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S. Nagy, A. Szigetvari, V. Ilkei et al.
Tetrahedron 81 (2021) 131827
compounds is uncommon in the sense that it is based on mapping
the full conformational space in order to obtain reliable results,
rather than arbitrarily restricting the conformational space to
several representative conformers.
2867, 1460, 1185, 1081, 1045 cmꢁ1.1H NMR (500 MHz, CDCl3)
d
(ppm) 1.10 (18H; d; J ¼ 7.5 Hz; CH3); 1.45 (3H; spt; J ¼ 7.5 Hz;
CH(CH3)2); 6.30e6.33 (2H; m; H-3, H-4); 6.77e6.82 (2H; m; H-2, H-
5). 13C NMR (126 MHz, CDCl3)
(ppm) 11.7 (CH(CH3)2); 17.8 (CH3);
110.0 (C-3, C-4); 124.0 (C-2, C-5). Lit. 1H NMR (500 MHz, CDCl3)
d
4. Experimental section
d
(ppm) 1.09 (18 H; d; J ¼ 7.4 Hz; CH3); 1.45 (3H; spt; J ¼ 7.4 Hz;
CH(CH3)2); 6.32 (2H; t*; H-3, H-4); 6.80 (2H; t*; H-2, H-5); *should
be interpreted as apparent multiplicity; no coupling constants were
Melting points were measured on a SANYO Gallenkamp appa-
ratus and are uncorrected. IR spectra were recorded on a Bruker FT-
IR instrument and a PerkinElmer Spectrum 100 FT-IR Spectrometer
equipped with Universal ATR (diamond/ZnSe) accessory. NMR
measurements (1H, 13C, COSY, 1D NOESY, 1D ROESY, 2D ROESY,
HSQC, HMBC, 1,1-ADEQUATE) were performed on Varian VNMRS
400 MHz (equipped with 5 mm OneNMR 15Ne31 P/{1He19F} PFG
Probe), Varian VNMRS 500 MHz (equipped with 1H{13C,15N} 5 mm
PFG Triple Resonance 13C Enhanced Cold Probe) and Varian VNMRS
800 MHz (equipped with 1H{13C,15N} Triple Resonance 13C
Enhanced Salt Tolerant Cold Probe), Bruker Avance III HDX
500 MHz (equipped with 1H {13C,15N} 5 mm TCI CryoProbe), and
Bruker Avance III HDX 800 MHz (equipped with 1H/19F {13C,15N}
5 mm TCI CryoProbe) spectrometers. 1H and 13C chemical shifts are
given on the delta scale in parts per million (ppm) relative to tet-
ramethylsilane (TMS). 1H multiplicities are given as d (doublet), t
(triplet), q (quartet), spt (septet) and their combinations or as m
(multiplet); br corresponds to broad. Coupling constants are given
in Hz in descending order. NMR spectra were processed using
VnmrJ 2.2 Revision C (Varian, Inc., Palo Alto, CA, USA), Bruker
TopSpin 3.5 pl 6 (Bruker Corporation, Billerica, MA, USA) and ACD/
Spectrus Processor version 2017.1.3 (Advanced Chemistry Devel-
opment, Inc., Toronto, ON, Canada); Daisy plugin of TopSpin was
used for spin system simulations. HRMS and MS analyses were
performed on a Finnigan MAT 95 XP and a Thermo LTQ FT Ultra as
well as a Thermo LTQ XL (Thermo Fisher Scientific, Bremen, Ger-
many) system. The ionization method was EI operated in positive
ion mode on a Finnigan MAT 95 XP. The electron energy was 70 eV
and the source temperature was set to 220 ꢀC. The ionization
method was ESI operated in positive ion mode on the other two
systems. For the CID experiment helium was used as the collision
gas, and normalized collision energy (expressed in percentage),
which is a measure of the amplitude of the resonance excitation RF
voltage applied to the endcaps of the linear ion trap, was used to
induce fragmentation. The protonated molecular ion peaks were
fragmented by CID at a normalized collision energy of 35%. Data
acquisition and analysis were accomplished with Xcalibur software
version 2.0 (Thermo Fisher Scientific). TLC was carried out on TLC
Silica gel 60 F254 on 20 ꢂ 20 cm aluminium sheets (Merck), and
preparative TLC was carried out using Silica gel 60 PF254þ366
(Merck) coated glass plates. Column chromatography was per-
formed using Silica gel 60 (0.063e0.200 mm) (Merck). Kaempferol
was purchased from Xi’an Lyphar Biotech Co., Ltd (Xi’an, Shaanxi,
China) and used without further purification.
4.2. Pyrrole-3-carboxaldehyde (22)
Phosphoryl chloride (8.27 mL, 13.6 g, 88.7 mmol) was cooled to
0
ꢀC with stirring, then DMF (6.86 mL, 6.50 g, 88.9 mmol) was
slowly added at 0 ꢀC. To this mixture a solution of 1-(triisopro-
pylsilyl)pyrrole (21) (16.5 g, 73.8 mmol) in acetonitrile (60 mL) was
added over 30 min. The reaction mixture was let to warm up to
room temperature and was stirred for 2 h, then it was again cooled
to 0 ꢀC. The mixture was quenched with 2 M NaOH solution until
pH ¼ 9. The mixture was extracted with diethyl ether (3 ꢂ 30 mL).
The ether solution was dried (Na2SO4), then the solvent was
removed under reduced pressure. The crude product was purified
by column chromatography, using hexane:EtOAc (1:4) as the
eluent, giving the title compound 22 as a pale brown crystalline
solid (4.56 g, 65%), mp 65 ꢀC (lit.: 68 ꢀC) [23]; Rf
(hexane:EtOAc ¼ 1:4) 0.63; nmax (KBr) 3258, 3116, 1653, 1505, 1435,
1416, 1402, 1377, 1297, 1091, 1061, 1052 cmꢁ1
CDCl3)
7.47e7.48 (1H; m; H-2); 9.20e9.54 (1H; br m; NH); 9.82 (1H; ~s;
CHO). 13C NMR (201 MHz, CDCl3)
(ppm) 107.5 (C-4); 120.7 (C-5);
;
1H NMR (800 MHz,
d
(ppm) 6.69e6.70 (1H; m; H-4); 6.85e6.87 (1H; m; H-5);
d
126.7 (C-3); 127.4 (C-2); 186.1 (CHO). EI-HRMS: M ¼ 95.0353
(C5H5ON; calc.: 95.0366); EI-MS (rel. int. %): 95(100); 66(16).
4.3. 3-Methylpyrrole (23)
To a solution of KOH (10.8 g, 192 mmol) in ethylene glycol
(72 mL) a solution of pyrrole-3-carboxaldehyde (22) (4.56 g,
47.9 mmol) was added in hydrazine hydrate (2.33 mL, 2.40 g,
48.0 mmol). The flask was fitted for distillation, and the mixture
was slowly heated to 200 ꢀC with vigorous stirring. The pure frac-
tions of the product were collected at 140e145 ꢀC. The distillate
was extracted with diethyl ether (3 ꢂ 30 mL). The ether solution
was dried (Na2SO4), then the solvent was removed under reduced
pressure, giving the title compound 23 as a colorless liquid (2.84 g,
73%), bp 143e145 ꢀC (lit.: 142e143 ꢀC) [41]; Rf
(hexane:EtOAc ¼ 4:1) 0.60; nmax (neat film) 3387, 3091, 2924, 2867,
4.1. 1-(Triisopropylsilyl)pyrrole (21)
To a solution of pyrrole (5.17 mL, 5.00 g, 74.5 mmol) in dry THF
(100 mL) at ꢁ75 ꢀC, n-butyllithium solution (33.0 mL, 2.5 M soln. In
hexanes, 82.5 mmol) was slowly added under argon. The solution
was stirred at ꢁ75 ꢀC for 10 min, then triisopropylsilyl chloride
(16.0 mL, 14.4 g, 74.8 mmol) was added over 10 min. After the
addition, the mixture was let to warm up to room temperature,
then it was quenched with water (100 mL). The mixture was
extracted with diethyl ether (3 ꢂ 50 mL). The ether solution was
dried (Na2SO4), then the solvent was removed under reduced
pressure, giving the title compound 21 as a colorless oil (16.5 g,
99%), Rf (hexane:EtOAc ¼ 1:4) 0.95; nmax (neat film) 2946, 2892,
2744, 1601, 1560, 1485, 1429, 1254, 1137, 1059 cmꢁ1
(800 MHz; CDCl3)
4); 6.59e6.61 (1H; m; H-2); 6.74e6.76 (1H; m; H-5); 7.82e8.18 (1H;
br m; NH). 13C NMR (201 MHz; CDCl3)
(ppm) 11.7 (CH3); 109.6 (C-
;
1H NMR
d
(ppm) 2.19 (3H; s; CH3); 6.12e6.13 (1H; m; H-
d
4); 115.5 (C-2); 117.7 (C-5); 118.7 (C-3). EI-HRMS: M ¼ 81.0571
(C5H7N; calc.: 81.0573); EI-MS (rel. int. %): 81(65); 80(100); 53(21).
12