1,2,4-Trisubstituted pyrroles were synthesized with an original one-pot domino allylic amination/palladium-catalysed Sonogashira cross-coupling and heterocyclisation process. 1H and 13C NMR spectra were assigned for twelve new compounds containing different substituents in positions 1 and 2, and a carboxylic acid or ester group in position 4. Each assignment was based on the combination of one, and two-dimensional experiments (APT, COSY, HMBC).
Pyrroles are key structural motifs in various classes of natural products [
In continuation of our interest in the design of new reactions for the synthesis of lactones and lactams through tandem C–C bond formation/heterocyclisation [
One-pot synthesis of 1,2,4-trisubstituted pyrroles.
We describe here the spectral assignment containing a subjective analysis of the chemical shifts for these pyrroles. We report the complete assignment of each of their 1H and 13C NMR spectra.
Pyrroles
All NMR spectra were recorded in CDCl3 at room temperature on either a Bruker AC-200 or a Bruker Avance-300 instrument using 5 mm sample tubes. All samples were freshly dissolved in CDCl3 (0.6 mL). Chemical shifts (
The complete assignment of each 1H and 13C NMR chemical shift for these pyrroles was achieved by 1D and 2D NMR techniques, including APT experiments, 1H–1H COSY, 1H–13C Hetcor exp, and HMBC spectra.
1H NMR spectra were recorded at a proton frequency of 300.13 MHz with a spectral width of 4 kHz with 32 K data points, using a 90° pulse and repetition time of 3 s. The 13C NMR spectra were obtained with a pulse angle of 90°, an acquisition time of 1.3 s and a sweep width of 220 ppm. The pulse repetition time was 3 s. Exponential multiplication was applied before the Fourier transformation in both cases.
A typical proton-proton Cosy experiment at 200 MHz was performed at a spectral width of 2000 Hz in the F2 domain and 2000 Hz in the F1 domain. Spectra were acquired with 1 K data points in F2 with eight transients, two dummy scans and 256 experiments.
A typical carbon-proton correlated 2D spectrum at 50 MHz (or 75 MHz) was acquired with a spectral width of 14000 Hz in the F2 domain and 1000 Hz (2000 Hz) in the F1 domain. Spectra were acquired with 1 K data points in F2 and 256 W in F1 with 64 transients (two dummy scans) over 128 experiments. The delay between scans was 2 s.
The APT experiment was run with 90° and 180° pulse widths of 21 and 42
The long-range 1H–13C correlation (HMBC) spectra were obtained using the following sequence: spectra resulted from a
The structures and numbering schemes for 1,2,4-trisubstituted pyrroles
1H NMR chemical shift assignments (ppm) for pyrroles
H |
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H-3 | 6.25 |
6.01 (brs) | 6.15 (brs) | 6.03 |
5.94 (brs) | 6.19 |
6.27 |
6.28 |
6.17 |
6.44 |
6.21 |
6.19 (brs) |
H-5 | 6.70 |
6.62 (brs) | 6.63 (brs) | 6.56 |
6.57 (brs) | 6.71 |
6.71 |
6.60 |
6.76 |
6.93 |
6.73 |
6.72 (brs) |
H-6 | 3.59 (s) | 3.58 (s) | 3.49 (s) | 3.51 (s) | 3.47 (s) | 3.58 (s) | 3.47 (s) | 3.47 (s) | 3.10 (s) | 3.64 (s) | 3.59 (s) | 3.59 (s) |
H-7 | — | 10.20 (bs) | — | — | 10.25 (brs) | 10.35 (brs) | — | — | — | — | — | 9.90 (bs) |
H-8 | 5.11 (s) | 5.05 (s) | 5.10 (s) | 5.08 (s) | 5.04 (s) | 5.16 (s) | 5.13 (s) | 5.06 (s) | 3.92 |
— | 4.51 |
4.50 |
H-9 | — | — | — | — | — | — | — | — | 1.66–1.69 (m) | 7.11–7.48 (m, 10Har) | 5.98 |
5.97 |
H-10 | 7.03–7.06 (m, 2Har) | 7.07–7.10 (m, 2Har) | 7.07–7.10 (m, 2Har) | 7.01–7.03 (m, 2Har) | 7.01–7.04 (m, 2Har) | 7.10–7.13 (m, 2Har) | 7.04–7.07 (m, 2Har) | 7.04–7.09 (m, 2Har) | 1.21–1.32 (m) | 7.11–7.48 (m, 10Har) | 5.09 |
5.10 |
H-11 | 7.27–7.35 (m, 8Har) | 7.31–7.44 (m, 3Har) | 7.27–7.33 (m, 3Har) | 7.24–7.37 (m, 3Har) | 7.26–7.36 (m, 3Har) | 7.37–7.41 (m, 8Har) | 7.23–7.37 (m, 8Har) | 7.24–7.35 (m, 3Har) | 0.87 |
7.11–7.48 (m, 10Har) | — | — |
H-12 | 7.27–7.35 (m, 8Har) | 7.31–7.44 (m, 3Har) | 7.27–7.33 (m, 3Har) | 7.24–7.37 (m, 3Har) | 7.26–7.36 (m, 3Har) | 7.37–7.41 (m, 8Har) | 7.23–7.37 (m, 8Har) | 7.24–7.35 (m, 3Har) | — | 7.11–7.48 (m, 10Har) | 7.27–7.41 (m, 5Har) | 7.32 |
H-13 | 7.27–7.35 (m, 8Har) | 7.31–7.44 (m, 3Har) | 7.27–7.33 (m, 3Har) | 7.24–7.37 (m, 3Har) | 7.26–7.36 (m, 3Har) | 7.37–7.41 (m, 8Har) | 7.23–7.37 (m, 8Har) | 7.24–7.35 (m, 3Har) | 7.30–7.43 (m, 5Har) | 7.11–7.48 (m, 10Har) | 7.27–7.41 (m, 5Har) | 7.22 |
H-14 | 7.03–7.06 (m, 2Har) | 7.07–7.10 (m, 2Har) | 7.07–7.10 (m, 2Har) | 7.01–7.03 (m, 2Har) | 7.01–7.04 (m, 2Har) | 7.10–7.13 (m, 2Har) | 7.04–7.07 (m, 2Har) | 7.04–7.09 (m, 2Har) | 7.30–7.43 (m, 5Har) | — | 7.27–7.41 (m, 5Har) | — |
H-15 | — | 2.50 (t, |
4.28 (s) | 2.79 |
3.09 |
3.75 (s) | — | 6.10 |
7.30–7.43 (m, 5Har) | 7.11–7.48 (m, 10Har) | 7.27–7.41 (m, 5Har) | 2.40 (s) |
H-16 | 7.27–7.35 (m, 8Har) | 1.55–1.58 (m, 2H) | 3.36 (s) | 4.53 |
3.56 |
3.63 (s) | 7.23–7.37 (m, 8Har) | 5.75 |
7.30–7.43 (m, 5Har) | 7.11–7.48 (m, 10Har) | 7.27–7.41 (m, 5Har) | 7.22 |
H-17 | 7.27–7.35 (m, 8Har) | 1.25–1.30 (m, 2H) | — | 3.37–3.66 (m, 4H) | 4.17 |
— | 7.23–7.37 (m, 8Har) | 1.93–2.08 (m, 3H) | 7.30–7.43 (m, 5Har) | 7.11–7.48 (m, 10Har) | — | 7.32 |
H-18 | 7.27–7.35 (m, 8Har) | 1.25–1.30 (m, 2H) | — | 1.16 |
1.23 |
7.37–7.41 (m, 8Har) | 7.23–7.37 (m, 8Har) | — | — | 7.11–7.48 (m, 10Har) | — | — |
H-19 | 7.27–7.35 (m, 8Har) | 1.22 (t, 3H) | — | 3.37–3.66 (m, 4H) | 4.17 |
7.37–7.41 (m, 8Har) | 7.23–7.37 (m, 8Har) | 5.37-5.38 (m) | — | 7.11–7.48 (m, 10Har) | — | |
H-20 | 7.27–7.35 (m, 8Har) | — | — | 1.16 (t, 6H, |
1.23 |
7.37–7.41 (m, 8Har) | 7.23–7.37 (m, 8Har) | 1.93–2.08 (m, 3H) | — | — | — | — |
H-21 | — | — | — | — | — | 7.37–7.41 (m, 8Har) | — | 1.55–1.67 (m) | — | — | — | — |
H-22 | — | — | — | — | — | 7.37–7.41 (m, 8Har) | 1.51 (s) | — | — | — | — | — |
H-23 | — | — | — | — | — | — | 1.51 (s) | 0.76 (s) | — | — | — | — |
H-24 | — | — | — | — | — | — | 1.51 (s) | 0.86 (s) | — | — | — | — |
H-25 | — | — | — | — | — | — | — | 1.48 |
— | — | — | — |
H-26 | — | — | — | — | — | — | — | 4.17 |
— | — | — | — |
H-27 | — | — | — | — | — | — | — | 1.28 |
— | — | — | — |
13C NMR chemical shift assignments (ppm) for pyrroles
H |
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C-2 | 133.4 | 134.6 | 138.7 | 129.0 | 129.6 | 128.1 | 133.6 | 132.5 | 133.7 | 133.1 | 133.4 | 134.6 |
C-3 | 110.3 | 107.4 | 112.1 | 109.5 | 108.6 | 111.5 | 110.2 | 107.1 | 110.1 | 112.1 | 110.0 | 109.1 |
C-4 | 115.6 | 114.3 | 114.5 | 114.4 | 114.4 | 114.2 | 116.9 | 115.9 | 114.4 | 116.3 | 115.2 | 114.7 |
C-5 | 122.6 | 120.1 | 122.6 | 120.6 | 121.0 | 122.2 | 122.0 | 120.3 | 121.5 | 123.7 | 121.7 | 120.9 |
C-6 | 31.3 | 33.6 | 33.4 | 33.5 | 33.3 | 33.5 | 34.8 | 33.5 | 33.8 | 33.2 | 33.4 | 32.9 |
C-7 | 178.8 | 179.4 | 178.7 | 179.0 | 178.9 | 179.2 | 172.2 | 178.9 | 178.7 | 178.3 | 179.2 | 178.2 |
C-8 | 51.1 | 50.6 | 50.9 | 50.9 | 50.7 | 50.8 | 51.0 | 51.0 | 47.8 | 134.4 | 49.9 | 49.3 |
C-9 | 139.1 | 138.9 | 138.7 | 138.9 | 138.3 | 138.5 | 139.3 | 138.6 | 32.6 | 126.1 | 135.2 | 134.7 |
C-10 | 129.3 | 129.2 | 129.2 | 129.1 | 129.2 | 129.3 | 129.2 | 129.1 | 20.8 | 128.5 | 117.6 | 116.9 |
C-11 | 127.0 | 126.9 | 127.3 | 127.0 | 126.9 | 127.3 | 126.9 | 126.9 | 14.2 | 126.8 | 133.4 | 130.0 |
C-12 | 127.5 | 127.8 | 127.9 | 127.7 | 127.9 | 127.5 | 127.3 | 127.7 | 135.8 | 128.5 | 128.8 | 128.6 |
C-13 | 127.0 | 126.9 | 127.3 | 127.0 | 126.9 | 127.3 | 126.9 | 126.9 | 129.0 | 126.1 | 129.2 | 128.9 |
C-14 | 129.3 | 129.2 | 129.2 | 129.1 | 129.2 | 129.3 | 129.2 | 129.1 | 129.6 | 140.7 | 127.4 | 136.6 |
C-15 | 135.6 | 32.1 | 66.3 | 32.1 | 25.8 | 27.4 | 135.3 | 121.3 | 127.5 | 128.7 | 129.2 | 21.1 |
C-16 | 128.9 | 26.7 | 57.5 | 103.5 | 52.0 | 36.0 | 128.8 | 130.9 | 129.6 | 129.4 | 128.8 | 128.9 |
C-17 | 129.1 | 28.8 | 62.6 | 62.0 | 138.9 | 129.1 | 55.3 | 129.0 | 127.0 | 128.6 | ||
C-18 | 127.8 | 23.0 | 15.6 | 14.4 | 129.6 | 127.7 | 134.5 | 129.4 | ||||
C-19 | 129.1 | 14.5 | 62.6 | 62.0 | 129.0 | 129.1 | 121.1 | 128.7 | ||||
C-20 | 128.9 | 15.6 | 14.4 | 128.0 | 128.8 | 23.5 | ||||||
C-21 | 169.2 | 129.0 | 80.7 | 31.9 | ||||||||
C-22 | 169.2 | 129.6 | 28.6 | 32.9 | ||||||||
C-23 | 28.6 | 27.9 | ||||||||||
C-24 | 28.6 | 27.3 | ||||||||||
C-25 | 23.2 | |||||||||||
C-26 | 61.0 | |||||||||||
C-27 | 14.6 |
Structure of 1,2,4-trisubstituted pyrroles with numbering.
The carbon type (C, CH, CH2, CH3) was determined using an APT experiment. Assignment of each protonated carbon was performed by 2D heteronuclear-correlated experiments using delay values that corresponded to 1
The 1,2,4-trisubstituted pyrrole structure was determined through the H-3 and H-5 signal appearing as a doublet with 4
H-6 and H-8 appearing as singlets and the non-protonated carbons C-2 and C-4 were assigned using delays in the 2D experiment to emphasize the long range coupling (HMBC), with either 2
Attribution of the aromatic carbon for compounds
For all phenyl substituents the aromatic carbons were attributed using delays in the 2D experiment to emphasize the long range coupling (HMBC), with either 2
Assignment of protons and carbons of saturated chains was determined using the multiplicity of the proton signals, their coupling constant, a typical proton-proton Cosy experiment and heteronuclear-correlated experiments using delay values that corresponded to 1
Protons of the allyl group in compound
Concerning compound
Using the 2D heteronuclear-correlated experiment, we determined that the downfield methyl proton resonance (H-23) correlated with the upfield methyl carbon resonance (C-23). Carbonyl carbons of
The authors thank MESR and CNRS for providing financial support and the “Service d’analyse Chimique du Vivant de Tours” for recording NMR.