A Novel Approach for the Synthesis of N-Arylpyrroles

Abstract

Treatment of quinazolin-4(3H)-one bromides with acetylenic dipolarophiles in 1,2-epoxybutane medium gave, in good yields, N-arylpyrroles instead of the corresponding pyrrolo[1,2-a]quinazolines. The structures of the pyrroles were deduced by NMR spectroscopy and confirmed by X-ray crystal structure analysis. The ^¹H NMR spectra of ethyl esters revealed hindered rotation about the N-Ar bond.

Key words

1,3-dipolar cycloaddition - N-ylide - pyrroles - pyrrolo[1,2-a]quinazoline - one-pot reaction

References and Notes

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4

General Procedure for Obtaining the Bromide Salts 3
3-Methyl-4(3H)-quinazolin-4-one (1, 10 mmol) and
2-bromoacetophenone 2 (10 mmol) in EtOH (30 mL) was stirred under reflux for 20 h. The obtained precipitate was filtered and then recrystallized from MeOH.


1-(2-Phenyl-2-oxoethyl)-3-methyl-4(3 H )-quinazolinon-1-ium Bromide Colorless crystals with mp 287-289 ˚C were obtained by recrystallization from MeOH; yield 81%. Anal. Calcd C₁₇H₁₅BrN₂O₂: N, 7.80. Found: N, 8.04. FT-IR: 1687, 1709, 2927 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 3.87 (s, 3 H, MeN), 6.34 (s, 2 H, CH₂), 7.43 (d, 1 H, J = 8.5 Hz, H-8), 7.57-7.62 (m, 2 H, H-3′,H-5′), 7.74-7.97 (m, 1 H, H-4′), 7.83 (t, 1 H, J = 7.8 Hz, H-6), 7.98 (dt, 1 H, J = 8.5, 1.65 Hz, H-7), 8.09-8.12 (m, 2 H, H-2′, H-6′), 8.53 (dd, 1 H, J = 7.8, 1.65 Hz, H-5), 9.88 (s, 1 H, H-2). ^¹³C NMR (75 MHz, CDCl₃): δ = 36.9 (MeN), 58.7 (CH₂), 117.4 (C-8), 128.9, 129.7 (C-5, C-2′, C-3′, C-5′, C-6′), 131.0 (C-6), 119.6, 132.6, 137.8 (C-4a, C-8a, C-1′), 136.3 (C-4′), 137.7 (C-7), 154.4 (C-2), 157.9 (CON), 190.4 (COAr).

5

General Procedure for Obtaining the Pyrroles 4
Quaternary salt (5 mmol) and dipolarophile (7.5 mmol) are heated under reflux in 30 mL 1,2-epoxybutane for 60 h. The obtained precipitate is filtered and then recrystallized from MeOH.
Ethyl 2-(4-Fluorobenzoyl)-1-(2-methylaminocarbonyl-phenyl)pyrrole-4-carboxylate (4h)
Colorless crystals with mp 158-160 ˚C were obtained by recrystallization from MeOH; yield 61%. Anal. Calcd C₂₂H₁₉FN₂O₄: N, 7.10. Found: N, 7.28. FT-IR: 1635, 1660, 1708, 3389 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 1.33 (t, 3 H, J = 7.1 Hz, MeCH₂), 2.67 (d, 1 H, J = 4.9 Hz, MeNH), 4.30 (sext, 2 H, J = 9.5, 7.1 Hz, CH₂), 6.66 (q, 1 H, J = 4.9 Hz, NH), 7.15-7.22 (m, 3 H, H-6′′, H-3′, H-5′), 7.26 (d, 1 H, J = 1.6 Hz, H-5), 7.41-7.52 (m, 2 H, H-4′′, H-5′′), 7.61 (d, 1 H, J = 1.6 Hz, H-3), 7.65-7.68 (m, 1 H, H-3′′), 7.98 (dd, 2 H, J = 8.8, 5.5 Hz, H-2′, H-6′).^¹³C NMR (75 MHz, CDCl₃): δ = 14.4 (MeCH₂), 26.6 (MeNH), 60.6 (CH₂O), 115.7 (d, J = 21.9 Hz, C-3′, C-5′), 117.3 (C-4), 122.1 (C-5), 127.1 (C-6′′), 128.9 (C-3′′), 129.4, 130.7 (C-4′′, C-5′′), 132.5, 133.5, 136.7 (C-2, C-1′′, C-2′′), 132.6 (d, J = 9.0 Hz, C-2′, C-6′), 133.4 (d, J = 3.0 Hz, C-1′), 135.0 (C-3), 163.5 (COO), 167.7 (CONH), 166.0 (d, J = 245.9 Hz, C-4′), 184.8 (COAr).
Dimethyl 2-Benzoyl-1-(2-methylaminocarbonylphenyl)-pyrrole-3,4-dicarboxylate (4m) Colorless crystals with mp 163-165 ˚C were obtained by recrystallization from MeOH; yield 53%. Anal. Calcd C₂₃H₂₀N₂O₆: C, 65.71; H, 4.79; N, 6.66. Found: C, 65.97; H, 5.03; N, 6.51. FT-IR: 1649, 1651, 1724, 3285 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 2.72 (1 H, d, J = 4.9 Hz, MeNH), 3.29, 3.81 (6 H, 2 s, 2 MeO), 7.03 (1 H, q, J = 4.9 Hz, NH), 7.05-7.08 (1 H, m, H-6′′), 7.34-7.40, 7.45-7.52 (4 H, 2 m, H-3′, H-5′, H-4′′, H-5′′), 7.50 (1 H, s, H-5), 7.59-7.65 (1 H, m, H-4′), 7.66-7.69 (1 H, m, H-3′′), 7.83-7.87 (2 H, m, H-2′,H-6′).^¹³C NMR (75 MHz, CDCl₃): δ = 26.7 (MeNH), 51.9, 52.0 (2 MeO), 115.4, 123.0, 132.9, 135.2, 135.4, 137.4 (C-2, C-3, C-4, C-1′, C-1′′, C-2′′), 127.0, 129.1, 129.3, 130.8, 132.7 (C-5, C-3′′, C-4′′, C-5′′, C-6′′), 128.8, 129.5
(C-2′, C-3′, C-5′, C-6′), 134.1 (C-4′), 162.8, 163.8, 167.2 (2 COO, CONH), 188.2 (COAr).

8

Crystal Data for 4h
C₂₂H₁₉FN₂O₄; colorless prism; M = 394.39, monoclinic,
C2/c, a = 32.702 (1) Å, b = 7.6703 (3) Å, c = 18.6347 (6) Å, β = 123.376 (1)˚, V = 3903.3 (2) Å^³, Z = 8, T = 100 (2) K, F ₀₀₀ = 1648, R1 = 0.0374, wR2 = 0.1028. CCDC 750004 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc. cam.ac.uk/data_request/cif.


Crystal Data for 4m
C₂₃H₂₀N₂O₆; colorless prism; M = 420.41, monoclinic,
P2₁/c, a = 13.874 (3) Å, b = 9.111 (2) Å, c = 17.175 (3) Å, β = 105.53 (3)˚, V = 2087.7 (8) Å^³, Z = 4, T = 173 (2) K, F ₀₀₀ = 880, R1 = 0.0401, wR2 = 0.1072. The CCDC deposition number is 750005.

10

Dimethyl 1-Benzoyl-4-methyl-1,3a-dihydro-5(4 H )-pyrrolo[1,2- a ]quinazoline-5-one-2,3-dicarboxylate (6m) Colorless crystals with mp 156-158 ˚C were obtained by recrystallization from MeOH; yield 51%. Anal. Calcd C₂₃H₂₀N₂O₆: C, 65.71; H, 4.79; N, 6.66. Found: C, 66.01; H, 5.68; N, 6.89. FT-IR: 1632, 1659, 1705, 3387 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 3.10 (s, 3 H, MeN), 3.54, 3.90 (s, 6 H, 2 CO₂Me), 6.32 (d, 1 H, J = 6.0 Hz, H-1), 6.34 (d, 1 H, J = 8.0 Hz, H-9), 6.45 (d, 1 H, J = 6.0 Hz, H-3a), 6.93 (t, 1 H, J = 7.5 Hz, H-7), 7.22 (ddd, 1 H, J = 7.5, 1.6 Hz, H-8), 7.54-7.59 (m, 2 H, H-3′, H-5′), 7.67-7.72 (m, 1 H, H-4′), 8.02 (dd, 1 H, J = 7.5, 1.6 Hz, H-6), 7.09-7.12 (m, 2 H, H-2′, H-6′). ^¹³C NMR (75 MHz, CDCl₃): δ = 29.4 (MeN), 52.7, 53.0 (CO₂Me), 71.7 (C-3a), 79.6 (C-1), 114.5 (C-9), 120.9 (C-7), 129.1 (C-2′, C-6′), 129.2 (C-3′, C-5′), 129.5 (C-6), 133.8 (C-8), 134.6 (C-4′), 117.6, 135.2, 137.7, 139.7, 143.11 (C-2, C-3, C-5, C-5a, C-1′), 161.8, 163.3, 163.4 (3 CO), 195.2 (CO).