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Synlett 2024; 35(15): 1799-1806
DOI: 10.1055/a-2239-6657
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Synthesis of a New Heterocyclic System: Pyrimidine Structural Analogues of Natural Integrastatins A, B

Semyon Y. Chikunov
a   Institute of Chemistry, Tyumen State University, 15a Perekopskaya St., Tyumen 625003, Russian Federation
b   Laboratory of Theory and Optimization of Chemical and Technological Processes, Tyumen State University, 15a Perekopskaya St., Tyumen, 625003, Russian Federation
,
Irina A. Pustolaikina
c   Karagandy University of the name of academician E.A. Buketov, Karaganda, 100024, Kazakhstan
,
Yuriy V. Gatilov
d   N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Science, 9 Akademika Lavrientieva Ave., Novosibirsk 630090, Russian Federation
,
Ivan V. Kulakov  ∗
a   Institute of Chemistry, Tyumen State University, 15a Perekopskaya St., Tyumen 625003, Russian Federation
› Author AffiliationsThe study was supported by a grant from the Russian Science Foundation (No. 22-23-01015, https://rscf.ru/project/22-23-01015/).
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Abstract

In this paper for the first time, we report a simple one-step synthesis of 5-methyl-11,12-dihydro-5H-5,11-epoxybenzo[7,8]oxocino[4,3-d]pyrimidine derivatives by acid-catalyzed cyclization reaction of various 4-methyl-5-acetyl pyrimidine derivatives with salicylic aldehyde. It was shown that 2-substituted 4-methyl-5-acetylpyrimidines successfully react to form a cyclization product. At the same time, 4-methyl-5-acetylpyrimidines with a substituent in the 6th position do not enter into the cyclization reaction. This may be caused by the negative effect of substituents in the 6th position, which hinder the free rotation of the acetyl group and prevent the formation of a stable pre-reaction complex. The structures of the obtained 5-methyl-11,12-dihydro-5H-5,11-epoxybenzo[7,8]oxocino[4,3-d]pyrimidine derivatives were confirmed using 1H NMR and 13C NMR spectroscopy, mass spectrometry, and X-ray diffraction analysis.

Key words

integrastatins - 4-methyl-5-acetyl derivatives of pyrimidine - salicylic aldehyde - intramolecular cyclization - epoxybenzo[7,8]oxocino[4,3-d]pyrimidines

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-2239-6657.
  • Supporting Information


Publication History

Received: 06 November 2023

Accepted after revision: 05 January 2024

Accepted Manuscript online:
05 January 2024

Article published online:
07 February 2024

© 2024. Thieme. All rights reserved

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  • 39 Synthesis of Compounds 2a–e: General Procedure In a round-bottom one-neck flask 10 mmol of initial pyrimidine, 15 mmol of salicylic aldehyde, and 15 mol% (80 mol% for initial pyrimidine 1e) of trifluoroacetic acid were placed. To the mixture was added 5 mL of isopropyl alcohol and boiled with a reflux condenser for 10 h. The obtained reaction mixture was diluted with 30 mL of dichloromethane and treated with 20% sodium hydroxide solution until complete removal of salicylic aldehyde from the mixture, determined by the absence of yellow coloring of the aqueous phase. The aqueous solutions were additionally extracted three times with 15 mL of dichloromethane. The combined organic phases were dried with anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified chromatographically (silica gel, ethyl acetate/hexane, 1:3) or recrystallized from a suitable solvent.
  • 40 5-Methyl-11,12-dihydro-5H-5,11-epoxybenzo[7,8]oxocino[4,3-d]pyrimidine (2a) Сolorless crystals, 1.92 g, 80%, mp 186–188 °С (2-PrOH). 1H NMR (500 MHz, CDCl3): δ = 1.99 (s, 3 H, 5-CH3), 3.06 (d, J = 17.8 Hz, 1 H, H-12a), 3.64 (dd, J = 17.8, 5.6 Hz, 1 H, H-12b), 5.43 (d, J = 5.6 Hz, 1 H, H-11), 6.76 (dd, J = 8.3, 1.1 Hz, 1 H, H-7), 6.91 (td, J = 7.5, 1.2 Hz, 1 H, H-9), 7.03 (dd, J = 7.7, 1.6 Hz, 1 H, Н-10), 7.12 (td, J = 8.5, 1.6 Hz, 1 H, Н-8), 8.80 (s, 1 H, H-4), 9.02 (s, 1 H, H-2) ppm. 13C NMR (CDCl3, 126 MHz): δ = 162.8, 156.6, 153.5, 150.2, 130.9, 129.3, 125.6, 122.1, 121.7, 117.0, 95.0, 68.9 (CH), 38.8 (CH2), 25.6 (CH3) ppm. MS (EI): m/z (Irel, %) = [M+] 240.01 (29), 222.97 (100), 197.00 (12). HRMS: m/z calcd for [C14H12N2O2 +]: 240.0899; found [M+]: 240.0894.
  • 41 2,5-Dimethyl-11,12-dihydro-5H-5,11-epoxybenzo[7,8]oxocino[4,3-d]pyrimidine (2b) Colorless crystals, 0.99 g, 39%, mp 146–148 °С (2-PrOH). 1H NMR (500 MHz, CDCl3): δ = 1.97 (s, 3 H, 5-CH3), 2.67 (s, 3 H, 2-CH3), 3.00 (d, J = 17.6 Hz, 1 H, H-12a), 3.59 (dd, J = 17.6, 5.6 Hz, 1 H, H-12b), 5.41 (d, J = 5.5 Hz, 1 H, H-11), 6.76 (dd, J = 8.3, 1.1 Hz, 1 H, H-7), 6.90 (td, J = 7.48, 1.15 Hz, 1 H, H-9), 7.03 (dd, J = 1.6, 7.7 Hz, 1 H, H-10), 7.12 (td, J = 8.6, 1.6 Hz, 1 H, H-8), 8.68 (s, 1 H, H-4) ppm. 13C NMR (CDCl3, 126 MHz): δ = 167.6, 162.0, 154.2, 150.6, 129.2, 127.5, 125.7, 122.6, 121.5, 117.1, 95.5, 69.2 (CH), 39.0 (CH2), 25.8 (CH3), 25.6 (CH3) ppm. MS (EI): m/z (Irel, %) = [M+] 254.15 (100), 253.14 (35), 239.13 (20), 237.13 (20), 212.15 (13), 211.07 (75), 170.10 (13), 115.08 (16), 53.06 (13), 43.08 (40). HRMS: m/z calcd for [C15H14N2O2 +]: 254.1055; found [M+]: 254.1050.
  • 42 5-Methyl-2-phenyl-11,12-dihydro-5H-5,11-epoxybenzo[7,8]oxocino[4,3-d]pyrimidine (2c) Сolorless crystals, 1.26 g, 40%, mp 190–192°С (2-PrOH). 1H NMR (500 MHz, CDCl3): δ = 2.01 (s, 3 H, 5-CH3), 3.09 (d, J = 17.4 Hz, 1 H, H-12a), 3.65 (dd, J = 17.5, 5.6 Hz, 1 H, H-12b), 5.44 (d, J = 5.5 Hz, 1 H, H-11), 6.77 (dd, J = 8.2, 1.1 Hz, 1 H, Н-7), 6.89 (td, J = 7.5, 1.2 Hz, 1 H, H-9), 7.04 (dd, J = 7.7, 1.6 Hz, 1 H, H-10), 7.11 (td, J = 8.5, 1.6 Hz, 1 H, H-8), 7.43–7.46 (m, 3 H, H-3′, 4′, 5′ Ph), 8.34–8.40 (m, 2 H, H-2′, 6′ Ph), 8.82 (s, 1 H, H-4) ppm. 13C NMR (126 MHz, CDCl3): δ = 164.2, 161.8, 154.6, 150.6, 137.1, 130.9, 129.0, 128.5 (2 С), 128.2 (2 С), 127.8, 125.6, 122.6, 121.3, 117.0, 95.6, 69.3 (CH), 39.1 (CH2), 25.7 (CH3) ppm. MS (EI): m/z (Irel, %) = [M+] 316.16 (100), 315.16 (23), 273.10 (45), 170.07 (22), 104.07 (16), 43.04 (28). HRMS: m/z calcd for [C20H16N2O2 +]: 316.1212; found [M+]: 316.1214.
  • 43 2-Methoxy-5-methyl-11,12-dihydro-5H-5,11-epoxybenzo[7,8]oxocino[4,3-d]pyrimidine (2d) Сolorless crystals, 1.32 g, 49%, mp 125–127 °С (hexane). 1H NMR (81 MHz, CDCl3): δ = 1.95 (s, 3 H, 5-CH3), 2.91 (d, J = 17.8 Hz, 1 H, H-12a), 3.54 (dd, J = 17.6, 5.5 Hz, 1 H, H-12b), 3.94 (s, 3 H, ОCH3), 5.36 (d, J = 4.9 Hz, 1 H, H-11), 6.60–7.20 (m, 4 H, Н-7, 8, 9, 10), 8.54 (s, 1 H, Н-4) ppm. 13C NMR (20 MHz, CDCl3): δ = 164.9, 164.4, 156.8, 150.6, 129.0, 125.6, 124.0, 122.6, 121.3, 117.0, 95.6, 69.1 (CH), 54.9 (OCH3), 39.1 (CH2), 25.9 (CH3) ppm. MS (EI): m/z (Irel, %) = [M+] 269.50 (100), 256.09 (32), 254.71 (84), 252.89 (62), 226.87 (57), 212.04 (23), 176.93 (15), 110.08 (13), 51.05 (14), 43.05 (32). HRMS: m/z calcd for [C15H14N2O3 +]: 270.1004; found [M+]: 270.1005.
  • 44 5-Methyl-11,12-dihydro-5H-5,11-epoxybenzo[7,8]oxocino[4,3-d]pyrimidin-2-amine (2e) Сolorless crystals, 0.25 g, 10%, mp 186–188 °С (2-PrOH). 1H NMR (81 MHz, CDCl3): δ = 1.92 (s, 3 H, 5-CH3), 2.75 (d, J = 17.3 Hz, 1H, H-12a), 3.43 (dd, J = 17.4, 5.5 Hz, 1 H, H-12b), 5.21 (br s, 2 H, NH2), 5.33 (d, J = 5.6 Hz, 1 H, H-11), 6.60–7.21 (m, 4 H, H-7, 8, 9, 10), 8.33 (s, 1 H, H-4) ppm. 13C NMR (20 MHz, CDCl3): δ = 163.0, 162.5, 156.1, 150.9, 129.0, 125.7, 122.9, 121.2, 120.7, 117.1, 96.0, 69.2 (CH), 39.0 (CH2), 26.0 (CH3) ppm. MS (EI): m/z (Irel, %) = [M+]: 255.07 (100), 238.07 (46), 238.07 (46), 212.05 (67), 95.04 (25), 65.06 (24), 51.03 (23), 43.03 (84). HRMS: m/z calcd for [C14H13N3O2 +]: 255.1008; found [M+]: 255.1006.
  • 45 X-ray Structural Study: Crystal Data for 2c Formula: C20H16N2O2, T = 296 K, M r = 316.35 gmol–1 , crystal size = 0.11 × 0.17 × 0.43 mm3, monoclinic, space group Cc, a = 16.7979(14) Å, b = 15.5100(11) Å, c = 25.2706(18) Å, β = 106.496(3)°, V = 6312.9(8) Å3 , Z = 16, ρ calcd = 1.331 g cm–3, μ = 0.087 mm–1 , θ max = 25.09°, 32245 reflections measured, 9755 unique, 6228 with I > 2σ(I), R int = 0.049, R(I > 2σ(I)) = 0.0719, wR2 (all data) = 0.2220, GOF = 1.017, Δρ(min/max) = –0.29/0.49 eÅ3. CCDC 2292626 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
  • 46 Computational Details Computational studies were performed by DFT method49, 50 using Gaussian 16 software.51 B3LYP functional and 6-311++G(d,p) basis sets[52,53] with CPCM54 approach to account the solvent effect (ethanol, dielectric constant ε = 24.852) were used for geometry optimization and Mulliken population analysis procedures. DFT B3LYP 6-311++G(d,p) has been considered as a suitable method for computational purposes due to many successful combined experimental and computational studies.55–57 The structural formulas of the initial substances were used to obtain the starting geometries, which were then optimized without any constraints. After that frequency calculations were performed to ensure that the optimized structures are true energy minima. Optimized geometries of pyridines were used to analyze steric factors, as well as the Mulliken charges distribution on atoms. Basicity of pyrimidines was evaluated by the charge on nitrogen atom, CH acidity was estimated by the maximum charge on the hydrogen atom of the corresponding CH3 group. The visualization of molecular structures and charge distribution was obtained using GaussView 6.58.
  • 47 X-ray Crystallographic Analysis of Compounds Crystal data collection and reduction were performed on a Bruker Kappa Apex II diffractometer with sealed-tube Mo Kα radiation using the APEX259 program. The absorption correction was made with the SADABS-2008/160 program. The crystal structure was solved using the SHELXT61 and it was refined using SHELXL62 programs. The H atoms were refined in riding model.
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