Synthesis of 5-oxo-4,5,6,7-tetrahydro-1H-pyrrolo-[3,2-b]pyridine-3- carboxylic acids by three-component condensation of 3-aminopyrrole derivatives

Article abstract of DOI:10.1016/j.mencom.2010.09.004

5-Oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acids were prepared by three-component condensation of 3-aminopyrroles, (het)aromatic aldehydes and Meldrum's acid. The labile intermediate 3-aminopyrrole derivative was generated in situ by regioselective (at 2-position) decarboxylation of 3-aminopyrrole-2,4-dicarboxylic acid.

Full text of DOI:10.1016/j.mencom.2010.09.004

Mendeleev
Communications
Mendeleev Commun., 2010, 20, 255–256
Synthesis of 5-oxo-4,5,6,7-tetrahydro-1H-pyrrolo-
[3,2-b]pyridine-3-carboxylic acids by three-component
condensation of 3-aminopyrrole derivatives
Boris V. Lichitsky, Arkady A. Dudinov, Andrey N. Komogortsev and Mikhail M. Krayushkin*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 499 135 5328; e-mail: mkray@ioc.ac.ru
DOI: 10.1016/j.mencom.2010.09.004
5-Oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acids were prepared by three-component condensation of
3-aminopyrroles, (het)aromatic aldehydes and Meldrum’s acid. The labile intermediate 3-aminopyrrole derivative was generated
in situ by regioselective (at 2-position) decarboxylation of 3-aminopyrrole-2,4-dicarboxylic acid.
Recently,1–6 we elaborated the general method for the synthesis
MeO2C
NH2
KO2C
NH2
CO2K
of fused heterocyclic systems 1 containing dihydropyridin-2-one
unit based on condensation of labile heterocyclic amines 2
with carbonyl compounds 3 and Meldrum’s acid (2,2-dimethyl-
1,3-dioxane-4,6-dione) 4. The obvious advantage of this approach
is the possibility to directly generate unstable amino heterocycles
2 in situ either from vicinal amino carboxylic acids 5 which are
formed on alkaline hydrolysis of the corresponding esters or
by neutralization of stable hydrochlorides 6 on treatment with
sodium acetate.
KOH
CO2Me
N
R
N
R
EtOH/H2O
9a R = Ph
9b R = Me
7a R = Ph
7b R = Me
O
O
O
HO2C
H
O
N
O
Me Me
ArCHO
CO2H
Z
N
R
Y
Ar
NH2
X
8a–g
5
– CO2
Z
8a R = Ar = Ph
8b R = Ph, Ar = 4-ClC6H4
8c R = Ph, Ar = 4-MeOC6H4
8d R = Ph, Ar = 3,4-(MeO)2C6H3
8e R = Ph, Ar = thiophen-3-yl
8f R = Me, Ar = 4-ClC6H4
8g R = Me, Ar = 3,4-methylenedioxyphenyl
Y
NH2
X
AcONa
Z
2
Y
NH2 · HCl
X
O
O
R
R'
6
O
O
O
Scheme 2
Me Me
3
4
Dipotassium salts 7a,b were obtained by hydrolysis of esters
9 using a 5-fold excess of potassium hydroxide in water–ethanol
mixture (3:7).8 We have shown that the optimal conditions for
the synthesis of 5-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-b]-
pyridine-3-carboxylic acids 8f,g comprised heating of salt 7b
with corresponding aldehydes and Meldrum’s acid in acetic acid
for 30 min. Prolongation of the reaction leads to the destruction
of target pyrrolopyridinones. It is worth noting that decarboxyla-
tion occurs regiospecifically at the 2-positioned CO2H group.
Apparently, such a discrimination between two CO2H groups
proceeds synchronically and involves relocation of bonds with
participation of amino and carboxylic groups fixed with enamine
fragment of the pyrrole ring.
In the case of N-methyl substituted reactant 9b we have ob-
served the drastic drop in the yield of target products, probably,
due to the lack of additional stabilization of pyrrole ring which
occurred in aryl-substituted analogue 8a.
Compounds 8 are stable crystalline solids. Their structure
was confirmed by elemental analysis, NMR spectroscopy and
mass spectrometry. The NMR spectra contained characteristic
signals of proton of the dihydropyridinone system1–6 at 4.28–
R
R'
Z
Y
X
N
O
H
1
Scheme 1
In the present work the condensation, outlined in Scheme 1,
was performed using 3-aminopyrrole derivatives (X = Y = CH,
Z = NMe or NPh). Due to the low stability of aminopyrroles7
such a condensation is possible only for their derivatives equipped
with electron withdrawing group, for example, the carboxylic
one. We carried out this condensation according to our earlier
protocol2,3,5,6 in acetic acid using salts 7 as precursors of free
amines. The supposed pathway of the process includes a Michael
addition of the liberating N-R-3-aminopyrrole-4-carboxylic acid
at the arylmethylidene derivatives of Meldrum’s acid and sub-
sequent intramolecular cyclization followed by CO2 and acetone
elimination (Scheme 2, for the mechanism see refs. 1–6).
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© 2010 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2010, 20, 255–256
4.43 ppm for methine fragment and at 2.45–3.29 ppm for non-
formation of by-products. We developed a simple and effective
preparation of diester 9b from available ethyl sarcosinate hydro-
chloride 10 (Scheme 3).‡ The intermediate 11 readily cyclised
under the action of sodium methoxide.
equivalent methylene protons. Mass spectra of compounds 8
displayed molecular ion peaks.†
The starting amino ester 9a (R = Ph) was obtained by method
described in literature.8 The synthesis of dimethyl 3-amino-
1-methylpyrrole-2,4-dicarboxylate 9b (R = Me) according to the
reported procedure9,10 provided moderate yield of 9b due to
Me
OEt
Et3N
NH · HCl
+
CH2Cl2
†
1H NMR spectra were recorded on a Bruker AM-300 (300 MHz) instru-
CO2Et
EtO2C
CN
ment in DMSO-d6. Mass spectra were collected on a FINNIGAN MAT
INCOS 50 (direct inlet, EI, 70 eV) mass spectrometer. Melting points
were measured on a Boetius hot stage and not corrected.
Dimethyl 3-amino-1-phenyl-1H-pyrrole-2,4-dicarboxylate 9a was obtained
analogously to the published method.7 Yield 56%, mp 120–121 °C.
1H NMR, d: 3.55 (s, 3H, OMe), 3.76 (s, 3H, OMe), 5.97 (s, 2H, NH2),
7.31–7.52 (m, 6H, HAr, CH). Found (%): C, 61.57; H, 5.25; N, 10.38.
Calc. for C14H14N2O4 (%): C, 61.31; H, 5.14; N, 10.21.
10
MeO2C
NH2
CO2Me
Me
N
CO2Et
MeONa
MeOH
N
EtO2C
CN
Me
11
9b
5-Oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-b]pyridine-3-carboxcylic acids
8a–g (general procedure). A mixture of ester 9a (0.55 g, 2 mmol) or 9b
(0.42 g, 2 mmol), KOH (0.56 g, 10 mmol) in EtOH (1.75 ml) and water
(0.75 ml) was refluxed for 0.5 h, then evaporated to dryness. Meldrum’s
acid (0.32 g, 2.2 mmol), the corresponding aldehyde (2.1 mmol) and
acetic acid (7 ml) were added to the residue. The mixture was refluxed
for 4 h, then evaporated, ethanol (3 ml) was added and the mixture was
heated to boiling. After cooling, conc. HCl (1.1 g) was added and the
mixture was left overnight. The precipitate was filtered off and washed
with ethanol and water. Then the mixture of collected product and
NaHCO3 (0.5 g) in water (80 ml) was refluxed for 10 min, cooled and
filtered through folded paper filter. Conc. HCl (0.6 g) was added to
the filtrate, the precipitate was filtered off and washed with water.
5-Oxo-1,7-diphenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-b]pyridine-3-
Scheme 3
References
1
2
3
A. A. Dudinov, B. V. Lichitsky, I. A. Antonov, A. N. Komogortsev,
P. A. Belyakov and M. M. Krayushkin, Izv. Akad. Nauk, Ser. Khim.,
2008, 1707 (Russ. Chem. Bull., Int. Ed., 2008, 57, 1740).
B. V. Lichitsky, A. N. Komogortsev, A. A. Dudinov and M. M. Krayushkin,
Izv. Akad. Nauk, Ser. Khim., 2008, 2133 (Russ. Chem. Bull., Int. Ed.,
2008, 57, 2175).
B. V. Lichitsky, R. M. Belyi, A. N. Komogortsev, A. A. Dudinov and
M. M. Krayushkin, Izv. Akad. Nauk, Ser. Khim., 2009, 382 (Russ.
Chem. Bull., Int. Ed., 2009, 58, 387).
4
5
A. A. Dudinov, B. V. Lichitsky, A. N. Komogortsev and M. M. Krayushkin,
Mendeleev Commun., 2009, 19, 87.
1
carboxylic acid 8a. Yield 51%, mp 231–232 °C. H NMR, d: 2.49 (dd,
B. V. Lichitsky, A. N. Komogortsev, A. A. Dudinov and M. M. Krayushkin,
Izv. Akad. Nauk, Ser. Khim., 2009, 1460 (Russ. Chem. Bull., Int. Ed.,
2009, 58, 1504).
B. V. Lichitsky, A. N. Komogortsev, R. M. Belyi, A. A. Dudinov and
M. M. Krayushkin, Izv. Akad. Nauk, Ser. Khim., 2009, 1493 (Russ.
Chem. Bull., Int. Ed., 2009, 58, 1538).
K. Schofield, Hetero-aromatic Nitrogen Compounds – Pyrolles and
Pyridines, Butterworths, London, 1967, pp. 97–152.
K. Gewald, H. Schaefer, P. Bellmann and U. Hain, J. Prakt. Chem.,
1992, 334, 491.
1H, HCH, J 19 Hz, J 0 Hz), 3.29 (dd, 1H, HCH, J 19 Hz, J 8 Hz), 4.35
(dd, 1H, CH, J 8 Hz, J 0 Hz), 6.91 (d, 2H, HAr, Ar', CH, J 8 Hz), 7.15–7.46
(m, 9H, HAr, Ar', CH), 8.50 (s, 1H, NH), 12.59 (br. s, 1H, CO2H). Found (%):
C, 72.01; H, 4.97; N, 8.60. Calc. for C20H16N2O3 (%): C, 72.28; H, 4.85;
N, 8.43.
7-(4-Chlorophenyl)-5-oxo-1-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-b]-
pyridine-3-carboxylic acid 8b. Yield 64%, mp > 300 °C. 1H NMR, d:
2.49 (dd, 1H, HCH, J 16 Hz, J 0 Hz), 3.25 (dd, 1H, HCH, J 16 Hz, J 7 Hz),
4.38 (dd, 1H, CH, J 7 Hz, J 0 Hz), 6.93 (d, 2H, HAr, Ar', CH, J 8 Hz),
7.28–7.47 (m, 8H, HAr, Ar', CH), 8.53 (s, 1H, NH), 12.51 (br. s, 1H, CO2H).
Found (%): C, 65.73; H, 4.00; N, 7.79. Calc. for C20H15ClN2O3 (%):
C, 65.49; H, 4.12; N, 7.64.
6
7
8
9
L. Selic and B. Stanovnik, Heterocycles, 1999, 51, 1087.
10 L. Selic and B. Stanovnik, Helv. Chim. Acta, 1998, 81, 1634.
7-(4-Methoxyphenyl)-5-oxo-1-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo-
[3,2-b]pyridine-3-carboxylic acid 8c. Yield 45%, mp 221–222 °C. 1H NMR,
d: 2.48 (dd, 1H, HCH, J 16 Hz, J 0 Hz), 3.20 (dd, 1H, HCH, J 16 Hz,
J 7 Hz), 3.71 (s, 3H, OMe), 4.28 (dd, 1H, CH, J 7 Hz, J 0 Hz), 6.73–6.91
(m, 4H, HAr, Ar', CH), 7.21–7.53 (m, 6H, HAr, Ar', CH), 8.47 (s, 1H, NH),
12.49 (br. s, 1H, CO2H). Found (%): C, 69.83; H, 5.13; N, 7.90. Calc. for
C21H18N2O4 (%): C, 69.60; H, 5.01; N, 7.73.
7-(3,4-Dimethoxyphenyl)-5-oxo-1-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo-
[3,2-b]pyridine-3-carboxylic acid 8d. Yield 68%, mp 238–239 °C. 1H NMR,
d: 2.52 (dd, 1H, HCH, J 16 Hz, J 0 Hz), 3.20 (dd, 1H, HCH, J 16 Hz,
J 7 Hz), 3.60 (s, 3H, OMe), 3.68 (s, 3H, OMe), 4.27 (dd, 1H, CH, J 7 Hz,
J 0 Hz), 6.38 (d, 1H, HAr, J 8 Hz), 6.50 (s, 1H, HAr), 6.79 (d, 1H, HAr,
J 8 Hz), 7.28–7.42 (m, 6H, HAr, Ar', CH), 8.48 (s, 1H, NH), 12.48 (br. s, 1H,
CO2H), Found (%): C, 67.13; H, 5.02; N, 7.30. Calc. for C22H20N2O5 (%):
C, 67.34; H, 5.14; N, 7.14.
Received: 9th March 2010; Com. 10/3486
7-(Benzo[1,3]dioxol-5-yl)-1-methyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrrolo-
[3,2-b]pyridine-3-carboxylic acid 8g. Yield 0.12 g (20%), mp 249–250 °C.
1H NMR, d: 2.45 (dd, 1H, HCH, J 16 Hz, J 0 Hz), 3.17 (dd, 1H, HCH,
J 16 Hz, J 8 Hz), 3.31 (s, 3H, Me) 4.35 (dd, 1H, CH, J 8 Hz, J 0 Hz),
6.01 (s, 2H, OCH2O), 6.49 (d, 1H, C6H3, J 8 Hz), 6.61 (s, 1H, C6H3),
6.83 (d, 1H, C6H3, J 8 Hz), 7.21 (s, 1H, CHpyrrole), 8.32 (s, 1H, NH),
2.18 (br. s, 1H, CO2H). Found (%): C, 60.90; H, 4.60; N, 9.07. Calc. for
C16H14N2O5 (%): C, 61.14; H, 4.49; N, 8.91.
‡
Diethyl 2-cyano-4-methyl-4-azahex-2-enedioate 11 (mixture of E- and
Z-isomers). Triethylamine (6.36 g) was added to a solution of ethyl
sarcosinate hydrochloride (9.68 g, 63 mmol) and ethyl (ethoxymethyl-
idene)cyanoacetate (8.94 g, 53 mmol) in CH2Cl2 (400 ml). The solution
was stirred at room temperature for 3 h, then evaporated, and water (100 ml)
was added to the residue. The separated oil was left to crystallization at
4 °C. The crystallized product was filtered off and washed with water.
Yield 7.05 g (48%), mp 77–78 °C. 1H NMR, d: 1.21–1.42 (m, 6H,
2Me), 3.25, 3.42 (s, 3H, Me), 4.05, 4.41 (s, 2H, CH2), 4.18–4.38 (m, 4H,
2CH2), 7.67, 7.80 (s, 1H, CH). Found (%): C, 55.22; H, 6.82; N, 11.82.
Calc. for C11H16N2O4 (%): C, 54.99; H, 6.71; N, 11.66.
5-Oxo-1-phenyl-7-(thiophen-3-yl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-b]-
pyridine-3-carboxylic acid 8e. Yield 48%, mp 235–237 °C. 1H NMR, d:
2.51 (dd, 1H, HCH, J 16 Hz, J 0 Hz), 3.16 (dd, 1H, HCH, J 16 Hz, J 7 Hz),
4.39 (dd, 1H, CH, J 7 Hz, J 0 Hz), 6.61 (m, 1H, HAr, Ar', CH), 6.80 (m, 1H,
HAr, Ar', CH), 7.31–7.51 (m, 7H, HAr, Ar', CH), 8.45 (s, 1H, NH), 12.47 (br. s,
1H, CO2H). Found (%): C, 64.10; H, 4.29; N, 8.05. Calc. for C18H14N2O3S
(%): C, 63.89; H, 4.17; N, 8.28.
Dimethyl 3-amino-1-methyl-1H-pyrrole-2,4-dicarboxylate 9b. Sodium
metal (1.38 g, 60 mmol) was dissolved in absolute methanol (60 ml),
and ester 11 (9.61 g, 40 mmol) was added to the solution. The solution
was refluxed for 1 h, cooled, the product was filtered off and washed with
7-(4-Chlorophenyl)-1-methyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-b]-
pyridine-3-carboxylic acid 8f. Yield 0.13 g (21%), mp 255–256 °C.
1H NMR, d: 2.49 (dd, 1H, HCH, J 16 Hz, J 0 Hz), 3.19 (dd, 1H, HCH,
J 16 Hz, J 8 Hz), 3.31 (s, 3H, Me), 4.43 (dd, 1H, CH, J 8 Hz, J 0 Hz),
7.08 (d, 2H, C6H4, J 8 Hz), 7.21 (s, 1H, CHpyrrole), 7.39 (d, 2H, C6H4,
J 8 Hz), 8.32 (s, 1H, NH), 2.18 (br. s, 1H, CO2H). Found (%): C, 59.34;
H, 4.42; N, 9.35. Calc. for C15H13ClN2O3 (%): C, 59.12; H, 4.30; N, 9.19.
1
methanol and water. Yield 7.12 g (84%), mp 130–131 °C. H NMR, d:
3.62–3.80 (m, 9H, 3Me), 5.80 (s, 2H, NH2), 7.48 (s, 1H, CHpyrrole).
Found (%): C, 51.16; H, 5.82; N, 13.37. Calc. for C11H16N2O4 (%):
C, 50.94; H, 5.70; N, 13.20.
– 256 –