Original S_RN1 Reactions on New Non-Nitrated Heterocyclic System

Abstract

A new 3-bromo-2-(chloromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one was prepared and reacted under experimental conditions of S_RN1 reactions with different sulfur- and carbon-centered nucleophiles. A S_RN1 reaction in non-nitrated 4H-pyrido[1,2-a]pyrimidin-4-one series is described for the first time.

Key words

single-electron transfer - 4H-pyrido[1,2-a]pyrimidin-4-one - inhibitors - alkylation - spectroscopy

References and Notes

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22

Analytical Data for 3-Bromo-7-chloro-2-(chloromethyl)-4 H -pyrido[1,2- a ]pyrimidin-4-one (1) White needles, mp 175 ˚C (i-PrOH). ^¹H NMR (200 MHz, CDCl₃): δ = 4.75 (s, 2 H), 7.67 (dd, J = 9.4, 0.7 Hz, 1 H), 7.75 (dd, J = 9.4, 2.2 Hz, 1 H), 9.06 (dd, J = 2.2, 0.7 Hz, 1 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 46.0, 103.0, 125.3, 125.5, 127.4, 137.9, 147.7, 154.1, 159.7. Anal. Calcd for C₉H₅BrCl₂N₂O: C, 35.10; H, 1.64; N, 9.10. Found: C, 35.11; H, 1.65; N, 8.96.

25

Analytical Data for 3-Bromo-7-chloro-2-(2-methylprop-1-enyl)-4 H -pyrido[1,2- a ]pyrimidin-4-one (2) Shiny white plates, mp 175 ˚C (EtOH-Et₂O). ^¹H NMR (200 MHz, CDCl₃): δ = 2.03 (d, J = 1.2 Hz, 3 H), 2.18 (d, J = 1.2 Hz, 3 H), 6.58 (sept, J = 1.2 Hz, 1 H, CH), 7.55 (dd, J = 9.5, 0.8 Hz, 1 H), 7.64 (dd, J = 9.5, 2.2 Hz, 1 H), 9.02 (dd, J = 2.2, 0.8 Hz, 1 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 20.5, 28.1, 102.4, 122.4, 124.2, 125.2, 127.1, 137.0, 146.5, 149.2, 154.4, 159.7. Anal. Calcd for C₁₂H₁₀BrClN₂O: C, 45.96; H, 3.21; N, 8.93. Found: C, 45.74; H, 3.24; N, 8.86.
Crystal Data for Compound 2
C₁₂H₁₀BrClN₂O, colorless prism (0.3 × 0.2 × 0.05 mm^³), MW = 313.58, monoclinic, space group P2₁/c (T = 293 K), a = 7.1901(2) Å, b = 15.5874(4) Å, c = 11.3226(3) Å, β = 107.471(1)˚; V = 1210.44(6) Å^³, Z = 4, D _calc = 1.721 g cm^-¹, µ = 3.600 mm^-¹, F(000) = 624, index ranges -9 £ h £ 9, 0 £ k £ 21, 0 £ l £ 15; θ range = 2.29-28.68˚, 154 variables and 0 restraints, were refined for 2136 reflections with I ³ 2σ(I) to R1 = 0.0403, wR2 = 0.1078, GooF = 1.050. CCDC 691139 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge at www.ccdc.cam.ac.uk/data_request/cif of from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax:[phone]; email: [e-mail].

27

General Procedure and Analytical Data for Compounds 3-5 A solution of 60% NaH (3 equiv) in DMSO under an inert atmosphere was treated with dialkyl malonate (3 equiv) and stirred for 20 min. A solution of 1 (1 equiv) in DMSO was then added and the mixture was irradiated with a 60 W tungsten lamp and stirred until disappearance of the starting material as monitored by TLC. At this time, the mixture was poured into cold H₂O. The aqueous solution was extracted with EtOAc. The organic layers were washed with brine, dried over anhyd Na₂SO₄, and evaporated under reduced pressure. The residue was purified by chromatography column on SiO₂. Wanted products were recrystallized with BuOH or i-PrOH.
Dimethyl 2-{(3-Bromo-7-chloro-4-oxo-4 H -pyrido[1,2- a ]pyrimidin-2-yl)methyl}malonate (3)
Pale yellow crystals, mp 147 ˚C (i-PrOH). ^¹H NMR (200 MHz, CDCl₃): δ = 3.55 (d, J = 7.4 Hz, 2 H), 3.77 (s, 6 H), 4.24 (t, J = 7.4 Hz, 1 H), 7.55 (d, J = 9.4 Hz, 1 H), 7.70 (dd, J = 9.4, 2.2 Hz, 1 H), 9.04 (d, J = 2.2 Hz, 1 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 14.1, 36.0, 49.3, 61.6, 102.9, 124.9, 125.3, 127.0, 137.4, 146.9, 153.6, 162.2, 168.8. Anal. Calcd for C₁₄H₁₂BrClN₂O₅: C, 41.66; H, 3.00; N, 6.94. Found: C, 41.52; H, 2.94; N, 6.94.
Diethyl 2-{(3-Bromo-7-chloro-4-oxo-4 H -pyrido[1,2- a ]pyrimidin-2-yl)methyl}malonate (4)
White needles, mp 111 ˚C (BuOH). ^¹H NMR (200 MHz, CDCl₃): δ = 1.27 (t, J = 7.1 Hz, 6 H), 3.53 (q, J = 7.4 Hz, 2 H), 4.22 (m, 5 H), 7.49 (d, J = 9.5 Hz, 1 H), 7.68 (dd, J = 9.5, 2.3 Hz, 1 H), 9.03 (d, J = 2.3 Hz, 1 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 14.1, 36.0, 49.3, 61.6, 102.9, 124.9, 125.3, 127.0, 137.4, 146.9, 153.6, 162.2, 168.8. Anal. Calcd for C₁₆H₁₆BrClN₂O₅: C, 44.52; H, 3.74; N, 6.49. Found: C, 44.76; H, 3.76; N, 6.46.
Crystal Data for Compound 4
C₁₆H₁₆BrClN₂O₅, colorless prism (0.3 × 0.2 × 0.05 mm^³), MW = 431.67, triclinic, space group P 1 (T = 293 K), a = 8.0149(2) Å, b = 8.9522(2) Å, c = 12.8072(3) Å, α = 81.6805(9)˚, β = 76.2696(8)˚, γ = 81.9220(9)˚; V = 877.87(4) Å^³, Z = 2, D _calc = 1.633 g cm^-¹, µ = 2.523 mm^-¹, F(000) = 436, index ranges -10 £ h £ 10, -11 £ k £ 11, 0 £ l £ 17; θ range = 1.65-28.69˚, 228 variables and 0 restraints, were refined for 3563 reflections with I ³ 2σ(I) to R1 = 0.0330, wR2 = 0.0889, GooF = 1.047. CCDC 691140 contains the supplementary crystallographic data for this paper.
Benzyl Ethyl 2-{(3-Bromo-7-chloro-4-oxo-4 H -pyrido-[1,2- a ]pyrimidin-2-yl)methyl}malonate (5)
Yellowish solid, mp 275 ˚C (BuOH). ^¹H NMR (200 MHz, CDCl₃): δ = 1.23 (t, J = 7.2 Hz, 3 H), 3.54 (dd, J = 7.9, 7.0 Hz, 2 H), 4.20 (q, J = 7.2 Hz, 2 H), 4.24 (dd, J = 7.9, 7.0 Hz, 1 H), 5.18 (s, 2 H), 7.24-7.32 (m, 6 H), 7.64 (dd, J = 9.4, 2.3 Hz, 2 H), 8.97 (d, J = 2.3 Hz, 1 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 14.0, 36.0, 49.3, 61.7, 67.0, 102.8, 128.8, 125.2, 126.9, 128.2, 128.3, 128.4, 135.4, 137.3, 146.7, 153.4, 161.8, 168.5, 168.6. Anal. Calcd for C₂₁H₁₈BrClN₂O₅: C, 51.09; H, 3.67; N, 5.67. Found: C, 51.24; H, 3.76; N, 5.74.

29

Analytical Data for Compounds 6-93-Bromo-7-chloro-2-(phenylsulfonyl-methyl)-4 H -pyrido-[1,2- a ]pyrimidin-4-one (6)
Beige needles, mp 234 ˚C (i-PrOH). ^¹H NMR (200 MHz, CDCl₃): δ = 4.81 (s, 2 H), 7.48-7.57 (m, 3 H), 7.64-7.74 (m, 2 H), 7.84-7.89 (m, 2 H), 9.01 (d, J = 2.0 Hz, 1 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 63.9, 105.9, 125.3, 125.6, 127.3, 128.6, 129.2, 134.1, 137.9, 139.4, 147.0, 153.3, 153.9. Anal. Calcd for C₁₅H₁₀BrClN₂O₃S: C, 43.55; H, 2.44; N, 6.77; S, 7.75. Found: C, 44.08; H, 2.53; N, 6.72; S, 7.78.
3-Bromo-7-chloro-2-(tosylmethyl)-4 H -pyrido[1,2- a ]pyrimidin-4-one (7)
White needles, mp 225 ˚C (i-PrOH). ^¹H NMR (200 MHz, CDCl₃): δ = 2.45 (s, 3 H), 4.79 (s, 2 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.55 (dd, J = 9.5, 0.7 Hz, 1 H), 7.69-7.76 (m, 3 H), 9.01 (dd, J = 2.3, 0.7 Hz, 1 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 21.7, 64.0, 105.9, 125.2, 125.6, 127.4, 128.6, 129.8, 136.5, 137.9, 145.3, 147.0, 153.5, 153.9. Anal. Calcd for C₁₆H₁₂BrClN₂O₃S: C, 44.93; H, 2.83; N, 6.55; S, 7.50. Found: C, 44.93; H, 2.78; N, 6.45; S, 7.23.
3-Bromo-7-chloro-2-[(4-chlorophenyl-sulfonyl)methyl]-4 H -pyrido[1,2- a ]pyrimidin-4-one (8)
White needles, mp 263 ˚C (EtOAc). ^¹H NMR (200 MHz, CDCl₃): δ = 4.80 (s, 2 H), 7.49 (dd, J = 9.5, 0.7 Hz, 1 H), 7.50 (d, J = 8.8 Hz, 2 H), 7.73 (dd, J = 9.5, 2.2 Hz, 1 H), 7.80 (d, J = 8.8 Hz, 2 H), 9.02 (dd, J = 2.2, 0.7 Hz, 1 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 63.9, 105.8, 125.3, 125.7, 127.2, 129.5, 130.1, 137.9, 138.1, 141.0, 147.0, 153.1, 153.8. Anal. Calcd for C₁₅H₉BrCl₂N₂O₃S: C, 40.20; H, 2.02; N, 6.25; S, 7.16. Found: C, 40.31; H, 2.02; N, 6.30; S, 6.92.
3-Bromo-7-chloro-2-(phenylthiomethyl)-4 H -pyrido[1,2- a ]pyrimidin-4-one (9)
White plates, mp 156 ˚C (i-PrOH). ^¹H NMR (200 MHz, CDCl₃): δ = 4.37 (s, 2 H), 7.19-7.35 (m, 3 H), 7.45-7.48 (m, 2 H), 7.71 (d, J = 9.5 Hz, 1 H), 8.06 (dd, J = 9.5, 2.3 Hz, 1 H), 8.92 (d, J = 2.3 Hz, 1 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 40.2, 101.6, 124.3, 125.4, 126.7, 127.3, 129.2, 129.6, 135.5, 138.5, 147.5, 153.6, 161.3. Anal. Calcd for C₁₅H₁₀BrClN₂OS: C, 47.20; H, 2.64; N, 7.34; S, 8.40. Found: C, 47.00; H, 2.60; N, 7.46; S, 8.21.