Three-component synthesis of tetrasubstituted pyrroles by condensation with amines and arylglyoxals

Article abstract of DOI:10.1007/s10593-016-1869-8

[Figure not available: see fulltext.] A one-pot three-component condensation for the synthesis of functionalized pyrroles from arylglyoxal hydrates, acetylacetone or acetoacetic ester, and halo-substituted anilines has been developed. The reaction of ethyl 3-aminocrotonate and arylglyoxal led to the respective ethyl 5-aryl-4-hydroxy-2-methyl-(1H)-pyrrole-3-carboxylates.

Full text of DOI:10.1007/s10593-016-1869-8

DOI 10.1007/s10593-016-1869-8
Chemistry of Heterocyclic Compounds 2016, 52(4), 237–243
Three-component synthesis of tetrasubstituted
pyrroles by condensation with amines
and arylglyoxals
Nadezhda N. Kolos1*, Viktoriya V. Zubar1,
Irina V. Omelchenko2, Vladimir I. Musatov2
1 V. N. Karazin Kharkiv National University,
4 Svobody Sq., Kharkiv 61022, Ukraine; e-mail: kolos_n@ukr.net
2 State Scientific Institution "Institute for Single Crystals"of National Academy of Sciences of Ukraine,
60 Nauki Ave., Kharkiv 61072, Ukraine; e-mail: irina@xray.isc.kharkov.com
Submitted February 25, 2016
Accepted March 28, 2016
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2016, 52(4), 237–243
A one-pot three-component condensation for the synthesis of functionalized pyrroles from arylglyoxal hydrates, acetylacetone or
acetoacetic ester, and halo-substituted anilines has been developed. The reaction of ethyl 3-aminocrotonate and arylglyoxal led to the
respective ethyl 5-aryl-4-hydroxy-2-methyl-(1H)-pyrrole-3-carboxylates.
Keywords: acetoacetic ester, acetylacetone, anilines, arylglyoxals, ethyl 3-aminobuten-2-oate, pyrroles, multicomponent reactions.
The pyrrole ring is a part of many biologically important
compounds, such as hemoglobin and chlorophyll, as well
as medications (psychotropic, antiemetic, anticholinergic,
antihistaminic, and antihypertensive agents).1,2 Several
classical methods of synthesis (Paal–Knorr, Knorr,
Hantzsch3–9) and modern approaches to the formation of
pyrrole ring (for example, cyclizations using α,β-un-
saturated nitro compounds,10 nitro compounds and iso-
cyanoacetates (Barton–Zard synthesis),11–13 and one-pot
procedures involving aldehydes, β-dicarbonyl compounds,
nitromethane, and aromatic amines14) have been described
in the literature. Formation of 3-acetyl(alkoxycarbonyl)-1,4-
diaryl-2-methylpyrrole derivatives was proposed by
authors of the latter work. Only a few examples have been
reported were pyrrole derivatives were synthesized using
arylglyoxals,15–20 and the ring closure always occurred by a
Paal–Knorr type reaction.21
While continuing the study of the reactivity of aryl-
glyoxal hydrates in condensation reactions involving
β-dicarbonyl compounds and nucleophilic reagents,22–25 we
discovered a convenient method for the synthesis of tetra-
substituted pyrroles. Refluxing of arylglyoxal hydrates 1a–d,
acetylacetone (2а) or acetoacetic ester (2b), nitromethane,
and substituted anilines 3a–d in methanol with added
catalytic amounts of acetic acid was found to result in
precipitation of a mixture of pyrroles 4a–g from the hot
reaction mixture after 30 min (Scheme 1). Substituents in
the aniline and arylglyoxal fragments practically did not
affect the reaction duration and the yield of products. We
should note that anilines with electron-withdrawing
substituents (p-nitroaniline, m-nitroaniline) did not produce
the target products and were isolated from the reaction
mixture in unchanged form, as should be expected from the
proposed reaction mechanism.
The synthesized compounds 4 were obtained after
purification as white crystals. The molecular structures of
these compounds were established based on elemental
1
analysis, IR spectroscopy, Н and 13С NMR spectroscopy,
and mass spectrometry. The obtained results pointed to the
presence of three aromatic rings and an acetyl group in the
molecule. Besides that, 1Н NMR spectra indicated the
presence of an АВХ spin-spin coupling pattern, manifested
as double doublets of methylene group protons and a
broadened triplet at 4.7–5.0 ppm, which disappeared due to
deuterium exchange. This gave evidence that the methylene
group protons were non-equivalent and there were steric
obstacles to free rotation, caused by bulky aromatic groups.
1
The analysis of Н NMR signals in the aromatic region
0009-3122/16/52(4)-0237©2016 Springer Science+Business Media New York
237

Chemistry of Heterocyclic Compounds 2016, 52(4), 237–243
Scheme 1
O
R2
N
59–66%
Hal
NH
R1
Hal
NH2
AcOH (cat.)
OH
OH
Me
R2
4a–g
MeOH
Hal
+
+ 2
R1
, 30 min
O
2a b
O
O
O
O
1a–d
3a–d
R2
,
R1
Me
N
1a, 4a,b R1 = H, 1b, 4c R1 = 4-Et, 1c, 4d,g R1 = 3-F; 1d, 4e,f R1 = 4-Me;
2a, 4a–e R2 = Me, 2b, 4f,g R2 = OEt;
Hal
3a, 4c,d,g Hal = 2-Cl, 3b, 4a,e Hal = 2-Br, 3c, 4f Hal = 4-Br, 3d, 4b Hal = 2-I
5
allowed to reach a conclusion about the presence of two
substituted aniline fragments and an aromatic ring from
arylglyoxal in the molecules of compounds 4, which did
not match the structure of the expected 3-acetyl
relative to the pyrrole ring plane, preventing conjugation
between the π-systems of rings; this was confirmed by
lengthening of the N(1)–C(5) bond (1.437(4) Å) compared
to the average value (1.371 Å).27 The aryl substituent at the
С(4) atom was rotated by 37.8(6)° relative to the pyrrole ring,
allowing the possibility of conjugation (the С(4)–С(18)
bond length (1.469(5) Å) matched the average value for
conjugated systems (1.470 Å)). The N(2) atom had a
flattened pyramidal configuration (the sum of valence angles
was 352(3)°), probably caused by the shift in the Н(2) atom
position that enhanced the intramolecular N(2)–H(2)···O(1)
hydrogen bond (H···O 2.32(4) Å, N–H···O 128(3)°). The
N(2)–C(12) bond (1.379(4) Å) had an intermediate length
between conjugated and non-conjugated bonds of similar type
(1.353/1.419 Å), while the N(2)–C(11) bond (1.446(4) Å)
was substantially shortened (1.469 Å).27
We should note that mass spectra of the synthesized
compounds contained molecular ion peaks of relatively low
intensity. For example, the strongest peak in the mass
spectrum of compound 4b had m/z 400, corresponding to
the loss of 2-iodophenylimine radical.
Taking into account the unusual course of this reaction,
including the need for 2 mol of aniline in the formation of
products 4, we performed the reaction with a double excess
of substituted aniline, but the product yield increased
insignificantly (by 10–15%).
(ethoxycarbonyl)-4-aroyl-1-aryl-2-methylpyrroles
5
(by
analogy to published data14) and provided evidence that
nitromethane, which is a synthon containing one carbon
atom, did not participate in the reaction. The structure of
condensation products was proved conclusively by X-ray
structural analysis in the case of compound 4b (Fig. 1),
identified as 3-acetyl-1-(2-iodophenyl)-2-{[(2-iodophenyl)-
amino]methyl}-5-phenylpyrrole.
The N(1) atom in compound 4b had a planar
configuration (the sum of valence angles was 359.6(5)°),
all parameters of pyrrole ring geometry matched the
average values for tetrasubstituted pyrroles of analogous
structure (according to the structural database data for 21
compounds26). The С(2)–С(24) bond (1.474(5) Å) was longer
than the average value for carbonyl substituents at β-position
(1.451 Å), while the С(24)–О(1) bond (1.209(5) Å) was
shortened (1.222 Å), indicating a disrupted π-conjugation
between the С(1)=С(2) and С(24)=О(1) bonds. The aryl
substituent at the N(1) atom was rotated by 72.1(6)°
The probable mechanism leading to the synthesis of the
target compounds included the formation of hydroxy
ketone А, which was converted to aminal В by the action
of aromatic amine 3 (Scheme 2). The further cyclization by
Paal–Knorr reaction led to the formation of pyrrole ring.
The subsequent α-elimination of water and 1,4-addition of
the second molecule of aniline 3 to the intermediate s-trans-
diene С eventually led to the pyrrole 4.
The authors of a publication14 considered in four-
component condensation of aldehydes, anilines, acetyl-
acetone, and nitromethane the formation of an enamino-
ketone intermediate with the participation of aniline and
β-diketone, which reacted with an α,β-unsaturated nitro
compound, formed by the condensation of aromatic
aldehyde with nitromethane. We decided to test the
possibility of analogous three-component condensation
Figure 1. The molecular structure of compound 4b with atoms
represented by thermal vibration ellipsoids of 50% probability.
238

Chemistry of Heterocyclic Compounds 2016, 52(4), 237–243
Scheme 2
Me
O
NHAr
OH
Me
NH2Ar
3
HO
R2
O
O
OH
OH
Me
R1
R1
+
O
OH
O
O
R2
R2
2 O
A
R1
2
1
R
O
O
B
O
O
R2
R2
NH2Ar
3
– H2O
HO
Me
OH
OH
R1
N
– H2O
H2C
N
– H2O
R1
N
Ar
NH
Ar
Ar
R1
Ar
4
C
presence of π-conjugation with aryl substituent, which was
confirmed by the coplanar ring orientation (the angle
between ring planes was 10.0(3)°). The hydroxy group
О(3)–Н(3) formed intramolecular hydrogen bonds – a
classical О(3)–Н(3)···О(2) hydrogen bond (Н···О 1.85(2) Å,
О–Н···О 148(2)°) and a non-classical С(14)–Н(14)···О(3)
hydrogen bond (Н···О 2.31(2) Å, C–Н···О 129(2)°), which
stabilized the planar molecular configuration. The
molecules in crystal structure formed chains along the
crystallographic direction (100) linked by paired intermole-
cular hydrogen bonds N(1)–H(1)···O(5)' (0.5+x, –0.5–y, 1–z;
H···O 2.17 Å, N–Н···О 175°) and С(10)–H(10)···O(5)' (0.5+x,
–0.5–y, 1–z; H···O 2.40 Å, С–Н···О 161°).
occurring between arylglyoxals 1, enaminocrotonate 6, and
nitromethane. However, only pyrroles 7 were isolated in all
cases as products of two-component condensation between
glyoxal hydrates 1 and aminoester 6 (Scheme 3), isolated
examples of which have been already described in the
literature.15,16,20 Similarly to the reaction that we described
above, nitromethane did not participate in this reaction.
The structures of previously undescribed compounds
7b–d,f–j were established by spectral methods, and
compound 7f was also characterized by X-ray structural
analysis (Fig. 2). Similarly to structure 4b, the nitrogen
atom in pyrrole ring was planar (the sum of valence angles
was 360(1)°). Its geometry, however, was substantially
different from the parameters of N-substituted ring systems.
The asymmetry of N–C bond lengths in structure 7f,
characteristic for β-carbonyl-substituted pyrroles (results
from structural database,26 averaged for 139 structures),
was quite pronounced (N(1)–C(4) 1.345(2) Å with the
mean value of 1.357 Å, N(1)–C(1) 1.398(2) Å with the
mean value of 1.377 Å). Taking into account the shortening
of С(1)–С(2) bond to 1.377 Å (1.382 Å) and lengthening of
С(2)–О(3) bond to 1.355(2) Å (the average value for enols
is 1.333 Å),27 these data suggest some disruption of
conjugation in the HN(1)–C(1)=C(2)–O(3)H chain, while
favoring conjugation in the HN(1)–C(4)=C(3)–C(6)=O(2)
chain. Remarkably, the С(1)–С(9) bond (1.441(2) Å) at the
same time was markedly shortened even compared to
typical conjugated systems (1.470 Å),27 indicating the
Figure 2. The molecular structure of compound 7f with atoms
represented by thermal vibration ellipsoids of 50% probability.
Scheme 3
239

Chemistry of Heterocyclic Compounds 2016, 52(4), 237–243
The presence of hydroxy group at position 3 of pyrrole
(1H, d, J = 8.0, H Ar). 13C NMR spectrum, δ, ppm: 29.3
(COCH3); 39.7 (NCH2); 85.6; 86.2; 88.3; 101.2; 110.0; 111.4;
118.9; 123.0; 127.4; 128.3 (2C); 129.2; 129.4 (2C); 130.8;
131.3; 134.0; 135.9; 138.9; 139.6; 139.8; 146.6; 194.7 (C=O).
Mass spectrum, m/z (Irel, %): 400 [М–(2-IC6H4NH)]+
(100), 230 (26). Found, %: С 48.52; Н 3.29; N 4.55.
C25H20I2N2O. Calculated, %: С 48.57; Н 3.26; N 4.53.
1-[1-(2-Chlorophenyl)-2-{[(2-chlorophenyl)amino]me-
ring was additionally confirmed by an acylation reaction,
when the treatment of pyrroles 7b,d with chloroacetyl
chloride in acetonitrile in the presence of triethylamine
gave the esters 8а,b (Scheme 3).
Thus, we have demonstrated that a three-component
reaction involving arylglyoxals, acetylacetone or aceto-
acetic ester, and halo-substituted anilines in 1:1:2 ratio
offers a convenient method for the synthesis of 3-acetyl-
(ethoxycarbonyl)-1,2-diaryl-5-(arylaminomethyl)pyrroles.
The condensation of ethyl β-aminocrotonate, hydrates of
arylglyoxals, and nitromethane was found to proceed with-
out participation of the latter, and led to the formation of
ethyl 5-aryl-4-hydroxy-2-methyl-1H-pyrrole-3-carboxylates.
thyl}-5-(4-ethylphenyl)-1H-pyrrol-3-yl]ethanone
(4c).
Yield 0.28 g (61%), white powder, mp 143–144°С. IR
spectrum, ν, cm–1: 636, 790, 1030, 1244, 1478, 1630, 1662,
2970, 3069, 3362. 1H NMR spectrum, δ, ppm (J, Hz): 1.07
(3Н, t, J = 7.0, СН2СН3); 2.52 (3Н, s, СН3); 2.70 (2Н, q,
J = 7.0, СН2СН2); 4.30 (1Н, dd, JАВ = 14.4, JАХ = 7.2) and
4.46 (1Н, dd, JАВ = 14.4, JВХ = 5.2, СН2); 5.02 (1H, t,
JВХ = 5.2, NH); 6.33 (1H, d, J = 8.2, H Ar); 6.52 (1H, t,
J = 8.8, H Ar); 6.90–7.17 (7Н, m, H-4, H Ar); 7.41–7.58
(4Н, m, H Ar). Found, %: С 70.11; Н 5.30; N 6.11.
C27H24Cl2N2O. Calculated, %: С 69.98; Н 5.22; N 6.05.
1-[1-(2-Chlorophenyl)-2-{[(2-chlorophenyl)amino]me-
thyl}-5-(3-fluorophenyl)-1H-pyrrol-3-yl]ethanone (4d).
Yield 0.30 g (66%), white powder, mp 149–150°С. IR
spectrum, ν, cm–1: 638, 785, 1058, 1246, 1476, 1628, 1670,
2920, 3054, 3362. 1H NMR spectrum, δ, ppm (J, Hz): 2.51
(3Н, s, СН3); 4.32 (1Н, dd, JАВ = 14.6, JАХ = 7.0) and 4.46
(1Н, dd, JАВ = 14.4, JВХ = 5.4, СН2); 4.98 (1H, t, JВХ = 5.4,
NH); 6.34 (1H, d, J = 8.2, H Ar); 6.52 (1H, t, J = 8.8,
H Ar); 6.85–7.24 (6Н, m, H-4, H Ar); 7.47–7.68 (4Н, m,
Experimental
IR spectra were recorded on a Perkin Elmer Spectrum
1
One FT-IR spectrometer in KBr pellets. Н NMR spectra
were acquired on a Varian Mercury VX-200 spectrometer
(200 MHz), 13C NMR spectra – on a Bruker AM-400
spectrometer (100 MHz) in DMSO-d6 solution, the internal
standard was TMS. Mass spectra were recorded on a Hewlett-
Packard LC/MSD 1100 instrument (EI, 70 eV). Elemental
analysis was performed on a Eurovector EА 3000 Elemental
Analyzer. Melting points were determined on a Kofler
bench. The reaction progress and purity of the obtained
compounds were controlled by TLC on Silufol UV-254
plates with 1:1 toluene–EtOAc and 10:1 СHCl3–2-PrOH
mobile phases, visualization with iodine vapor.
H Ar). Found, %:
C
66.04;
Н
3.92;
N
6.15.
C25H19Cl2FN2O. Calculated, %: С 66.24; Н 4.22; N 6.18.
1-[1-(2–Bromophenyl)-2-{[(2-bromophenyl)amino]me-
thyl}-5-(4-methylphenyl)-1H-pyrrol-3-yl]ethanone (4e).
Yield 0.35 g (65%), white powder, mp 155–156°С. IR
spectrum, ν, cm–1: 648, 1020, 1249, 1480, 1628, 1666,
2926, 3060, 3368. 1H NMR spectrum, δ, ppm (J, Hz): 2.17
(3Н, s, СН3); 2.51 (3Н, s, СН3); 4.26 (1Н, dd, JАВ = 14.2,
JАХ = 7.0) and 4.47 (1Н, dd, JАВ = 14.2, JВХ = 5.2, СН2);
4.92 (1H, t, JВХ = 5.2, NH); 6.30 (1H, d, J = 8.2, H Ar);
6.46 (1H, t, J = 8.8, H Ar); 6.93–6.97 (5Н, m, H-4, H Ar);
7.28–7.52 (4Н, m, H Ar); 7.71 (1H, d, J = 7.8, H Ar).
13C NMR spectrum, δ, ppm: 20.7 (CH3); 28.8 (COCH3);
38.0 (NCH2); 89.6; 109.0; 110.6; 111.6; 117.9 (2C); 122.7;
123.3; 127.9 (2C); 128.5; 128.9 (2C); 131.4 (2C); 132.3;
133.5; 134.4; 135.8; 136.2; 136.8; 144.1; 195.2 (C=O).
Mass spectrum, m/z (Irel, %): 540 (5), 538 (10), 536 [M]+
(5), 368 (100), 244 (68), 155 (8), 91 (16). Found, %:
С 58.09; Н 3.97; N 5.15. C26H22Br2N2O. Calculated, %:
С 58.01; Н 4.12; N 5.20.
Synthesis of compounds 4a–g (General method). A
mixture of acetylacetone (2a) (0.10 ml, 1.0 mmol) or
acetoacetic ester (2b) (0.15 ml, 1.1 mmol), arylglyoxal
hydrate 1a–d (1.0 mmol), substituted aniline 3a–d
(2.0 mmol), and AcOH (5–7 drops) in MeOH (10 ml) was
refluxed for 30 min. The reaction mixture was cooled, the
precipitate was filtered off, washed with warm water, cold
MeOH, and recrystallized from MeOH.
1-[1-(2-Bromophenyl)-2-{[(2-bromophenyl)amino]-
methyl}-5-phenyl-1H-pyrrol-3-yl]ethanone (4а). Yield
0.34 g (65%), white powder, mp 148–149°С. IR spectrum, ,
cm–1: 640, 1016, 1244, 1482, 1630, 1668, 2924, 3063, 3366.
1H NMR spectrum, δ, ppm (J, Hz): 2.51 (3Н, s, СН3); 4.25
(1Н, dd, JАВ = 14.4, JАХ = 7.0) and 4.45 (1Н, dd, JАВ = 14.4,
JВХ = 5.0, СН2); 4.94 (1H, t, JВХ = 5.0, NH); 6.32 (1H, d,
J = 7.8, H Ar); 6.47 (1H, t, J = 8.0, H Ar); 6.99–7.55 (11Н, m,
Н-4, H Ar); 7.72 (1H, d, J = 7.8, H Ar). Mass spectrum, m/z
(Irel, %): 526 (10), 524 [M]+ (19), 522 (9), 354 (100), 230 (49),
157 (8), 77 (15). Found, %: С 57.20; Н 3.77; N 5.45.
C25H20Br2N2O. Calculated, %: С 57.28; Н 3.85; N 5.34.
1-(1-(2-Iodophenyl)-2-{[(2-iodophenyl)amino]methyl}-
5-phenyl-1H-pyrrol-3-yl)ethanone (4b). Yield 0.39 g
(63%), white powder, mp 153–154°С. IR spectrum, ν, cm–1:
680, 1027, 1244, 1478, 1632, 1660, 2982, 3075, 3370.
1H NMR spectrum, δ, ppm (J, Hz): 2.51 (3Н, s, СН3); 4.14
(1Н, dd, JАВ = 14.0, JАХ = 7.0) and 4.47 (1Н, dd,
Ethyl 1-(4-bromophenyl)-2-{[(4-bromophenyl)amino]-
methyl}-5-(4-methylphenyl)-1H-pyrrole-3-carboxylate
(4f). Yield 0.33 g (60%), white powder, mp 130–132°С
(MeОН). IR spectrum, ν, cm–1: 650, 797, 997, 1051, 1219,
1252, 1466, 1597, 1698, 2977, 3366. 1H NMR spectrum, δ,
ppm (J, Hz): 1.17 (3Н, t, J = 7.0, СН3); 2.19 (3Н, s, СН3);
4.18–4.26 (4Н, m, 2СН2); 4.82 (1H, t, J = 5.2, NH); 6.40
(2H, d, J = 8.0, H Ar); 6.66 (1H, s, H-4); 6.91–7.24 (8Н, m,
H Ar); 7.56 (2H, d, J = 7.8, H Ar). 13C NMR spectrum, δ,
ppm: 14.7 (ОСН2CH3); 21.0 (ArCH3); 38.1 (NCH2); 59.8
(OCH2СН3); 106.9; 108.6; 110.0 (2C); 114.3; 122.3; 127.4;
J
АВ = 14.0, JВХ = 5.4, СН2); 4.77 (1H, t, JВХ = 5.4, NH);
6.22 (1H, d, J = 8.0, H Ar); 6.33 (1H, t, J = 8.0, H Ar); 6.96–
7.27 (8Н, m, Н-4, H Ar); 6.46–7.55 (3Н, m, H Ar); 7.92
240

Chemistry of Heterocyclic Compounds 2016, 52(4), 237–243
128.5 (2C); 128.9; 129.4; 130.8 (2C); 131.6 (2C); 132.5
161 (100), 146 (7); 122 (11), 67 (80). Found, %: С 63.92;
Н 5.27; N 5.27. C14H14FNO3. Calculated, %: С 63.87;
Н 5.36; N 5.32.
(2C); 135.0 (2C); 136.7; 137.1; 147.9; 164.3 (C=O).
Found, %: С 57.09; Н 4.23; N 4.95. C27H24Br2N2O2.
Calculated, %: С 57.06; Н 4.26; N 4.93.
Ethyl 5-(2-fluorophenyl)-4-hydroxy-2-methyl-1H-
pyrrole-3-carboxylate (7d). Yield 0.15 g (57%), cream-co-
Ethyl 1-(2-Chlorophenyl)-2-{[(2-chlorophenyl)amino]-
methyl}-5-(3-fluorophenyl)-1H-pyrrole-3-carboxylate
(4g). Yield 0.28 g (59%), white powder, mp 96–98°С. IR
spectrum, ν, cm–1: 790, 825, 949, 1069, 1069, 1245, 1493,
1695, 2977, 3361. 1H NMR spectrum, δ, ppm (J, Hz): 1.26
(3Н, t, J = 7.0, СО2СН2СН3); 4.26 (2Н, q, J = 7.0,
СО2СН2СН3); 4.32 (1Н, dd, JАВ = 14.6, JАХ = 7.0) and 4.46
(1Н, dd, JАВ = 14.4, JВХ = 5.6, СН2); 4.79 (1H, t, JВХ = 5.6,
NH); 6.47–6.57 (2Н, m, H Ar); 6.68 (1H, s, Н-4); 6.83–7.23
(6Н, m, H Ar); 7.47–7.67 (4Н, m, H Ar). 13C NMR
spectrum, δ, ppm: 14.7 (ОСН2CH3); 37.8 (NCH2); 60.2
(OCH2CH3); 110.9; 111.7; 114.4; 114.6; 114.8; 114.9;
117.7; 118.5; 124.2; 128.3; 128.7; 129.3; 130.6; 130.8;
131.7; 132.7; 133.8; 134.8; 137.8; 143.4; 160.9; 163.3;
164.5 (C=O). Found, %: С 64.69; Н 4.33; N 5.85.
C26H21Cl2FN2O2. Calculated, %: С 64.61; Н 4.38; N 5.80.
Synthesis of compounds 7a–j (General method). A
mixture of ethyl 3-amino-2-butenoate (6) (0.3 g, 1 mmol)
and arylglyoxal hydrate 1a–c,e–k (1 mmol) in MeOH (10 ml)
was refluxed for 1 h. The precipitate that formed after
cooling was filtered off, washed on filter with МеOH, and
recrystallized from MeOH.
1
lored crystals, mp 110–111°С. H NMR spectrum, δ, ppm
(J, Hz): 1.27 (3Н, t, J = 7.0, СО2СН2СН3); 2.40 (3Н, s,
СН3); 4.24 (2Н, q, J = 7.0, СО2СН2СН3); 7.16–7.25 (3Н,
m, H Ar); 7.66–7.75 (1Н, m, H Ar); 8.19 (1Н, s, OH);
10.96 (1Н, s, NH). Mass spectrum, m/z (Irel, %): 263 [M]+
(23), 218 (19), 217 (100), 122 (18). 84 (5). Found, %:
С 63.92; Н 5.27; N 5.27. C14H14FNO3. Calculated, %:
С 63.87; Н 5.36; N 5.32.
Ethyl 5-(4-bromophenyl)-4-hydroxy-2-methyl-1H-
pyrrole-3-carboxylate (7e). Yield 0.20 g (62%), beige
crystals, mp 144–146°С (mp 145°С (decomp., EtOH)15).
IR spectrum, ν, cm–1: 825, 889, 1076, 1164, 1336, 1491,
1
1606, 1689, 2981, 3382, 3458. H NMR spectrum, δ, ppm
(J, Hz): 1.28 (3Н, t, J = 7.2, СО2СН2СН3); 2.36 (3Н, s,
СН3); 4.23 (2Н, q, J = 7.2, СО2СН2СН3); 7.50 (2Н, d,
J = 8.0, H-2,6, H Ar); 7.63 (2Н, d, J = 8.0, H-3,5, H Ar);
8.37 (1Н, s, OH); 11.26 (1Н, s, NH). 13C NMR spectrum,
δ, ppm: 13.8 (2-CH3); 14.7 (OCH2CH3); 59.2 (OCH2СН3);
101.0; 111.4; 123.6; 128.5 (2C); 132.0 (2C); 132.4; 134.0;
145.3; 167.8 (C=O). Mass spectrum, m/z (Irel, %): 323 [M]+
(40), 279 (37), 277 (100), 182 (43), 115 (7). Found, %:
С 52.03; Н 4.29; N 4.37. C14H14BrNO3. Calculated, %:
С 51.87; Н 4.35; N 4.32.
Ethyl
4-hydroxy-2-methyl-5-phenyl-1H-pyrrole-
3-carboxylate (7а). Yield 0.16 g (65%), cream-colored
crystals, mp 157–158°С (mp 159–161°С (EtOH)15).
1H NMR spectrum, δ, ppm (J, Hz): 1.28 (3Н, t, J = 7.0,
СО2СН2СН3); 2.39 (3Н, s, СН3); 4.25 (2Н, q, J = 7.0,
СО2СН2СН3); 7.04–7.31 (3Н, m, H Ar); 7.67 (2Н, d, J = 7.6,
H-2,6 Ar); 8.26 (1Н, s, OH); 11.18 (1Н, s, NH). Mass
spectrum, m/z (Irel, %): 245 [M]+ (94), 199 (90), 159 (32),
128 (40), 104 (50), 67 (100). Found, %: С 68.40; Н 6.07;
N 5.65. C14H15NO3. Calculated, %: С 68.56; Н 6.16; N 5.71.
Ethyl 4-hydroxy-2-methyl-5-(4-nitrophenyl)-1H-
pyrrole-3-carboxylate (7f). Yield 0.18 g (60%), light-
1
orange crystals, mp 176°С . H NMR spectrum, δ, ppm
(J, Hz): 1.29 (3Н, t, J = 7.0, СО2СН2СН3); 2.43 (3Н, s,
СН3); 4.25 (2Н, q, J = 7.0, СО2СН2СН3); 7.87 (2Н, d,
J = 8.0, H-2,6 H Ar); 8.20 (2Н, d, J = 8.0, H-3,5 H Ar);
8.84 (1Н, s, OH); 11.53 (1Н, s, NH). Mass spectrum, m/z
(Irel, %): 290 [M]+ (40), 245 (18), 244 (100), 214 (10), 198
(12), 149 (15), 67 (32). Found, %: С 58.02; Н 4.92; N 9.57.
C14H14N2O5. Calculated, %: С 57.93; Н 4.86; N 9.65.
Ethyl
5-(4-ethylphenyl)-4-hydroxy-2-methyl-1H-
pyrrole-3-carboxylate (7b). Yield 0.20 g (73%), beige
crystals, mp 143–144°С. IR spectrum, ν, cm–1: 700, 832,
1099, 1262, 1483, 1606, 1688, 2971, 3381, 3450. H NMR
Ethyl 5-(3,4-dimethylphenyl)-4-hydroxy-2-methyl-
1
1H-pyrrole-3-carboxylate (7g). Yield 0.19 g (70%), light
1
spectrum, δ, ppm (J, Hz): 1.15 (3Н, t, J = 6.8, СН2СН3);
1.27 (3Н, t, J = 7.2, СО2СН2СН3); 2.39 (3Н, s, СН3); 2.52
(2Н, q, J = 6.8, СН2СН3); 4.23 (2Н, q, J = 7.2,
СО2СН2СН3); 7.16 (2Н, d, J = 8.2, H-2,6 H Ar); 7.59 (2Н,
d, J = 8.0, H-3,5 H Ar); 8.18 (1Н, s, OH); 11.20 (1Н, s,
NH). 13C NMR spectrum, δ, ppm: 13.7 (2-CH3); 14.7
(OCH2CH3); 16.0 (CH2CH3); 28.3 (CH2CH3); 59.7
(OCH2СН3); 100.9; 111.1; 123.2 (2C); 128.2 (2C); 129.8;
131.4; 139.9; 142.9 (C); 167.1 (C=O). Mass spectrum, m/z
(Irel, %): 273 [M]+ (87), 227 (100), 212 (15), 132 (16), 67
(13). Found, %: С 70.39; Н 7.09; N 5.17. C16H19NO3.
Calculated, %: С 70.31; Н 7.01; N 5.12.
cream-colored crystals, mp 152°С. H NMR spectrum,
δ, ppm (J, Hz): 1.27 (3Н, t, J = 7.0, СО2СН2СН3); 2.16
(3Н, s, СН3 Ar); 2.20 (3Н, s, СН3 Ar); 2.38 (3Н, s, СН3);
4.23 (2Н, q, J = 7.0, СО2СН2СН3); 7.07 (1Н, d, J = 8.2,
H Ar); 7.40–7.47 (2Н, m, H Ar); 8.16 (1Н, s, OH); 11.10
(1Н, s, NH). Mass spectrum, m/z (Irel, %): 273 [M]+ (10),
228 (23), 227 (100), 171 (28), 132 (23), 77 (8). Found, %:
С 70.62; Н 7.07; N 5.15. C16H19NO3. Calculated, %:
С 70.31; Н 7.01; N 5.12.
Ethyl 5-(3,4-dimethoxyphenyl)-4-hydroxy-2-methyl-
1H-pyrrole-3-carboxylate (7h). Yield 0.21 g (69%),
cream-colored crystals, mp 157–158°С. 1H NMR spectrum,
δ, ppm (J, Hz): 1.27 (3Н, t, J = 7.2, СО2СН2СН3); 2.40
(3Н, s, СН3); 3.72 (3Н, s, ОСН3 ); 3.76 (3Н, s, ОСН3); 4.24
(2Н, q, J = 7.3, СО2СН2СН3); 6.92 (1Н, d, J = 8.2, H-6
Ar); 7.20–7.30 (2Н, m, H Ar); 8.13 (1Н, s, OH); 11.08
(1Н, s, NH). 13C NMR spectrum, δ, ppm: 13.7 (2-CH3);
14.8 (OCH2СН3); 56.0 (2OCH3); 59.6 (OCH2СН3); 100.9;
Ethyl 5-(3-fluorophenyl)-4-hydroxy-2-methyl-1H-
pyrrole-3-carboxylate (7c). Yield 0.15 g (57%), cream-
1
colored crystals, mp 132–134°С. H NMR spectrum, δ,
ppm (J, Hz): 1.28 (3Н, t, J = 7.0, СО2СН2СН3); 2.40 (3Н,
s, СН3); 4.25 (2Н, q, J = 7.0, СО2СН2СН3); 7.30–7.70 (4Н,
m, H Ar); 8.42 (1Н, s, OH); 11.30 (1Н, s, NH). Mass
spectrum, m/z (Irel, %): 263 [M]+ (53), 218 (24), 217 (77),
241

Chemistry of Heterocyclic Compounds 2016, 52(4), 237–243
107.7; 111.1; 112.7; 115.7; 125.5; 131.5; 142.1; 146.3;
structures were solved directly and refined by F2 with full
matrix method of least squares in anisotropic approxi-
mation for non-hydrogen atoms, using the OLEX228
software with SHELXS and SHELXL29 modules. The
positions of all hydrogen atoms were revealed from
differential synthesis of electron density and localized
during further refinement, except for the Н(2) atoms in
compound 4b, as well as H(1) and H(3) atoms in
compound 7f, the coordinates of which were refined
independently. The length of the N(2)–H(2) bond in
compound 4b was constrained at 0.86(1) Å. The
temperature parameters for hydrogen atoms were refined
with the "rider" model with Uiso = 1.2Ueq (1.5Ueq for
methyl groups), except for the H(1) and H(3) atoms in
compound 7f, which were refined isotropically. The
crystallographic data, atomic coordinates, and geometry
parameters for structures of compounds 4b and 7f were
deposited at the Cambridge Crystallographic Data Center
(deposits CCDC 1453290, CCDC 1453291, respectively).
149.2; 166.9 (C=O). Mass spectrum, m/z (Irel, %): 305 [M]+
(30), 260 (19), 259 (100), 244 (13), 203 (6). Found, %:
С 62.74; Н 6.38; N 4.65. C16H19NO5. Calculated, %:
С 62.94; Н 6.27; N 4.59.
Ethyl 5-(3,4-Dichlorophenyl)-4-hydroxy-2-methyl-1H-
pyrrole-3-carboxylate (7i). Yield 0.22 g (70%), white
crystals, mp 144–146°С. 1H NMR spectrum, δ, ppm (J, Hz):
1.27 (3Н, t, J = 7.0, СО2СН2СН3); 2.38 (3Н, s, СН3); 4.23
(2Н, q, J = 7.0, СО2СН2СН3); 7.56 (1Н, d, J = 7.8, H Ar);
7.65 (1Н, d, J = 7.8, H Ar); 7.89 (1Н, s, H Ar); 8.51 (1Н, s,
OH); 11.30 (1Н, s, NH). 13C NMR spectrum, δ, ppm: 13.8
(2-CH3); 14.7 (OСН2CH3); 59.8 (OCH2СН3); 101.3; 109.2;
122.8; 123.9; 125.8; 131.0; 131.7; 132.8; 133.8; 145.0;
168.5 (C=O). Mass spectrum, m/z (Irel, %): 269 (40), 269
(18), 267 [M–C2H5OH]+ (100), 232 (8), 172 (25). Found,
%: С 53.74; Н 4.28; N 4.55. C14H13Cl2NO3. Calculated, %:
С 53.52; Н 4.17; N 4.46.
Ethyl 4-hydroxy-2-methyl-5-(2-oxo-2H-chromen-3-yl)-
1H-pyrrole-3-carboxylate (7j). Yield 0.19 g (60%), light-
yellow powder, mp 204–205°С (decomp.). IR spectrum, ν,
cm–1: 750, 985, 1138, 1287, 1473, 1610, 1666, 1704, 2981,
3329, 3400. 1H NMR spectrum, δ, ppm (J, Hz): 1.27 (3Н, t,
J = 7.0, СО2СН2СН3); 2.43 (3Н, s, СН3); 4.24 (2Н, q,
J = 7.0, СО2СН2СН3); 7.31 (1Н, t, J = 7.6, H Ar); 7.38 (1Н,
d, J = 7.8, H Ar); 7.48 (1Н, t, J = 7.6, H Ar); 7.66 (1Н, d,
J = 7.8, H Ar); 8.22 (1Н, s, СH); 8.83 (1Н, s, ОH); 10.97 (1Н,
s, NH). Found, %: С 65.24; Н 4.70; N 4.50. C17H15NO5.
Calculated, %: С 65.17; Н 4.83; N 4.47.
Ethyl 4-(2-chloroacetoxy)-5-(4-ethylphenyl)-2-methyl-
1H-pyrrole-3-carboxylate (8а). Chloroacetyl chloride
(0.24 ml, 3 mmol) and Et3N (0.40 ml, 3 mmol) were added
to a solution of compound 7b (0.27 g, 1 mmol) in
acetonitrile (5 ml). The mixture was stirred at 50°С for
approximately 1 h (TLC control), then the solvent was
evaporated to dryness on a vacuum evaporator, and the
obtained precipitate was recrystallized from methanol.
Yield 0.21 g (60%), light-beige crystals, mp 140°С. 1H NMR
spectrum, δ, ppm (J, Hz): 1.13–1.19 (6Н, m, СО2СН2СН3,
СН2СН3); 2.47 (3Н, s, СН3); 2.56 (2Н, q, J = 7.2,
СН2СН3); 4.10 (2Н, q, J = 7.2, СО2СН2СН3); 4.65 (2Н, s,
CH2); 7.22 (2Н, d, J = 7.0, H-3,5 H Ar); 7.42 (2Н, d,
J = 7.0, H-2,6 H Ar); 11.59 (1Н, s, NH). Found, %:
С 61.60; Н 5.76; N 4.09. C18H20ClNO4. Calculated, %:
С 61.80; Н 5.76; N 4.00.
References
1. Trofimov, B. A.; Mikhaleva, A. I.; Shmidt, E. Yu.; Sobenina, L. N.
New Pages in the Chemistry of Pyrrole [in Russian];
Tolstikov, G. A., Ed.; Nauka: Novosibirsk, 2012.
2. Pyrroles. The Synthesis, Reactivity and Physical Properties of
Substituted Pyrroles, Part II; Jones, R. A., Ed.; Wiley: New
York, 1992.
3. Trofimov, B. A.; Sobenina, L. N.; Demenev, A. P.;
Mikhaleva, A. I. Chem. Rev. 2004, 104, 2481.
4. Black, D. S. In Science of Synthesis; Thieme: Stuttgart, 2001,
Chapt. 13, p. 441.
5. Liu, J.-H.; Yang, Q.-C.; Mak, T. C. W.; Wong, H. N. C. J.
Org. Chem. 2000, 65, 3587.
6. Zhang, X.; Sui, Z. Tetrahedron Lett. 2003, 44, 3071.
7. Azizian, J.; Karimi, A. R.; Arefrad, H.; Mohammadi, A. A.;
Mohammadizadeh, M. R. Mol. Diversity 2003, 6, 223.
8. Kim, J. T.; Kel'in, A. V.; Gevorgyan, V. Angew. Chem., Int.
Ed. 2003, 42, 98.
9. Balme, G. Angew. Chem., Int. Ed. 2004, 43, 6238.
10. Ranu, B. C.; Dey, S. S. Tetrahedron Lett. 2003, 44, 2865.
11. Barton, D. H. R.; Zard, S. Z. J. Chem. Soc., Chem. Commun.
1985, 1098.
12. Barton, D. H. R.; Kervagorel, J.; Zard, S. Z. Tetrahedron
1990, 46, 7587.
13. Boelle, J.; Shcneider, R.; Gerardin, P.; Loubinoux, B.
Synthesis 1997, 1451.
Ethyl 4-(2-chloroacetoxy)-5-(2-fluorophenyl)-2-methyl-
1H-pyrrole-3-carboxylate (8b) was obtained analogously.
Yield 0.23 g (68%), light-beige crystals, mp 118–119°С.
1H NMR spectrum, δ, ppm (J, Hz): 1.21 (3Н, t, J = 7.2,
СО2СН2СН3); 2.47 (3Н, s, СН3); 4.11 (2Н, q, J = 7.2,
СО2СН2СН3); 4.60 (2Н, s, CH2); 7.23–7.39 (4Н, m, Ar);
11.69 (1Н, s, NH). Found, %: С 56.82; Н 4.37; N 4.18.
C16H15ClFNO4. Calculated, %: С 56.56; Н 4.45; N 4.12.
X-ray structural analysis of pyrroles 4b and 7f.
Crystals of compounds 4b and 7f (white and light-orange,
respectively) were obtained by recrystallization from
acetonitrile. X-ray structural study was performed on an
Xcalibur-3 diffractometer (MoKα-radiation, ССD-detector,
graphite monochromator, ω-scanning, Т 298 K). The
14. Li, B.-L.; Li, P.-H.; Fang, X.-N.; Li, Ch.-X.; Sun, J.-L.;
Mo, L.-P.; Zhang, Z.-H. Tetrahedron 2013, 69, 7011.
15. Feliciano, A. S.; Caballero, E.; Pereira, J. A. P.; Puebla, P.
Tetrahedron 1989, 45, 6553.
16. Caballero, E.; Puebla, P.; Domercq, M.; Medarde, M.; López, J.-L.;
Feliciano, A. S. Tetrahedron 1994, 50, 7849.
17. Khalili, B.; Jajarmi, P.; Eftekhari-Sis, B.; Hashemi, M. M. J.
Org. Chem. 2008, 73, 2090.
18. Eftekhari-Sis, B.; Zirak, M.; Akbari, A.; Hashemi, M. M. J.
Heterocycl. Chem. 2010, 47, 463.
19. Yin, G.; Wang, Z.; Chen, A.; Gao, M.; Wu, A.; Pan, Y. J.
Org. Chem. 2008, 73, 3377.
20. Bhat, S. I.; Trivedi, D. R. Tetrahedron Lett. 2013, 54, 5577.
21. Estevez, V.; Villacampa, M.; Menendez, J. C. Chem. Soc.
Rev. 2014, 43, 4633.
242

Chemistry of Heterocyclic Compounds 2016, 52(4), 237–243
22. Gozalishvili, L. L.; Beryozkina, T. V.; Оmelchenko, I. V.;
25. Chechina, N. V.; Kravchuk, О. F.; Оmelchenko, I. V.;
Shishkin, О. V.; Kolos N. N. ARKIVOC 2015, (vii), 77.
26. Groom, C. R.; Allen, F. H. Angew. Chem., Int. Ed. Engl.
2014, 53, 662.
Zubatyuk, R. I.; Shishkin, О. V.; Kolos, N. N. Tetrahedron
Lett. 2008, 64, 8759.
23. Kolos, N. N.; Zamigaylo, L. L.; Chechina, N. V.;
Omelchenko, I. V.; Shishkin, O. V.; Vashchenko, E. V.
Chem. Heterocycl. Compd. 2012, 48, 1817. [Khim.
Geterotsikl. Soedin. 2012, 1941.]
24. Kolos, N. N.; Kibkalo, B. V.; Zamigaylo, L. L.; Оmel'chenko, I. V.;
Shishkin, О. V. Russ. Chem. Bull., Int. Ed. 2015, 64, 1. [Izv.
Akad. Nauk, Ser. Khim. 2015, 864.]
27. Structure Correlation, Bürgi, H-B.; Dunitz, J. D., Eds.; VCH:
Weinheim, 1994, Vol. 2.
28. Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A.
K.; Puschmann, H. J. Appl. Crystallogr. 2009, 42, 339.
29. Sheldrick, G. M. Acta Crystallogr., Sect. A: Found.
Crystallogr. 2008, A64, 112.
243