Next Article in Journal
Isolation of a Nitromethane Anion in the Calix-Shaped Inorganic Cage
Previous Article in Journal
Recent Progress in Bioconjugation Strategies for Liposome-Mediated Drug Delivery
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 25
Issue 23
10.3390/molecules25235673
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Angular Regioselectivity in the Reactions of 2-Thioxopyrimidin-4-ones and Hydrazonoyl Chlorides: Synthesis of Novel Stereoisomeric Octahydro[1,2,4]triazolo[4,3-a]quinazolin-5-ones

by
Awad I. Said
1,2,
Márta Palkó
1,3,*,
Matti Haukka
4 and
Ferenc Fülöp
1,3
1
Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary
2
Chemistry Department, Faculty of Science, Assiut University, Assiut 71516, Egypt
3
Interdisciplinary Excellence Center, Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Hungary
4
Department of Chemistry, University of Jyväskulä, FIN-40014 Jyväskulä, Finland
*
Author to whom correspondence should be addressed.
Molecules 2020, 25(23), 5673; https://doi.org/10.3390/molecules25235673
Submission received: 4 November 2020 / Revised: 25 November 2020 / Accepted: 27 November 2020 / Published: 1 December 2020
Browse Figures
Versions Notes

Abstract

:
The regioselective synthesis of cis and trans stereoisomers of variously functionalized octahydro[1,2,4]triazolo[4,3-a]quinazolin-5-ones was performed. The 2-thioxopyrimidin-4-ones used in the synthesis reacted with hydrazonoyl chlorides in a regioselective manner to produce the angular regioisomers [1,2,4]triazolo[4,3-a]quinazolin-5-ones rather than the linear isomers [1,2,4]triazolo[4,3-a]quinazolin-5-ones. The synthesis process took place with electronic control. The angular regiochemistry of the products was confirmed by X-ray experiments and two-dimensional NMR studies.

Graphical Abstract

1. Introduction

The [1,2,4]triazolo[4,3-a]pyrimidinone scaffold has been known to exhibit a wide range of pharmacological activities such as antitumor, anti-inflammatory, antimicrobial, and antifungal activity, as well as macrophage activation [1,2,3,4,5,6,7,8,9].
A reaction between hydrazonoyl chlorides decorated with different functionalities [10,11,12] and 2-thioxopyrimidin-4-ones is an efficient strategy for incorporating the [1,2,4]triazolo moiety into [1,2,4]triazolo[4,3-a]pyrimidinones [13,14].
Recently, we reported that 2-thioxopyrimidin-4-one constructed on the norbornene skeleton gave an angular regioisomer ([1,2,4]triazolo[4,3-a]pyrimidin-7(1H)-one), functionalized with various hydrazonoyl chlorides, as the sole product of the reaction [15]. This was in contrast to findings observed previously, where [1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-one, the linear regioisomer, was the sole product of the reaction [16,17,18,19,20,21].
Herein, we report the extension of our research for the regioselective synthesis of novel cis- and trans-octahydro[1,2,4]triazolo[4,3-a]quinazolin-5-ones 4a–g and 5a–g via the reaction of cyclohexane-fused cis- or trans-2-thioxopyrimidin-4-ones 1 and 2 with hydrazonoyl chlorides 3a–g, taking place under electronic control. Moreover, X-ray and two-dimensional NMR studies were used to prove the stereochemistry of the products.

2. Results and Discussion

Cyclohexane-fused cis- and trans-2-thioxopyrimidin-4-one 1 and 2 were prepared according to previously described procedures [22]. The thioxopyrimidinone derivatives 1 or 2 thus prepared were reacted with the hydrazonoyl chlorides 3a–g bearing varied functionalities in dioxane in the presence of triethylamine as a base under reflux conditions (Scheme 1). According to the reaction mechanism depicted in Scheme 2, the angular regioisomers [1,2,4]triazolo[4,3-a]quinazolin-5(3H)-one 4a–g and 5a–g and linear regioisomers [1,2,4]triazolo[4,3-a]quinazolin-5(3H)-one 6a–g and 7a–g were expected to be formed. The outcome of the reactions depends on the involvement of the tautomeric structures I or II of the cyclohexane-fused 2-thioxopyrimidin-4-ones 1 and 2. The reactions proceeded through S-alkylation [17,18,19,20,21] to give S-alkylated products A followed by Smiles rearrangement [23], affording intermediates B, which cyclized in situ under the employed reaction conditions via the elimination of hydrogen sulfide gas to give the desired products 4a–g and 5a–g [20]. As evidenced by TLC and NMR spectroscopy, the transformations took place in a regioselective manner, producing the corresponding angular regioisomers as the sole products.
The steric structure of the angular regioisomers was evidenced with information acquired through various instrumental techniques, namely, 1H-NMR, 13C-NMR, and two-dimensional NMR including NOESY (neighboring Overhauser effect spectroscopy correlation), HMBC (heteronuclear multiple bond correlation), and X-ray crystallographic analysis. The 1H-NMR spectra of the products formed by the hydrazonoyl chloride ethyl esters 3a–f show a more multiplicated signal pattern corresponding to the CH2 moiety of the ester functional group (Supplementary Materials), which suggests the steric proximity of the ester group and the cyclohexane skeleton. Moreover, the NOESY spectra exhibit a mutual correlation between the hydrogens of CH2 and cyclohexane. In addition, the HMBC spectra show a mutual correlation between H-9a and C-1, which are separated by three bonds in the angular regioisomers. However, this correlation cannot exist in the linear regioisomers, because the C-3 and H-9a atoms are separated by five bonds (Figure 1a). Last but not least, the 13C-NMR spectra reveal the signal of the carbonyl carbon of the pyrimidinone ring residue at nearly 176 ppm. These chemical shift values are similar to those of annelated pyrimidinones of type A rather than those of type B (Figure 1b) [24]. Finally, the X-ray crystallographic analysis of 5b provided conclusive evidence for the angular regiochemistry of the products (Figure 2).
On the basis of the above evidence, the angular structures 4a–g and 5a–g were assigned for the products, and, consequently, the linear structures 6a–g and 7a–g could be rejected.
The regioselectivity of these reactions delivering the angular regioisomers was ascribed to electronic factors rather than steric factors. That is, since the tautomeric form I is electronically and energetically predominant, the reaction proceeds through tautomeric form I and leads to the formation of the angular regioisomer (Scheme 2).

3. Materials and Methods

3.1. General Methods

NMR analyses were performed 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 a Double Resonance Broad Band Probe (BBO). Tetramethylsilane (TMS) was used as an internal standard. The reactions were monitored by thin-layer chromatography (TLC) using aluminum sheets coated with silica gel (POLYGRAM®SIL G/UV254, Merck, Kenilworth, NJ, USA). The TLC plates were visualized under UV light. The melting points were measured using a Hinotek-X4 micro melting point apparatus (Hinotek, Ningbo, China).
The cyclohexane-fused cis- and trans-2-thioxopyrimidin-4-ones 1 and 2 were prepared from the corresponding amino esters according to reported procedures [25,26,27]. The hydrazonoyl chlorides 2a–h were synthesized according to procedures reported previously [27,28].
X-ray diffraction data were collected on a Rigaku Oxford Diffraction Supernova diffractometer using Cu Kα radiation, measured at a temperature of 120 K using a crystal of 5b immersed in cryo-oil and mounted in a loop. The CrysAlisPro [29] software package was used for cell refinement and data reduction. An analytical absorption correction (CrysAlisPro) was applied to the intensities before structure solution. The structure was solved by an intrinsic phasing method (SHELXT [30,31]). Structural refinement was carried out using the SHELXL [30] software with the SHELXLE [31] graphical user interface. Hydrogen atoms were positioned geometrically and constrained to ride on their parent atoms, with C–H = 0.95–1.00 Å and Uiso = 1.2–1.5·Ueq (parent atom). The crystallographic details are summarized in Table S1.

3.2. Synthesis of Cis- and Trans-[1,2,4]triazolo[4,3-a]quinazolin-5(3H)-one 4a–g and 5a–g

A mixture of 0.5 mmol of cyclohexane-fused 2-thioxopyrimidin-4-one 1 or 2 and 0.5 mmol of hydrazonoyl chloride (3a–g) in dioxane (10 mL) was treated at reflux temperature in the presence of 100 µL of triethylamine (TEA) for 5–7 h. The reactions were monitored by TLC (n-hexane/EtOAC = 1:1 as the eluent) until completion. After solvent evaporation under reduced pressure, the residue was dissolved in CHCl3 (20 mL), followed by extraction with water (3 × 10 mL). The CHCl3 solution was dried on Na2SO4, the solvent was evaporated, and the residue was purified by column chromatography using n-hexane/EtOAC = 1:1 as the eluent.
(5aR*,9aS*)-Ethyl 5-oxo-3-phenyl-3,5,5a,6,7,8,9,9a-octahydro-[1,2,4]triazolo[4,3-a]quinazoline-1-carboxylate (4a): 69%, m.p. 223–225 °C 1H NMR (500 MHz, CDCl3) δ = 8.09 (d, J = 7.7, 2H), 7.45 (t, J = 8.0, 2H), 7.33 (t, J = 7.4, 1H), 5.08–4.98 (m, 1H, H-4a), 4.58–4.45 (m, 2H, CH2CH3), 2.92 (d, J = 4.2, 1H), 2.68 (d, J = 12.5, 1H), 2.03 (d, J = 9.5, 1H), 1.86 (d, J = 10.9, 1H), 1.47 (t, J = 7.1, 3H, CH2CH3), 1.51–1.41 (m, 5H). 13C NMR (126 MHz, CDCl3) δ = 176.0(C=O), 156.3 (C=O), 153.2(C), 136.85(C), 136.3(C), 129.1(CH), 127.8(CH), 121.8(CH), 63.3(OCH2), 55.4(CH), 55.2(CH), 38.2(CH2), 28.8(CH2), 24.7(CH2), 24.6(CH2), 21.22(CH), 14.29, 14.1(CH3).
(5aR*,9aS*)-Ethyl 5-oxo-3-(p-tolyl)-3,5,5a,6,7,8,9,9a-octahydro-[1,2,4]triazolo[4,3-a]quinazoline-1-carboxylate (4b): 62%, m.p. 263–264 °C. 1H NMR (500 MHz, CDCl3) δ = 7.94 (d, J = 8.5, 2H), 7.24 (d, J = 8.3, 2H), 5.10–4.95 (m, 1H, H-4a), 4.52 (pd, J = 7.6, 3.6, 1H, CH2CH3), 2.91 (d, J = 5.5, 1H, H-8a), 2.68 (d, J = 12.2, 1H), 2.37 (s, 3H, p-tolyl), 2.03 (d, J = 12.1, 1H), 1.86 (d, J = 11.1, 1H), 1.47 (t, J = 7.1, 3H, CH2CH3). 1.62–1.4 (m, 4H). 13C NMR (126 MHz, CDCl3) δ = 176.1(C=O), 156.4(C=O), 153.1(C), 137.9(C), 136.6(C), 133.9(C), 129.7(CH), 121.7(CH), 63.3(OCH2), 55.3(CH), 38.1(CH), 28.8(CH2), 24.7(CH2), 24.6(CH2), 21.3 (CH2), 21.11(CH3, p-tolyl), 14.13(CH2CH3).
(5aR*,9aS*)-Ethyl 5-oxo-3-(4-nitrophenyl)-3,5,5a,6,7,8,9,9a-octahydro-[1,2,4]triazolo[4,3-a]quinazoline-1-carboxylate (4c): 61%, m.p. 262–265 °C. 1H NMR (500 MHz, CDCl3) δ = 8.51 (d, J = 9.3, 2H), 8.33 (d, J = 12.2, 2H), 5.07 (ddd, J = 11.3, 6.5, 4.4, 1H), 4.60–4.49 (m, 2H, CH2CH3), 2.95 (d, J = 6.0, 1H), 2.68 (d, J = 8.0, 1H), 2.05 (d, J = 12.5, 1H), 1.88 (d, J = 10.2, 1H), 1.50 (t, J = 7.1, 3H, CH2CH3), 1.63–1.43 (m, 5H). 13C NMR (126 MHz, CDCl3) δ = 176.0(C=O), 156.0(C=O), 155.6(C), 146.0(C), 141.4(C), 137.6(C), 124.8(CH), 121.2(CH), 77.3(OCH2), 77.0(CH), 76.8(CH), 63.7(CH2), 55.5(CH), 38.2(CH), 28.8(CH2), 24.6(CH2), 24.5(CH2), 21.1(CH2), 14.11(CH3).
(5aR*,9aS*)-Ethyl 5-oxo-3-(4-methoxyphenyl)-3,5,5a,6,7,8,9,9a-octahydro-[1,2,4]triazolo[4,3-a]quinazoline-1-carboxylate (4d): 69%, m.p. 215–216 °C. 1H NMR (500 MHz, CDCl3) δ 7.94 (d, J = 9.1 Hz, 2H), 6.96 (d, J = 9.1 Hz, 2H), 5.15–4.92 (m, 1H), 4.67–4.39 (m, 2H, CH2CH3), 3.83 (s, 3H), 2.93 (d, J = 5.7 Hz, 1H), 2.68 (d, J = 12.2 Hz, 1H), 2.03 (d, J = 12.5 Hz, 1H), 1.86 (d, J = 12.5 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H, CH2CH3). 1.62–1.4 (m, 4H). 13C NMR (126 MHz, CDCl3) δ 175.9(C=O), 159.1(C=O), 156.3(C), 152.9(C), 136.6(C), 129.2(C), 123.7(CH), 114.3(CH), 63.3(OCH2), 55.6(OCH3), 55.4(CH), 38.2(CH), 28.8(CH2), 24.7(CH2), 24.62, 2(CH2).25, 1(CH2).14.1(CH3).
(5aR*,9aS*)-Ethyl 5-oxo-3-(4-chlorophenyl)-3,5,5a,6,7,8,9,9a-octahydro-[1,2,4]triazolo[4,3-a]quinazoline-1-carboxylate (4e): 68%, m.p. 239–241 °C. 1H NMR (500 MHz, CDCl3) δ = 8.12 (d, J = 9.0, 2H), 7.42 (d, J = 9.1, 2H), 5.04 (ddd, J = 11.3, 6.5, 4.4, 1H), 4.62–4.45 (m, 2H,CH2CH3), 2.92 (d, J = 6.0, 1H), 2.68 (d, J = 7.5, 1H), 2.03 (d, J = 12.4, 1H), 1.86 (d, J = 10.3, 1H), 1.48 (t, J = 7.1, 3H, CH2CH3), 1.69–1.41 (m, 5H). 13C NMR (126 MHz, CDCl3) δ = 176.0(C=O), 156.2(C=O), 153.1(C), 136.9(C), 134.9(C), 133.4(C), 129.3(CH), 122.7(CH), 63.5(OCH2), 55.4(CH), 38.1(CH), 28.8(CH2), 24.6(CH2), 24.6(CH2), 21.2(CH2), 14.1(CH3).
(5aR*,9aS*)-Ethyl 5-oxo-3-(4-(trifluoromethyl)phenyl)-3,5,5a,6,7,8,9,9a-octahydro-[1,2,4]triazolo[4,3-a]quinazoline-1-carboxylate (4f): 62%, m.p. 202–206 °C. 1H NMR (500 MHz, CDCl3) δ = 8.56 (dd, J = 8.3, 3.0, 1H), 8.27 (s, 1H), 7.62–7.58 (m, 2H), 5.20–4.89 (m, 1H), 4.66–4.39 (m, 2H, CH2CH3), 2.94 (d, J = 3.8, 1H), 2.68 (d, J = 9.9, 1H), 2.05 (dd, J = 8.7, 3.7, 1H), 1.87 (d, J = 10.2, 1H), 1.74 (s, 1H), 1.50 (t, J = 7.1, 3H, CH2CH3), 1.61–1.41 (m, 4H). 13C NMR (126 MHz, CDCl3) δ = 176.02 (C=O), 156.16(C=O), 153.38(C), 137.2(C), 136.84(C), 131.7(q, J = 38 Hz, CCF3), 129.9(CH), 124.3(q, J = 3.5 Hz, CHCCF3), 123.5(q, J = 273 Hz, CF3), 118.2(q, J = 4 Hz, CHCCF3), 63.6(OCH2), 55.4(CH), 38.2(CH), 28.8(CH2), 24.6(CH2), 24.6(CH2), 21.2(CH2), 14.1(CH3).
(5aR*,9aS*)-1-Acetyl-3-(p-tolyl)-5a,6,7,8,9,9a-hexahydro[1,2,4]triazolo[4,3-a]quinazoline-5(3H)-one (4g): 66%, m.p. 196–198 °C. 1H NMR (500 MHz, CDCl3) δ = 7.96 (d, J = 8.5, 2H), 7.27 (d, J = 7.0, 2H), 5.13–5.00 (m, 1H), 2.92 (d, J = 2.3, 1H), 2.69 (s, 3H, COCH3), 2.66 (d, J = 7.7, 1H), 2.39 (s, 3H, CH3, p-tolyl), 1.98 (d, J = 12.3, 1H), 183 (br, 2H), 1.62–1.45 (m, 4H). 13C NMR (126 MHz, CDCl3) δ 188.1(C=O), 176.0(C=O), 153.6(C), 141.4(C), 138.1(C), 133.9(C), 129.8(CH), 121.6(CH), 55.0(CH), 38.2(CH2), 28.6(COCH3), 26.5, 24.6(CH2), 24.5(CH2), 21.3(CH2), 21.1(CH3, p-tolyl).
(5aR*,9aR*)-Ethyl 5-oxo-3-phenyl-3,5,5a,6,7,8,9,9a-octahydro-[1,2,4]triazolo[4,3-a]quinazoline-1-carboxylate (5a): 65%, m.p. 203–206 °C. 1H NMR (500 MHz, CDCl3) δ 8.04 (d, J = 7.6 Hz, 2H), 7.48–7.41 (m, 2H), 7.33 (t, J = 7.4 Hz, 1H), 4.58–4.44 (m, 2H, CH2CH3), 4.08–3.97 (m, 1H), 2.82 (d, J = 7.5 Hz, 1H), 2.50 (d, J = 13.0 Hz, 1H), 2.30–2.21 (m, 2H), 1.94 (t, J = 9.2 Hz, 1H), 1.46 (t, J = 7.1 Hz, 3H, CH2CH3), 1.54–1.35 (m. 4H). 13C NMR (126 MHz, CDCl3) δ 176.7(C=O), 157.5(C=O), 153.3(C), 138.9(C), 136.2(C), 129.1(CH), 127.7(CH), 121.7(CH), 63.8(OCH2), 58.2(CH), 43.4(CH), 31.2(CH2), 25.4(CH2), 25.0(CH2), 24.2(CH2), 14.0. (CH3).
(5aR*,9aR*)-Ethyl 5-oxo-3-(p-tolyl)-3,5,5a,6,7,8,9,9a-octahydro-[1,2,4]triazolo[4,3-a]quinazoline-1-carboxylate (5b): 67%, m.p. 213–214 °C 1H NMR (500 MHz, CDCl3) δ 7.89 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 4.71–4.35 (m, 2H, CH2CH3), 4.17–3.87 (m, 1H), 2.82 (d, J = 7.4 Hz, 1H), 2.50 (d, J = 10.5 Hz, 1H), 2.37 (s, 3H), 2.32–2.19 (m, 1H), 1.93 (t, J = 7.3 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H, CH2CH3). 1.47–1.132 (m, 4H). 13C NMR (126 MHz, CDCl3) δ 176.7(C=O), 157.5(C=O), 153.2(C), 138.7(C), 137.8(C), 133.8(C), 129.7(CH), 121.7(CH), 63.7(CH2), 58.2(CH), 43.4(CH), 31.2(CH2), 25.4(CH2), 25.1(CH2), 24.2(CH2), 21.1(CH3, p-tolyl), 14.0(CH3).
(5aR*,9aR*)-Ethyl 5-oxo-3-(4-nitrophenyl)-3,5,5a,6,7,8,9,9a-octahydro-[1,2,4]triazolo[4,3-a]quinazoline-1-carboxylate (5c): 71%, m.p. 255–258 °C. 1H NMR (500 MHz, CDCl3) δ 8.47–8.42 (m, 2H), 8.34–8.27 (m, 2H), 4.54 (qq, J = 10.8, 7.2 Hz, 2H, CH2CH3), 4.14–3.97 (m, 1H), 2.90–2.70 (m, 1H), 2.50 (dd, J = 17.3, 6.6 Hz, 1H), 2.33–2.20 (m, 1H), 1.96 (dd, J = 11.5, 6.0 Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H, CH2CH3), 1.56–1.34 (m, 4H). 13C NMR (126 MHz, CDCl3) δ 176.5(C=O), 157.2(C=O), 153.5(C), 145.9(C), 141.3(C), 139.7(C), 124.8(CH), 121.0(CH), 64.1(OCH2), 58.2(CH), 43.3(CH), 31.1(CH2), 25.3(CH2), 24.9(CH2), 24.1(CH2), 14.0(CH3).
(5aR*,9aR*)-Ethyl 5-oxo-3-(4-methoxyphenyl)-3,5,5a,6,7,8,9,9a-octahydro-[1,2,4]triazolo[4,3-a]quinazoline-1-carboxylate (5d): 69%, m.p. 204–206 °C 1H NMR (500 MHz, CDCl3) δ 7.92–7.85 (m, 2H), 6.99–6.91 (m, 2H), 4.58–4.41 (m, 2H, CH2CH3), 4.06–3.98 (m, 1H), 3.83 (s, 3H), 2.83 (dt, J = 15.4, 7.6 Hz, 1H), 2.51 (d, J = 12.8 Hz, 1H), 2.28–2.20 (m, 1H), 1.93 (t, J = 7.9 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H, CH2CH3), 1.53–1.25 (m,4H). 13C NMR (126 MHz, CDCl3) δ 176.7(C=O), 159.0(C=O), 157.5(C), 153.1(C), 138.7(C), 129.3(C), 123.6(CH), 114.3(CH), 63.7(OCH2), 58.3(CH), 55.6(CH), 43.4(OCH3), 31.2(CH2), 25.4(CH2), 25.1(CH2), 24.2(CH2), 14.0(CH3).
(5aR*,9aR*)-Ethyl 5-oxo-3-(4-chlorophenyl)-3,5,5a,6,7,8,9,9a-octahydro-[1,2,4]triazolo[4,3-a]quinazoline-1-carboxylate (5e): 68%, m.p. 240–245 °C. 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 8.9 Hz, 2H), 7.41 (d, J = 8.9 Hz, 2H), 4.51 (qq, J = 10.8, 7.1 Hz, 2H, CH2CH3), 4.06–3.95 (m, 1H), 2.79 (d, J = 7.7 Hz, 1H), 2.49 (d, J = 12.5 Hz, 1H), 2.25 (t, J = 12.2 Hz, 1H), 1.94 (t, J = 8.7 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H, CH2CH3), 1.53–1.26 (m, 4H). 13C NMR (126 MHz, CDCl3) δ 176.4(C=O), 157.4(C=O), 153.2(C), 139.0(C), 134.9(C), 133.2(C), 129.2(CH), 122.6(CH), 63.8(OCH2), 58.3(CH), 43.4(CH), 31.2(CH2), 25.4(CH2), 25.0(CH2), 24.2(CH2), 14.0(CH3).
(5aR*,9aR*)-Ethyl 5-oxo-3-(4-(trifluoromethyl)phenyl)-3,5,5a,6,7,8,9,9a-octahydro-[1,2,4]triazolo[4,3-a]quinazoline-1-carboxylate (5f): 70%, m.p. 173–175 °C. 1H NMR (500 MHz, CDCl3) δ 8.60–8.42 (m, 1H), 8.22 (d, J = 0.6 Hz, 1H), 7.66–7.50 (m, 2H), 4.60–4.36 (m, 2H, CH2CH3), 4.13–3.93 (m, 1H). 2.80 (d, J = 8.0 Hz, 1H), 2.50 (d, J = 13.0 Hz, 1H), 2.34–2.19 (m, 1H), 1.95 (t, J = 8.4 Hz, 2H), 1.48 (t, J = 7.2 Hz, 3H, CH2CH3), 1.55–1.23 (m, 4H). 13C NMR (126 MHz, CDCl3) δ 176.6(C=O), 157.3(C=O), 153.4(C), 139.3(C), 136.8(C), 131.7 (q, J = 33 Hz, C-CF3), 129.9, 124.8, 124.1 (q, J = 3.6 Hz, CHCCF3), 123.4 (q, J = 271 Hz, CF3), 118.1 (q, J = 3.7 Hz), 64.0(OCH2), 58.2(CH), 43.4(CH), 31.2(CH2), 25.3(CH2), 25.0(CH2), 24.2(CH2), 14.0(CH3).
(5aR*,9aR*)-1-Acetyl-3-(p-tolyl)-5a,6,7,8,9,9a-hexahydro[1,2,4]triazolo[4,3-a]quinazoline-5(3H)-one (5g): 67%, m.p. 158–162 °C 1H NMR (500 MHz, CDCl3) δ 7.91 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H), 4.06–3.98 (m, 1H), 2.92 (d, J = 8.5 Hz, 1H), 2.71 (s, 3H), 2.49 (d, J = 13.2 Hz, 1H), 2.39 (s, 3H), 2.25 (t, J = 13.5 Hz, 1H), 1.92 (d, J = 11.0 Hz, 2H), 1.49 (dd, J = 24.4, 14.6 Hz, 1H), 1.42–1.22 (m, 3H). 13C NMR (126 MHz, CDCl3) δ 187.9(C=O), 176.8(C=O), 153.7(C), 144.2(C), 138.0(C), 133.8(C), 129.7(CH), 121.6(CH), 58.5(COCH3), 43.6(CH), 31.9(CH2), 27.6(CH), 25.5(CH2), 25.2(CH2), 24.3(CH2), 21.1(CH3, p-tolyl).

4. Conclusions

Herein, we report the unexpected regioselectivity of the reaction between 2-thioxopyrimidin-4-ones with hydrazonoyl chlorides to produce the angular regioisomers [1,2,4]triazolo[4,3-a]quinazolin-5-ones, rather than the linear isomers [1,2,4]triazolo[4,3-a]quinazolin-5-ones. The transformations are controlled by electronic factors of 2-thioxopyrimidin-4-one. This phenomenon was exploited in the synthesis of the novel stereoisomeric octahydro[1,2,4]triazolo[4,3-a]quinazolin-5-ones 4a–g and 5a–g starting from cis or trans cyclohexane-fused 2-thioxopyrimidin-4-one 1 or 2, respectively. The stereochemistry of the products was assigned on the basis of one- and two-dimensional NMR spectra and by X-ray measurements providing conclusive evidence.

Supplementary Materials

NMR spectra of all the synthesized compounds and crystallographic data for 5b are available online.

Author Contributions

F.F., A.I.S., and M.P. planned and designed the project. A.I.S. and M.P. performed the syntheses and characterized the synthesized compounds. M.H. performed and analyzed the X-ray measurements of compound 5b. A.I.S. prepared the manuscript for publication, and all the authors discussed the results and commented on the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

We are grateful to the Hungarian Research Foundation (OTKA No. K 115731). The financial support of the GINOP-2.3.2-15-2016-00014 project is acknowledged. The Ministry of Human Capacities, Hungary, grant TUDFO/47138-1/2019, is acknowledged.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Fan, W.-Q.; Katritzky, A.R. 1,2,3-Triazoles. In Comprehensive Heterocycle Chemistry II; Katritzky, A.R., Rees, C.W., Scriven, E.F.V., Eds.; Pergamon Press: New York, NY, USA, 1996; Volume 4, pp. 1–126. [Google Scholar]
  2. Su, N.N.; Li, Y.; Yu, S.J.; Zhang, X.; Liu, X.H.; Zhao, W.G. Microwave-assisted synthesis of some novel 1,2,3-triazoles by click chemistry, and their biological activity. Res. Chem. Intermed. 2013, 39, 759–766. [Google Scholar] [CrossRef]
  3. Astakhov, A.V.; Chernyshev, V.M. Molecular structure of 3-amino[1,2,4]triazolo-[4,3-a] pyrimidin-5-one in various tautomeric forms: Investigation by DFT and QTAIM methods. Chem. Heterocycl. Compd. 2014, 50, 319–326. [Google Scholar] [CrossRef]
  4. Abdelhamid, A.O.; Gomha, S.M.; Abdelriheem, N.A.; Kandeel, S.M. Synthesis of New 3-Heteroarylindoles as Potential Anticancer Agents. Molecules 2016, 21, 929. [Google Scholar] [CrossRef]
  5. Gomha, S.M. A facile one-pot synthesis of 6,7,8,9-tetrahydrobenzo[4,5]thieno[2,3-d]-1,2,4-triazolo [4,5-a]pyrimidin-5-ones. Mon. Chem. 2009, 140, 213–220. [Google Scholar] [CrossRef]
  6. Fares, M.; Abou-Seri, S.M.; Abdel-Aziz, H.A.; Abbas, S.E.S.; Youssef, M.M.; Eladwy, R.A. Synthesis and antitumor activity of pyrido[2,3-d]pyrimidine and pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine derivatives that induce apoptosis through G(1) cell-cycle arrest. Eur. J. Med. Chem. 2014, 83, 155–166. [Google Scholar] [CrossRef]
  7. Gomha, S.M.; Ahmed, S.A.; Abdelhamid, A.O. Synthesis and cytotoxicity evaluation of some novel thiazoles, thiadiazoles, and pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-one incorporating triazole moiety. Molecules 2015, 20, 1357–1376. [Google Scholar] [CrossRef] [Green Version]
  8. Liu, X.H.; Sun, Z.H.; Yang, M.Y.; Tan, C.X.; Weng, J.Q.; Zhang, Y.G.; Ma, Y. Microwave assistant one pot synthesis, crystal structure, antifungal activities and 3D-QSAR of novel 1,2,4-triazolo[4,3-a]pyridines. Chem. Biol. Drug Des. 2014, 84, 342–347. [Google Scholar] [CrossRef]
  9. Gomha, S.M.; Badrey, M.G. Ecofriendly regioselective one-pot synthesis of chromeno[4,3-d][1,2,4]triazolo [4,3-a]pyrimidine. Eur. J. Chem. 2013, 4, 180–184. [Google Scholar] [CrossRef] [Green Version]
  10. Dieckmann, W.; Platz, L. Ueber eine neue Bildungsweise von Osotetrazonen. Ber. Dtsch. Chem. Ges. 1905, 38, 2986–2990. [Google Scholar] [CrossRef] [Green Version]
  11. Silvestri, R.; Cascio, M.G.; La Regina, G.; Piscitelli, F.; Lavecchia, A.; Brizzi, A.; Pasquini, S.; Botta, M.; Novellino, E.; Di Marzo, V.; et al. Synthesis, cannabinoid receptor affinity, and molecular modeling studies of substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides. J. Med. Chem. 2008, 51, 1560–1576. [Google Scholar] [CrossRef]
  12. Liu, J.; Nie, M.; Wang, Y.; Hu, J.; Zhang, F.; Gao, Y.; Liu, Y.; Gong, P. Design, synthesis and structure-activity relationships of novel 4-phenoxyquinoline derivatives containing 1,2,4-triazolone moiety as c-Met kinase inhibitors. Eur. J. Med. Chem. 2016, 123, 431–446. [Google Scholar] [CrossRef]
  13. Abdelhamid, A.O.; Shawali, A.S.; Gomha, S.M.; El-Enany, W.M.A. Synthesis and antimicrobial evaluation of some novel thiazole, 1,3,4-thiadiazole and pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine derivatives incorporating pyrazole moiety. Heterocycles 2015, 91, 2126–2142. [Google Scholar] [CrossRef]
  14. Riyadh, S.M. Enaminones as building blocks for the synthesis of substituted pyrazoles with antitumor and antimicrobial activities. Molecules 2011, 16, 1834–1853. [Google Scholar] [CrossRef] [Green Version]
  15. Said, A.I.; Palkó, M.; Haukka, M.; Fülöp, F. Retro Diels Alder Protocol for Regioselective Synthesis of Novel [1,2,4]triazolo[4,3-a]pyrimidin-7(1H)-ones. RSC Adv. 2020, 10, 33937–33943. [Google Scholar] [CrossRef]
  16. Said, A.I.; Haukka, M.; Fülöp, F. Microwave-Assisted Regioselective Synthesis of Variously Functionalized [1,2,4]triazolo[3,4-b]quinazolin-5(1H)-ones. Curr. Org. Chem. 2020, 24, 1892–1896. [Google Scholar] [CrossRef]
  17. Hassaneen, H.M.; Abdelhadi, H.A.; Abdallah, T.A. Novel synthesis of 1,2,4-triazolo[4,3-a]pyrimidin-5-one derivatives. Tetrahedron 2001, 57, 10133–10138. [Google Scholar] [CrossRef]
  18. Hassneen, H.M.; Abdallah, T.A. New Routes to Pyridino[2,3-d]pyrimidin-4-one and Pyridino[2,3-d] triazolino[4,5-a]pyrimidin-5-one Derivatives. Molecules 2003, 8, 333–341. [Google Scholar] [CrossRef] [Green Version]
  19. Abdel Hafez, N.A.; Farghaly, T.A.; Al-Omar, M.A.; Abdall, M.M. Synthesis of bioactive polyheterocyclic ring systems as 5α-reductase inhibitors. Eur. J. Med. Chem. 2010, 45, 4838–4844. [Google Scholar] [CrossRef]
  20. Abdallah, M.A.; Gomha, S.M.; Morad, M.A.; Elaasser, M.M. Synthesis of Pyridotriazolopyrimidines as Antitumor Agents. J. Heterocyclic Chem. 2017, 54, 1242–1251. [Google Scholar] [CrossRef]
  21. Abdallah, T.A.; Darwish, M.A.; Hassaneen, H.M. A Novel Synthesis of 1,2,4-Triazolopteridines. Molecules 2002, 7, 494–500. [Google Scholar] [CrossRef] [Green Version]
  22. Sohár, P.; Szöke-Molnár, Z.; Stájer, G.; Bernáth, G. Preparation and structure of cycloalkane-condensed [1,3]thiazino[3,2-a] pyrimidinones. Magn. Reson. Chem. 1989, 27, 959–963. [Google Scholar] [CrossRef]
  23. Elliott, A.J.; Callaghan, P.D.; Gibson, M.S.; Nemeth, S.T. Rearrangement of arylthiohydrazonates. Can. J. Chem. 1975, 53, 1484–1490. [Google Scholar] [CrossRef]
  24. Shawali, A.S.; Abbas, I.M.; Mahran, A.M. Facile Entries for Regioselective Synthesis of [1,2,4]Triazolo[4,3-a]pyrimidin-5(1H)-ones from 2-Thiouracil. JICS 2004, 1, 33–39. [Google Scholar] [CrossRef]
  25. Stajer, G.; Szabo, A.E.; Sohar, P. Synthesis and structure of norbornane/ene-fused thiouracils and thiazino[3,2-a]pyrimidinones. Heterocycles 1999, 51, 1849–1854. [Google Scholar] [CrossRef]
  26. Stájer, G.; Szabó, A.E.; Pintye, J.; Bernáth, G.; Sohár, P. Stereochemical Studies. Part 86. Saturated Heterocycles. Part 81 Preparation of New Thiouracils via Retrodiene Decomposition of Methylene-bridged Quinazolone Thiones. J. Chem. Soc. Perkin Trans. I 1985, 2483–2487. [Google Scholar] [CrossRef]
  27. Soliman, H.M.; Basuny, A.M.; Arafat, S.M. Utilization of Stearic acid Extracted from Olive Pomace for Production of Triazoles, Thiadiazoles and Thiadiazines Derivatives of Potential Biological Activities. J. Oleo. Sci. 2015, 64, 1019–1032. [Google Scholar] [CrossRef] [Green Version]
  28. Matiychuk, V.S.; Potopnyk, M.A.; Luboradzki, R.; Obushak, M.D. New Method for the Synthesis of 1-Aryl-1,2,4-triazole Derivatives. Synthesis 2011, 11, 1799–1813. [Google Scholar] [CrossRef]
  29. Rikagu Oxford Diffraction. CrysAlisPro; Agilent Technologies Inc.: Yarnton, UK, 2018. [Google Scholar]
  30. Sheldrick, G.M. Crystal structure refinement with SHELXL. Acta Cryst. 2015, C71, 3–8. [Google Scholar] [CrossRef]
  31. Hübschle, C.B.; Sheldrick, G.M.; Dittrich, B. ShelXle: A Qt graphical user interface for SHELXL. J. Appl. Cryst. 2011, 44, 1281–1284. [Google Scholar] [CrossRef] [Green Version]
Sample Availability: Samples of all compounds are available from the authors.
Molecules 25 05673 sch001 550
Scheme 1. Synthesis of [1,2,4]triazolo[4,3-a]quinazolin-5(3H)-one 4a–g and 5a–g.
Scheme 1. Synthesis of [1,2,4]triazolo[4,3-a]quinazolin-5(3H)-one 4a–g and 5a–g.
Molecules 25 05673 sch001
Molecules 25 05673 sch002 550
Scheme 2. Proposed reaction pathways to form angular and linear regioisomers.
Scheme 2. Proposed reaction pathways to form angular and linear regioisomers.
Molecules 25 05673 sch002
Molecules 25 05673 g001 550
Figure 1. (a) Heteronuclear multiple bond correlation (HMBC) and neighboring Overhauser effect (NOE) mutual correlations in angular regioisomers, and the lack of a similar correlation in their linear counterparts. (b) 13C-NMR data used for assigning the stereochemistry of the products.
Figure 1. (a) Heteronuclear multiple bond correlation (HMBC) and neighboring Overhauser effect (NOE) mutual correlations in angular regioisomers, and the lack of a similar correlation in their linear counterparts. (b) 13C-NMR data used for assigning the stereochemistry of the products.
Molecules 25 05673 g001
Molecules 25 05673 g002 550
Figure 2. TELP image of 5b at 50% probability level.
Figure 2. TELP image of 5b at 50% probability level.
Molecules 25 05673 g002
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Said, A.I.; Palkó, M.; Haukka, M.; Fülöp, F. Angular Regioselectivity in the Reactions of 2-Thioxopyrimidin-4-ones and Hydrazonoyl Chlorides: Synthesis of Novel Stereoisomeric Octahydro[1,2,4]triazolo[4,3-a]quinazolin-5-ones. Molecules 2020, 25, 5673. https://doi.org/10.3390/molecules25235673

AMA Style

Said AI, Palkó M, Haukka M, Fülöp F. Angular Regioselectivity in the Reactions of 2-Thioxopyrimidin-4-ones and Hydrazonoyl Chlorides: Synthesis of Novel Stereoisomeric Octahydro[1,2,4]triazolo[4,3-a]quinazolin-5-ones. Molecules. 2020; 25(23):5673. https://doi.org/10.3390/molecules25235673

Chicago/Turabian Style

Said, Awad I., Márta Palkó, Matti Haukka, and Ferenc Fülöp. 2020. "Angular Regioselectivity in the Reactions of 2-Thioxopyrimidin-4-ones and Hydrazonoyl Chlorides: Synthesis of Novel Stereoisomeric Octahydro[1,2,4]triazolo[4,3-a]quinazolin-5-ones" Molecules 25, no. 23: 5673. https://doi.org/10.3390/molecules25235673

Article Metrics

Back to TopTop