(S)NH). 13C DEPTQ NMR (101 MHz, DMSO-d6): 25.6* (CH3), 25.9* (CH3), 42.6* (N–CH3), 45.2* (CH–Ar), 52.6 (CH2NCH2), 63.5 (CH2OCH2), 71.3* (CH–CSNHPh), 74.9 (C–C=O), 99.8 (O–CMe2–O), 122.1* (C-3 C-5 4-NO2C6H4), 123.0* (C-2, C-6 Ph), 123.3* (C-2, C-6 Ph), 125.8* (C-4 Ph), 126.0* (C-4 Ph), 128.28* (C-3, C-5 Ph), 128.34* (C-3, C-5 Ph), 129.5* (C-2 C-6 4-NO2C6H4), 139.4 (C-1 Ph), 139.6 (C-1 Ph), 144.9 (C-4 4-NO2C6H4), 152.5 (C–1 4-NO2C6H4), 164.8 (C–O−), 197.0 (C=S), 198.8 (C=S). *Signals with a negative phase. FTIR, νmax, cm−1: 3175, 2987, 2863 (N–H, C–H); 1516 (NO2 asym); 1346 (NO2 sym). Elemental Analysis (C33H36N4O7S2, M 664.81): calculated (%): C, 59.62; H, 5.46; N, 8.43; found (%): C, 59.70; H, 5.55; N, 8.42.
When a mixture of dithiomalondianilide 1 (240 mg, 0.838 mmol), Michael acceptor 14a (369 mg, 1.33 mmol), and N-methylmorpholine (0.13 mL, 1.18 mmol) was refluxed in acetone (15 mL) for 2.5 h, and then, left to stand overnight, the initially formed crystals of adduct 15a disappeared; acetone was evaporated under reduced pressure, and the residue was treated with cold n-BuOH. The crystalline solid was filtered off and washed with BuOH and light petroleum to give 226 mg of yellow powder. According to 1H NMR, the product consisted of adduct 15a and 4-(4-nitrophenyl)-3-(phenylimino)-4,5-dihydro-3H-[1,2]dithiolo[3,4-b]pyridin-6(7H)-one 17a in a ~54:46 molar ratio (corresponds to ~136 mg of adduct 15a (24%), and ~73 mg of dithiolopyridine 17a (21%)) with trace amounts (~3.5% by weight) of starting dithiomalondianilide 1 (Table 1, entry 5). The observed signals of dithiolopyridine 17a: 1H NMR (400 MHz, DMSO-d6): 2.89 (br d, 2J = 16.5 Hz, 1H, cis H-5), 3.64 (dd, 2J = 16.5 Hz, 3J = 8.2 Hz, 1H, trans H-5), 4.61–4.63 (m, 1H, H-4). 13C DEPTQ NMR (101 MHz, DMSO-d6): 36.3* (C-4), 37.7 (C-5), 112.5 (C-3a), 120.0* (CH Ar), 123.0* (CH Ph), 124.2* (CH Ph), 124.6* (CH Ph), 128.1* (CH Ph), 129.1* (CH Ar), 129.6* (CH Ph), 130.2* (CH Ph), 136.5 (C-1 Ph), 146.7 (C-1 Ph), 148.9 (C-1 4-NO2C6H4), 150.7 (C Ar), 158.0 (C-7a), 163.5 (C-3), 168.2 (C-6). *Signals with a negative phase. HRMS for 15a (ESI) m/z: calculated for C33H37N4O7S2 [M + H]+: 665.21037; found: 665.2104 (Δ 0.05 ppm). HRMS for 17a (ESI) m/z: calculated for C24H18N3O3S2 [M + H]+: 460.0784; found: 460.0790 (Δ 1.3 ppm).
N-Methylmorpholinium 2,2-dimethyl-5-(1-(2-nitrophenyl)-3-(phenylamino)-2-(N-phenyl-thiocarbamoyl)-3-thioxopropyl)-4-oxo-4H-1,3-dioxin-6-olate (15b) (Table 1, entry 6). To a clear solution of 2,2-dimethyl-5-(2-nitrobenzylidene)-1,3-dioxane-4,6-dione 14b (250 mg, 0.9 mmol) and dithiomalondianilide 1 (260 mg, 0.9 mmol) in anhydrous acetone (15 mL), an excess (0.15 mL, 1.36 mmol) of N-methylmorpholine was added. The mixture was refluxed under vigorous stirring for 1.5 h. Then, acetone was partly evaporated under reduced pressure to half of its volume and the reaction mixture was left to stand overnight at ambient temperature in a stoppered flask. The precipitated bright yellow crystals were filtered off and washed with acetone and light petroleum to give 341 mg (57%) of adduct 15b. The product contained trace amounts of starting dithiomalondianilide 1 and thiolate 16b. 1H NMR (400 MHz, DMSO-d6): 1.32 (br s, 6H, Me), 2.74 (s, 3H, NMe), 3.09–3.12 (m, 4H, CH2NCH2), 3.72–3.77 (m, 4H, CH2OCH2), 5.42 (d, 3J = 12.0 Hz, 1H, CH), 6.00 (d, 3J = 12.0 Hz, 1H, CH), 7.13–7.17 (m, 1H, H-4 Ph), 7.19–7.25 (m, 1H, H-4 Ph and H-4 2-NO2C6H4 overlapped), 7.27–7.31 (m, 2H, H-3, H-5 Ph), 7.36–7.44 (m, 3H, H-3, H-5 Ph and H-5 2-NO2C6H4 overlapped), 7.49 (dd, 3J = 8.0 Hz, 4J = 0.9 Hz, 1H, H-3 2-NO2C6H4), 7.54 (d, 3J = 7.6 Hz, 2H, H-2, H-6 Ph), 7.75 (d, 3J = 7.7 Hz, 2H, H-2, H-6 Ph), 8.43 (d, 3J = 7.7 Hz, 1H, H-6 2-NO2C6H4), 9.75 (br s, 1H, HN+), 11.44 (s, 1H, C(S)NH), 11.74 (s, 1H, C(S)NH). 13C DEPTQ NMR (101 MHz, DMSO-d6): 27.2* (2 CH3), 38.7* (CH–Ar), 42.8* (N–CH3), 52.8 (CH2NCH2), 63.6 (CH2OCH2), 72.7* (CH–CSNHPh), 74.3 (C–C=O), 99.7 (O–CMe2–O), 122.5* (C-3 2-NO2C6H4), 123.0* (C-2, C-6 Ph), 123.9* (C-2, C-6 Ph), 125.9* (2C, C-4 Ph and C-4 2-NO2C6H4 overlapped), 126.1* (C-4 Ph), 128.2* (C-3, C-5 Ph), 128.3* (C-3, C-5 Ph), 130.3* (C-5 2-NO2C6H4), 131.6* (C-6 2-NO2C6H4), 135.7 (C-1 2-NO2C6H4), 139.4 (C-1 Ph), 139.8 (C-1 Ph), 149.9 (C-2 2-NO2C6H4), 165.5 (C–O−), 197.5 (C=S), 197.8 (C=S). *Signals with a negative phase. HRMS (ESI) m/z: calculated for C33H37N4O7S2 [M + H]+: 665.21037; found: 665.2106 (Δ 0.3 ppm). Elemental Analysis (C33H36N4O7S2, M 664.81): calculated (%): C, 59.62; H, 5.46; N, 8.43; found (%): C, 59.76; H, 5.47; N, 8.53.
When a mixture of dithiomalondianilide 1 (260 mg, 0.9 mmol), Michael acceptor 14b (250 mg, 0.9 mmol), and N-methylmorpholine (0.15 mL, 1.36 mmol) was refluxed in acetone (15 mL) for 2.5 h, and then, left to stand overnight, a small number of yellow crystals appeared. The mixture was concentrated under reduced pressure, and the crystalline residue was filtered off and washed with EtOH and light petroleum to give 283 mg of yellow solid. According to the NMR, the product was a mixture of Michael adduct 15b and pyridine-2-thiolate 16b in a ~3:1 molar ratio (corresponds to ~217 mg of adduct 15b (36%) and ~66 mg of thiolate 16b (13%)) (Table 1, entry 7). The identified signals of N-methylmorpholinium 4-(2-nitrophenyl)-6-oxo-1-phenyl-3-(N-phenylthiocarbamoyl)-1,4,5,6-tetrahydropyridine-2-thiolate 16b: 1H NMR (400 MHz, DMSO-d6): 2.65 (dd, 2J = 15.7 Hz, 3J = 1.5 Hz, 1H, cis H-5), 2.73 (s, 3H, NMe), 3.09–3.13 (m, 4H, CH2NCH2), 3.19 (dd, 2J = 15.7 Hz, 3J = 7.7 Hz, 1H, trans H-5), 3.72–3.77 (m, 4H, CH2OCH2), 5.99–6.00 (m, 1H, H-4), 7.01–7.05 (m, 1H, H-4 Ph), 15.89 (br s, 1H, C(S)NHPh). The signals of most of the aromatic protons were difficult to identify due to complete or partial overlap with the signals of adduct 15b. 13C DEPTQ NMR (101 MHz, DMSO-d6): 37.6* (C-4), 38.9 (C-5), 42.8* (N–CH3), 52.7 (CH2NCH2), 63.6 (CH2OCH2), 115.7 (C-3), 123.4* (CH Ar), 123.8* (CH Ar), 124.4* (CH Ar), 126.2* (CH Ar), 126.4* (CH Ar), 127.2* (CH Ar), 127.8* (CH Ar), 128.0* (CH Ar), 128.5* (CH Ar), 129.2* (CH Ar), 133.1* (CH Ar), 139.1 (C-1 2-NO2C6H4), 141.26 (C-1 Ph), 141.31 (C-1 Ph), 149.4 (C-2 2-NO2C6H4), 167.4 (C-2), 168.0 (C=O), 188.8 (C=S). *Signals with a negative phase.
N-Methylmorpholinium 5-(1-(2-chlorophenyl)-3-(phenylamino)-2-(N-phenylthiocarbamo-yl)-3-thioxopropyl)-2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-olate (15c) (Table 1, entry 8). To a clear solution of 5-(2-chlorobenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione 14c (250 mg, 0.93 mmol) and dithiomalondianilide 1 (270 mg, 0.93 mmol) in anhydrous acetone (15 mL), an excess (0.15 mL, 1.36 mmol) of N-methylmorpholine was added. The mixture was refluxed under vigorous stirring, and a bright yellow crystalline adduct 15c started to precipitate almost immediately. The mixture was heated under reflux for 20 min. The bright yellow crystals were filtered off and washed with acetone and light petroleum. The yield of pure 15c was 268 mg (43%). 1H NMR (400 MHz, DMSO-d6): 1.31 (br s, 3H, Me), 1.34 (br s, 3H, Me), 2.75 (s, 3H, NMe), 3.12–3.16 (m, 4H, CH2NCH2), 3.73–3.77 (m, 4H, CH2OCH2), 5.44 (d, 3J = 12.1 Hz, 1H, CH-Ar), 5.86 (d, 3J = 12.1 Hz, 1H, CH-CSNHPh), 6.97–7.01 (m, 1H, H-4 2-ClC6H4), 7.05–7.08 (m, 1H, H-3 2-ClC6H4), 7.12–7.16 (m, 1H, H-4 Ph), 7.19–7.22 (m, 2H, H-4 Ph and H-5 2-ClC6H4 overlapped), 7.26–7.30 (m, 2H, H-3, H-5 Ph), 7.35–7.39 (m, 2H, H-3, H-5 Ph), 7.57 (d, 3J = 7.6 Hz, 2H, H-2, H-6 Ph), 7.79 (d, 3J = 7.7 Hz, 2H, H-2, H-6 Ph), 8.18 (d, 3J = 7.0 Hz, 1H, H-6 2-ClC6H4), 9.68 (br s, 1H, HN+), 11.52 (s, 1H, C(S)NH), 11.95 (s, 1H, C(S)NH). 13C DEPTQ NMR (101 MHz, DMSO-d6): 23.9* (CH3), 27.4* (CH3), 40.2* (CH–Ar), 42.7* (N–CH3), 52.7 (CH2NCH2), 63.5 (CH2OCH2), 73.1* (CH–CSNHPh), 73.4 (C–C=O), 99.6 (O–CMe2–O), 123.4* (C-2, C-6 Ph), 124.0* (C-2, C-6 Ph), 124.7* (C-3 2-ClC6H4), 125.75* (C-4 Ph), 125.78* (C-4 Ph), 126.0* (C-4 2-ClC6H4), 128.11* (C-3, C-5 Ph), 128.13* (C-3, C-5 Ph and C-5 2-ClC6H4 overlapped), 131.1* (C-6 2-ClC6H4), 133.5 (C-Cl), 139.6 (C-1 2-ClC6H4), 139.9 (C-1 Ph), 140.1 (C-1 Ph), 164.1, 167.1 (br s, 2 C–O−), 197.4 (C=S), 199.1 (C=S). *Signals with a negative phase. FTIR, νmax, cm−1: 3134, 2982, 2866 (N–H, C–H).
Elemental Analysis (C33H36ClN3O5S2, M 654.24): calculated (%): C, 60.58; H, 5.55; N, 6.42; found (%): C, 60.73; H, 5.60; N, 6.51.
When a solution of dithiomalondianilide 1 (1.97 g, 6.9 mmol), Michael acceptor 14c (1.85 g, 6.9 mmol), and N-methylmorpholine (1.35 mL, 10.35 mmol) in acetone (35–40 mL) was refluxed for 40 min, the yield of Michael adduct 15c markedly increased (2.73 g, 60%). According to the NMR, the product contained only trace amounts of starting thioanilide 1 and pyridine-2-thiolate 16c (Table 1, entry 9). Upon a longer heating period (3 h), the yields of 15c were comparable but the yield of thiolate by-product 16c increased (Table 1, entry 10).
The reaction of 5-(4-chlorobenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione 14d and dithiomalondianilide 1 (Table 1, entry 11). To a clear solution of 5-(4-chlorobenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione 14d (250 mg, 0.94 mmol) and dithiomalondianilide 1 (270 mg, 0.94 mmol) in anhydrous acetone (15 mL), an excess (0.15 mL, 1.4 mmol) of N-methylmorpholine was added. The mixture was refluxed under vigorous stirring, and a bright yellow crystalline solid started to precipitate within 3–5 min. The mixture was heated under reflux for 40 min (monitored via TLC until the starting reagents were consumed). The crystals were filtered off and washed with acetone and light petroleum to give 214 mg of a bright yellow solid. According to the NMR, the product was a mixture of Michael adduct 15d and pyridine-2-thiolate 16d in a ~1:1 molar ratio (corresponds to ~116 mg of adduct 15d (19%) and ~98 mg of thiolate 169 (19%)) (Table 1, entry 11). The identified signals of N-methylmorpholinium 5-(1-(4-chlorophenyl)-3-(phenylamino)-2-(N-phenylthiocarbamoyl)-3-thioxopropyl)-2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-olate (15d): 1H NMR (400 MHz, DMSO-d6): 1.31 (br s, 6H, Me), 2.72 (s, 3H, NMe), 3.07–3.11 (m, 4H, CH2NCH2), 3.72–3.76 (m, 4H, CH2OCH2), 5.08 (d, 3J = 12.1 Hz, 1H, CH-Ar), 5.85 (d, 3J = 12.1 Hz, 1H, CH-CSNHPh), 6.84–7.85 (m, 14H, Ar), 9.65 (br s, 1H, HN+), 10.88 (s, 1H, C(S)NH), 11.85 (s, 1H, C(S)NH). 13C DEPTQ NMR (101 MHz, DMSO-d6): 25.8* (2 CH3), 42.9* (N–CH3), 44.6* (CH–Ar), 52.8 (CH2NCH2), 63.7 (CH2OCH2), 72.6* (CH–CSNHPh), 75.5 (C–C=O), 99.6 (O–CMe2–O), 123.1* (C-2, C-6 Ph), 123.5* (C-2, C-6 Ph), 130.6* (C-2, C-6 4-ClC6H4), 143.0 (C-1 4-ClC6H4), 164.7 (C–O−), 197.4 (C=S), 199.3 (C=S). The signals of most of the aromatic protons and carbons were difficult to identify due to complete or partial overlap with the signals of 16d. *Signals with a negative phase. The identified signals of N-methylmorpholinium 4-(4-chlorophenyl)-6-oxo-1-phenyl-3-(N-phenylthiocarbamoyl)-1,4,5,6-tetrahydropyridine-2-thiolate 16d: 1H NMR (400 MHz, DMSO-d6): 2.72 (s, 3H, NMe), 2.80 (dd, 2J = 15.5 Hz, 3J = 2.3 Hz, 1H, cis H-5), 3.00 (dd, 2J = 15.7 Hz, 3J = 5.8 Hz, 1H, trans H-5), 3.09–3.13 (m, 4H, CH2NCH2), 3.72–3.77 (m, 4H, CH2OCH2), 5.75–5.78 (m, 1H, H-4), 6.84–7.85 (m, 14H, Ar), 15.91 (br s, 1H, C(S)NHPh). 13C DEPTQ NMR (101 MHz, DMSO-d6): 39.1 (C-5), 39.6* (C-4), 42.9* (N–CH3), 52.8 (CH2NCH2), 63.7 (CH2OCH2), 116.7 (C-3), 129.3* (C-2, C-6 4-ClC6H4), 143.0 (C-1 4-ClC6H4), 166.4 (C-2), 168.4 (C=O), 188.9 (C=S). The signals of most of the aromatic protons and carbons were difficult to identify due to complete or partial overlap with the signals of 15d. *Signals with a negative phase.
HRMS for 15d (ESI) m/z: calculated for C33H37ClN3O5S2 [M + H]+: 654.1863; found: 654.1859 (Δ 0.6 ppm); calculated for C28H26ClN2O4S2 [M + H–NMM]+: 553.1023; found: 553.1014 (Δ 1.3 ppm); HRMS for 16d (ESI) m/z: calculated for C25H20ClN3O2S2 [M + H + CO2–NMM]+: 495.0604; found: 495.0599 (Δ 1.0 ppm).
The reaction of 5-(2,4-dichlorobenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione 14e and dithiomalondianilide 1 (Table 1, entry 12). To a clear solution of 5-(2,4-dichlorobenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione 14e (250 mg, 0.84 mmol) and dithiomalondianilide 1 (240 mg, 0.84 mmol) in anhydrous acetone (15 mL), an excess (0.14 mL, 1.25 mmol) of N-methylmorpholine was added. The mixture was refluxed under vigorous stirring and a bright yellow crystalline solid started to precipitate almost immediately. The mixture was heated under reflux for 35 min (monitored via TLC until the starting reagents were consumed). The crystals were filtered off and washed with acetone and light petroleum to give 360 mg of a bright yellow solid. According to the NMR, the product was a mixture of Michael adduct 15e and pyridine-2-thiolate 16e in a ~2:1 molar ratio (corresponds to ~253 mg of adduct 15e (44%) and ~107 mg of thiolate 16e (22%)) (Table 1, entry 12). The identified signals of N-methylmorpholinium 5-(1-(2,4-dichlorophenyl)-3-(phenylamino)-2-(N-phenylthiocarbamoyl)-3-thioxopropyl)-2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-olate (15e): 1H NMR (400 MHz, DMSO-d6): 1.31 (br s, 3H, Me), 1.34 (br s, 3H, Me), 2.74 (s, 3H, NMe), 3.08–3.15 (m, 4H, CH2NCH2), 3.72–3.79 (m, 4H, CH2OCH2), 5.43 (d, 3J = 12.0 Hz, 1H, CH-Ar), 5.82 (d, 3J = 12.0 Hz, 1H, CH-CSNHPh), 7.02–7.39 (m, 9H, Ar), 7.62 (d, 3J = 7.8 Hz, 2H, Ar), 7.78 (d, 3J = 7.8 Hz, 2H, Ar), 9.63 (br s, 1H, HN+), 11.47 (s, 1H, C(S)NH), 11.98 (s, 1H, C(S)NH). 13C DEPTQ NMR (101 MHz, DMSO-d6): 23.9* (CH3), 27.4* (CH3), 40.0* (CH–Ar), 42.8* (N–CH3), 52.8 (CH2NCH2), 63.7 (CH2OCH2), 72.9* (CH–CSNHPh), 73.0 (C–C=O), 99.8 (O–CMe2–O), 123.2* (C-2, C-6 Ph), 124.0* (C-2, C-6 Ph), 128.19* (C-3, C-5 Ph), 128.21* (C-3, C-5 Ph), 139.2 (C-1 Ar), 139.5 (C-1 Ar), 140.0 (C-1 Ar), 197.1 (C=S), 198.8 (C=S). The signals of most of the aromatic protons and carbons were difficult to identify due to complete or partial overlap with the signals of 16e. *Signals with a negative phase. The identified signals of N-methylmorpholinium 4-(2,4-dichlorophenyl)-6-oxo-1-phenyl-3-(N-phenylthiocarbamoyl)-1,4,5,6-tetrahydropyridine-2-thiolate 16e: 1H NMR (400 MHz, DMSO-d6): 2.67 (dd, 2J = 15.5 Hz, 3J = 1.7 Hz, 1H, cis H-5), 2.74 (s, 3H, NMe), 3.06 (dd, 2J = 15.5 Hz, 3J = 6.7 Hz, 1H, trans H-5), 3.08–3.15 (m, 4H, CH2NCH2), 3.72–3.79 (m, 4H, CH2OCH2), 5.87–5.88 (m, 1H, H-4), 7.02–7.39 (m, 7H, Ar), 7.45 (dd, 3J = 8.4 Hz, 4J = 1.8 Hz, 1H, H-5 2,4-Cl2C6H3), 7.53 (d, 4J = 1.8 Hz, 1H, H-3 2,4-Cl2C6H3), 7.69 (d, 3J = 7.8 Hz, 2H, Ar), 8.21 (d, 3J = 8.7 Hz, 2H, Ar), 9.63 (br s, 1H, HN+), 15.90 (br s, 1H, C(S)NHPh). 13C DEPTQ NMR (101 MHz, DMSO-d6): 37.5 (C-5), 38.8* (C-4), 42.8* (N–CH3), 52.8 (CH2NCH2), 63.7 (CH2OCH2), 115.1 (C-3), 141.2 (C-1 Ar), 141.4 (C-1 Ar), 167.2 (C-2), 167.9 (C=O), 188.7 (C=S). The signals of most of the aromatic protons and carbons were difficult to identify due to complete or partial overlap with the signals of 15e. *Signals with a negative phase. For adduct 15e: HRMS (ESI) m/z: calculated for C33H36Cl2N3O5S2 [M + H]+: 688.1473; found: 688.1470 (Δ 0.43 ppm).
The reaction of 2,2-dimethyl-5-(2-thienylmethylene)-1,3-dioxane-4,6-dione 14f and dithiomalondianilide 1 (Table 1, entries 13,14). To a clear solution of 2,2-dimethyl-5-(2-thienylmethylene)-1,3-dioxane-4,6-dione 14f (250 mg, 1.05 mmol) and dithiomalondianilide 1 (300 mg, 1.05 mmol) in anhydrous acetone (15 mL), an excess (0.17 mL, 1.58 mmol) of N-methylmorpholine was added. The mixture was refluxed under vigorous stirring and the formation of a small amount of crystalline product was detected within ~15 min. After 80 min, heating was stopped and the acetone was evaporated under reduced pressure. The residue (369 mg of yellow powder) contained, along with substantial amounts of starting reagents (about 50% of initial amounts), adduct 15f and thiolate 16f in a ~14:1 molar ratio. Full conversion was achieved in 3 h, acetone was removed in vacuo, and the residue contained 247 mg of yellow powder. NMR analysis revealed a complex mixture consisting of adduct 15f (~35%), thiolate 16f (~20%), and dithiolopyridine 17f (~8%). The Michael adduct (N-methylmorpholinium 5-(3-(phenylamino)-2-(N-phenylthiocarbamoyl)-1-(2-thienyl)-3-thioxopropyl)-2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-olate) 15f was identified by characteristic signals in the 1H and 13C NMR spectra: 1H NMR (400 MHz, DMSO-d6): 1.35 (br s, 6H, Me), 2.54 (s, 3H, NMe), 2.82–2.90 (m, 4H, CH2NCH2), 3.65–3.75 (m, 4H, CH2OCH2), 5.31 (d, 3J = 11.5 Hz, 1H, CH-Ar), 5.73 (d, 3J = 11.5 Hz, 1H, CH-CSNHPh), 10.78 (br s, 1H, C(S)NH), 11.78 (br s, 1H, C(S)NH). 13C DEPTQ NMR (101 MHz, DMSO-d6): 25.3* (2 CH3), 40.7* (CH–Ar), 43.8* (N–CH3), 53.5 (CH2NCH2), 64.4 (CH2OCH2), 74.6* (CH–CSNHPh), 99.6 (O–CMe2–O), 197.0 (C=S), 199.5 (C=S). Other signals of protons and carbons were difficult to identify due to complete or partial overlap. *Signals with a negative phase. Side products 16f and 17f were identified via two characteristic ABX-patterns of –CH2–CH– fragments at δ 2.65–3.08 ppm and 5.00–5.70 ppm. In addition, thiolate 16f was recognized via a peak at δ 15.81 ppm (C(S)NH) in 1H NMR and via peaks at δ 115.5 (C-3) and δ 188.7 (C=S) ppm in the 13C NMR spectrum. HRMS for 15f (ESI) m/z: calculated for C31H36N3O5S3 [M + H]+: 626.1817; found: 626.1813 (Δ 0.6 ppm); calculated for C26H25N2O4S3 [M + H–NMM]+: 525.0977; found: 525.0974 (Δ 0.6 ppm).
The reaction of 2,2-dimethyl-5-(3-nitrobenzylidene)-1,3-dioxane-4,6-dione 14g and dithiomalondianilide 1 (Table 1, entry 15). To a clear solution of 2,2-dimethyl-5-(3-nitro-benzylidene)-1,3-dioxane-4,6-dione 14b (250 mg, 0.9 mmol) and dithiomalondianilide 1 (260 mg, 0.9 mmol) in anhydrous acetone (15 mL), an excess (0.15 mL, 1.36 mmol) of N-methylmorpholine was added. The mixture was refluxed under vigorous stirring for 80 min (TLC control). No crystals appeared when the reaction mass was allowed to cool to room temperature. Acetone was evaporated under reduced pressure to give a viscous orange mass. Treatment with the cold mixture EtOH:acetone (1:1) resulted in the formation of a dark yellow crystalline solid (223 mg). According to the NMR, the product was a mixture of Michael adduct 15g, pyridine-2-thiolate 16g, and [1,2]dithiolo[3,4-b]pyridine 17g in a ~42:32:26 molar ratio (corresponds to ~110 mg of adduct 15g (18%), ~65 mg of thiolate 16g (14%), and ~48 mg of dithiolopyridine 17g (12%)) along with trace amounts of starting thioanilide 1. The identified signals of N-methylmorpholinium 2,2-dimethyl-5-(1-(3-nitro-phenyl)-3-(phenylamino)-2-(N-phenylthiocarbamoyl)-3-thioxopropyl)-4-oxo-4H-1,3-dioxin-6-olate (15g): 1H NMR (400 MHz, DMSO-d6): 1.31 (br s, 6H, Me), 2.69 (s, 3H, NMe), 2.98–3.06 (m, 4H, CH2NCH2), 3.70–3.77 (m, 4H, CH2OCH2), 5.22 (d, 3J = 12.1 Hz, 1H, CH-Ar), 5.93 (d, 3J = 12.1 Hz, 1H, CH-CSNHPh), 6.87–8.48 (m, 14H, Ar), 10.92 (s, 1H, C(S)NH), 11.95 (s, 1H, C(S)NH). 13C DEPTQ NMR (101 MHz, DMSO-d6): 25.9* (2 CH3), 43.4* (N–CH3), 45.3* (CH–Ar), 53.2 (CH2NCH2), 64.1 (CH2OCH2), 71.8* (CH–CSNHPh), 74.9 (C–C=O), 99.7 (O–CMe2–O), 197.0 (C=S), 198.8 (C=S). The signals of most of the aromatic protons and carbons were difficult to identify due to complete or partial overlap with the signals of side products. *Signals with a negative phase. The identified signals of N-methylmorpholinium 4-(3-nitrophenyl)-6-oxo-1-phenyl-3-(N-phenylthiocarbamoyl)-1,4,5,6-tetrahydropyridine-2-thiolate 16g: 1H NMR (400 MHz, DMSO-d6): 2.69 (s, 3H, NMe), 2.85 (dd, 2J = 15.7 Hz, 3J = 2.3 Hz, 1H, cis H-5), 2.98–3.06 (m, 4H, CH2NCH2), 3.10 (dd, 2J = 15.7 Hz, 3J = 6.0 Hz, 1H, trans H-5), 3.70–3.77 (m, 4H, CH2OCH2), 5.87–5.88 (m, 1H, H-4), 15.92 (br s, 1H, C(S)NHPh). 13C DEPTQ NMR (101 MHz, DMSO-d6): 36.0* (C-4), 38.0 (C-5), 43.4* (N–CH3), 53.2 (CH2NCH2), 64.1 (CH2OCH2), 116.1 (C-3), 166.9 (C-2), 168.2 (C=O), 188.8 (C=S). *Signals with a negative phase. The identified signals of 4-(3-nitrophenyl)-7-phenyl-3-(phenylimino)-4,5-dihydro-3H-[1,2]-dithiolo[3,4-b]pyridin-6(7H)-one 17g: 1H NMR (400 MHz, DMSO-d6): 2.95 (br d, 2J = 16.6 Hz, 1H, cis H-5), 3.63 (dd, 2J = 16.6 Hz, 3J = 8.1 Hz, 1H, trans H-5), 4.64–4.66 (m, 1H, H-4). 13C DEPTQ NMR (101 MHz, DMSO-d6): 40.2 (C-5), 40.3* (C-4), 112.8 (C-3a), 158.0 (C-7a), 163.6 (C-3), 168.4 (C-6). *Signals with a negative phase.
The reaction of 5-(4-methoxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione 14h and dithiomalondianilide 1 (Table 1, entries 16,17). To a clear solution of compound 14h (250 mg, 0.95 mmol) and dithiomalondianilide 1 (270 mg, 0.95 mmol) in anhydrous acetone (15 mL), an excess (0.16 mL, 1.43 mmol) of N-methylmorpholine was added. The mixture was refluxed under vigorous stirring and the formation of a small amount of crystalline product was detected within ~20 min. When the reaction was quenched after 1 h, acetone was evaporated under reduced pressure and the residue was treated with cold EtOH to give a yellow solid. According to the NMR, the product consisted mostly of unreacted 1 and 14h, but also contained the adduct 15h (27%), thiolate 16h (7%), and traces of dithiolopyridine 17h. According to the TLC, the reaction was completed in 4 h. The acetone was evaporated and the residue was treated with cold EtOH to give 220 mg of a yellow solid. However, the NMR spectrum revealed the signals of the starting thioamide 1. The main products were adduct 15h and dithiolopyridine 17h, along with small amounts of thiolate 16h (molar ratio ~53:37:10, corresponds to ~120 mg (19%) of 15h, 57 mg (13%) of 17h, and ~22 mg (4%) of 16h). The identified signals of N-methylmorpholinium 5-(1-(4-methoxyphenyl)-3-(phenylamino)-2-(N-phenylthiocarbamoyl)-3-thioxopropyl)-2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-olate (15h): 1H NMR (400 MHz, DMSO-d6): 1.29 (br s, 6H, 2 Me), 2.62 (s, 3H, NMe), 2.92–2.98 (m, 4H, CH2NCH2), 3.64 (s, 3H, MeO), 3.65–3.75 (m, 4H, CH2OCH2), 4.99 (d, 3J = 12.1 Hz, 1H, CH-Ar), 5.82 (d, 3J = 12.1 Hz, 1H, CH-CSNHPh), 6.64 (d, 3J = 8.7 Hz, 2H, H-3, H-5 4-MeOC6H4), 7.07–7.86 (m, 12H, Ar), 10.88 (s, 1H, C(S)NH), 11.77 (s, 1H, C(S)NH). 13C DEPTQ NMR (101 MHz, DMSO-d6): 25.5* (CH3), 26.2* (CH3), 43.4* (N–CH3), 44.3* (CH–Ar), 53.2 (CH2NCH2), 54.7* (OCH3), 64.1 (CH2OCH2), 73.5* (CH–CSNHPh), 76.2 (C–C=O), 99.4 (O–CMe2–O), 112.1* (C-3, C-5 4-MeOC6H4), 197.9 (C=S), 199.8 (C=S). The signals of most of the aromatic protons and carbons were difficult to identify due to complete or partial overlap with the signals of side products. *Signals with a negative phase. The identified signals of N-methylmorpholinium 4-(4-methoxyphe-nyl)-6-oxo-1-phenyl-3-(N-phenylthiocarbamoyl)-1,4,5,6-tetrahydropyridine-2-thiolate 16g: 1H NMR (400 MHz, DMSO-d6): 2.62 (s, 3H, NMe), 2.92–2.98 (m, 4H, CH2NCH2), 3.85 (s, 3H, MeO), 3.65–3.75 (m, 4H, CH2OCH2), 5.70–5.71 (m, 1H, H-4), 15.92 (s, 1H, CSNHPh). 13C DEPTQ NMR (101 MHz, DMSO-d6): 43.4* (N–CH3), 53.2 (CH2NCH2), 55.8* (OCH3), 64.1 (CH2OCH2), 113.2* (C-3, C-5 4-MeOC6H4), 117.4 (C-3), 165.9 (C-2), 168.7 (C=O), 189.0 (C=S). *Signals with a negative phase. The identified signals of 4-(4-methoxyphenyl)-7-phenyl-3-(phenylimino)-4,5-dihydro-3H-[1,2]dithiolo[3,4-b]pyridin-6(7H)-one 17g: 1H NMR (400 MHz, DMSO-d6): 2.81 (br d, 2J = 16.2 Hz, 1H, cis H-5), 3.51 (dd, 2J = 16.2 Hz, 3J = 7.8 Hz, 1H, trans H-5), 3.74 (s, 3H, MeO), 4.39–4.41 (m, 1H, H-4). 13C DEPTQ NMR (101 MHz, DMSO-d6): 35.7* (C-4), 38.5 (C-5), 55.1* (OCH3), 114.2 (C-3a), 114.3* (C-3, C-5 4-MeOC6H4), 133.0 (C1 4-MeOC6H4), 157.0 (C-7a), 158.3 (C4 4-MeOC6H4), 163.6 (C-3), 168.8 (C=O). *Signals with a negative phase. HRMS for 15h (ESI) m/z: calculated for C34H40N3O6S2 [M + H]+: 650.2359; found: 650.2353 (Δ 0.9 ppm); calculated for C29H29N2O5S2 [M + H–NMM]+: 549.1518; found: 549.1511 (Δ 1.3 ppm); HRMS for dithiolopyridine 17h (ESI) m/z: calculated for C25H21N2O2S2 [M + H]+: 445.1044; found: 445.1043 (Δ 0.2 ppm).
The reaction of 5-(4-hydroxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione 14i and dithiomalondianilide 1 (Table 1, entry 18). To a clear solution of compound 14i (250 mg, 1.007 mmol) and dithiomalondianilide 1 (290 mg, 1.007 mmol) in anhydrous acetone (15 mL), an excess (0.17 mL, 1.51 mmol) of N-methylmorpholine was added. The mixture was refluxed under vigorous stirring for 1.5 h (no crystalline precipitate appeared). Then, the reaction was quenched, the acetone was evaporated under reduced pressure, and the residue was treated with cold EtOH to give a yellow solid (167 mg). According to the NMR, the product consisted mostly of unreacted 1 and 14i, but also contained the adduct 15i (~20%) and traces of thiolate 16i (7%). The identified signals of N-methylmorpholinium 5-(1-(4-hydroxyphenyl)-3-(phenylamino)-2-(N-phenylthiocarbamoyl)-3-thioxopropyl)-2,2-di-methyl-4-oxo-4H-1,3-dioxin-6-olate (15i): 1H NMR (400 MHz, DMSO-d6): 1.30 (br s, 6H, 2 Me), 2.54 (s, 3H, NMe), 2.80–2.88 (m, 4H, CH2NCH2), 3.65–3.71 (m, 4H, CH2OCH2), 4.93 (d, 3J = 12.1 Hz, 1H, CH-Ar), 5.78 (d, 3J = 12.1 Hz, 1H, CH-CSNHPh), 6.47 (d, 3J = 8.4 Hz, 2H, H-3, H-5 4-HOC6H4), 7.36–7.37 (m, 2H, H-2, H-6 4-HOC6H4), 8.80 (br s, 1H, OH), 10.87 (s, 1H, C(S)NH), 11.71 (s, 1H, C(S)NH). 13C DEPTQ NMR (101 MHz, DMSO-d6): 25.4* (CH3), 26.3* (CH3), 43.8* (N–CH3), 44.4* (CH–Ar), 53.5 (CH2NCH2), 64.4 (CH2OCH2), 73.8* (CH–CSNHPh), 76.3 (C–C=O), 99.4 (O–CMe2–O), 113.5* (C-3, C-5 4-HOC6H4), 123.2* (C-2, C-6 Ph), 123.7* (C-2, C-6 Ph), 129.8* (C-2, C-6 4-HOC6H4), 134.4 (C-1 4-HOC6H4), 154.4 (C–OH), 163.7 (C–O−), 198.0 (C=S), 200.0 (C=S). The signals of most of the aromatic protons and carbons were difficult to identify due to complete or partial overlap with the signals of side products. *Signals with a negative phase. The identified signals of N-methylmorpholinium 4-(4-hydroxyphenyl)-6-oxo-1-phenyl-3-(N-phenylthiocarbamoyl)-1,4,5,6-tetrahydropyridine-2-thiolate (16i): 1H NMR (400 MHz, DMSO-d6): 2.54 (s, 3H, NMe), 2.66–2.75 (m, 1H, H-5), 2.80–2.88 (m, 4H, CH2NCH2), 3.65–3.71 (m, 4H, CH2OCH2), 5.66–5.68 (m, 1H, H-4), 15.92 (s, 1H, CSNHPh). The identified signals of starting dithiomalondianilide 1: 1H NMR (400 MHz, DMSO-d6): 4.28 (s, 2H, CH2), 7.84–7.87 (m, 4H, 2 H–2, H–6 Ph), 11.85 (br s, 2H, 2 NH). 13C DEPTQ NMR (101 MHz, DMSO-d6): 62.8 (CH2), 123.0* (2 C–2, 2 C–6 Ph), 126.2* (2 C–4 Ph), 128.6* (2 C–3, 2 C–5 Ph), 139.4 (2 C–1 Ph), 195.4 (C=S). The identified signals of 14i: 1H NMR (400 MHz, DMSO-d6): 1.71 (s, 6H, 2 Me), 6.89 (d, 3J = 8.8 Hz, 2H, H-3, H-5 4-HOC6H4), 8.17 (d, 3J = 8.8 Hz, 2H, H-2, H-6 4-HOC6H4), 8.25 (s, 1H, –CH=), 8.80 (br s, 1H, OH). 13C DEPTQ NMR (101 MHz, DMSO-d6): 26.9* (2 CH3), 103.9 (O–CMe2–O), 109.8 (C=CHAr), 115.9* (C-3, C-5 4-HOC6H4), 137.9* (C-2, C-6 4-HOC6H4), 157.0 (C–OH), 163.7 (C=O). HRMS for 15i (ESI) m/z: calculated for C33H38N3O6S2 [M + H]+: 636.2202; found: 636.2199 (Δ 0.5 ppm); calculated for C28H27N2O5S2 [M + H–NMM]+: 535.1361; found: 535.1356 (Δ 0.9 ppm); HRMS for unreacted dithiomalondianilide 1 (ESI) m/z: calculated for C15H15N2S2 [M + H]+: 287.0677; found: 287.0672 (Δ 1.7 ppm).
4-(4-(Dimethylamino)phenyl)-7-phenyl-3-(phenylimino)-4,5-dihydro-3H-[1,2]dithiolo[3,4-b]pyridin-6(7H)-one17j (Table 1, entry 19). To a clear solution of 5-[4-(dimethylamino)-benzylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione 14j (250 mg, 0.91 mmol) and dithio-malondianilide 1 (260 mg, 0.91 mmol) in anhydrous acetone (15 mL), an excess (0.15 mL, 1.36 mmol) of N-methylmorpholine was added. The mixture was refluxed under vigorous stirring for 80 min (monitored via TLC until the starting reagents were consumed). No crystalline precipitate appeared; the acetone was evaporated under reduced pressure and the tar residue was treated with warm (40 °C) BuOH to give a yellow solid. It was filtered off, and washed with BuOH, EtOH, and light petroleum to give 120 mg (29%) of pure dithiolopyridine 17j. 1H NMR (400 MHz, DMSO-d6): 2.78 (br d, 2J = 16.0 Hz, 1H, cis H-5), 2.87 (s, 6H, NMe2), 3.47 (dd, 2J = 16.0 Hz, 3J = 7.7 Hz, 1H, trans H-5), 4.33–4.35 (m, 1H, H-4), 6.74 (d, 3J = 8.7 Hz, 2H, H-3, H-5 4-Me2NC6H4), 6.91 (d, 3J = 7.5 Hz, 2H, H-2, H-6 N(7)Ph), 7.08–7.12 (m, 1H, H-4 N(7)Ph), 7.19 (d, 3J = 8.7 Hz, 2H, H-2, H-6 4-Me2NC6H4), 7.33–7.45 (m, 4H, Ph), 7.54–7.56 (m, 3H, Ph). 13C DEPTQ NMR (101 MHz, DMSO-d6): 35.6* (C-4), 38.6 (C-5), 40.2* (NMe2), 112.8* (C-3, C-5 4-Me2NC6H4), 114.7 (C-3a), 120.0* (C-2, C-6 PhN(7)), 124.5* (C-4 PhN(7)), 127.1* (C-2, C-6 4-Me2NC6H4), 128.4 (C-1 4-Me2NC6H4), 129.0* (C-2, C-6=N-Ph), 129.8* (4C, C-3, C-5 of both phenyls overlapped), 130.0* (C-4 Ph), 136.7 (C-1=N-Ph), 149.6 (C-4 4-Me2NC6H4), 150.9 (C-1 PhN(7)), 156.7 (C-7a), 163.7 (C-3), 168.9 (C-6). *Signals with a negative phase. Elemental Analysis (C26H23N3OS2, M 457.61): calculated (%): C, 68.24; H, 5.07; N, 9.18; found (%): C, 68.20; H, 5.19; N, 9.10.
4-(2-Chlorophenyl)-7-phenyl-3-(phenylimino)-4,5-dihydro-3H-[1,2]dithiolo[3,4-b]pyridin-6(7H)-one (17c). To a solution of Michael adduct 15c (225 mg, 0.344 mmol) in DMF (2 mL), an aqueous 10% solution of KOH (0.19 mL, 0.35 mmol) and corresponding chloroacetamide 20a–c (0.35 mmol) were added. The reaction mixture was stirred for 1.5 h, and then, diluted with water (15 mL). A yellowish solid was filtered off and recrystallized from EtOH–acetone (4:1) to give dithiolopyridine 17c as a yellow powder in a 45–56% yield. 1H NMR (400 MHz, DMSO-d6): 2.74 (dd, 2J = 16.3 Hz, 3J = 1.4 Hz, 1H, cis H-5), 3.64 (dd, 2J = 16.3 Hz, 3J = 8.3 Hz, 1H, trans H-5), 4.76–4.78 (m, 1H, H-4), 6.84 (dd, 3J = 8.3 Hz, 4J = 1.0 Hz, 2H, H-2, H-6 N(7)Ph), 7.06–7.10 (m, 1H, H-4 N(7)Ph), 7.31–7.43 (m, 3H, H-Ar), 7.37 (dd, 3J = 7.6 Hz, 4J = 1.6 Hz, 1H, H-Ar), 7.43–7.47 (m, 1H, H-Ar), 7.50–7.52 (m, 2H, H-Ar), 7.54–7.58 (m, 4H, H-Ar).
13C DEPTQ NMR (101 MHz, DMSO-d6): 34.2* (C-4), 36.9 (C-5), 112.0 (C-3a), 120.0* (C-2, C-6 PhN(7)), 124.5* (C-4 PhN(7)), 127.3* (CH-Ar), 128.2* (CH-Ar), 129.0* (C-2, C-6=N-Ph), 129.2* (CH-Ar), 129.7* (4C, C-3, and C-5 of both phenyls overlapped), 130.1* (C-4 Ph), 130.3* (CH-Ar), 132.6 (C-1 Ar), 136.5 (C-1=N-Ph), 137.4 (C–Cl), 150.6 (C-1 PhN(7)), 158.6 (C-7a), 163.2 (C-3), 167.9 (C-6). *Signals with a negative phase. FTIR, νmax, cm−1: 2982, 2868 (C-H); 1653 (C=N). Elemental Analysis (C24H17ClN2OS2, M 448.99): calculated (%): C, 64.20; H, 3.82; N, 6.24; found (%): C, 64.16; H, 3.95; N, 6.20.
X-ray studies for single crystals of 15b.
Single crystals of N-methylmorpholinium 2,2-dimethyl-5-(1-(2-nitrophenyl)-3-(phenylamino)-2-(N-phenylthiocarbamoyl)-3-thioxopropyl)-4-oxo-4H-1,3-dioxin-6-olate 15b (C33H36N4O7S2, M 664.78) were isolated from the reaction mixture (acetone solution). The crystal was kept at 100.01(11) K during data collection. Using Olex2 [94], the structure was solved with the olex2.solve structure solution program using Charge Flipping and refined with the SHELXL [95] package using Gauss-Newton minimization. The crystals were monoclinic, at 100.01(11) K: a = 14.39109(7) Å; b = 22.46449(13) Å; c = 20.81473(12) Å; α = 90°; β = 98.9856(5)°; γ = 90°; V = 6646.58(7) Å3; T = 100.01(11); space group P21/n (no. 14); Z = 8; μ(Cu Kα) = 1.896 mm−1; dcalc = 1.329 mg/mm3; F(000) = 2800.0; and 51297 reflections measured, 13563 unique (Rint = 0.0349), which were used in all calculations. The final wR2 was 0.0882 (all data) and the final R1 was 0.0336 (I > 2σ(I)). A full set of crystallographic data has been deposited at the Cambridge Crystallographic Data Center (CCDC 2218133).

4. Conclusions

Generally, the reaction of arylmethylidene Meldrum’s acids 14 with N,N′-diphenyldithiomalondiamide 1 leads to complex mixtures containing the expected Michael adducts 15 as the products of their further heterocyclization (pyridines 16) and oxidative transformation (dithiolopyridines 17). Pure Michael adducts 15 as sole products were isolated only in a few cases. Seemingly, the main factors determining the outcome of the reaction are the presence of electron-withdrawing substituents in the aromatic fragment of arylmethylidene Meldrum’s acids 14 (due to greater reactivity) and the low solubility of some Michael adducts 15 in a chosen solvent, as this prevents them from undergoing further transformations. The presence of donor substituents leads to longer reaction times and the incomplete conversion of starting reagents, and favors the formation of N-methylmorpholinium 4-aryl-6-oxo-3-(N-phenylthiocarbamoyl)-1,4,5,6-tetrahydro-pyridin-2-thiolates 16 and 4,5-dihydro-3H-[1,2]dithiolo[3,4-b]pyridin-6(7H)-ones 17 as side products. The attempts to run the alkylation of Michael adducts 15 with certain α-chloroacetamides proved to be unsuccessful, and only the oxidation products of [1,2]dithiolo[3,4-b]pyridin-6(7H)-ones 17 were isolated. A logical continuation of this study would involve, firstly, improvement of the reaction regiocontrol and, secondly, direct and selective synthesis of the adducts’ 15 transformation products—1,4,5,6-tetrahydropyridin-2-thiolates 16 and [1,2]dithiolo[3,4-b]pyridines 17.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijms232415997/s1.

Author Contributions

V.V.D.—conceptualization, supervision, investigation, data analysis, funding acquisition, writing (original draft, review and editing); A.V.A.—conceptualization, supervision, writing (review and editing); A.E.S.—investigation; E.A.V.—investigation; A.A.R.—investigation; A.G.L.—investigation; N.A.A.—data analysis; I.V.A.—supervision, data analysis. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Russian Science Foundation, grant number 22–23-00458, https://rscf.ru/en/project/22-23-00458/, accessed on 8 November 2022.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The file Electronic Supplementary Materials contains 1H and 13C DEPTQ NMR; 2D NMR 1H-13C HSQC; and 1H-13C HMBC, FTIR, and HRMS spectral charts for all the newly synthesized compounds (Figures S1–S72, S74–S81, Tables S1–S4), as well as X-ray crystallography data (Figure S73 and Tables S5–S11).

Acknowledgments

The authors are grateful to Azamat Z. Temerdashev (Environmental Analysis Center, Kuban State University) for enabling us to register the HRMS spectra using the equipment at the Environmental Analysis Center, unique identifier: RFMEFI59317X0008.

Conflicts of Interest

The authors declare no conflict of interest.

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Ijms 23 15997 sch001 550
Scheme 1. The diversity of reported dithiomalondianilide reactions.
Scheme 1. The diversity of reported dithiomalondianilide reactions.
Ijms 23 15997 sch001
Ijms 23 15997 sch002 550
Scheme 2. Synthesis and reactions of the Michael adducts 6.
Scheme 2. Synthesis and reactions of the Michael adducts 6.
Ijms 23 15997 sch002
Ijms 23 15997 sch003 550
Scheme 3. Synthesis of the Michael adduct 15a′.
Scheme 3. Synthesis of the Michael adduct 15a′.
Ijms 23 15997 sch003
Ijms 23 15997 sch004 550
Scheme 4. The reaction between dithiomalondianilide 1 and arylmethylidene Meldrum acids 14: products and possible mechanistic pathway.
Scheme 4. The reaction between dithiomalondianilide 1 and arylmethylidene Meldrum acids 14: products and possible mechanistic pathway.
Ijms 23 15997 sch004
Ijms 23 15997 g001 550
Figure 1. Hydrogen bonding in Michael adducts 15.
Figure 1. Hydrogen bonding in Michael adducts 15.
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Figure 2. ORTEP drawing of X-ray structure for N-methylmorpholinium 2,2-dimethyl-5-(1-(2-nitrophenyl)-3-(phenylamino)-2-(N-phenylthiocarbamoyl)-3-thioxopropyl)-4-oxo-4H-1,3-dioxin-6-olate 15b (CCDC deposition number 2218133).
Figure 2. ORTEP drawing of X-ray structure for N-methylmorpholinium 2,2-dimethyl-5-(1-(2-nitrophenyl)-3-(phenylamino)-2-(N-phenylthiocarbamoyl)-3-thioxopropyl)-4-oxo-4H-1,3-dioxin-6-olate 15b (CCDC deposition number 2218133).
Ijms 23 15997 g002
Ijms 23 15997 sch005 550
Scheme 5. Synthesis and plausible mechanism of formation of 4-(2-chlorophenyl)-7-phenyl-3-(phenylimino)-4,5-dihydro-3H-[1,2]dithiolo[3,4-b]pyridin-6(7H)-one 17c.
Scheme 5. Synthesis and plausible mechanism of formation of 4-(2-chlorophenyl)-7-phenyl-3-(phenylimino)-4,5-dihydro-3H-[1,2]dithiolo[3,4-b]pyridin-6(7H)-one 17c.
Ijms 23 15997 sch005
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Dotsenko, V.V.; Aksenov, A.V.; Sinotsko, A.E.; Varzieva, E.A.; Russkikh, A.A.; Levchenko, A.G.; Aksenov, N.A.; Aksenova, I.V. The Reactions of N,N′-Diphenyldithiomalondiamide with Arylmethylidene Meldrum’s Acids. Int. J. Mol. Sci. 2022, 23, 15997. https://doi.org/10.3390/ijms232415997

AMA Style

Dotsenko VV, Aksenov AV, Sinotsko AE, Varzieva EA, Russkikh AA, Levchenko AG, Aksenov NA, Aksenova IV. The Reactions of N,N′-Diphenyldithiomalondiamide with Arylmethylidene Meldrum’s Acids. International Journal of Molecular Sciences. 2022; 23(24):15997. https://doi.org/10.3390/ijms232415997

Chicago/Turabian Style

Dotsenko, Victor V., Alexander V. Aksenov, Anna E. Sinotsko, Ekaterina A. Varzieva, Alena A. Russkikh, Arina G. Levchenko, Nicolai A. Aksenov, and Inna V. Aksenova. 2022. "The Reactions of N,N′-Diphenyldithiomalondiamide with Arylmethylidene Meldrum’s Acids" International Journal of Molecular Sciences 23, no. 24: 15997. https://doi.org/10.3390/ijms232415997

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