6-Amino-4-phenylpyrrolo[2,3-c][1,2,6]thiadiazine-5-carbonitrile

Abstract

The reaction of 2-(3-chloro-5-phenyl-4H-1,2,6-thiadiazin-4-ylidene)malononitrile with ammonia in anhydrous THF, at ca. 20 °C, for 24 h, gave 6-amino-4-phenylpyrrolo[2,3-c][1,2,6]thiadiazine-5-carbonitrile in 95% yield. The product was characterized by ¹H and ¹³C NMR, SC-XRD, MALDI-TOF mass spectrometry, FTIR, and UV-vis spectroscopy. Intermolecular hydrogen bonding interactions were observed in the solid state between the C≡N and N-H groups of adjacent molecules.

1. Introduction

Pyrroles are versatile heterocycles that continue to attract significant attention due to their broad utility across medicinal and materials chemistry. In drug development, pyrrole motifs are present in clinically important compounds such as the antilipemic agent atorvastatin [1], the anti-inflammatory drug tolmetin [2], and the kinase inhibitor sunitinib [3] (Figure 1). Beyond pharmaceuticals, pyrrole derivatives have been employed in organic electronics, including organic photovoltaics, field-effect transistors [4], gas sensors [4,5], and functional dyes [6]. Comprehensive reviews of their synthesis, reactivity, and applications are available [7,8].

Several [b]-fused pyrrole systems incorporating six-membered rings are known, the most prominent being indoles [9]. Nitrogen-containing analogs such as azaindoles [10], pyrrolopyrimidines [11], and pyrrolopyridazines [12] are also well established. In contrast, pyrroles fused to six-membered sulfur- or mixed sulfur/nitrogen-heterocycles are considerably less common, with only a few examples, such as tetrahydrothiopyrane analogs, reported [6].

We are interested in pyrrolo[2,3-c][1,2,6]thiadiazines, of which only five examples have been reported to date: compounds 2ab, 3ab, and 4 (Figure 2). Notably, four of these are derived from 2-(3,5-dichloro-4H-1,2,6-thiadiazin-4-ylidene)malononitrile (1) [13,14], while compound 2a originates from 2-(3-chloro-5-phenyl-4H-1,2,6-thiadiazin-4-ylidene)malononitrile (5) [15]. In all cases, the pyrrole ring is formed via intramolecular cyclization of an amine onto one of the nitrile groups of the corresponding ylidene. Consequently, all analogs retain the remaining 5-cyano substituent and feature a 6-imine group (Figure 2).

2. Results and Discussion

Inspired by the reaction of 2-(3-chloro-5-phenyl-4H-1,2,6-thiadiazin-4-ylidene)malononitrile (5) with aniline to afford the pyrrolo[2,3-c][1,2,6]thiadiazine 2a [15], we investigated the synthesis of the primary amine analog 6 (Scheme 1). Treatment of ylidene 5 with gaseous ammonia in anhydrous THF at ca. 20 °C gave pyrrole 6 in 95% yield. The product was isolated as yellow needles [mp 295–296 °C (from PhH/MeCN)], and its yellow color in solution [λ_max (DCM) 440 nm, log ε 4.45] indicated the presence of the thiadiazine chromophore. Mass spectrometry [m/z 254 (MH⁺)] and elemental analysis were consistent with the molecular formula C₁₂H₇N₅S. The FTIR spectrum showed absorptions corresponding to a nitrile [ν(C≡N) 2220 cm⁻¹] and an amine [ν(N-H) 3343 cm⁻¹]. The ¹³C NMR spectrum confirmed the presence of 7 quaternary carbon atoms (see Supporting Information, SI).

Single crystals of compound 6, obtained as yellow plates, were prepared by vapor diffusion of water into a DMSO solution, and their structure was determined by single-crystal X-ray diffraction (Figure 3). The thiadiazine moiety of 6 was planar, while the phenyl group exhibited a torsion angle of 48° relative to the thiadiazine ring (Figure 3). The crystal structure confirmed the exocyclic amino tautomer depicted above, ruling out the possible exocyclic imine form (Scheme 1).

The ¹H NMR spectrum showed two distinct signals for the amino protons at δ 8.79 and 8.37, indicating hindered rotation characteristic of amidine-type primary amines [13,16]. In contrast, related compounds, such as 3-amino-4-cyanopyrazole [17,18] and 3-cyano-4-aminofurazan [19,20], typically display a single broad signal. The more upfield resonance at δ 8.79 is likely due to shielding by the anisotropic cone of the adjacent nitrile group; a phenomenon well demonstrated for cyano substituents [21,22].

In the solid state, compound 6 adopts a herringbone packing motif (Figure 4), featuring intermolecular hydrogen bonds between cyano (C≡N) and amino (N-H) groups of adjacent molecules, with distances [d_(N…H-N)] of 3.009 and 3.038 Å (Figure 5).

We tentatively propose two possible mechanisms for the formation of compound 6 (Scheme 2), both initiated by nucleophilic attack by ammonia. In Route A, ammonia displaces the C3-chloride of thiadiazine 5 to give intermediate 7. Cyclization then occurs onto the adjacent cyano group to form pyrrole 8, followed by tautomerization to yield 6. It is also possible that initial addition occurs at the trans cyano group of 5, with subsequent rotation of the ylidene double bond (facilitated by electron donation from the ring sulfur), leading again to intermediate 7.

In Route B, ammonia instead adds to the electrophilic cyano group, generating amidine intermediate 9. Cyclization then takes place onto the C3 position of the thiadiazine ring to directly afford product 6. At this stage, it is unclear which part of the amidine cyclizes; the process may proceed via a resonance form, involving electron delocalization from the primary to the secondary nitrogen. Regardless of the pathway, the key step appears to be the initial nucleophilic attack, either at C3 or at the nitrile.

Pyrrolo[2,3-c][1,2,6]thiadiazine 6 may serve as a useful synthetic scaffold due to the presence of the readily functionalizable amino and cyano groups, which could enable incorporation of this rare bicyclic motif into biologically active molecules, although such applications are not currently the focus of our work.

3. Materials and Methods

The reaction mixture was monitored by TLC using commercial glass-backed thin-layer chromatography (TLC) plates (Merck Kieselgel 60 F₂₅₄). The plates were observed under UV light at 254 and 365 nm. The melting point was determined using a PolyTherm-A, Wagner & Munz, Kofler—Hotstage Microscope apparatus (Wagner & Munz, Munich, Germany). The solvent used for recrystallization is indicated after the melting point. The UV-vis spectrum was obtained using a Perkin-Elmer Lambda-25 UV/vis spectrophotometer (Perkin-Elmer, Waltham, MA, USA) and inflections are identified by the abbreviation “inf”. The IR spectrum was recorded on a Shimadzu FTIR-NIR Prestige-21 spectrometer (Shimadzu, Kyoto, Japan) with Pike Miracle Ge ATR accessory (Pike Miracle, Madison, WI, USA) and strong, medium and weak peaks are represented by s, m, and w, respectively. ¹H and ¹³C NMR spectra were recorded on a Bruker Avance 500 machine at 500 and 125 MHz, respectively (Bruker, Billerica, MA, USA). Deuterated solvents were used for homonuclear lock, and the signals are referenced to the deuterated solvent peaks. Attached proton test (APT) NMR studies were used for the assignment of the ¹³C peaks as CH₃, CH₂, CH, and Cq (quaternary). The MALDI-TOF mass spectrum (+ve mode) was recorded on a Bruker Autoflex III Smartbeam instrument (Bruker). For the X-ray crystallography, each crystal was coated in paraffin oil and mounted on a Molecular Dimensions Litholoop and placed directly into the cold stream of the Bruker D8 Venture diffractometer (Bruker, Billerica, MA, USA). Single crystal X-ray diffraction data were collected using a Cu-Kα (λ = 1.5418 Å) on a XtaLAB Synergy, Single source at home/near, HyPix diffractometer (Rigaku, Tokyo, Japan), using Bruker’s APEX3 program suite [23], with the crystal kept at 180.0 K during data collection. The structures were solved using Olex2 [24], with the olex2.solve [25] structure solution program using Charge Flipping and refined with the SHELXL [26] refinement package using Least Squares minimization. The program Mercury 2022.2.0 (Cambridge, UK) was used to generate all the X-ray pictures. 2-(3-Chloro-5-phenyl-4H-1,2,6-thiadiazin-4-ylidene)malononitrile (5) [15] was prepared according to the literature procedure.

6-Amino-4-phenylpyrrolo[2,3-c][1,2,6]thiadiazine-5-carbonitrile (6)

A stirred solution of 2-(3-chloro-5-phenyl-4H-1,2,6-thiadiazin-4-ylidene)malononitrile (5) (27.3 mg, 0.100 mmol) in anhydrous THF (2 mL) at ca. 0 °C was purged with NH₃ (g) for 1 min. The flask was then sealed with a suba seal^® septa and allowed to warm to ca. 20 °C and stirred at this temperature until no starting material remained (TLC, 24 h). The mixture was then adsorbed onto silica and chromatographed (Acetone) to give the title compound 6 (24.1 mg, 95%) as yellow needles, mp 295-296 °C; R_f 0.89 (Acetone); (found: C, 56.98; H, 2.64; N, 27.41. C₁₂H₇N₅S requires C, 56.91; H, 2.79; N, 27.65%); λ_max(CH₂Cl₂)/nm 274 (log ε 4.73), 326 (4.13), 426 inf (4.43), 440 (4.45); ν_max/cm⁻¹ 3343m (N-H), 3238w and 3152m (C-H), 2220m (C≡N), 1667s, 1655s, 1651s, 1572s, 1566s, 1551m, 1500m, 1489m, 1447w, 1408m, 1379m, 1344s, 1314m, 1290w, 1200w, 1175w, 1155w, 1125w, 1096w, 1080m, 1026w, 1001w, 986w, 943w, 870m, 858m, 804s, 797m, 781m, 756s, 735m; δ_H(500 MHz; DMSO-d₆) 8.79 (1H, br. S, NH), 8.37 (1H, br. S, NH), 7.72–7.70 (2H, m, Ar CH), 7.58–7.55 (3H, m, Ar CH); δ_C(125 MHz; DMSO-d₆) 169.9 (Cq), 162.4 (Cq), 152.3 (Cq), 135.8 (Cq), 130.3 (CH), 128.8 (CH), 128.3 (CH), 125.0 (Cq), 113.7 (Cq), 84.9 (Cq); m/z (MALDI-TOF) 254 (MH⁺, 100%), 238 (MH⁺-NH₂, 31), 237 (M⁺-NH₂, 71), 227 (MH⁺-CN, 49), 207 (45).