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

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.

It is worth noting that while cyanothioacetamide NCCH 2 C(S)NH 2 [24][25][26][27] and βketothioamides [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.

Results and Discussion
Initially, we choose 4-nitrobenzylidene Meldrum's acid (2,2-dimethyl-5-(4-nitrobenzyli dene)-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 Et 3 N, yielding 34% of the stable Michael adduct 15a (Scheme 3) ( Table 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 CH 2 Cl 2 and ClCH 2 CH 2 Cl partially dissolve 1, but cannot be used because of their alkylating effects.
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-NO 2 C 6 H 4 ) 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 ã 3:1 ratio (Table 1, entries 6,7) (Scheme 4). Meanwhile, the NMR spectra of Michael adduct 15c prepared by heating 1 with 2,2dimethyl-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-ClC 6 H 4 ) and 14e (Ar = 2,4-Cl 2 C 6 H 3 ) 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). 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).
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.
The structure of all the prepared compounds was confirmed via FT-IR and NMR spectroscopy (including DEPTQ 13 C, 2D NMR 1 H- 13  In turn, the 1 H and 13 C 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 1 H chemical shifts between C(S)NH peaks reaches ∆ 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 ∆ 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, NO 2 ). Another characteristic feature of the 1 H NMR spectra of the Michael adducts 15 is that the signals of CH-CH protons appear as a pair of doublets with coupling constants, 3 J = 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 αchloroacetamides 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.

Materials and Methods
1 H and 13 C DEPTQ NMR spectra were recorded and 2D NMR experiments conducted in solutions of DMSO-d 6 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-d 6 (2.49 ppm for 1 H, and 39.50 ppm for 13 C 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 HCO 2 Na-HCO 2 H 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].