Retro Diels Alder protocol for regioselective synthesis of novel [1,2,4]triazolo[4,3-a]pyrimidin-7(1H)-ones

Abstract

Reactions of diastereochemically varied norbornene-condensed 2-thioxopyrimidin-4-ones 6 and 10 with variously functionalized hydrazonoyl chlorides 2a–h gave regioselectively angular norbornene-based [1,2,4]triazolo[4,3-a]pyrimidin-7(1H)-ones 7a–h and 11a,c–e, respectively. Thermal retro Diels–Alder (RDA) reaction of 7a–h and 11a,c–e resulted in the target compounds 4a–h as single products. On the other hand, reactions of thiouracil 1 and hydrozonoyl chlorides 2a–e gave regioselectively [1,2,4]triazolo[4,3-a]pyrimidinone-5(1H)-ones 3a–e. The opposite regioselectivity of thiouracil 1 and norbornene-condensed 2-thioxopyrimidin-4-ones 6 and 10 was attributed to electronic factors according to DFT calculations. The angular structure of norbornene based [1,2,4]triazolo[4,3-a]pyrimidin-7(1H)-ones was confirmed by single crystal X-ray crystallography.

---

Introduction

Fused pyrimidines are important compounds, because of their wide spectrum of biological and pharmacological applications.^1–4 Compounds bearing the [1,2,4]triazolo[4,3-a]pyrimidinone ring system were reported to possess a wide range of pharmacological activities including antitumor,⁵ antiallergic,⁶ antimicrobial,⁷ and 5α-reductase inhibitor properties.⁸

Hydrazonoyl halides, known since 1930, have attracted the interest of synthetic chemists in designing and synthesizing different heterocycles.⁹ For example, [1,2,4]triazolo[4,3-a]pyrimidinones decorated with different functionalities can be incorporated into 2-thioxopyrimidin-4-ones by reacting the latter with the appropriate hydrazonoyl halide in the presence of a base.¹⁰ To the best of our knowledge, the reported reactions of thiouracil derivatives with hydrazonoyl chlorides gave substituted [1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-ones in a regioselective manner.^11–15

Recently, synthetic chemists have utilized RDA protocols for designing and synthesizing novel heterocyclic scaffolds. This method is highly efficient to build a double bond into the heterocyclic system.^16–23

In the present work, we report the formation of novel [1,2,4]triazolo[4,3-a]pyrimidin-7(1H)-ones 4a–h by reacting norbornene-condensed 2-thioxopyrimidin-4-ones 6 and 10 with hydrazonyl chlorides 2a–h with various functionalities followed by applying the RDA protocol. Note that 4a–h, cann't accessible significantly from the reactions of thiouracil with hydrazonoyl chlorides.

Results and discussion

The reaction of thiouracil 1 with varied functionalized hydrazonoyl chlorides 2a–e gave, as described earlier,^11–15 [1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-ones 3a–e as the major and [1,2,4]triazolo[4,3-a]pyrimidin-7(1H)-ones 4a–e as the minor products. The ratio of 3a–e and 4a–e was 8–2 : 1 (Scheme 1). The regioisomers could be easily separated by column chromatography via elution with EtOAc.

Scheme 1 Solvents and conditions: dioxane, TEA, reflux 4–6 h. The ratio of compounds 3 : 4 was calculated from the ¹H-NMR spectrum of the crude reaction mixture using the signals at around 6.1 ppm and 6.5 ppm for H-6 of regioisomers 3 and 4, respectively. Separation of the regioisomers by column chromatography, eluent: EtOAc, R_f = 3: 0.4; 4 : 0.05.

The challenge hence is how to have 4a–e as major products. Since 2-thioxopyrimidin-4-one 6 condensed to norbornene can easily be converted to thiouracil 1 by the RDA strategy,²⁴ we used 6 instead of thiouracil 1 in the reaction with hydrazonoyl chlorides 2a–h (Scheme 2). Strikingly, the regioselectivity of the reaction was inversed. Only angular regioisomers, [1,2,4]triazolo[4,3-a]pyrimidin-7(1H)-ones 7a–h, were formed and isolated in moderate yields (Table 1).

Scheme 2 Solvents and conditions: (i) CSCl₂, NaHCO₃, CHCl₃;²⁷ (ii) NH₃, MeOH;²⁷ (iii) dioxane, TEA, reflux, 4–6 h; (iv) MW: in 1,2-DCM, 200 °C, 30–120 min, 200 W.

Table 1 Energy difference (kJ mol⁻¹) between angular regioisomers 7,11 and their linear counterparts 8,12. Isolated yields of angular regioisomers 7,11 were given

Entry	Energy difference ΔE^a kJ mol^−1	Yield^b %	Entry	Energy difference ΔE^a kJ mol^−1	Yield^b %
a Energy calculations were performed at the density functional theory (DFT) using the B3LYP functional. The 6-311G(d,p) basis sets were employed on all atoms. b The yield of isolated pure [1,2,4]triazolo[4,3-a]pyrimidin-7(1H)-ones by column chromatography.
7a	50.75	66	7g	50.7	68
8a			8g
7b	51.32	69	7h	47.75	67
8b			8h
7c	47.48	60	11a	51.13	72
8c			12a
7d	61.58	60	11c	46.07	75
8d			12c
7e	38.84	45	11d	58.16	70
8e			12d
7f	62.89	77	11e	44.58	50
8f			12e

---

In a similar manner, the reaction of diendo norbornene-condensed 2-thioxopyrimidin-4-one 10 with functionalized hydrazonoyl chlorides 2a,c–e was also found to be regioselective towards the formation of angular regioisomers, [1,2,4]triazolo[4,3-a]pyrimidin-7(1H)-ones 11a,c–e (Scheme 2) (Table 1). The effect of norbornene on the stereochemical outcome was attributed to electronic, rather, than steric factors. Specifically, the C=C bond in thiouracil enforces the reaction towards the formation of [1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-ones 3a–e because (i) the nitrogen located closer to the C=C double bond is more basic and (ii) tautomeric structure 1A is thermodynamically more stable than 1B (Scheme 3).

Scheme 3 Reaction pathways of thiouracil 1 and hydrazonoyl chlorides 2 to form regioisomers 3 and 4.

The lower yields of the reactions specially with hydrazonoyl chloride 2e was ascribed to the tendency of hydrazonoyl chlorides, whose configuration is Z,²⁵ to isomerize to its E isomer under the reaction conditions as was deduced from the NMR spectra of the separated side product (ESI†). E isomer of hydrazonoyl chloride is more stable by hydrogen bonding and is hindered to be attacked by thione 6,10 to replace its chlorine atom (Scheme 4).

Scheme 4 Isomerization of hydrazonoyl chlorides (2e as an example).

After heating in 1,2-dichlorobenzene (1,2-DCB) at 200 °C under microwave conditions, norbornene-fused triazolo[4,3-a]pyrimidin-7(1H)-ones (7a–h and 11a,c–e) underwent RDA reaction producing triazolo[4,3-a]pyrimidin-7(1H)-ones 4a–h in moderate yields in a short time (30–90 minutes, Scheme 2 and Table 2). The RDA reaction was monitored by TLC and could also be noticed by the odor of cyclopentadiene. RDA reactions of diexo isomers are easier than their diendo counterparts (entries 6–9) due to higher stability of diendo isomers as was confirmed from DFT calculations (ESI†).

Table 2 MW process for the synthesis of triazolo[4,3-a]pyrimidin-7(1H)-ones 4a–h under the optimized reaction conditions

Entry	Starting material	Product	Reaction time^a (min)	Isolated yield^b (%)
a T = 200 °C, Pmax = 200 W, in 1,2-DCB. b After column chromatography.
1	7a (exo)	4a	45	42
2	11a (endo)		60	52
3	7b (exo)	4b	60	54
4	7c (exo)	4c	90	41
5	11c (endo)		30	45
6	7d (exo)	4d	30	78
7	11d (endo)		30	67
8	7e (exo)	4e	120	90
9	11e (endo)		30	57
10	7f (exo)	4f	60	41
11	7g (exo)	4g	40	58
12	7h (exo)	4h	30	48

---

Geometry optimization and total energies calculations were performed at the density functional theory (DFT) using Becke's three-parameter Lee–Yang–Parr (B3LYP) exchange functional with 6-311G(d,p) basis sets, using Gaussian-09 program.²⁶ Angular regioisomers 7a–h and 11a,c–e are thermodynamically more stable than their linear counterparts 8a–h and 12a,c–e, respectively (Table 1).

Fig. 1 shows the electron distribution and relative stability of tautomers A and B. The C=C bond (such as in thiouracil) directs the tautomerism towards an excess of A. When it is absent (such as in 6,10), the tautomeric equilibrium is shifted towards B. Tautomer A is responsible for the formation of linear triazolo[4,3-a]pyrimidin-5(1H)-one regioisomers, while tautomer B leads to the formation of angular triazolo[4,3-a]pyrimidin-7(1H)-one regioisomers.

Fig. 1 Optimized geometric structure and HOMO energy levels of tautomers A and B of compounds 1, 6 and 10.

A conclusive evidence for the angular stereochemistry of the products of the reaction of norbornene-condensed 2-thioxopyrimidin-4-one 6,10 with hydrazonoyl chlorides 2a–h was obtained by X-ray crystallographic analysis of compounds 7e and 11d (Fig. 2 and 3).

Fig. 2 TELP image of 7e at 50% probability level. There are two independent molecules in the asymmetric unit.

Fig. 3 TELP image of 11d at 50% probability level.

Experimental section

Materials and methods

NMR spectra were recorded at 500.20 MHz for ¹H-NMR and at 125.62 MHz for ¹³C-NMR in CDCl₃ at room temperature, using a Bruker AV NEO Ascend 500 spectrometer (Bruker Biospin, Karlsruhe, Germany) with Double Resonance Broad Band Probe (BBO). Tetramethylsilane (TMS) was used as internal standard. Microwave-promoted reactions were performed using sealed reaction vials (10 mL) in a microwave (CEM, Discover, SP) cavity (CEM Corporation, Matthews, NC, USA). Reactions were monitored by thin layer chromatography (TLC) using aluminum sheets coated with silica gel (POLYGRAM®SIL G/UV254, Merck). TLC plates were inspected under UV light. Melting points were measured with a Hinotek-X4 micro melting point apparatus (Hinotek, Ningbo, China) and are uncorrected. All theoretical calculations were performed using the Gaussian 09 package. The geometrical optimization was performed at the density functional theory (DFT) using the B3LYP. The 6-311G(d, p) basis sets were employed by all atoms.

Diexo 6 and diendo10 norbornene-fused 2-thioxopyrimidin-4-ones were prepared from the corresponding norbornene amino ester 5 and 9, respectively, according to the reported procedures.²⁷ Hydrazonoyl chlorides 2a–h were synthesized according to the reported procedures.^28–30

X-ray diffraction data of 7e and 11d were collected on a Rigaku Oxford Diffraction Supernova diffractometer using Mo Kα (7e) or Cu Kα (11d) radiation. The CrysAlisPro^X software package³¹ was used for cell refinements and data reductions. The structures were solved by intrinsic phasing method using the SHELX^X software.³² The data was corrected with empirical absorption correction based of equivalent reflections (7e) or analytical absorption correction (11d) CrysAlisPro^X structural refinements³¹ were carried out using SHELXL^X software.³² The NH hydrogen atoms were located from the difference Fourier map and refined isotropically. Other hydrogen atoms were positioned geometrically and constrained to ride on their parent atoms, with C–H = 0.95–1.00 Å and U_iso = 1.2–1.5U_eq (parent atom). The crystallographic details are summarized in Table S7.†

General procedure for the synthesis of [1,2,4]triazolo-[4,3-a]pyrimidin-5(1H)-ones 3a–e and 5,8-methano[1,2,4]-triazolo[4,3-a]quinazolinones 7a–h and 11a,c–e

To a mixture of 0.5 mmol of 2-thioxopyrimidin-4-one (1,6,10) and 0.5 mmol of hydrazonyl chloride 2a–h in dioxane (10 mL), 100 μL triethyl amine (TEA) were added. The mixture was heated under reflux conditions with stirring until completion of the reaction as confirmed by the disappearance of H₂S odor and TLC monitoring (n-hexane/EtOAC = 2 : 1 as the eluent). The solvent was evaporated under reduced pressure, the residue was dissolved in CHCl₃ (50 mL) and extracted with water (3 × 10 mL). Then the CHCl₃ layer was dried on Na₂SO₄, the solvent was evaporated, and the residue was dissolved in 5 mL EtOAc and purified by column chromatography on silica gel eluted by EtOAc. In the reaction of thiouracil 1 with hydrazonoyl chloride 2a–e, the major 3a–e and minor 4a–e regioisomers were separated using TLC on silica gel (eluent EtOAc): 3a–e, R_f 0.4, 4a–eR_f 0.05. The products were crystallized from Et₂O to produce white or light yellow crystals.

Ethyl 5-oxo-1-phenyl-1,5-dihydro[1,2,4]triazolo[4,3-a]pyramidine-3-carboxylate (3a). Yield 45%, mp 116–120 °C, ¹H NMR (500 MHz, CDCl₃) δ 8.13 (d, J = 7.6 Hz, 2H, Ar.), 8.06 (d, J = 6.5 Hz, 1H, H-7), 7.61–7.49 (m, 2H, Ar.), 7.42 (t, J = 7.5 Hz, 1H, Ar.), 6.14 (d, J = 6.6 Hz, 1H, H-6), 4.60 (q, J = 7.2 Hz, 2H, CH₂CH₃), 1.48 (t, J = 7.2 Hz, 3H, CH₂CH₃). ¹³C NMR (126 MHz, CDCl₃) δ 156.6(C=O), 155.9(CH), 155.3(C=O), 147.9(C), 136.2(C), 135.9(C), 129.5(CH), 128.1(CH), 121.1(CH), 103.2(CH), 64.1(CH₂), 13.9(CH₃).

Ethyl 5-oxo-1-(p-tolyl)-1,5-dihydro[1,2,4]triazolo[4,3-a]pyramidine-3-carboxylate (3b). Yield 43%, mp 175–176 °C, ¹H NMR (500 MHz, CDCl₃) δ 8.04 (d, J = 6.5 Hz, 1H, H-7), 7.96 (d, J = 8.5 Hz, 2H, Ar.), 7.33 (d, J = 8.2 Hz, 2H, Ar.), 6.11 (d, J = 6.5 Hz, 1H, H-6), 4.59 (q, J = 7.2 Hz, 2H, CH₂CH₃), 2.42 (s, 3H, p-tolyl), 1.47 (t, J = 7.2 Hz, 3H, CH₂CH₃). ¹³C NMR (126 MHz, CDCl₃) δ 156.7(C=O), 155.9(CH), 155.4(C=O), 147.8(C), 138.3(C), 135.7(C), 133.7(C), 129.9(CH), 121.2(CH), 102.9(CH), 64.0(CH₂), 21.1(CH₃, p-tolyl), 13.9(CH₃).

Ethyl 1-(4-nitrophenyl)-5-oxo-1,5-dihydro[1,2,4]triazolo[4,3-a]pyrimidine-3-carboxylate (3c). Yield 48%, mp 165–168 °C, ¹H NMR (500 MHz, CDCl₃) δ 8.55 (d, J = 9.4 Hz, 2H, Ar.), 8.41 (d, J = 9.4 Hz, 2H, Ar.), 8.08 (d, J = 6.6 Hz, 1H, H-7), 6.22 (d, J = 6.6 Hz, 1H, H-6), 4.61 (q, J = 7.2 Hz, 2H, CH₂CH₃), 1.49 (t, J = 7.2 Hz, 3H, CH₂CH₃). ¹³C NMR (126 MHz, CDCl₃) δ 156.2(C=O), 155.4(CH), 154.9(C), 147.9(C), 146.1(C), 141.1(C), 136.7(C), 125.1(CH), 120.3(CH), 104.8(CH), 64.4(CH₂), 13.9(CH₃).

5-Oxo-N-phenyl-1-(p-tolyl)-1,5-dihydro[1,2,4]triazolo[4,3-a]pyramidine-3-carboxamide (3d). Yield 52%, mp 213–214 °C, ¹H NMR (500 MHz, CDCl₃) δ 13.36 (s, 1H, NH), 8.16 (d, J = 6.2 Hz, 1H, H7), 8.04 (d, J = 8.5 Hz, 2H, Ar.), 7.82 (dd, J = 8.6, 1.0 Hz, 2H, Ar.), 7.42–7.37 (m, 2H, Ar.), 7.35 (d, J = 8.2 Hz, 2H, Ar.), 7.18 (t, J = 7.4 Hz, 1H, Ar.), 6.29 (d, J = 6.2 Hz, 1H, H-6), 2.43 (s, 3H, p-tolyl). ¹³C NMR (126 MHz, CDCl₃) δ 159.0(C=O), 156.8(CH), 150.8(C=O), 148.6(C), 139.7(C), 139.0(C), 137.6(C), 133.3(C), 129.9(CH), 129.1(CH), 125.2(CH), 122.0(CH), 120.4(CH), 102.8(CH), 21.2(CH₃, p-tolyl).

3-Acetyl-1-(p-tolyl)-[1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-one (3e). Yield 42%, mp 120–125 °C, ¹H NMR (500 MHz, CDCl₃) δ 8.04 (d, J = 6.5 Hz, 1H, H-7), 7.98 (d, J = 8.6 Hz, 2H, Ar.), 7.35 (d, J = 8.2 Hz, 2H, Ar.), 6.16 (d, J = 10.5 Hz, 1H, H-6), 2.82 (s, 3H, COCH₃), 2.43 (s, 3H, p-tolyl). ¹³C NMR (126 MHz, CDCl₃) δ 186.3(C=O), 155.6(C=O), 155.5(CH), 148.4(C), 141.4(C), 138.5(C), 133.6(C), 130.0(CH), 121.3(CH), 103.5(CH), 29.8(COCH₃), 21.1(CH₃, p-tolyl).

Ethyl (4aS*,5S*,8R*,8aR*)-1-phenyl-9-oxo-1,4a,5,8,8a,9-hexahydro-5,8-methano[1,2,4]triazolo[4,3-a]quinazoline-3-carboxylate (7a). Yield 66%, mp 190–192 °C, ¹H NMR (500 MHz, CDCl₃) δ 8.07 (d, J = 7.8 Hz, 2H, Ar.), 7.46 (t, J = 7.9 Hz, 2H, Ar.), 7.36 (t, J = 7.4 Hz, 1H, Ar.), 6.48 (dd, J = 5.5, 2.9 Hz, 1H), 6.28 (dd, J = 5.3, 3.1 Hz, 1H), 4.56 (m, 3H), 3.58 (s, 1H), 3.30 (s, 1H), 2.70 (d, J = 9.0 Hz, 1H), 1.54 (s, 2H), 1.50 (t, J = 7.1 Hz, 3H, CH₂CH₃). ¹³C NMR (126 MHz, CDCl₃) δ 176.8(C=O), 156.3(C=O), 154.1(C), 140.3(CH), 137.7(C), 136.1(C), 134.3(CH), 129.1(CH), 128.2(CH), 122.2(CH), 63.3(CH₂), 57.3(CH), 52.8(CH), 49.7(CH), 43.9(CH₂), 40.5(CH), 14.2(CH₃).

Ethyl (4aS*,5S*,8R*,8aR*)-1-(p-tolyl)-9-oxo-1,4a,5,8,8a,9-hexahydro-5,8-methano[1,2,4]triazolo[4,3-a]quinazoline-3-carboxylate (7b). Yield 69%, mp 191–193 °C, ¹H NMR (500 MHz, CDCl₃) δ 7.93 (d, J = 8.1 Hz, 2H, Ar.), 7.25 (d, J = 8.1 Hz, 2H, Ar.), 6.47 (s, 1H), 6.27 (s, 1H), 4.53–4.57 (m, 3H), 3.58 (s, 1H), 3.29 (s, 1H), 2.69 (d, J = 9.0 Hz, 1H), 2.38 (s, 3H, p-tolyl), 1.53 (s, 2H), 1.49 (t, J = 7.1 Hz, 3H, CH₂CH₃). ¹³C NMR (126 MHz, CDCl₃) δ 176.7(C=O), 156.4(C=O), 153.9(C), 140.5(CH), 138.1(C), 137.5(C), 134.3(CH), 133.7(C), 130.1(CH), 122.2(CH), 63.5(CH₂), 57.3(CH), 52.9(CH), 49.5(CH), 43.7(CH₂), 40.5(CH), 21.0(CH₃, p-tolyl), 14.0(CH₃).

Ethyl (4aS*,5S*,8R*,8aR*)-1-(4-nitrophenyl)-9-oxo-1,4a,5,8,8a,9-hexahydro-5,8-methano[1,2,4]triazolo[4,3-a]quinazoline-3-carboxylate (7c). Yield 60%, mp 238–240 °C, ¹H NMR (500 MHz, CDCl₃) δ 8.51 (d, J = 9.2 Hz, 2H, Ar.), 8.32 (d, J = 9.2 Hz, 2H, Ar.), 6.49 (dd, J = 5.5, 2.9 Hz, 1H), 6.29 (dd, J = 5.3, 3.1 Hz, 1H), 4.6–4.55 (m, 3H), 3.59 (s, 1H), 3.30 (s, 1H), 2.72 (d, J = 9.0 Hz, 1H), 1.58–1.5 (m, 5H). ¹³C NMR (126 MHz, CDCl₃) δ 176.6(C=O), 156.0(C=O), 154.4(C), 146.1(C), 141.2(C), 140.2(CH), 138.5(C), 134.4(CH), 124.7(CH), 121.6(CH), 63.8(CH₂), 57.4(CH), 53.0(CH), 49.8(CH), 44.1(CH₂), 40.6(CH), 14.2(CH₃).

(4aS*,5S*,8R*,8aR*)-N-Phenyl-1-(p-tolyl)-9-oxo-1,4a,5,8,8a,9-hexahydro-5,8-methano[1,2,4]triazolo[4,3-a]quinazoline-3-carboxamide (7d). Yield 60%, mp 224–226 °C, ¹H NMR (500 MHz, CDCl₃) δ 8.87 (s, 1H, NH), 7.92 (d, J = 8.1 Hz, 2H, Ar.), 7.69 (d, J = 7.9 Hz, 2H, Ar.), 7.43 (t, J = 7.7 Hz, 2H, Ar.), 7.31–7.20 (m, 3H, Ar.), 6.51–6.39 (m, 1H), 6.37–6.27 (m, 1H), 4.61 (d, J = 9.0 Hz, 1H), 3.55 (s, 1H), 3.44 (s, 1H), 2.68 (d, J = 8.9 Hz, 1H), 2.37 (s, 3H, p-tolyl), 1.52 (s, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 176.8(C=O), 154.0(C=O), 153.0(C=O), 139.9(CH), 139.4(C), 138.3(C), 136.1(C), 134.8(CH), 133.5(C), 129.7(CH), 129.4(CH), 125.7(CH), 122.0(CH), 120.4(CH), 57.4(CH), 52.9(CH), 49.8(CH), 43.9(CH₂), 40.5(CH), 21.1(CH₃).

(4aS*,5S*,8R*,8aR*)-3-Acetyl-1-(p-tolyl)-9-oxo-1,4a,5,8,8a,9-hexahydro-5,8-methano[1,2,4]triazolo[4,3-a]quinazoline (7e). Yield 45%, mp 118–120 °C, ¹H NMR (500 MHz, CDCl₃) δ 7.96 (d, J = 8.5 Hz, 2H, Ar.), 7.27 (d, J = 8.1 Hz, 2H, Ar.), 6.45 (dd, J = 5.4, 2.9 Hz, 1H), 6.30 (dd, J = 5.3, 3.1 Hz, 1H), 4.51 (d, J = 8.9 Hz, 1H), 3.55 (s, 1H), 3.18 (s, 1H), 2.72 (s, 3H, COCH₃), 2.65 (d, J = 9.0 Hz, 1H), 2.39 (s, 3H, p-tolyl), 1.57–1.42 (m, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 187.7(C=O), 176.7(C=O), 154.1(C), 142.1(C), 140.0(CH), 138.1(C), 134.7(CH), 133.8(C), 129.7(CH), 122.1(CH), 57.4(CH), 52.7(CH), 49.8(CH), 44.4(CH₂), 40.6(CH), 26.5(COCH₃), 21.1(CH₃, p-tolyl).

Ethyl (4aS*,5S*,8R*,8aR*)-1-(4-methoxyphenyl)-9-oxo-1,4a,5,8,8a,9-hexahydro-5,8-methano[1,2,4]triazolo-[4,3-a]quinazoline-3-carboxylate (7f). Yield 77%, mp 185–187 °C, ¹H NMR (500 MHz, CDCl₃) δ 7.92 (d, J = 9.0 Hz, 2H, Ar.), 6.95 (d, J = 9.0 Hz, 2H, Ar.), 6.47 (dd, J = 5.4, 2.8 Hz, 1H), 6.27 (dd, J = 5.2, 3.1 Hz, 1H), 4.60–4.46 (m, 3H), 3.83 (s, 3H, OCH₃), 3.57 (s, 1H), 3.29 (s, 1H), 2.68 (d, J = 9.0 Hz, 1H), 1.53 (s, 2H), 1.49 (t, J = 7.1 Hz, 3H, CH₂CH₃). ¹³C NMR (126 MHz, CDCl₃) δ 176.8(C=O), 159.0(C=O), 156.3(C), 153.7(C), 140.4(CH), 137.4(C), 134.3(CH), 129.1(C), 123.9(CH), 114.2(CH), 63.3(CH₂), 57.3(CH), 55.5(CH), 52.8(CH), 49.7(CH), 43.9(CH₂), 40.5(OCH₃), 14.1(CH₃).

Ethyl (4aS*,5S*,8R*,8aR*)-1-(4-chlorophenyl)-9-oxo-1,4a,5,8,8a,9-hexahydro-5,8-methano[1,2,4]triazolo-[4,3-a]quinazoline-3-carboxylate (7g). Yield 68%, mp 218–224 °C, ¹H NMR (500 MHz, CDCl₃) δ 8.11 (d, J = 8.9 Hz, 2H, Ar.), 7.43 (d, J = 8.9 Hz, 2H, Ar.), 6.48 (dd, J = 5.5, 2.9 Hz, 1H), 6.28 (dd, J = 5.4, 3.1 Hz, 1H), 4.59–4.50 (m, 3H), 3.58 (s, 1H), 3.29 (s, 1H), 2.70 (d, J = 9.0 Hz, 1H), 1.53 (d, J = 7.9 Hz, 2H), 1.50 (t, J = 7.1 Hz, 3H, CH₂CH₃). ¹³C NMR (126 MHz, CDCl₃) δ 176.6(C=O), 156.1(C=O), 154.0(C), 140.3(CH), 137.8(C), 134.8(C), 134.3(CH), 133.6(C), 129.2(CH), 123.1(CH), 63.5(OCH₂), 57.3(CH), 52.8(CH), 49.7(CH), 43.9(CH₂), 40.4(CH), 14.1(CH₃).

Ethyl (4aS*,5S*,8R*,8aR*)-1-(3-(trifluoromethyl)phenyl)-9-oxo-1,4a,5,8,8a,9-hexahydro-5,8-methano[1,2,4]triazolo-[4,3-a]quinazoline-3-carboxylate (7h). Yield 67%, mp 160–162 °C, ¹H NMR (500 MHz, CDCl₃) δ 8.61–8.48 (m, 1H, Ar.), 8.25 (s, 1H, Ar.), 7.64–7.57 (m, 2H, Ar.), 6.49 (dd, J = 5.5, 2.9 Hz, 1H), 6.29 (dd, J = 5.4, 3.1 Hz, 1H), 4.61–4.56 (m, 3H), 3.58 (s, 1H), 3.30 (s, 1H), 2.71 (d, J = 9.0 Hz, 1H), 1.58–1.48 (m, 5H). ¹³C NMR (126 MHz, CDCl₃) δ 176.6(C=O), 156.1(C=O), 154.3(C), 140.4(CH), 138.1(C), 136.7(C), 134.5(CH), 131.8(C), 131.7(C), 130.0(CH), 125.4(CH), 124.5(CH), 118.6(CH), 63.7(CH₂), 57.3(CH), 53.0(CH), 49.8(CH), 44.0(CH₂), 40.3(CH), 14.2(CH₃).

Ethyl (4aR*,5S*,8R*,8aS*)-1-phenyl-9-oxo-1,4a,5,8,8a,9-hexa-hydro-5,8-methano[1,2,4]triazolo[4,3-a]quinazoline-3-carboxylate (11a). Yield 72%, mp 191–193 °C, ¹H NMR (500 MHz, CDCl₃) δ 8.01 (d, J = 7.8 Hz, 2H, Ar.), 7.44 (t, J = 7.9 Hz, 2H, Ar.), 7.33 (t, J = 7.4 Hz, 1H, Ar.), 6.42 (dd, J = 5.5, 2.7 Hz, 1H), 5.94 (dd, J = 5.5, 2.7 Hz, 1H), 5.14 (dd, J = 10.0, 3.5 Hz, 1H), 4.55 (q, J = 7.1 Hz, 2H, CH₂CH₃), 3.71 (s, 1H), 3.68 (s, 1H), 3.27 (dd, J = 10.0, 3.9 Hz, 1H), 1.58 (dd, J = 27.1, 9.3 Hz, 2H), 1.50 (t, J = 7.1 Hz, 3H, CH₂CH₃). ¹³C NMR (126 MHz, CDCl₃) δ 176.8(C=O), 156.3(C=O), 154.1(C), 140.3(CH), 137.8(C), 136.1(C), 132.1(CH), 129.1(CH), 127.9(CH), 122.2(CH), 63.4(CH₂), 57.1(CH), 49.5(CH), 49.4(CH), 46.4(CH₂), 41.2(CH), 14.1(CH₃).

Ethyl (4aR*,5S*,8R*,8aS*)-1-(4-nitrophenyl)-9-oxo-1,4a,5,8,8a,9-hexahydro-5,8-methano[1,2,4]triazol[4,3-a]quinazoline-3-carboxylate (11c). Yield 75%, mp 190–192 °C, ¹H NMR (500 MHz, CDCl₃) δ 8.45 (d, J = 9.2 Hz, 2H, Ar.), 8.30 (d, J = 9.2 Hz, 2H, Ar.), 6.42 (dd, J = 5.4, 2.6 Hz, 1H), 5.97 (dd, J = 5.4, 2.6 Hz, 1H), 5.15 (dd, J = 10.0, 3.4 Hz, 1H), 4.58 (q, J = 7.1 Hz, 2H, CH₂CH₃), 3.71 (s(broad), 2H), 3.30 (dd, J = 10.0, 3.8 Hz, 1H), 1.60 (dd, J = 32.6, 9.4 Hz, 2H), 1.52 (t, J = 7.1 Hz, 3H, CH₂CH₃). ¹³C NMR (126 MHz, CDCl₃) δ 176.7(C=O), 156.0(C=O), 154.5(C), 146.0(C), 141.2(C), 140.4(CH), 138.5(C), 132.2(CH), 124.6(CH), 121.6(CH), 63.8(CH₂), 57.2(CH), 49.6(CH), 49.4(CH), 46.5(CH₂), 41.2(CH), 14.2(CH₃).

(4aR*,5S*,8R*,8aS*)-N-Phenyl-1-(p-tolyl)-9-oxo-1,4a,5,8,8a,9-hexahydro-5,8-methano[1,2,4]triazolo[4,3-a]quinazoline-3-carboxamide (11d). Yield 70%, mp 236–238 °C, ¹H NMR (500 MHz, CDCl₃) δ 8.90 (s, 1H), 7.85 (d, J = 8.3 Hz, 2H, Ar.), 7.71 (d, J = 7.9 Hz, 2H, Ar.), 7.43 (t, J = 7.8 Hz, 2H, Ar.), 7.25 (dd, J = 16.3, 6.2 Hz, 3H, Ar.), 6.38 (d, J = 5.2 Hz, 1H), 5.95 (d, J = 5.1 Hz, 1H), 5.22–5.12 (m, 1H), 3.86 (s, 1H), 3.65 (s, 1H), 3.30–3.18 (m, 1H), 2.37 (s, 3H, p-tolyl), 1.56 (dd, J = 22.5, 9.1 Hz, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 176.8(C=O), 154.0(C), 153.0(C), 140.1(CH), 139.6(C), 138.1(C), 136.3(C), 133.6(C), 132.4(CH), 129.6(CH), 129.3(CH), 125.7(CH), 121.9(CH), 120.2(CH), 57.2(CH), 49.6(CH), 49.5(CH), 46.4(CH₂), 41.2(CH), 21.1(CH₃).

(4aR*,5S*,8R*,8aS*)-3-Acetyl-1-(p-tolyl)-9-oxo-1,4a,5,8,8a,9-hexahydro-5,8-methano[1,2,4]triazolo[4,3-a]quinazoline (11e). Yield 50%, mp 210–212 °C, ¹H NMR (500 MHz, CDCl₃) δ 7.89 (d, J = 8.4 Hz, 2H, Ar.), 7.25 (d, J = 8.3 Hz, 2H, Ar.), 6.39 (s, 1H), 5.90 (s, 1H), 5.10 (d, J = 10.0 Hz, 1H), 3.66 (s, 2H), 3.25 (d, J = 13.4 Hz, 1H), 2.72 (s, 3H), 2.38 (s, 3H), 1.57 (dd, J = 20.6, 9.2 Hz, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 187.6(C=O), 177.0(C=O), 154.1(C), 142.3(C), 140.2(CH), 138.1(C), 133.7(C), 132.2(CH), 129.7(CH), 121.9(CH), 57.1(CH), 49.5(CH), 49.3(CH), 46.3(CH₂), 41.2(CH), 26.6(COCH₃), 21.1(CH₃, p-tolyl).

RDA protocol for the synthesis of [1,2,4]triazolo[4,3-a]pyrimidines 4a–h

Norbornene-fused [1,2,4]triazolo[4,3-a]pyrimidinones 7a–h or 11a,c–e (0.1 mmol) was dissolved in 1,2-DCM (2 mL) in a 10 mL sealed reaction vial. The solution was stirred at 200 °C for 30–120 min. at max. 200 W microwave irradiation. After completing the reaction, monitored by TLC, the solvent was evaporated, the residue was dissolved in EtOAc and purified by column chromatography on silica gel eluting with EtOAc.

Ethyl 7-oxo-1-phenyl-1,7-dihydro[1,2,4]triazolo-[4,3-a]pyrimidine-3-carboxylate (4a). Yield 42% from 7a, 52% from 11a, mp 215–218 °C, ¹H NMR (500 MHz, CDCl₃) δ 8.64 (d, J = 7.9 Hz, 1H, H-5), 8.19 (d, J = 7.9 Hz, 2H, Ar.), 7.51 (d, J = 7.9 Hz, 2H, Ar.), 7.39 (t, J = 7.4 Hz, 1H, Ar.), 6.50 (d, J = 7.8 Hz, 1H, H-6), 4.59 (q, J = 7.2 Hz, 2H, CH₂CH₃), 1.51 (t, J = 7.1 Hz, 3H, CH₂CH₃).¹³C NMR (125 MHz, CDCl₃) 168.5(C=O), 156.2(C=O), 149.2(C), 135.9(C), 132.4(C), 130.6(CH), 129.4(CH), 128.2(CH), 121.4(CH), 114.9(CH), 63.9(OCH₂), 14.2(CH₃).

Ethyl 7-oxo-1-(p-tolyl)-1,7-dihydro[1,2,4]triazolo[4,3-a]pyramidine-3-carboxylate (4b). Yield 54%, mp 193–195 °C, ¹H NMR (500 MHz, CDCl₃) δ 8.63 (d, J = 7.7 Hz, 1H, H-5), 8.05 (d, J = 8.6 Hz, 2H, Ar.), 7.29 (d, J = 7.9 Hz, 2H, Ar.), 6.49 (d, J = 7.8 Hz, 1H, H-6), 4.58 (q, J = 7.2 Hz, 2H, CH₂CH₃), 2.40 (s, 3H, p-tolyl), 1.50 (t, J = 7.2 Hz, 3H, CH₂CH₃). ¹³C NMR (126 MHz, CDCl₃) δ 168.5(C=O), 156.2(C=O), 149.1(C), 138.3(C), 133.4(C), 132.2(C), 130.5(CH), 129.8(CH), 121.3(CH), 114.9(CH), 63.8(OCH₂), 21.1(CH₃), 14.1(CH₃).

Ethyl 1-(4-nitrophenyl)-7-oxo-1,7-dihydro[1,2,4]triazolo-[4,3-a]pyrimidine-3-carboxylate (4c). Yield 41% from 7c, 45% from 11c, mp 205–207 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.66 (d, J = 7.6 Hz, 1H, H-5), 8.59 (d, J = 9.7 Hz, 2H, Ar.),8.37 (d, J = 9.2 Hz, 2H, Ar.), 6.53 (d, J = 7.6 Hz, 1H, H-6), 4.61 (q, J = 7.2 Hz, 2H, CH₂CH₃),1.53 (t, J = 7.3 Hz, 3H, CH₂CH₃). ¹³C NMR (126 MHz, CDCl₃) δ 168.0(C=O), 155.8(C=O), 149.3(C), 146.3(C), 140.7(C), 133.2(C), 130.8(CH), 125.0(CH), 120.9(CH), 114.9(CH), 64.2(OCH₂), 14.1(CH₃).

7-Oxo-N-phenyl-1-(p-tolyl)-1,7-dihydro[1,2,4]triazolo[4,3-a]pyrimidine-3-carboxamide (4d). Yield 78% from 7d, 67% from 11d, mp 253–255 °C, ¹H NMR (500 MHz, CDCl₃) δ 8.85 (d, J = 7.9 Hz, 1H, H-5), 8.77 (br, 1H, NH), 8.01 (d, 2H, J = 8.2 Hz, Ar.), 7.69 (d, J = 8.0 Hz, 2H, Ar.), 7.40–7.48 (m, 3H, Ar.), 7.27–7.33 (m, 2H, Ar.), 6.49 (d, J = 7.9 Hz, 1H, H-6), 2.41 (s, 3H, CH₃). ¹³C NMR (126 MHz, CDCl₃) δ 168.6(C=O), 152.9(C=O), 138.4(C), 135.8(C), 134.0(C), 133.3(C), 131.1(CH), 130.5(CH), 129.9(CH), 129.4(CH), 127.7(CH), 126.0(CH), 121.1(CH), 120.4(CH), 114.7(CH), 21.1(CH₃).

3-Acetyl-1-(p-tolyl)-[1,2,4]triazolo[4,3-a]pyrimidin-7(1H)-one (4e). Yield 90% from 7e, 57% from 11e, mp 216–217 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.70 (d, J = 7.8 Hz, 1H, H-5), 8.05 (d, J = 8.4 Hz, 2H, Ar.), 7.31 (d, J = 8.7 Hz, 2H, Ar.), 6.46 (d, J = 7.8 Hz, 1H, H-6), 2.77 (s, 3H, COCH₃), 2.41 (s, 3H, p-tolyl). ¹³C NMR (126 MHz, CDCl₃) δ 187.8(C=O), 168.5(C=O), 149.1(C), 138.5(C), 136.8(C), 133.5(C), 131.1(CH), 129.9(CH), 121.1(CH), 114.9(CH), 26.4(CH₃), 21.1(CH₃).

Ethyl 1-(4-methoxyphenyl)-7-oxo-1,7-dihydro[1,2,4]triazolo-[4,3-a]pyrimidine-3-carboxylate (4f). Yield 41%, mp 171–175 °C, ¹H NMR (500 MHz, CDCl₃) δ 8.63 (d, J = 7.7 Hz, 1H, H-5), 8.04 (d, J = 9.2 Hz, 2H, Ar.), 7.00 (d, J = 9.1 Hz, 2H, Ar.), 6.49 (d, J = 7.7 Hz, 1H, H-6), 4.58 (q, J = 7.2 Hz, 2H, CH₂CH₃), 3.85 (s, 3H, OCH₃), 1.50 (t, J = 7.2 Hz, 3H, CH₂CH₃). ¹³C NMR (126 MHz, CDCl₃) δ 168.5(C=O), 159.3(C=O), 156.2(C), 149.0(C), 132.1(C), 130.5(CH), 128.8(C), 123.2(CH), 114.9(CH), 114.4(CH), 63.7(OCH₂), 55.6(OCH₃), 14.1(CH₃).

Ethyl 1-(4-chlorophenyl)-7-oxo-1,7-dihydro[1,2,4]triazolo-[4,3-a]pyrimidine-3-carboxylate (4g). Yield 58%, mp 178–180 °C, ¹H NMR (500 MHz, CDCl₃) δ 8.65 (d, J = 7.7 Hz, 1H, H-5), 8.22 (d, J = 8.8 Hz, 2H, Ar.), 7.48 (d, J = 9.1 Hz, 2H, Ar.), 6.55 (d, J = 7.5 Hz, 1H, H-6), 4.59 (q, J = 7.3 Hz, 2H, CH₂CH₃), 1.51 (t, J = 7.1 Hz, 3H, CH₂CH₃). ¹³C NMR (126 MHz, CDCl₃) δ 168.3(C=O), 156.1(C=O), 149.1(C), 134.5(C), 133.9(C), 132.5(C), 130.6(CH), 129.5(CH), 122.3(CH), 115.0(CH), 64.0(OCH₂), 14.1(CH₃).

Ethyl 7-oxo-1-(3-(trifluoromethyl)phenyl)-1,7-dihydro[1,2,4]triazolo[4,3-a]pyrimidine-3-carboxylate (4h). Yield 48%, mp 193–195 °C, ¹H NMR (500 MHz, CDCl₃) δ 8.70–8.72 (m, 2H, Ar, H-5), 8.30 (brs, 1H, Ar.), 7.64–7.69 (m, 2H, Ar.), 6.53 (d, J = 7.8 Hz, 1H, H-6), 4.60 (q, J = 7.1 Hz, 2H, CH₂CH₃), 1.53 (t, J = 7.2 Hz, 3H, CH₂CH₃). ¹³C NMR (126 MHz, CDCl₃) δ 168.2(C=O), 156.0(C=O), 149.2(C), 136.4(C), 132.8(C), 130.2(C), 124.7(CH), 124.7(CH), 124.5(CH), 117.8(CH), 117.8(CH), 115.0(CH), 64.1(CH₂), 14.1(CH₃).

Conclusions

In the present work, we prepared triazolo[4,3-a]pyrimidin-7(1H)-ones 4a–h. These compounds cannot be prepared by the reactions of thiouracil 1 and hydrazonoyl chloride 2a–h, because these reactions are regioselective towards [1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-ones 3a–d. For overcoming this obstacle, we used diexo6 or diendo10 norbornene-condensed 2-thioxopyrimidin-4-ones characterized by two structural features: (i) the absence of the C=C bond in the pyrimidinone moiety that ensures the direction of the regioselectivity towards triazolo[4,3-a]pyrimidin-7(1H)-ones and (ii) the easy removal of cyclopentadiene by the RDA reaction and the concomitant rebuilding the C=C bond in the pyrimidinone moiety to obtain triazolo[4,3-a]pyrimidin-7(1H)-ones 4a–h as the final products.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful to the Hungarian Research Foundation (OTKA No. K 115731). The financial support of the GINOP-2.3.2-15-2016-00038 project is acknowledged. Ministry of Human Capacities, Hungary grant 20391-3/2018/FEKUSTRAT is acknowledged. In addition, Tempus Public Foundation is also acknowledged for its financial support (No. AK-00167-002/2019).

Notes and references

1. H. Dong, Z. Gao, R. Li, Y. Hu, H. Dong and Z. Xie, RSC Adv., 2014, 4, 55827.
2. B. Jafari, N. Yelibayeva, M. Ospanov, S. A. Ejaz, S. Afzal, S. U. Khan, Z. A. Abilov, M. Z. Turmukhanova, S. N. Kalugin, S. Safarov, J. Lecka, J. Sévigny, Q. Rahman, P. Ehlers, J. Iqbal and P. Langer, RSC Adv., 2016, 6, 107556.
3. V. S. Dinakaran, B. Bomma and K. K. Srinivasan, Der Pharma Chem., 2012, 4, 255.
4. R. Mishra and I. Tomar, Int. J. Pharm. Sci. Res., 2011, 2, 758.
5. M. Fares, S. M. Abou-Seri, H. A. Abdel-Aziz, S. E. S. Abbas, M. M. Youssef and R. A. Eladwy, Eur. J. Med. Chem., 2014, 83, 155; A. O. Abdelhamid, S. M. Gomha, N. A. Abdelriheem and S. M. Kandeel, Molecules, 2016, 21, 929.
6. B. Loev, J. H. Musser, R. E. Brown, H. Jones, R. Kahen, F. C. Huang, A. Khandwala, P. Sonnino-Goldman and M. J. Leibowitz, J. Med. Chem., 1985, 28, 363; B. A. El-Gazzar, M. M. El-Enanyb and M. N. Mahmoud, Bioorg. Med. Chem., 2008, 16, 3261.
7. M. S. M. Ahmed and T. A. Farghaly, Lett. Org. Chem., 2018, 15, 183; S. M. Riyadh, J. Chin. Chem. Soc., 2005, 52, 545.
8. T. A. Farghaly, S. M. Gomha, E. M. H. Abbas and M. M. Abdalla, Arch. Pharm., 2012, 345, 117.
9. A. S. Shawali, Chem. Rev., 1993, 2731; A. S. Shawali, J. Adv. Res., 2016, 7, 873.
10. S. M. Riyadh, Molecules, 2011, 16, 1834.
11. H. M. Hassaneen, H. A. Abdelhadi and T. A. Abdallah, Tetrahedron, 2001, 57, 10133.
12. H. M. Hassneen and T. A. Abdallah, Molecules, 2003, 8, 333; N. A. Abdel Hafez, T. A. Farghaly, M. A. Al-Omar and M. M. Abdall, Eur. J. Med. Chem., 2010, 45, 4838.
13. S. M. Riyadh, Molecules, 2011, 16, 1834; S. M. Gomha, S. A. Ahmed and A. O. Abdelhamid, Molecules, 2015, 20, 1357.
14. T. A. Abdallah, M. A. Darwish and H. M. Hassaneen, Molecules, 2002, 7, 494.
15. G. S. Masaret and T. A. Farghaly, Curr. Org. Synth., 2018, 15, 126.
16. K. Suzuki, K. Inomata and Y. Endo, Org. Lett., 2004, 6, 409.
17. I. Nekkaa, M. Palkó, I. M. Mándity, F. Miklós and F. Fülöp, Eur. J. Org. Chem., 2018, 32, 4456.
18. F. Miklós, Z. Tóth, M. M. Hänninen, R. Sillanpää, E. Forró and F. Fülöp, Eur. J. Org. Chem., 2013, 22, 4887.
19. B. Fekete, M. Palkó, S. Mándity, M. Haukka and F. Fülöp, Eur. J. Org. Chem., 2016, 21, 3519.
20. S. H. Frayne, R. M. Stolz and B. H. Northrop, Org. Biomol. Chem., 2019, 17, 7878.
21. B. Zhang, Y. Li, Z. Zhang, Y. An, Y. Wen, X. Gou, S. Quan, X. Wang and Y. Liang, J. Am. Chem. Soc., 2019, 141, 9731.
22. F. Csende, G. Stájer and F. Fülöp, in Comprehensive Organic Synthesis, ed. P. Knochel and G. A. Molander, Elsevier, 2014, vol. 5, p. 518.
23. S. Kotha and S. Banerjee, RSC Adv., 2013, 3, 7642.
24. M. Palkó, M. El Haimer, Z. Kormányos and F. Fülöp, Molecules, 2019, 24, 772.
25. A. M. Asiri, A. O. Al-Youbi, M. E. M. Zayed and S. W. Ng, Acta Crystallogr., Sect. E: Struct. Rep. Online, 2011, 67, o1964.
26. C. T. Lee, W. T. Yang and R. G. Parr, Phys. Rev., 1988, 37, 785; A. D. Becke, J. Chem. Phys., 1993, 98, 5648.
27. G. Stajer, A. E. Szabo and P. Sohar, Heterocycles, 1999, 51, 1849.
28. V. S. Matiychuk, M. A. Potopnyk, R. Luboradzki and M. D. Obushak, Synthesis, 2011, 11, 1799.
29. R. Silvestri, M. G. Cascio, G. La Regina, F. Piscitelli, A. Lavecchia, A. Brizzi, S. Pasquini, M. Botta, E. Novellino, V. Di Marzo and F. Corell, J. Med. Chem., 2008, 51, 1560.
30. J. Liu, M. Nie, Y. Wang, J. Hu, F. Zhang, Y. Gao, Y. Liu and P. Gong, Eur. J. Med. Chem., 2016, 123, 431.
31. Rikagu Oxford Diffraction, CrysAlisPro, Rikagu Oxford Diffraction inc., Yarnton, Oxfordshire, England, 2013.
32. G. M. Sheldrick, Acta Crystallogr., Sect. C: Struct. Chem., 2015, 71, 3.

---

Footnote

† Electronic supplementary information (ESI) available. CCDC 1980577 and 1980578. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d0ra04345a

---