The First Synthesis of [1,2]oxaphosphinino[6,5-c]pyrazoles by Thiophosphorylation of 6-Aminopyrano[2,3-c]pyrazole-5-Carbonitriles ^†

Abstract

The reaction of 6-amino-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles with phosphorus sulfide in boiling pyridine leads to the formation of the unexpected [1,2]oxaphosphinino[6,5-c]pyrazoles. The structure of the products was confirmed with 2D Nuclear Magnetic Resonance (NMR) spectroscopy and X-ray analysis.

6-Аmino-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles 1, which is easily available using three-component condensation of aldehydes with malononitrile and pyrazole-5-ones (Scheme 1), attract attention due to their exceptional availability and simple preparation. This class of compounds and their analogs of 2-amino-3-cyano-4H-pyran and -chromene series have an interesting profile of biological activity (for reviews, see [1,2,3,4]).

However, despite the availability, the reactions of compounds 1 are relatively poorly studied [1]. Meanwhile, the presence of an enaminonitrile fragment in molecule 1 makes this class of compounds a promising substrate for further transformations. Thiophosphorylation of enaminonitriles (ortho-aminocarbonitriles) using P₄S₁₀ or Lawesson reagent (LR, 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane) was reported to afford 1,3,2λ⁵-diazaphosphinanes [5,6,7,8,9,10,11]. For 2-amino-3-cyano-4H-pyran and chromenes, such reactions have been described in only a few recent papers. Thus, according to the known data, 1,3,2λ⁵-diazaphosphinanes 2–4 [12,13,14] or 1,3,2λ⁵-thiaazaphosphinanes 5,6 [15] were prepared through the thiophosphorylation (Scheme 2). It is noteworthy that compound 6 possess promising fungicidal activity [16], while compounds 2 possess antitumor activity and are tyrosinase inhibitors [12].

In continuation of our studies of diazaphosphinanes’ chemistry [17], we report the reaction of 6-amino-4-aryl-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles with phosphorus sulfide. Aiming to obtain pyrazolo[4′,3′: 5,6]pyrano[2,3-d][1,3,2]diazaphosphinanes 7 (Scheme 3), we first reacted phosphorus sulfide with boiling pyridine to form the adduct P₂S₅ × 2 C₅H₅N 8, and then added pyranopyrazols 1 to the solution of the adduct 8. The analysis of the Nuclear Magnetic Resonance (NMR) spectra as well as the X-ray diffraction data of the prepared compounds allowed us to conclude that the products of the reactions are not diazaphosphinanes, but pyridinium 4-aryl-3,3-dicyano-5-methyl-2-thioxo-3,4-dihydro[1,2]oxaphosphinino[6,5-c]pyrazole-2(6H)-thiolates 9 (Scheme 3).

The proposed mechanism for the formation of compounds 9 probably involves the formation of dinitrile 10, an acyclic tautomer of the starting pyranopyrazole 1. Dinintrile 10 then was thiophosphorylated at oxygen atom with P₂S₅ × 2 C₅H₅N 8. The subsequent intramolecular nucleophilic attack of the dicyanomethyl anion on a phosphorus atom resulted in the closure of 1,2-oxaphosphinine ring. It is noteworthy that 1,2-oxaphosphinines are a relatively poorly studied heterocyclic system and [1,2]oxaphosphinino[6,5-c]pyrazoles were not described in the literature to date.

Figure 1. HSQC (Heteronuclear single quantum correlation) ¹H–¹³C Nuclear Magnetic Resonance (NMR) experiment (400/101 MHz, DMSO-d₆) spectrum of 9 (Ar = 2,4-Cl₂C₆H₃).

Figure 1. HSQC (Heteronuclear single quantum correlation) ¹H–¹³C Nuclear Magnetic Resonance (NMR) experiment (400/101 MHz, DMSO-d₆) spectrum of 9 (Ar = 2,4-Cl₂C₆H₃).

Figure 2. The chemical shifts in the ¹H NMR (left) and ¹³C NMR (right) spectra of 9а.

Figure 2. The chemical shifts in the ¹H NMR (left) and ¹³C NMR (right) spectra of 9а.

Figure 3. HMBC (Heteronuclear Multiple Bond Correlation) ¹H–¹³C NMR experiment (400/101 MHz, DMSO-d₆) spectrum of 9а.

Figure 3. HMBC (Heteronuclear Multiple Bond Correlation) ¹H–¹³C NMR experiment (400/101 MHz, DMSO-d₆) spectrum of 9а.

Figure 4. Single crystal X-ray of compound 9а.

Figure 4. Single crystal X-ray of compound 9а.

Experimental

Infrared (IR) spectra were recorded on a Bruker Vertex 70 spectrometer. NMR spectra were recorded on a Bruker Avance III HD (400 MHz for ¹H, 162 MHz–³¹P, 101 MHz for ¹³С) in DMSO-d₆. Selected experimental procedure (synthesis of 9a) is given.

Pyridinium 4-(2,4-dichlorophenyl)-3,3-dicyano-5-methyl-2-thioxo-3,4-dihydro[1,2]oxaphosphinino[6,5-c]pyrazole-2(6H)-thiolate (9a), a solution of P₄S₁₀ (1.11 g, 2.5 mmol) in absolute pyridine (20 mL), was refluxed for 2 h to form a clear solution of the adduct P₂S₅ × 2 C₅H₅N. To the resulting solution of the adduct, a solution of pyrano[2,3-c]pyrazole 1a (0.8 g, 2.5 mmol) in 10 mL of absolute pyridine was added, and the mixture then was refluxed for another 6 h (TLC (thin layer chromatography) control). After cooling, the reaction mixture was poured into ice water and carefully adjusted with 5% HCl to pH 5. The precipitate formed was filtered off, washed with water, and recrystallized from absolute dioxane. The yield of compound 9a was 11%, yellow powder. For X-ray analysis, a pale-yellow monocrystalline material was prepared from an acetonic solution by slow evaporation.

IR spectrum, ν, cm⁻¹ is as follow: 3417, 3202 (N–H), 2237 (C ≡ N), 1634, 1582 (С = N, С = С). ¹H NMR spectrum (400 MHz), δ, ppm (J, Hz): 1.44 s (3Н, СН₃), 4.56 d (1Н, Н⁴, ³J_P-H 4.7 Hz), 7.53 d (1Н, H⁶ Ar, ³J 8.6 Hz), 7.57 dd (1Н, H⁵ Ar, ³J 8.6 Hz, ⁴J 1.7 Hz), 7.83 d (1Н, H³ Ar, ⁴J 1.7 Hz), 8.00-8.04 m (2Н, H³, H⁵ Py), 8.54 АВ₂-pattern (1H, H⁴ Py, ³J 7.7 Hz), 8.90 d (2H, H², H⁶ Py, ³J 5.6 Hz), 12.19 br.s (1Н, NH). The signal of NH⁺ was not detected probably due to H-D exchange.

³¹P NMR spectrum (162 МHz, DMSO-d₆), δ, ppm is as follows: 99.47.

¹³С NMR DEPTQ (distorsionless enhancement by polarization transfer including the detection of quaternary nuclei) spectrum (101 МHz, DMSO-d₆), δ_C, ppm is as follows: 10.9* (СН₃), 41.5* br.s (C⁴H), 49.2 d(С³, ¹J_P-С 35.2 Hz), 95.5 d (С^4а, ³J_P-С 7.3 Hz), 113.9 d (C≡N, ²J_P-С 26.4 Hz), 114.0 d (C ≡ N, ²J_P-С 32.3 Hz), 127.0* (C³, С⁵ Py), 128.1* (С⁵ Ar), 129.4* (С³ Ar), 132.2* (С⁶ Ar), 132.7 d (С¹ Ar, ³J_P-С 7.3 Hz), 134.2 (C² Ar), 134.9 (C⁴ Ar), 136.7 (C⁵), 142.8* (C²,С⁶ Py), 145.6* (C⁴ Py), 155.0 д (C^7a, ³J_P-С 5.9 Hz). *Opposite signals.