Rearrangement of O-vinyl-α-(amino-carbonyl)acetamidoximes to 2-aminopyrroles and 2-pyrrolinones

Article abstract of DOI:10.1007/s10593-007-0173-z

Rearrangement and cyclization of O-vinyl-α-(aminocarbonyl) acetamidoximes gives two isomeric 2-aminopyrroles and/or 2-pyrrolinones and this depends on the rearrangement route.

Full text of DOI:10.1007/s10593-007-0173-z

Chemistry of Heterocyclic Compounds, Vol. 43, No. 9, 2007
REARRANGEMENT OF O-VINYL-α-(AMINO-
CARBONYL)ACETAMIDOXIMES TO 2-AMINO-
PYRROLES AND 2-PYRROLINONES
A. V. Galenko, S. I. Selivanov, P. S. Lobanov, and A. A. Potekhin
Rearrangement and cyclization of O-vinyl-α-(aminocarbonyl)acetamidoximes gives two isomeric
2-aminopyrroles and/or 2-pyrrolinones and this depends on the rearrangement route.
Keywords: 2-aminopyrroles, substituted acetamidoximes, 2-pyrrolinones, rearrangement.
Under Trofimov reaction conditions O-vinyloximes with α-hydrogen atoms are converted to pyrroles.
The key stage in the reaction is a [3,3]-sigmatropic rearrangement of the enhydroxylamine tautomer form of the
oxime. The imino ketone product cyclizes to a pyrrole [1]. Similarly, O-vinylamidoximes rearrange via the
tautomeric imino form to amidino aldehydes or ketones which cyclize to form imidazoles [2].
We have studied the thermolysis of the O-vinyl-α-(aminocarbonyl)acetamidoximes 1a-g. These
compounds can potentially react both as oximes (route 1) and as amidoximes (route 2). The thermolysis was
carried out in refluxing mesitylene and the reaction products were separated chromatographically.
The main reaction scheme proved to be route 1. The rearrangement product cyclizes via either of the
nucleophilic nitrogen atoms to give the 2-aminopyrroles 2 or 2-pyrrolinones 3. With the presence of a secondary
amide (R1 = H) in the molecular fragment nucleophilic attack involving the amide nitrogen atom predominates
and this leads principally to the formation of the pyrrolinone 3. Increasing the bulk of the substituent on the
nitrogen atom (compound 1b) causes an increase in the fraction of the aminopyrrole 2. When changing to a
tertiary amide (compounds 1d,e) the aminopyrroles 2d,e become the sole reaction products. They were separated
as the ureas 6d,e after treatment of the reaction mixtures with phenyl isocyanate. We were unable to prepared the
pyrroles 2d,e in the pure state due to their degradation on silica gel. Such a low stability for these compounds
gave us grounds to propose that they can undergo tarring in the forcing reaction conditions which can then lead
to a low yield of their derivatives. Carrying out the pyrolysis in the presence of refluxing acetylacetone as a
"trap" gave the pyrrolopyrimidines 7d,e in greater yields and this indirectly supports our suggestion.
In several examples the formation of the aminopyrrole 4 was noted. In appears to be obtained by route 2
via cyclization of the intermediate involving a nucleophilic carbon atom. We did not identify the formation of
the imidazoles 5.
__________________________________________________________________________________________
St. Petersburg State University, St. Petersburg 198504, Russia; e-mail: pslob@mail.ru. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1328-1334, September, 2007. Original article submitted
January 15, 2007.
1124
0009-3122/07/4309-1124©2007 Springer Science+Business Media, Inc.

1125

R1R2 NOC
MeO2C
MeO2C
H
R1R2
O
CON
N
Me
H
N
H
N
N
N
H
H
H
H
Me
7d, e
6d, e
The structures 2 and 4 were assigned as the corresponding pyrroles on the basis of the direct C–H
spin-spin coupling constants for the pyrrole fragment in the NMR spectra. In this case of compound 2 J = 90-196
and for compound 4 J = 172-174 Hz which correspond to the spin-spin couplings for the α- and β- positions of
the pyrrole ring respectively [3]. NOESY correlations spectra were also obtained for compounds 6d,e and 7d,e.
The arrows shown on the scheme indicate the signals for which cross correlations were important in establishing
the structure.
Thermolysis of O-vinyl-α-(aminocarbonyl)acetamidoximes 1f,g in mesitylene gives the dimethyl esters
of 5-amino-4-(pyrrrolidin-1-ylcarbonyl)pyrrole-2,3-dicarboxylic acids 8f,g. In these examples the structure of
the aminopyrrole obtained does not permit a conclusion about the route of their formation. Alternatively
structured imidazole reaction products were not observed in this case.
R1R
2 NOC
CO2Me
O
CO2Me
CO2Me
O
N
R1R2 N
NH2
H2N
CO2Me
N
1f, g
8f, g
1, 8 f R1,R2 = (CH2)4; g R1,R2 = (CH2)2O(CH2)2
EXPERIMENTAL
1H and 13C NMR spectra were recorded on a Bruker DPX 300 (300 and 75 MHz respectively) using
1
13
DMSO-d6 as solvent and the residual signals for DMSO-d6 at 2.50 ppm (for H) and 39.52 ppm (for C NMR
nuclei) were used as internal standards. The spin spin couplings in the proton spectra were measured in first
order approximation. Mass spectra were obtained on a Finnigan MAT Incos 50 instrument with EI ionization
(70 eV energy). S,H,N analysis was carried out on a Hewlett-Packard HP-185B analyzer. The purity of the
products and reaction course were monitored by TLC on ALUGRAM SIL G/UV plates.
O-Vinyl-α-(aminocarbonyl)acetamidoximes 1a-e (General Method). A solution of methyl propiolate
(12 mmol) in acetonitrile (5 ml) was added dropwise over 1 h to a refluxing solution of the corresponding
amidoxime (10 mmol) and triethylamine (10 mmol) in acetonitrile (25 ml).
Compound 1a. Solvent was evaporated in vacuo and the thick, brown oil was flash chromatographed on
silica gel using methylene chloride–methanol (20:1) as eluent. Yield 60%. Brown oil. 1H NMR spectrum, δ, ppm
(J, Hz): 8.09 (1H, t, J = 5.0, NH); 7.70 (1H, d, J = 12.0, OCH=CH); 6.46 (2H, s, NH2); 5.45 (1H, d, J = 12.0,
OCH=CH); 3.59 (3H, s, CO2CH3); 3.37-3.32 (2H, m, OCH2CH2NH); 3.24 (3H, s, CH2OCH3); 3.25-3.20 (2H, m,
OCH2CH2NH); 2.95 (2H, s, CH2C(NH2)=NO).
1126

Compound 1b. The solution was treated with activated carbon and solvent removed in vacuo to give a
1
thick brown oil which slowly crystallized on standing. Yield 72%. Brown crystals, mp 102-105ºC. H NMR
spectrum, δ, ppm (J, Hz): 7.91 (1H, d, J = 7.3, NH); 7.70 (1H, d, J = 12.3, OCH=CH); 6.46 (2H, s, NH2); 5.44
(1H, d, J = 12.3, OCH=CH); 3.59 (3H, s, CO2CH3); 3.52-3.49 (1H, m, NHCH(CH2)5); 2.91 (2H, s,
CH2C(NH2)=NO); 1.75-1.52 and 1.32-1.10 (10H, m, cyclohexyl).
Compound 1c. The solution was concentrated in vacuo, cooled, and the precipitated crystals were
filtered and recrystallized from isopropanol. Yield 48%. Colorless crystals, mp 190-192ºC (with decomp.).
1H NMR spectrum, δ, ppm (J, Hz): 10.24 (1H, s, NH); 7.72 (1H, d, J = 12.0, OCH=CH); 7.61 (2H, d, J = 8.0,
ArH); 7.37 (2H, d, J = 8.0, ArH); 6.58 (2H, s, NH2); 5.46 (1H, d, J = 12.0, OCH=CH); 3.59 (3H, s, CO2CH3);
3.18 (2H, s, CH2C(NH2)=NO).
Compound 1d. Solvent was evaporated in vacuo and the thick brown oil was purified by flash
chromatography on silica gel using methylene chloride–methanol (20:1) as eluent. Yield 71%. Brown oil, slowly
1
crystallizing to light yellow crystals, mp 93-95ºC. H NMR spectrum, δ, ppm (J, Hz): 7.70 (1H, d, J = 12,
OCH=CH); 6.48 (2H, s, NH2); 5.44 (1H, d, J = 12.0, OCH=CH); 3.59 (3H, s, CO2CH3); 3.10 (2H, s,
CH2C(NH2)=NO); 3.46-3.41 (2H, m); 3.31-3.26 (2H, m) and 1.92-1.70 (4H, m) (N(CH2)4).
Compound 1e. Solvent was evaporated in vacuo and the thick brown oil was purified by flash
1
chromatography on silica gel using methylene chloride–methanol (30:1) as eluent. Yield 69%. Brown oil. H
NMR spectrum, δ, ppm (J, Hz): 7.70 (1H, d, J = 12.0, OCH=CH); 6.48 (2H, s, NH2); 5.45 (1H, d, J = 12.0,
OCH=CH); 3.60 (3H, s, CO2CH3); 3.60-3.50 (4H, m, morpholine); 3.58-3.40 (4H, m, morpholine); 3.21 (2H, s,
CH2C(NH2)=NO).
O-Vinyl-α-(aminocarbonyl)acetamidoximes 1f,g. A solution of dimethyl acetylenedicarboxylate
(12 mmol) in acetonitrile (5 ml) was added dropwise over 15 min to a solution of the corresponding amidoxime
(10 mmol) in acetonitrile (25 ml).
Compound 1f. The solution was concentrated by a factor of five at reduced pressure and the precipitate
formed on cooling was filtered off, washed with ether, and dried. Yield 49%. Colorless crystals, mp 144-145ºC.
1H NMR spectrum, δ, ppm (J, Hz): 6.60 (2H, br. s, NH2); 5.61 (1H, s, CHCO2CH3); 3.77 (3H, s, CO2CH3); 3.59
(3H, s, CO2CH3); 3.46-3.40 (2H, m); 3.32-3.26 (2H, m); 3.12 (2H, s, CH2C(NH2)=NO), and 1.92-1.70 (4H, m,
N(CH2)4).
Compound 1g. Solvent was removed in vacuo to give a thick, brown oil which was purified by flash
chromatography on silica gel with methylene chloride–methanol (30:1) as eluent. Yield 60%. Yellow oil. 1H NMR
spectrum, δ, ppm (J, Hz): 6.63 (2H, br. s, NH2); 5.61 (1H, s, CHCO2CH3); 3.77 (3H, s, CO2CH3); 3.59 (3H, s,
CO2CH3); 3.60-3.52 (4H, m, morpholine); 3.48-3.40 (4H, m, morpholine); 3.22 (2H, s, CH2C(NH2)=NO).
Thermolysis of O-vinyl-α-(aminocarbonyl)acetamidoximes. Compound 1 (2 mmol) was refluxed in
mesitylene (4 ml) for 15 min under a nitrogen atmosphere. The mixture was diluted five times with hexane and
the precipitate was filtered off and separated by column chromatography on silica gel using methylene
chloride–methanol (20:1) as eluent. The yields are given in the Scheme.
Methyl 5-Amino-4-(2-methoxyethylaminocarbonyl)pyrrole-3-carboxylate (2a). Colorless crystals,
1
mp 148-151ºC (ether). H NMR spectrum, δ, ppm (J, Hz): 10.81 (1H, s, H-1); 9.43 (1H, t, J = 5.1, NH); 7.05
(1H, d, J = 2.9, JCH = 195.0, H-2); 6.19 (2H, s, NH2); 3.71 (3H, s, CO2CH3); 3.43-3.38 (2H, m, OCH2CH2NH);
3.26 (3H, s, CH2OCH3); 3.27-3.21 (2H, m, OCH2CH2NH). 13C NMR spectrum, δ, ppm: 166.8 (CO2CH3); 165.6
(CONH); 148.1 (C-5), 121.2 (C-2); 108.7 (C-3); 92.3 (C-4); 71.2 (CH2OCH3); 58.0 (CH2OCH3); 51.4
(CO2CH3); 38.0 (OCH2CH2N). Mass spectrum, m/z (Irel, %); 241 [M]+ (25), 167 [M–NH(CH2)2OCH3]+ (84),
135 [M-NH(CH2)2OCH3-CH3OH]+ (100), 84 (42), 79 (57). Found, %: C 49.35; H 6.14; N 17.48. C10H15N3O4.
Calculated, %: C 49.79; H 6.27; N 17.42.
Methyl 4-(Diaminomethylene)-1-methoxyethyl-5-oxopyrroline-3-carboxylate (3a). Light green
1
crystals, mp 186-188ºC (methylene chloride). H NMR spectrum, δ, ppm (J, Hz): 9.35 (1H, br. s, NH2) and 8.88
(1H, br. s, NH2); 7.15 (1H, s, JCH = 192.0, H-2); 6.85 (2H, s, NH2); 3.74 (2H, t, J = 5.1, OCH2CH2NH); 3.69
1127

(3H, s, CO2CH3); 3.47 (2H, t, J = 5.1, OCH2CH2NH); 3.22 (3H, s, CH2OCH3). 13C NMR spectrum, δ, ppm: 166.4
(CO2CH3); 164.3 (C-5); 159.0 (=C(NH2)2); 126.0 (C-2); 104.5 (C-3); 81.2 (C-4); 70.4 (CH2OCH3); 57.9
(CH2OCH3); 51.2 (CO2CH3); 41.40 (OCH2CH2N). Mass spectrum, m/z (Irel, %): 241 [M]+ (100), 226 (9), 210 [M–
CH3O]+ (8), 196 [M–CH2OCH3]+ (20), 183 [M–CHCH2OCH3]+ (30), 166 (23), 140 (16), 134 (23), 82 (7).
Found, %: C 49.10; H 6.20; N 17.00. C10H15N3O4. Calculated, %: C 49.79; H 6.27; N 17.42.
Methyl 5-Amino-4-(2-methoxyethylaminocarbonyl)pyrrole-2-carboxylate (4a). Colorless crystals,
mp 163-164ºC (methylene chloride). 1Н NMR spectrum, δ, ppm (J, Hz): 10.75 (1H, s, H-1); 7.70 (1H, t, J = 5.0,
NH); 7.21 (1H, d, J = 2.9, JCH = 173.0, H-2); 5.91 (2H, s, NH2); 3.69 (3H, s, CO2CH3); 3.39-3.35 (2H, m,
13
OCH2CH2NH); 3.32-3.28 (2H, m, OCH2CH2NH); 3.24 (3H, s, CH2OCH3). C NMR spectrum, δ, ppm: 165.3
(CO2CH3); 160.6 (CONH); 148.0 (C-5); 114.7 (C-2); 112.0 (C-3); 98.3 (C-4); 70.9 (CH2OCH3); 57.9
(CH2OCH3); 50.7 (CO2CH3); 37.9 (OCH2CH2N). Mass spectrum, m/z (Irel, %): 241 [M]+ (54), 209 [M–CH3OH]+
(8), 183 [M–CHCH2OCH3]+ (24); 167 [M–NH(CH2)2OCH3]+ (86), 151 [M–CHCH2OCH3–CH3OH]+ (18); 135
[M–NH(CH2)2OCH3–CH3OH]+ (100), 108 (7), 84 (48), 79 (18). Found, %: C 49.52; H 6.25; N 17.13.
C10H15N3O4. Calculated, %: C 49.79; H 6.27; N 17.42.
Methyl 5-Amino-4-(cyclohexylaminocarbonyl)pyrrole-3-carboxylate (2b). Light gray crystals, mp
237-239ºC (decomp. from methylene chloride). 1Н NMR spectrum, δ, ppm (J, Hz): 10.80 (1H, s, H-1); 9.35 (1H, d,
J = 7.2, NH); 7.04 (1H, d, J = 2.0, JCH = 192.0, H-2); 6.16 (2H, s, NH2); 3.71 (3H, s, CO2CH3); 3.80-3.60 (1H, m,
13
NHCH(CH2)5); 1.82–1.50 and 1.35-1.19 (10H, m, cyclohexyl). C NMR spectrum , δ, ppm: 166.9 (CO2CH3);
164.6 (CONH); 147.8 (C-5); 121.1 (C-2); 108.6 (C-3); 92.6 (C-4); 51.4 (CO2CH3); 46.3 (cyclohexyl С-1'); 32.7
(cyclohexyl С-2',6'); 25.4 (cyclohexyl С-4'); 24.2 (cyclohexyl С-3',5'). Mass spectrum, m/z (Irel, %): 265 [M]+
(50), 222 (7), 183 [M+H–c-C6H11]+ (40), 167 [M–NH-c-C6H11]+ (100), 166 [M–NH2-c-C6H11]+ (50), 151 (7), 135 [M–
NH-c-C6H11–CH3 OH]+ (24), 108 (10), 88 (32), 79 (13). Found, %: C 58.67; H 7.20; N 15.76. C13H19N3O3.
Calculated, %: C 58.85; H 7.22; N 15.84.
Methyl 4-(Diaminomethylene)-1-cyclohexyl-5-oxopyrroline-3-carboxylate (3b). Gray crystals, mp
240-245ºC (decomp., from methylene chloride ). 1Н NMR spectrum, δ, ppm (J, Hz): 9.44 (1H, br. s, NH2) and 8.81
(1H, br. s, NH2); 7.17 (1H, s, JCH = 191.0, H-2); 6.83 (2H, s, NH2); 3.97 (1H, m, NHCH(CH2)5); 3.69 (3H, s,
CO2CH3); 1.80-1.14 (10H, m, cyclohexyl). 13C NMR spectrum, δ, ppm: 166.3 (CO2CH3); 163.8 (C-5); 159.0
(=C(NH2)2); 122.4 (C-2); 104.7 (C-3); 81.5 (C-4); 51.1 (CO2CH3); 49.9 (cyclohexyl С-1'); 32.3 (cyclohexyl
С-2',6'); 25.4 (cyclohexyl С-3',5'); 24.9 (cyclohexyl С-4'). Mass spectrum, m/z (Irel, %): 265 [M]+ (100), 249 [M–
NH2]+ (5), 234 [M–NH2–CH3O]+ (6), 183 [M+H–c-C6H11]+ (66), 166 [M–NH2-c-C6H11]+ (37), 151 (9), 134 (50),
123 (6), 85 (6), 79 (6). Found, %: C 58.43; H 7.19; N 15.41. C13H19N3O3. Calculated, %: C 58.85; H 7.22;
N 15.84.
Methyl 5-Amino-4-(cyclohexylaminocarbonyl)pyrrole-2-carboxylate (4b). Gray crystals, mp
1
163-164ºC (from methylene chloride). Н NMR spectrum, δ, ppm (J, Hz): 10.70 (1H, s, H-1); 7.37 (1H, d,
J = 8.0, NH); 7.28 (1H, s, JCH = 172.0, H-2); 5.90 (2H, s, NH2); 3.80-3.60 (1H, m, NHCH(CH2)5); 3.69 (3H, s,
13
CO2CH3); 1.80-1.10 (10H, m, cyclohexyl). C NMR spectrum, δ, ppm: 165.6 (CO2CH3); 160.2 (CONH); 147.6
(C-5); 114.8 (C-2); 109.9 (C-3); 98.4 (C-4); 51.0 (CO2CH3); 46.2 (cyclohexyl С-1'); 32.4 (cyclohexyl С-2',6');
25.4 (cyclohexyl С-4'); 24.3 (cyclohexyl С-3',5'). Mass spectrum, m/z (Irel, %): 265 [M]+ (83), 234 [M–CH3O]+
(15), 233 [M–CH3OH]+ (17), 183 [M+H–c-C6H11]+ (44), 167 [M–NH-c-C6H11]+ (75), 166 [M–NH2-c-C6H11]+
(52), 151 (54), 135 [M–NH-c-C6H11–CH3OH]+ (100), 140 (31), 135 (100), 107 (27), 98 (48). Found, %: C 59.07;
H 7.19; N 15.84. C13H19N3O3. Calculated, %: C 58.85; H 7.22; N 15.84.
Methyl 5-Amino-4-(4-chloroanilinocarbonyl)pyrrole-3-carboxylate (2c) was isolated as a mixture
with the pyrrole 4c in the ratio ~ 3:2. 1Н NMR spectrum, δ, ppm (J, Hz): 11.75 (1H, s, NH); 10.97 (1H, s, H-1);
7.65 (2H, d, J = 8.7, ArH); 7.35 (2H, d, J = 8.7, ArH); 7.16 (1H, d, J = 2.9, JCH = 190.0, H-2,); 6.42 (2H, s,
NH2); 3.80 (3H, s, CO2CH3).
Methyl 1-(4-Chlorophenyl)-4-(diaminomethylene)-5-oxopyrrol-2-ine-3-carboxylate (3c). Light yellow
crystals, mp 209-210ºC (acetonitrile). 1Н NMR spectrum, δ, ppm (J, Hz): 9.20 (1H, br. s, NH2) and
1128

8.90 (1H, br. s, NH2); 7.72 (2H, d, J = 8.7, ArH); 7.47 (2H, d, J = 8.7, ArH); 7.45 (1H, s, JCH = 193.0, H-2); 7.04
(2H, s, NH2); 3.75 (3H, s, CO2CH3). 13C NMR spectrum, δ, ppm: 166.4 (CO2CH3); 163.5 (C-5); 159.2
(=C(NH2)2); 136.4 (NHC6H4Cl-C-1'); 129.6 (NHC6H4Cl-C-4'); 128.7 (NHC6H4Cl-C-3',5'); 124.1 (NHC6H4Cl-C-4',6');
122.6 (C-2); 107.6 (C-3); 81.5 (C-4); 51.6 (CO2CH3). Mass spectrum, m/z (Irel, %): 293 [M]+ (100), 276 [M–NH3]+
(15), 244 [M–NH3–CH3OH]+ (36), 209 (20), 111 [C7H4Cl]+ (20). Found, %: C 51.94; H 4.11; N 12.82.
C13H12ClN3O3. Calculated, %: C 53.16; H 4.12; N 14.31.
Methyl 5-Amino-4-(4-chloroanilinocarbonyl)pyrrole-2-carboxylate (4c) was isolated as a mixture
1
with the pyrrole 2c in the ratio ~2: 3. Н NMR spectrum, δ, ppm (J, Hz): 10.88 (1H, s, H-1); 9.46 (1H, s, NH);
7.76 (2H, d, J = 8.7, ArH); 7.50 (1H, d, J = 2.2, JCH = 174.0, H-2); 7.32 (2H, d, J = 8.7, ArH); 6.08 (2H, s, NH2);
3.73 (3H, s, CO2CH3).
Methyl 5-Amino-4-pyrrolidin-1-ylcarbonyl)pyrrole-3-carboxylate (2d) could not be isolated in an
analytically pure state due to its decomposition on silica gel. However, treatment with phenyl isocyanate gave
methyl 4-(pyrrolidin-1-ylcarbonyl)-5-(3-phenylureido)pyrrole-3-carboxylate. Phenyl isocyanate (0.05 ml)
was added to a solution of the unpurified pyrrole 2d obtained after thermolysis (400 mg) in chloroform (5 ml)
and the product was heated to reflux. The solvent was evaporated and the residue was purified by column
chromatography on silica gel using methylene chloride–methanol (20:1) as eluent. The urea was separated
1
(165 mg, 23% calculated on compound 1d). Light gray crystals, mp 203-205ºC (from acetonitrile). Н NMR
spectrum, δ, ppm (J, Hz): 11.61 (1H, br. s, H-1); 9.29 (1H, br. s, C6H5NH); 8.59 (1H, br. s, C6H5NHCONH);
7.43 (2Н, d, J = 8.0, H-3',5'); 7.28 (2Н, t, J = 7.6, H-2',6'); 7.10 (1Н, d, J = 2.9, JCH = 196.0, H-2); 6.97 (1Н, t,
J = 7.3, H-4'); 3.68 (3Н, s, CO2СН3); 3.51-3.39 (2Н, m), 3.27-3.15 (2Н, m) and 1.88-1.65 (4Н, m) (N(СН2)4).
13C NMR spectrum, δ, ppm: 164.2 (CO2CH3); 163.9 (CON(CH2)4); 152.5 (CO(NH)2); 139.4 (C6H5 C-1'); 128.9
(C-5); 128.8 (C6H5 C-3',5'); 122.1 (C6H5 C-4'); 119.6 (C-2); 118.1 (C6H5 C-2',6'); 110.6 (C-3); 105.9 (C-4); 50.8
(CO2CH3); 47.2 and 45.3 (CH2NCH2); 24.0 ((CH2)2). Mass spectrum, m/z (Irel, %): 356 [M]+ (28); 264 [M–
NHC6H5]+ (100); 237 (17), 232 [M–NHC6H5–CH3OH]+ (28); 193 [M–NH2C6H5–N(CH2)4]+ (100); 167 (47), 163
(60), 161 [M–NH2C6H5–CH3OH–N(CH2)4]+ (35); 135 (53), 119 (47), 93 [NH2C6H5]+ (100). Found, %: С 60.53;
Н 5.64; N 15.49. C18H20N4O4. Calculated, %: С 60.66; Н 5.66; N 15.72.
Methyl 5-Amino-4-(morpholin-1-ylcarbonyl)pyrrole-3-carboxylate (2e) could not be isolated in an
analytically pure state due to its decomposition on silica gel. However, treatment with phenyl isocyanate gave
methyl 4-(morpholin-1-ylcarbonyl)-5-(3-phenylureido)pyrrole-3-carboxylate. Phenyl isocyanate (0.28 ml)
was added to a solution of the unpurified pyrrole 2e obtained after thermolysis (650 mg) in methylene chloride
(20 ml) and the product was heated to reflux. The solvent was evaporated and the residue was purified by
column chromatography on silica gel using methylene chloride–methanol (30:1) as eluent. The urea was
separated (320 mg, 28% calculated on compound 1e). Light brown crystals, mp 247-248ºC (acetonitrile).
1Н NMR spectrum, δ, ppm (J, Hz): 11.69 (1H, br. s, H-1); 9.17 (1H, br. s, C6H5NH); 8.48 (1H, br. s,
C6H5NHCONH); 7.44 (2Н, d, J = 8.0, H-3',5'); 7.28 (2Н, t, J = 7.6, H-2',6'); 7.15 (1Н, d, J = 2.9, JCH = 196.0,
H-2); 6.98 (1Н, t, J = 7.3, H-4'); 3.68 (3Н, s, CO2СН3); 3.51-3.39 (2Н, m), 3.27-3.15 (2Н, m) and 1.88-1.65 (4Н,
m, N(СН2)4). 13C NMR spectrum, δ, ppm: 164.4 (CO2CH3); 163.7 (CON(CH2)4); 152.7 (CO(NH)2); 139.4 (C6H5
C-1'); 128.9 (C6H5 C-3',5'); 128.7 (C-5); 122.2 (C6H5 C-4'); 120.1 (C-2); 118.1 (C6H5 C-2',6'); 110.9 (C-3); 105.0
(C-4); 66.1 (CH2OCH2); 51.0 (CO2CH3); 45.1 (CH2NCH2). Mass spectrum, m/z (Irel, %): 372 [M]+ (11); 285 [M–
NC4H8O]+ (5); 280 [M–NHC6H5]+ (21); 279 [M–NH2C6H5]+ (11); 253 (5); 193 [M–NH2C6H5–N(CH2)4O]+ (53);
167 (22); 163 (18); 161 [M–NH2C6H5–CH3OH–N(CH2)4O]+ (10); 135 (16); 119 (12); 93 [NH2C6H5]+ (100).
Found, %: С 57.92; Н 5.44; N 14. 97. C18H20N4O5. Calculated, %: С 58.06; Н 5.41; N 15.05.
Dimethyl 5-Amino-4-(pyrrolidin-1-ylcarbonyl)pyrrole-2,3-dicarboxylate (8f). Yield 47%. Light gray
crystals, mp 194-196ºC (from acetonitrile). 1Н NMR spectrum, δ, ppm (J, Hz): 11.02 (1H, br. s, H-1); 5.36 (2H,
br. s, NH2); 3.68 (6Н, s, 2CO2СН3); 3.45-3.32 (4Н, m) and 1.92-1.80 (4Н, m) (N(СН2)4). 13C NMR spectrum, δ,
ppm: 165.4 (3-CO2CH3); 163.9 (CON(CH2)4); 159.6 (2-CO2CH3); 143.1 (C-5); 121.3 (C-2); 110.9 (C-3); 101.3
(C-4); 51.8 (CO2CH3); 51.2 (CO2CH3); 46.3 (CH2NCH2); 24.9 ((CH2)2). Mass spectrum, m/z (Irel, %): 295 [M]+
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(22); 264 [M–CH3O]+ (5); 263 [M–CH3OH]+ (5), 225 [M–N(CH2)4]+ (12); 193 [M–CH3OH–N(CH2)4]+ (43); 163
(8), 135 (5), 108 (6), 70 [N(CH2)4]+ (100). Found, %: С 52.78; Н 5.66; N 14.11. C13H17N3O5. Calculated, %:
С 52.88; Н 5.8; N 14.23.
Dimethyl 5-amino-4-(morpholin-1-ylcarbonyl)pyrrole-2,3-dicarboxylate (8g). Yield 61%. Light gray
crystals, mp 163-165ºC (from acetonitrile). 1Н NMR spectrum, δ, ppm (J, Hz): 11.03 (1H, br. s, H-1); 5.32 (2H,
br. s, NH2); 3.69 (6Н, s, 2CO2СН3); 3.56-3.52 (4Н, m) and 3.45-3.35 (4Н, m) (morpholine). 13C NMR spectrum,
δ, ppm: 165.0 (3-CO2CH3); 164.6 (CON(CH2)4); 159.5 (2-CO2CH3); 142.4 (C-5); 122.0 (C-2); 111.2 (C-3);
99.5 C-4); 66.2 (CH2OCH2); 51.8 (CO2CH3); 51.2 (CO2CH3); 45.0 (CH2NCH2). Mass spectrum, m/z (Irel, %): 311
[M]+ (30); 280 [M–CH3O]+ (8); 279 [M–CH3OH]+ (15), 225 [M–N(CH2)4O]+ (36); 193 [M–CH3OH–N(CH2)4O]+
(100); 163 (15); 86 [N(CH2)4O]+ (62). Found, %: С 52.78; Н 5.66; N 14.11. C13H17N3O5. Calculated, %: С 52.88;
Н 5.8; N 14.23.
Methyl 2,4-dimethyl-8-(pyrrolidin-1-ylcarbonyl)pyrrolo[1,2-a]pyrimidine-7-carboxylate (7d). A
solution of compound 1d (0.55 g, 2 mmol) in 2,4-pentanedione (6 ml) was refluxed in a nitrogen atmosphere for
2 h. Solvent was evaporated and the residue was purified using column chromatography on silica gel with
methylene chloride–methanol (20:1) as eluent. The product separated as a brown oil (0.34 g, 52%) which slowly
crystallized to light brown crystals, mp 186-187ºC (from toluene). 1Н NMR spectrum, δ, ppm (J, Hz): 7.81 (1H,
s, JCH = 196.0, H-6); 6.69 (1H, s, H-3); 3.77 (3Н, s, CO2СН3); 2.56 (3H, s, 4-CH3); 2.40 (3H, s, 2-CH3);
3.52-3.46 (2H, m); 3.14-3.10 (2H, m) and 1.92-1.72 (4H, m) (N(CH2)4). 13C NMR spectrum, δ, ppm: 163.8
(CO2CH3); 163.2 (CON(CH2)4); 155.5 (C-2); 142.2 (C-8b); 136.5 (C-4); 117.0 (C-6); 110.5 (C-7); 109.0 (C-3);
108.7 (C-8); 51.5 (CO2CH3); 47.2 and 45.2 (CH2NCH2); 25.4 (2-CH3); 24.2 ((CH2)2); 17.2 (4-CH3). Mass
spectrum, m/z (Irel, %): 301 [M]+ (36); 231 [M–N(CH2)4]+ (100); 201 (17); 173 (29); 146 (17); 70 [N(CH2)4]+
(34). Found, %: С 63.62; Н 6.45; N 13.46. C16H19N3O3. Calculated, %: С 63.77; Н 6.36; N 13.40.
Methyl 2,4-dimethyl-8-morpholin-1-ylcarbonyl)pyrrolo[1,2-a]pyrimidine-7-carboxylate (7e) was
1
prepared similarly to compound 7d. Yield 53%. Light brown crystals, mp 231-233ºC (toluene). Н NMR
spectrum, δ, ppm (J, Hz): 7.86 (1H, s, JCH = 197.0, H-6); 6.71 (1H, s, H-3); 3.80 (3Н, s, CO2СН3); 2.58 (3H, s,
4-CH3); 2.41 (3H, s, 2-CH3); 3.70-3.63 (4H, m), 3.51-3.47 (2H, m) and 3.21-3.17 (2H, m) (N(CH2)4O). 13C NMR
spectrum, δ, ppm: 163.8 (CO2CH3); 163.6 (CON(CH2)4); 155.9 (C-2); 142.4 (C-8b); 136.7 (C-4); 117.5 (C-6);
110.9 (C-7); 109.1 (C-3); 106.2 (C-8); 66.2 and 66.1 (CH2OCH2); 51.5 (CO2CH3); 47.02 and 41.9 (CH2NCH2);
24.24 (2-CH3); 17.2 (4-CH3). Mass spectrum, m/z (Irel, %): 317 [M]+ (16); 231 [M–N(CH2)4O]+ (100); 201 (12);
173 (16); 146 (11); 86 [N(CH2)4O]+ (40). Found, %: С 60.51; Н 6.12; N 13.02. C16H19N3O4. Calculated, %:
С 60.56; Н 6.03; N 13.24.
REFERENCES
1.
2.
3.
S. E. Korostova, A. I. Mikhaleva, and B. A. Trofimov, Usp. Khim., 68, 506 (1999).
M. R. Grimmett, Imidazole and Benzimidazole Synthesis, Academic Press, London (1997).
E. Pretsch, P. Bühlmann, and K. Affolter, Determination of the Structure of Organic Compounds
[Russian translation], Mir, Moscow (2006).
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