Microwave Assisted Synthesis, Crystal Structure and Hirshfeld Surface Analysis of Some 2-Formimidate-3-carbonitrile Derivatives Bearing 4H-Pyran and Dihydropyridine Moieties

Abstract

Two 4H-pyran- and four dihydropyridine-based 2-formimidate-3-carbonitrile derivatives were synthesized via the conventional solvothermal and microwave radiation methods. The use of the latter technique led to the formation of the desired products in the order of minutes as compared to the former. The formation of the 2-formimidate-3-carbonitrile derivatives was confirmed using spectroscopic techniques whilst the molecular geometry and intermolecular interactions were investigated using single-crystal X-ray diffraction. The formimidate functional group was found to adopt an E configuration in all compounds and this coincides with those of closely related compounds on the Cambridge Structural Database (CSD). Classical but weak intermolecular C—H…O, C—H…N and C—H…π hydrogen bonds were observed in the crystal lattice. According to the Hirshfeld surface analysis, the C—H…π hydrogen bonds contributed the most towards the Hirshfeld surface (14.3–23.9%) than the other two hydrogen bonding types (9.6–12.7%).

1. Introduction

Compounds that contain 2-formimidate-3-carbonitrile moieties have gained attention in the synthesis of biologically active heterocycles, i.e., fused pyrimidines. The medicinal potency and function of fused pyrimidines can be tweaked by varying the nature of the ring that is adjoined to the pyrimidine [1]. For instance, 4H-pyran-fused pyrimidines have recently been used as potential antimicrobial [2,3,4], antiproliferative [5] and anticancer [6] agents whilst dihydropyridine-fused pyrimidines exhibit antidiabetic [7] and antioxidant [8] properties, amongst others. Although fused pyrimidines can be synthesized using precursors containing 2-formimidate-3-carbonitrile moieties, it is worth mentioning that they can also be formed using compounds bearing 2-formamidine-3-carbonitrile [2]. Using the former and latter precursors leads to the formation of ethanol [9] and dimethylamine [10] as by-products, respectively. Since ethanol is more environmentally friendly than dimethylamine, the use of 2-formimidate-3-carbonitrile precursors is ideal.

The conventional method of synthesizing 2-formimidate-3-carbonitrile derivatives involves a solvothermal reaction of the corresponding 2-amino-carbonitrile precursor and triethyl orthoformate in the presence of a suitable catalyst. Though the desired product is often isolated in good yields, the reaction times are often in the order of hours [11,12,13,14,15,16,17,18,19,20,21,22,23]. Thus, there is a need to explore other synthetic protocols that can significantly reduce the reaction times without compromising the reaction yields. Since these compounds are intermediates in the synthetic route of fused pyrimidines, there are very few structure-related reports on them.

In this work, we report the microwave-assisted synthesis of some novel 4H-pyran- and dihydropyridine-bearing 2-formimidate-3-carbonitrile derivatives. We hypothesize that using microwave radiation will lead to shorter reaction times whilst maintaining or improving the reaction yields. We also investigated their preferred molecular geometry and the intermolecular interactions in the solid-state using single-crystal X-ray diffraction. The intermolecular interactions were further studied using Hirshfeld surface analysis.

2. Materials and Methods

All chemicals used in the syntheses of target molecules were of reagent grade purchased from commercial sources. These included: 2-fluorobenzaldehyde, 9-anthracenecarboxaldehyde, benzaldehyde, malonitrile, dimedone, ethanol, methanol, triethyl orthoformate, acetic acid, 4-bromoaniline, 4-methylaniline, and aniline. DMSO-d₆ was used as a solvent in solution NMR studies. ¹H- and ¹³C-NMR spectra were recorded on a BRUKER 400 MHz (Karlsruh, German) spectrometer at room temperature and were referenced internally using the chosen deuterated solvent (see Supplementary Materials Figures S1–S12). Infrared spectra were recorded using a PerkinElmer (Waltham, MA, USA) spectrum 100 FT-IR spectrometer, and the data are reported as percentage transmittances from 4000 cm⁻¹ to 400 cm⁻¹ (see Supplementary Materials Figures S13–S17). Microwave reactions were carried out using a CEM Discover system. All reactions were performed in 30 mL pressurized vials fitted with “snap-on” caps. The 2-amino-4-(aryl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (i-a and i-b) and 2-amino-1-phenyl-7,7-dimethyl-5-oxo-4-(aryl)-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (i-c to i-f) precursors were synthesized using a modified procedure from the literature [24]. A Thermo-Scientific Flash 2000 was used to determine the elemental composition, and the melting-point determination was carried out using the Stuart Scientific SMP3 (Staffordshire, United Kingdom) melting-point apparatus.

2.1. General Procedure for the Conventional Solvothermal Synthesis of 2-Formimidate-3-carbonitrile Derivatives (ii-a to ii-f)

Triethyl orthoformate (20 mL), acetic acid (1 mL) and the corresponding 2-amino-3-carbonitrile precursor (2 mmol) were added to a 50 mL round bottom flask. The mixture was refluxed, and the reaction was monitored using TLC. Initially, the mixture had a very pale yellow colour, which gradually turned to dark red over the course of eight hours. The mixture was then left open overnight in the fume hood to allow evaporation of the excess triethyl orthoformate. The pure product was obtained by hot recrystallization using ethanol, filtered and dried under vacuum.

2.2. General Procedure for the Microwave Synthesis of 2-Formimidate-3-carbonitrile Derivatives (ii-a to ii-f)

Triethyl orthoformate (20 mL), acetic acid (1 mL) and the corresponding 2-amino-3-carbonitrile precursor (2 mmol) were added to a sealed 30 mL pressurized vial. The mixture was irradiated at 120 W in a single-mode microwave synthesis system. The reaction temperature was set at 150 °C for a duration of 20 min. The color of the mixture changed from colorless to dark red, signifying the completion of the reaction (confirmed via TLC). The mixture was then left open overnight in the fume hood to allow evaporation of the excess triethyl orthoformate. The pure product was obtained by hot recrystallization using ethanol, filtered and dried under vacuum.

2.2.1. Ethyl (E)-N-(3-Cyano-4-(2-fluorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromen-2-yl)formimidate (ii-a)

Compound i-a was used as the 2-amino-3-carbonitrile precursor. Pale brown solid, yield (conventional solvothermal reaction) = 0.630 g (85%), yield (using microwave-assisted reaction) = 0.648 g (88%); m.p: 205–207 °C; IR (selected ν_max, cm⁻¹): 2946 (C—H), 2213 (C≡N), 1612 (C=O); ¹H-NMR δ(ppm): 0.99 (s, 3H, CH₃), 1.06 (s, 3H, CH₃), 1.28–1.32 (t, 3H, ³J = 7.1 Hz, CH₃ formimidate), 2.12–2.16 (d, 1H, ²J = 16,2 Hz), 2.26–2.30 (d, 1H, ²J = 16.2 Hz), 2.53–2.58 (d, 1H, ²J = 17.9 Hz and ²J = 17.8 Hz), 4.28-4.34 (m, 2H, CH₂ formimidate), 4.70 (s,1H, H_methine), 7.15–7.19 (m, 2H, H_aromatic), 7.26–7.33 (m, 2H, H_aromatic), 8.56 (s, 1H, N=C(H_formimidate)—O); ¹³C-NMR δ (ppm): 14.3, 27.2, 28.8, 31.7, 32.4, 50.4, 64.6, 81.3, 110.9, 115.9, 116.1, 117.5, 125.1, 125.2, 129.7, 129.9, 130.6, 156.9, 159.2, 161.7, 162.5, 164.0, 196.1; Anal. Calcd. (%) for [C₂₁H₂₁FN₂O₃]: C, 68.47; H, 5.75; N, 7.60; O, 13.03; found (%): C, 68.23; H, 5.73; N, 7.57; O, 12.98.

2.2.2. Ethyl (E)-N-(4-(Anthracen-9-yl)-3-cyano-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromen-2-yl)formimidate (ii-b)

Compound i-b was used as the 2-amino-3-carbonitrile precursor. Yellow solid, yield (using microwave-assisted reaction) = 0.802 g (89%), yield (using microwave-assisted reaction) = 0.838 g (93%); m.p: 192–194 °C; IR (selected ν_max, cm⁻¹): 2957 (C—H), 2206 (C≡N), 1604 (C=O); ¹H-NMR δ(ppm): 0.83 (s, 3H, CH₃), 1.05 (s, 3H, CH₃), 1.26-1.30 (t, 3H, ³J = 7.1 Hz, CH₃ formimidate), 1.92-1.96 (d, 1H, ²J = 16,2 Hz), 2.13-2.17 (d, 1H, ²J = 16.2 Hz), 2.60–2.70 (overlapping doublets, 2H, ²J = 18.0 Hz and ²J = 18.0 Hz), 4.26–4.34 (m, 2H, CH₂ formimidate), 6.25 (s,1H, H_methine), 7.46–7.49 (m, 2H, H_aromatic), 7.54–7.62 (m, 2H, H_aromatic), 8.10–8.15 (m, 3H, H_aromatic), 8.59 (s, 1H, H_aromatic), 8.68 (s, 1H, N=C(H_formimidate)—O), 8.70–8.72 (d, 1H, ³J = 9.0 Hz, H_aromatic); ¹³C-NMR δ (ppm): 14.2, 27.1, 28.9, 31.6, 31.9, 50.4, 64.8, 82.8, 113.4, 117.4, 123.2, 124.8, 125.1, 125.6, 126.3, 126.9, 128.6, 129.4, 129.5, 130.4, 131.3, 132.9, 156.4, 162.4, 163.4, 196.7; Anal. Calcd. (%) for [C₂₉H₂₆N₂O₃]: C, 77.31; H, 5.82; N, 6.22; O, 10.65; found (%): C, 77.09; H, 5.80; N, 6.20; O, 10.62.

2.2.3. Ethyl (E)-N-(3-Cyano-4-(2-fluorophenyl)-7,7-dimethyl-5-oxo-1-phenyl-1,4,5,6,7,8-hexahydroquinolin-2-yl)formimidate (ii-c)

Compound i-c was used as the 2-amino-3-carbonitrile precursor. Pale yellow solid, yield (microwave-assisted reaction) = 0.833 g (94%), yield (microwave-assisted reaction) = 0.798 g (90%); m.p: 197–199 °C; ¹H-NMR δ(ppm): 0.78 (s, 3H, CH₃), 0.81–0.85 (t, 3H, ³J = 6.3 Hz, CH₃ formimidate) 0.88 (s, 3H, CH₃), 1.83–1.87 (d, 1H, ²J = 17,5 Hz), 1.97–2.01 (d, 1H, ²J = 16.2 Hz), 2.07 (2H, CH₂ formimidate), 2.17–2.22 (overlapping doublets, 2H, ²J = 18.5 Hz and ²J = 15.6 Hz), 4.89 (s,1H, H_methine), 7.14–7.22 (m, 2H, H_aromatic), 7.27–7.28 (m, 3H, H_aromatic), 7.39–7.52 (m, 4H, H_aromatic), 7.90 (s, 1H, N=C(H_formimidate)—O); ¹³C-NMR δ (ppm): 13.7, 26.6, 29.4, 31.1, 32.4, 32.9, 41.2, 49.6, 63.6, 74.2, 109.2, 115.8, 120.0, 125.2, 129.4, 129.9, 130.6, 132.2, 137.9, 152.0, 153.9, 159.1, 160.2, 161.6, 195.7; Anal. Calcd. (%) for [C₂₇H₂₆FN₃O₂]: C, 73.12; H, 5.91; N, 9.47; O, 7.21; found (%): C, 72.83; H, 5.89; N, 9.43; O, 7.18.

2.2.4. Ethyl (E)-N-(3-Cyano-7,7-dimethyl-5-oxo-1,4-diphenyl-1,4,5,6,7,8-hexahydroquinolin-2-yl)formimidate (ii-d)

Compound i-d was used as the 2-amino-3-carbonitrile precursor. Pale yellow solid, yield (conventional solvothermal reaction) = 0.774 g (91%), yield (microwave-assisted reaction) = 0.783 g (92%), m.p: 192–194 °C, IR (selected ν_max, cm⁻¹): 2965 (C—H), 2195 (C≡N), 1635 (C=O); ¹H-NMR δ (ppm): 0.78 (s, 3H,CH₃), 0.91 (overlapping triplet and singlet, 6H, 2CH₃), 1.87–1.91 (d,1H, ²J = 17,45), 2.02–2.04 (d, 1H, ²J = 16,13), 2.17–2.21 (d, 2H, ²J = 16.60), 3.85–3.86 (q, 2H, J= 6,82), 7.35–7.38 (m, 4H, H_aromatic), 7.58–7.61 (m, 4H, H_aromatic), 8.01 (s, 1H, N=C(H_formimidate)—O). ¹³C-NMR δ (ppm): 13.5, 26.3, 29.1, 31.5, 31.8, 36.3, 49.3, 50.2, 61.3, 64.8, 110.7, 113.8, 120.0, 127.4, 129.8, 132.5, 144.7, 149.5, 151.5, 161.3, 194. 2; Anal. Calcd. (%) for [C₂₇H₂₇N₃O₂]: C, 76.21; H, 6.40; N, 9.87; O, 7.52; found (%): C, 75.93; H, 6.38; N, 9.83; O, 7.49.

2.2.5. Ethyl (E)-N-(1-(4-Bromophenyl)-3-cyano-7,7-dimethyl-5-oxo-4-phenyl-1,4,5,6,7,8-hexahydroquinolin-2-yl)formimidate (ii-e)

Compound i-e was used as the 2-amino-3-carbonitrile precursor. Pale yellow solid, yield (using microwave-assisted reaction) = 0.938 g (93%), yield (using microwave-assisted reaction) = 0.908 g (90%); m.p:172–174 °C, IR (selected ν_max, cm⁻¹): 2957 (C—H), 2196 (C≡N), 1625 (C=O); ¹H-NMR δ (ppm): 0.78 (s, 3H,CH₃), 0.91 (overlapping triplet and singlet, 6H, 2CH₃), 1.87–1.91 (d,1H, ²J = 17,5 Hz), 2.02–2.04 (d, 1H, ²J = 16,1 Hz), 2.17–2.21 (d, 2H, ²J = 16.6 Hz), 3.85–3.86 (q, 2H, ³J = 6,8 Hz), 7.35–7.38 (m, 4H, H_aromatic), 7.58–7.61 (m, 4H, H_aromatic), 8.01 (s, 1H, N=C(H_formimidate)—O). ¹³C-NMR δ (ppm): 13.2, 26.2, 28.9, 31.2, 37.9, 38.9, 402.2, 50.1, 61.3, 64.8, 110.7, 119.5, 121.9, 126.9, 128.9, 132.3, 136.9, 145.16, 149.9, 160.02, 194.7; Anal. Calcd. (%) for [C₂₇H₂₆BrN₃O₂]: C, 64.29; H, 5.20; N, 8.33; O, 6.34; found (%): C, 64.08; H, 5.18; N, 8.30; O, 6.32.

2.2.6. Ethyl (E)-N-(3-Cyano-7,7-dimethyl-5-oxo-4-phenyl-1-(p-tolyl)-1,4,5,6,7,8-hexahydroquinolin-2-yl)formimidate (ii-f)

Compound i-f was used as the 2-amino-3-carbonitrile precursor. Pale yellow solid, yield (conventional solvothermal reaction) = 0.694 g (79%), yield (microwave-assisted reaction) = 0.747 g (85%); m.p:163–165 °C, IR (selected ν_max, cm⁻¹): 2958 (C—H), 2193 (C≡N), 1631 (C=O); ¹H-NMR δ(ppm): 0.78 (s, 3H,CH₃), 0.91 (overlapping triplet and singlet, 6H, 2CH₃), 1.87–1.91 (d, 1H, ²J = 17, 5 Hz), 1.99–2.04 (d, 1H, ²J = 16, 1 Hz), 2.05–2.03 (d, 2H, ²J = 16.6 Hz), 2,02 (s, 3H,CH₃) 3.85-3.86 (q, 2H, ³J = 6,8 Hz), 7.35-7.38 (m, 4H, H_aromatic), 7.58–7.61 (m, 4H, H_aromatic), 7.96 (s, 1H, N=C(H_formimidate)—O). ¹³C-NMR δ(ppm): 13.2, 20.7, 26.3, 30.6, 31.9, 49.3, 50.1, 61.3, 79.1, 110.3, 113.9, 126.7, 127.3, 126.8, 134.9, 138.3, 145.3, 150.5, 153.2, 161.3, 194.2; Anal. Calcd. (%) for [C₂₈H₂₉N₃O₂]: C, 76.51; H, 6.65; N, 9.56; O, 7.28; found (%): C, 76.23; H, 6.62; N, 9.53; O, 7.25.

2.3. Crystal Structure Determination

Light yellow block-shaped crystals of ii-b, ii-c and ii-f that were suitable for single-crystal X-ray diffraction were obtained via hot recrystallization using ethanol. Crystal evaluation and data collection for ii-b, ii-c and ii-f was performed on a Bruker Smart APEXII (Madison, WI, USA) diffractometer with a Mo Kα radiation source. Reflections were collected at different starting angles, and the APEXII program suite was used to index the reflections [25]. Data reduction was performed using the SAINT [26] software, and the scaling and absorption corrections were applied using the SADABS [27] multi-scan technique. The structures were solved by the direct method using the SHELXS [28] program and refined using the SHELXL program [29]. Graphics of the crystal structures were drawn using OLEX2 [30]. Non-hydrogen atoms were first refined isotropically and then by anisotropic refinement with the full-matrix least-squares method based on F² using SHELXL [29]. The disordered formimidate and 2-fluorophenyl moieties in ii-b and ii-c were modelled using PART instructions with the major components having 0.85 and 0.89 site occupancy factor, respectively. The crystallographic data and structure refinement details are summarized in

Table 1. Crystal data and structure refinement for ii-b, ii-c and ii-f.

Compound	ii-b	ii-c	ii-f
Empirical formula	C29H26N2O3	C27H26FN3O2	C28H29N3O2
Formula weight	450.52	443.51	439.54
Temperature/K	150	100	99.99
Crystal system	Monoclinic	Monoclinic	Triclinic
Space group	P21/n	P21	P-1
a/Å	12.811(3)	9.1077(8)	9.6966(2)
b/Å	13.560(2)	24.039(2)	10.2417(2)
c/Å	14.965(3)	11.0293(10)	12.4853(2)
α/°	90	90	103.850(1)
β/°	115.110(2)	105.3140(10)	90.328(1)
γ/°	90	90	102.621(1)
Volume/Å3	2354.0(8)	2329.0(4)	1172.57(4)
Z	4	4	2
ρcalcg/cm3	1.271	1.265	1.245
μ/mm−1	0.083	0.086	0.079
F(000)	952.0	936.0	468.0
Crystal size/mm3	0.24 × 0.16 × 0.11	0.34 × 0.26 × 0.21	0.23 × 0.18 × 0.14
2Θ range for data collection/°	4.25 to 52.256	3.388 to 54.268	4.206 to 56.9
Index ranges	−15 ≤ h ≤ 15 −16 ≤ k ≤ 15 −18 ≤ l ≤ 14	−11 ≤ h ≤ 10 −30 ≤ k ≤ 30 −14 ≤ l ≤ 14	−12 ≤ h ≤ 12 −13 ≤ k ≤ 13 −16 ≤ l ≤ 14
Reflections collected	17738	34566	23267
Independent reflections	4523 Rint = 0.0230 Rsigma = 0.0225	10,085 Rint = 0.0166 Rsigma = 0.0162	5772 Rint = 0.0262 Rsigma = 0.0269
Data/restraints/parameters	4523/0/328	10085/21/610	5772/0/302
Goodness-of-fit on F2	1.022	1.030	1.030
Final R indexes [I>=2σ (I)]	R1 = 0.0392 wR2 = 0.0950	R1 = 0.0323 wR2 = 0.0844	R1 = 0.0432 wR2 = 0.1090
Final R indexes [all data]	R1 = 0.0563 wR2 = 0.1059	R1 = 0.0346 wR2 = 0.0865	R1 = 0.0570 wR2 = 0.1171
Largest diff. peak/hole/e Å−3	0.26/−0.16	0.38/−0.18	0.36/−0.27
Flack parameter	-	0.07(14)	-

.

2.4. Hirshfeld Surface Analysis

The Hirshfeld surfaces for compounds ii-b, ii-c and ii-f, including their respective two-dimensional fingerprint plots [31,32,33], were generated using CrystalExplorer17 [34]. All C—H bond distances were constrained to 1.083 Å when a crystallographic information file of the respective compound was read into the CrystalExplorer17 program [34]. The Hirshfeld surface maps generated are of a normalized contact distance, d_norm. This contact distance is defined in terms of the distance to the nearest atoms outside (d_e), the distance to the nearest atoms inside (d_i) [35] and the van der Waals radii [36] of the two atoms external and internal to the surface. The isovalue for the d_norm property of the Hirshfeld surfaces of ii-b, ii-c and ii-f ranged from −0.300 to 1.300.

3. Results and Discussion

3.1. Synthesis Consideration and Spectroscopic Characterization

The microwave reaction of 2-amino-3-carbonitrile derivatives (i), excess triethyl orthoformate and catalytic amounts of acetic acid, formed the corresponding 2-formimidate-3-carbonitriles (ii) as shown in Scheme 1. The short reaction time (20 min) and excellent yields (88–95%) of the desired products were obtained using this microwave radiation technique. The conventional solvothermal method also formed the desired products (ii) at yields that are comparable to those obtained via a microwave-assisted method in this work. However, the long reaction times are a major drawback of the conventional solvothermal method, as noted in the literature [11,12,13,14,15,16,17,18,19,20,21,22,23]. The ¹H-NMR spectra of 4H-pyran-bearing ii derivatives in DMSO-d₆ exhibited triplet and quartet signals at 1.3 and 4.3 ppm, which were attributed to the resonance of ethoxy protons. Furthermore, the singlet at around 8.6 ppm was attributed to the —N=C(H)—O— proton, which signified the formation of the formimidate backbone. Interestingly, the —N=C(H)—O— and ethoxy protons in the dihydropyridine-bearing ii derivatives are all shifted upfield with respect to those containing the 4H-pyran core. This is due to the anisotropic effect of the anilinyl ring in dihydropyridine-bearing ii derivatives. The IR spectra of ii have absorption bands at 2946–2958 cm⁻¹ and 2193–2213 cm⁻¹ were attributed to C—H and C≡N vibration modes, respectively. The presence of the imine functional group (C=N) was confirmed by the absorption bands at 1664–1665 cm⁻¹ (in ii-a and ii-b) and 1568–1571 cm⁻¹ (in ii-c to ii-f). The NMR and IR data both confirm the conversion of the NH₂ functional group in i, to an imine in ii.

3.2. Crystal Structure Descriptions of ii-b, ii-c and ii-f

The crystal structures of ii-b and ii-f have one molecule in the asymmetric unit, whilst that of ii-c consist of two symmetrically non-equivalent molecules (Figure 1, Figure 2 and Figure 3). In each molecule, the aryl group bonded to the C7 atom is almost orthogonal with respect to either the 4H-pyran or dihydropyridine rings. In ii-c and ii-f, the anilinyl rings were also found to be almost perpendicular with respect to the dihydropyridine ring (C1—N1—C18—C19 torsion angle = 78.5(2)° (in ii-c) and 85.0(1)° (in ii-f)). The geometric orientation of the aryl rings is comparable to those of closely related 2-amino-3-carbonitrile in the literature [37,38,39,40]. The formimidate group in ii-b, ii-c and ii-f adopts an E configuration and is planar since the root mean squared deviation of the fitted atoms (N_imine=C_formimidate—O—C_methylene) ranged from 0.001 to 0.016 Å. Due to the two-part disorder in the crystal lattice in ii-b, near synperiplanar and synclinal conformations were observed between the formimidate group and 4H-pyran ring with C_formimidate=N_imine—C_pyran—O_pyran torsion angles of −12.6(2)° and 63.7(9)°, respectively. The disorder observed in ii-b can be attributed to the rotation along the C9—N1 bond. As for ii-c and ii-f, the formimidate group adopted an almost anticlinal conformation with respect to the dihydropyridine ring since the C_formimidate=N_imine—C_{dihydropyridine}—N_{dihydropuridine} torsion angles were −114.2(2)−121.3(2)° and 120.5(1)°, respectively. The C_formimidate=N_imine—C_{dihydropyridine}—N_{dihydropuridine} torsion angle is much wider than C_formimidate=N_imine—C_pyran—O_pyran, and this could be attributed to the steric demand of the anilinyl rings in ii-c and ii-f. All other intramolecular bond parameters are similar to those of previously reported compounds [11,41,42].

3.3. Evaluation of Intermolecular Interactions in the Crystal Packing of ii-b, ii-c and ii-f

The crystal packing of ii-b, ii-c and ii-f is stabilized by intermolecular hydrogen bonding interactions, which are depicted in Figure 4, Figure 5and Figure 6. The geometrical parameters of the various interactions are listed in

Table 2. Selected hydrogen bonds for ii-b, ii-c and ii-f.

D	H	A	d(D-H)/Å	d(H…A)/Å	d(D…A)/Å	D-H…A/°
Compound ii-b
C11	H11C	O3A i	0.98	2.66	3.481(3)	142
C15	H15	O2	0.95	2.62	3.559(2)	168
C23	H23	O1 ii	0.95	2.57	3.487(2)	164
C24	H24	N2 iii	0.95	2.63	3.574(2)	170
C28	H28A	πanthracenyl iv	0.98	2.92	3.692(2)	136
Compound ii-c
C12	H12	F2 i	0.95	2.58	3.361(3)	140
C19	H19	O3	0.95	2.56	3.396(3)	147
C50	H50	O1	0.95	2.52	3.371(3)	149
Compound ii-f
C19	H19	O1 i	0.95	2.52	3.440(2)	163
C12	H12	O2 ii	0.95	2.65	3.469(2)	145
C14	H14	O1 iii	0.95	2.55	3.484(2)	170
C22	H22	N3 iv	0.95	2.66	3.351(2)	131
C24	H24C	πphenyl iv	0.98	2.66	3.558(2)	152

Symmetry codes for ii-b: (i) 1/2- x,-1/2+ y,5/2- z; (ii) -1/2+ x,1/2- y,-1/2+ z; (iii) -1/2- x,-1/2+ y,3/2- z; (iv) -x,1- y,2- z; for ii-c: (i) x,+y,-1+ z; for ii-f: (i) 1- x,2- y,-z; (ii) x,-1+ y,+ z; (iii) -x,1- y,-z; (iv) 1- x,2- y,1- z.

. The alternating C23—H23…O1 and C11—H11B…O3A hydrogen bonds in ii-b sew together neighbouring molecules to form chains that extend diagonally with respect to the crystallographic a and c axes (Figure 4a). These chains are further linked by C24—H24…N2 (Figure 4b) and C28—C28A…π_anthracenyl (Figure 5a) interactions along the crystallographic b axis and form a two-dimensional supramolecular structure. In ii-c, C12—H12…F2 and C39—H39…F1 hydrogen bonds with the $R_2^2\left(8\right)$ graphset descriptor were observed between neighbouring 2-fluorophenyl moieties (Figure 5b). Intermolecular C—H…O were also observed in ii-c between the aromatic hydrogens (H19 and H50) and the carbonyl oxygen atoms (O1 and O3). The C—H…F and C—H…O hydrogen bonds connect neighbouring molecules form chains that extend along the crystallographic c axis (Figure 5b). Since the C11—H11B…O3A and C12—H12…F2 hydrogen bonds include some disordered atoms (O3A in ii-b, F2 in ii-c), these intermolecular interactions are not formed in all domains of each crystal. The carbonyl oxygen (O1) in ii-f is involved in bifurcated C—H…O hydrogen bonding with the aromatic H14 and H19 atoms and form chains that propagates diagonally with respect to the crystallographic a and b axes, as shown in Figure 6a. These chains are further linked together via C—H…O hydrogen bonds between the aromatic H12 atom and O2 of the formimidate group along the crystallographic b axis, thus forming a two-dimensional supramolecular architecture that extends with respect to the crystallographic ac plane. The resultant supramolecular architecture is further stabilized by C22—H22…N3 and C24—H24C…π_phenyl hydrogen bonds (Figure 6b).

3.4. CSD Survey of Closely Related Compounds

To put our work into some perspective, a survey of the Cambridge Structural Database (CSD; version 5.42, September 2021 update) [43] was conducted. Figure 7 shows the three hits that were obtained for closely related 2-formimidate-3-carbonitrle derivatives bearing a 4H-pyran moiety (CSD refcodes: BEPZAZ, GINZOT and ZAQFUV). The aryl rings bonded to the stereogenic centre in the three hits have a similar geometric orientation to those observed in ii-b, ii-c and ii-f. The formimidate functional group is almost syn-periplanar with the 4H-pyran ring in BEPZAZ, GINZOT and ZAQFUV since the C_formimidate=N_imine—C_pyran—O_pyran torsion angle was found to be 1.7(2)°, 8.0(2)° and 3.7(3)°, respectively. No crystal structure of 2-formimidate-3-carbonitrle derivatives bearing a dihydropyridine moiety exists on the CSD. Thus, the first CSD entry of crystal structures of such derivatives is reported in this work. Interestingly, the formimidate group seems to prefer to adopt an E configuration in the solid state despite the variation in the groups on the 4H-pyran or dihydropyridine core.

3.5. Hirshfeld Surface Analysis

Hirshfeld surface analysis was used to examine the contribution of the various intermolecular interactions observed in ii-b, ii-c and ii-f towards the stabilization of the crystal lattice. This was achieved by generating d_norm Hirschfeld surfaces and two-dimensional fingerprint plots as depicted in Figure 8. The red regions on the d_norm surface signify close intermolecular contacts attributed to the various hydrogen bonds discussed. The white regions on the d_norm surface indicate van der Waals contacts whilst the blue regions signify very weak intermolecular contacts. In all three compounds, the H…H contacts contribute the most towards (50.2–58.6%) the Hirshfeld surface. The reciprocal H..C contacts were attributed to C—H…π interactions, and they constitute 14.3–23.9% of the Hirshfeld surface. Compound ii-b had the highest contribution of H…C/C…H contacts, and this could be attributed to the presence of more aromatic rings than in ii-c and ii-f. The lowest contribution of reciprocal C…H contacts was observed in ii-c, and this deficit was attributed to the presence of C—H…F hydrogen bonds with reciprocal H…F contact contributions of 9.4%. There seems to be no significant difference in the contribution of N…H/H…N contacts across all three compounds. This is probably due to the very weak intermolecular van der Waals forces in N…H contacts. The reciprocal O…H contacts were attributed to intermolecular C—H…O hydrogen bonds, and the lowest contribution was observed in ii-c (9.6%) due to the existence of C—H…F hydrogen bonds. This deficit is further compounded by the low number of oxygen atoms in ii-c as compared to that in ii-a and ii-f.

4. Conclusions

The formation of 2-formimidate-3-carbonitrile derivatives via microwave reactions of triethyl orthoformate with corresponding 4H-pyran- and dihydropyridine-based 2-amino-3-carbonitrile precursors was successful. In comparison to the conventional synthesis protocol, the use of microwave radiation significantly reduced the reaction times from the order of hours to 20 min whilst maintaining the reaction yields. The synthesis of the desired products was confirmed using NMR and IR spectroscopy. In the solid state, the formimidate functional group adopts an E configuration based on the single-crystal X-ray diffraction. The 4H-pyran-based derivatives adopt syn-periplanar and synclinal conformations between the formimidate group and pyran ring whilst an anticlinal conformation was observed for dihydropyridine-based derivatives. The crystal lattices of 2-formimidate-3-carbonitrile derivatives in this work are stabilized by classical but weak intermolecular hydrogen bonds, which include C—H…O, C—H…N, C—H…F (in ii-c) and C—H…π. According to the Hirshfeld surface analysis, the 2-formimidate-3-carbonitrile derivative bearing 4H-pyran (ii-b) has larger contributions of C—H…π and C—H…O hydrogen bonds towards the Hirshfeld surface than those of the dihydropyridine-based derivatives (ii-c and ii-f). This was attributed to the presence of anthracenyl and 4H-pyran moieties in ii-b. However, the contribution of reciprocal H…N contacts towards the Hirshfeld surface seems to be independent of the nature of the central ring (4H-pyran or dihydropyridine) and the substituents on it. We are currently investigating the preferred isomerism of 2-formimidate-3-carbonitrile derivatives in solution state. These findings could provide better insight into how the choice of solvent and reaction conditions play a key role in the formation of fused pyrimidines.