One-pot synthesis of diethyl 4,4′-(1,4-phenylene)bis-[6-(halomethyl)- 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates] and their bispyrrolocyclization

Article abstract of DOI:10.1007/s00706-010-0354-9

A one-pot synthesis of diethyl 4,4′-(1,4-phenylene)bis[6- (chloromethyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates] is proposed via three-component condensation of terephthalic aldehyde, 4-chloroacetoacetic ester, and ureas under Biginelli reactio

Full text of DOI:10.1007/s00706-010-0354-9

Monatsh Chem (2010) 141:997–1000
DOI 10.1007/s00706-010-0354-9
ORIGINAL PAPER
One-pot synthesis of diethyl 4,40-(1,4-phenylene)bis-
[6-(halomethyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-
5-carboxylates] and their bispyrrolocyclization
•
Iryna O. Lebedyeva Mykhaylo V. Povstyanoy
•
•
Vyacheslav M. Povstyanoy Oleksandr G. Panasyuk
•
•
Evgen S. Guban’ Aleksey B. Ryabitskii
Received: 5 February 2010 / Accepted: 12 June 2010 / Published online: 30 July 2010
ꢀ Springer-Verlag 2010
Abstract A one-pot synthesis of diethyl 4,40-(1,4-phe-
nylene)bis[6-(chloromethyl)-2-oxo-1,2,3,4-tetrahydropyri-
midine-5-carboxylates] is proposed via three-component
condensation of terephthalic aldehyde, 4-chloroacetoacetic
ester, and ureas under Biginelli reaction conditions. Inter-
action of the obtained precursors that contain two highly
reactive binucleophilic groups with primary amines leads
to bis-heterocyclization with formation of (1,4-phenylene)-
bis(pyrrolo[3,4-d]pyrimidine-2,5-diones).
Low solubility of bis(tetrahydroprimidines) (DHPMs)
impedes bringing the halogen atom into the molecule of
DHPM, preventing the use of the latter as precursors for
further bis-heterocyclization [4, 5]. This fact explains the
absence of data on the reactivity, chemical properties,
ability to form new heterocyclic systems, regioselectivity,
and biological activity of the presented synthons.
The presented work is devoted to the development of
simplified synthetic approaches [5, 6] towards reactive
initial agents and study of their intramolecular ability to
form new heterocyclic systems at their interaction with
nucleophiles different in their nature.
Keywords Biginelli reaction ꢀ Bis-heterocyclization ꢀ
DHPM ꢀ Multicomponent reactions
Introduction
Results and discussion
Bis-heterocyclization, i.e., successive or simultaneous for-
mation of two analogous heterocycles within one reaction,
does not commonly occur in organic synthesis. In the
chemistry of the Biginelli reaction, the formation of the
initial bis(tetrahydropyrimidines) employing terephthalic
aldehyde has only been described in a few papers [1–3].
One-pot three-component condensation of methylurea or
1,3-dimethylurea (1a–1b, Scheme 1), 4-chloroacetoacetic
ester (2), and terephthalic aldehyde (3) at standard Biginelli
reaction conditions [7] was performed to synthesize the
initial diethyl 4,40-(1,4-phenylene)bis[6-(halomethyl)-2-
oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates] (4a–4b).
The implementation of the described heterocondensation
allowed us to obtain active precursors 4a–4b that contain
two electrophilic groups separated by the phenyl ring.
With the selection of appropriate cyclizing agents, a
wide ensemble of different hetaryl 5-, 6-, and 7-membered
cyclic systems can be synthesized from two electrophilic
ortho-groups. During the process of azabisheterocycle
construction, our attention was devoted to the formation
of five-membered heterocycles. It has been revealed that
bis-functionally substituted tetrahydropyrimidines, just as
their mono-analogues [4, 5] react with an excess of
primary amines (propylamine, monoethanolamine) or
aromatic amino acids (p-aminobenzoic acid), forming
I. O. Lebedyeva (&) ꢀ M. V. Povstyanoy ꢀ
V. M. Povstyanoy ꢀ E. S. Guban’
Kherson National Technical University,
Berislavske Highway 24, Kherson 73000, Ukraine
e-mail: ira_lebedeva2001@mail.ru
O. G. Panasyuk
Ukrainian State University of Chemical Engineering,
Gagarina Avenue 8, Dnipropetrovs’k 49005, Ukraine
A. B. Ryabitskii
Spoluka Chemical Company, 5 Murmanska str.,
Kiev 02660, Ukraine
123

998
I. O. Lebedyeva et al.
Scheme 1
O
O
Cl
1
1
O
O
R
R
O
N
O
N
1
R
R
2
N
O
N
O
+
N
H
N
H
HCl, 3h
EtOH
R
R
O
R= CH3, R1=H
R= R1= CH3
1a
1b
O
O
O
Cl
Cl
3
R= CH3, R1=H
R= R1= CH3
4a
4b
4,40-(1,4-phenylene)bis(3,4,6,7-tetrahydro-1H-pyrrolo[3,4-
d]pyrimidine-2,5-diones) (6a–6c, Scheme 2).
mentioning that the ensemble of the final bis-heterocycles
can be significantly widened due to the use of different S-,
N-, and O-nucleophilic reagents. The structure and purity of
both precursors and final samples were proved by 1H NMR,
IR spectroscopy, HPLC/MS, and elemental analyses.
HPLC/MS data revealed that the interaction of the initial
compounds with amines at a ratio of 1:1 forms a mixture that
consists of three main components—initial bis(chloromethyl-
tetrahydropyrimidin-2-one) (4a, 64%), monocyclized ethyl
4-(chloromethyl)-6-[4-(2,3,4,5,6,7-hexahydro-1-methyl-2,-
5-dioxo-6-propyl-1H-pyrrolo[3,4-d]pyrimidin-4-yl)phenyl]-
1,2,3,6-tetrahydro-3-methyl-2-oxopyrimidine-5-carboxylate
(5, 25%), and bisdialkylsubstituted tetrahydropyrrolo[3,4-d]-
pyrimidine (6a, 3–5%, Scheme 2). Having employed an
excess of a secondary amine (piperidine) in the reaction,
bis(6-aminomethyl)-substituted pyrimidines were obtained
as a result (7, Scheme 2).
Experimental
All chemicals were obtained from commercial sources and
used without any further purification. Melting points were
measured on an electrothermal capillary melting point
apparatus. IR spectra were recorded with a UR-20 spectro-
photometer (KBr platelets). The NMR measurements were
carried out on a Varian GEMINI 2000 spectrometer with 1H
and 13C frequencies of 400.07 and 100.61 MHz, respec-
In conclusion, the heterocyclization of bis(6-chloro-
methylpyrimidine) derivatives with primary amines proceeds
under mild conditions and includes amination at the chlo-
romethyl group followed by a nucleophilic attack on the
amino group at the ester fragment with removal of an ethyl
alcohol molecule. As a result of this two-stage cyclization,
closing of dihydropyrrol-2-one rings takes place, forming
tetrahydropyrrolo[3,4-d]pyrimidine-2,5-diones.
1
tively, at 293 K. H NMR spectra were recorded with a
spectral width of 8,000 Hz and 32 k data points; 13C NMR
spectra were recorded with spectral width of 30,000 Hz
and 128 k data points. DMSO-d6 was used as a solvent and
TMS as an internal standard. HPLC/MS was carried out on a
system consisting of an Agilent 1100 Series high-pressure
liquid chromatograph equipped with a diode matrix and
Agilent LC/MSD SL mass-selective detector. HPLC/MS
As a result a simple synthesis approach toward chemi-
cally active basic synthons has been developed. It is worth
Scheme 2
O
N
R1
N
R1
N
O
R
N R
H2N
R2
R2
O
H2N
O
O
N
R1
N
R1
N
O
N
R2
O
Cl
O
R1
R1
N
O
N
R
N R
R N
N R
1
2
5 R = CH , R = H, R = CH CH CH
3
2
2
3
O
O
O
O
Cl O
O Cl
N
R2
N
R2
HN
1
2
6a R = CH , R = H, R = CH CH CH
3
2
2
3
1
1
2
6b
4a
R = CH , R = H, R = CH CH OH
3 2 2
R = CH , R = H
3
O
N
R1
N
R1
N
O
1
2
1
6c R = R = CH , R = 4-C H COOH
4b R = R = CH
3
6 4
3
R
N
N R
N
O
O
O
O
1
7
R = CH , R = H
3
123

One-pot synthesis of diethyl 4,40-(1,4-phenylene)bis[6…
999
precipitate formed within 12 h. It was separated by
filtration, washed with acetone, and purified by crystalli-
zation from 2-PrOH:DMF 5:1. White solid; yield 19%;
m.p.: 263 ꢁC (2-PrOH/DMF); 1H NMR (400 MHz,
DMSO-d6): d = 7.72 (d, 3J = 1.2 Hz, 2H, 2 9 NH),
7.25 (br.s, 4H, C6H4), 5.15 (s, 2H, 2 9 NCH), 4.16 (m,
4H, 2 9 NCH2), 3.19 (m, 4H, CH2CH2CH3), 3.00 (s, 6H,
2 9 NCH3), 1.46 (m, 4H, 2 9 CH2CH3), 0.80 (t, 3J =
1.2 Hz, 6H, 2 9 CH2CH3) ppm; 13C NMR (100 MHz,
DMSO-d6): d = 164.25, 152.72, 147.27, 142.35, 126.24,
105.26, 95.39, 60.27, 51.98, 37.81, 28.86, 13.88 ppm; IR
(KBr): vꢀ ¼ 1; 610 (C=C), 1,670 (br, C=O), 3,340 (br, NH)
cm-1; HPLC/MS: m/z = 493 (M?).
parameters: column: Zorbax SB-C18, 1.8 lm, 4.6 9
30 mm; solvents: MeCN–H2O (95:5), 0.1% TFA; eluent
flow: 3 cm3 min-1; injected sample volume: 1 mm3; UV
detector: k = 215, 254, 265 nm; ionization method: chem-
ical ionization under atmospheric pressure; ionization mode:
simultaneous scanning of positive and negative ions in m/z
range 100–650. Elemental analysis was performed on a
Perkin-Elmer C, H, N Analyzer, and results were in good
agreement ( 0.2%) with the calculated values.
Diethyl 4,40-(1,4-phenylene)bis[6-(chloromethyl)-1,2,3,4-
tetrahydro-1-methyl-2-oxopyrimidine-5-carboxylate]
(4a, C24H28Cl2N4O6)
Monomethylurea (1a, 10 mmol) was mixed with 1.84 g 2
(11 mmol) and 0.67 g 3 (5 mmol). Three drops of conc.
HCl were added to the mixture. The reaction mixture was
refluxed for 3 h in 15 cm3 of EtOH, cooled down and left
overnight. The formed yellowish precipitate was separated
by filtration and purified by crystallization from 2-PrOH:
DMF 3:1. Yellow solid; yield 55%; m.p.: 263 ꢁC (2-PrOH/
DMF); 1H NMR (400 MHz, DMSO-d6): d = 8.09 (d,
3J = 3.6 Hz, 2H, 2 9 NH), 7.20 (m, 4H, C6H4), 5.18 (d,
4,40-(1,4-Phenylene)bis[3,4,6,7-tetrahydro-6-(2-hydroxy-
ethyl)-1-methyl-1H-pyrrolo[3,4-d]pyrimidine-2,5-dione]
(6b, C24H28N6O6)
Prepared in analogy to 6a. White solid; yield 24%; m.p.:
1
248 ꢁC (2-PrOH/DMF); H NMR (400 MHz, DMSO-d6):
d = 7.67 (br.s, 2H, 2 9 NH), 7.28 (s, 4H, C6H4), 5.16 (s,
2H, 2 9 NCH), 4.64 (t, J = 5.2 Hz, 2H, 2 9 CH2OH),
3
4.19 (m, 4H, 2 9 NCH2), 3.46 (m, 4H, 2 9 CH2OH), 3.30
(m, 4H, 2 9 CH2CH2OH), 3.02 (s, 6H, 2 9 CH3) ppm;
13C NMR (100 MHz, DMSO-d6): d = 168.08, 152.04,
151.42, 142.55, 126.12, 103.93, 95.37, 59.59, 52.38, 48.06,
43.96, 29.03 ppm; IR (KBr): vꢀ = 1,650 (C=C), 1,670,
1,700 (C=O), 3,260–3,430 (br, NH, OH) cm-1; HPLC/MS:
m/z = 497 (M?).
3
2J = 12.0 Hz, 2H, 2 9 CH2Cl), 5.15 (d, J = 3.6 Hz, 2H,
3
2 9 NCH), 4.93 (d, J = 12.0 Hz, 2H, 2 9 CH2Cl), 4.08
(m, 4H, 2 9 CH2CH3), 3.21 (s, 6H, 2 9 NCH3), 1.13
(t, 3J = 6.8 Hz, 6H, 2 9 CH2CH3) ppm; 13C NMR
(100 MHz, DMSO-d6): 164.35, 152.88, 147.27, 142.35,
126.22, 105.40, 60.26, 51.84, 37.81, 28.92, 13.95 ppm; IR
(KBr): vꢀ = 1,630 (C=C), 1,700, 1,720 (C=O), 3,220 (br,
NH) cm-1; HPLC/MS: m/z = 540 (M?).
4,40-[4,40-(1,4-Phenylene)bis(1,2,3,4,5,7-hexahydro-
1,3-dimethyl-2,5-dioxo-6H-pyrrolo[3,4-d]pyrimidine-
4,6-diyl)]dibenzoic acid (6c, C36H32N6O8)
Diethyl 4,40-(1,4-phenylene)bis[6-(chloromethyl)-1,2,3,4-
tetrahydro-1,3-dimethyl-2-oxopyrimidine-5-carboxylate]
(4b, C26H32Cl2N4O6)
Prepared in analogy to 6a. White solid; yield 28%; m.p.:
1
305 ꢁC (2-PrOH/DMF); H NMR (400 MHz, DMSO-d6):
3
d = 12.44 (br. s, 2H, 2 9 COOH), 7.82 (d, J = 8.4 Hz,
Prepared in analogy to 4a. Yellow solid; yield 49%, m.p.:
1
156 ꢁC (2-PrOH/DMF); H NMR (400 MHz, DMSO-d6):
4H, 2 9 C6H4COOH), 7.74 (d, 3J = 8.4 Hz, 4H, 2 9
C6H4COOH), 7.34 (s, 4H, C6H4), 5.34 (s, 2H, 2 9 NCH),
4.70 (m, 4H, 2 9 CH2), 3.18 (s, 6H, 2 9 1-CH3 Pyr), 2.80
(s, 6H, 2 9 3-CH3 Pyr) ppm; 13C NMR (100 MHz, DMSO-
d6): d = 171.94, 170.67, 160.19, 157.60, 154.63, 153.81,
152.50, 150.76, 149.07, 133.48, 115.84, 56.78, 55.34, 44.13,
43.81 ppm; IR (KBr): vꢀ ¼ 1; 590 (C=C), 1,690 (C=O),
1,380 (COOH) cm-1; HPLC/MS: m/z = 662 (M?).
d = 7.16 (br.s, 4H, C6H4), 5.87 (s, 2H, 2 9 NCH), 4.19
(m, 6H, 2 9 CH2CH3), 3.75 (d, 3J = 12.4 Hz, 2H,
2 9 CH2Cl), 3.34 (d, 3J = 12.4 Hz, 2H, 2 9 CH2Cl),
3.04 (s, 6H, 2 9 NCH3), 2.87 (s, 6H, 2 9 NCH3), 1.19
(t, 3J = 6.8 Hz, 6H, 2 9 CH2CH3) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 168.07, 151.56, 137.87,
135.33, 126.07, 99.27, 95.37, 61.34, 59.49, 45.93, 35.46,
31.29, 14.00 ppm; IR (KBr): vꢀ ¼ 1; 640 (C=C), 1,670,
1,750 (C=O) cm-1; HPLC/MS: m/z = 568 (M?).
Diethyl 4,40-(1,4-phenylene)bis[1,2,3,4-tetrahydro-
1-methyl-2-oxo-6-(piperidin-1-ylmethyl)pyrimidine-
5-carboxylate] (7, C34H48N6O6)
4,40-(1,4-Phenylene)bis(3,4,6,7-tetrahydro-1-methyl-
6-propyl-1H-pyrrolo[3,4-d]pyrimidine-2,5-dione)
(6a, C26H32N6O4)
Prepared in analogy to 6a. White solid; yield 18%; m.p.:
1
216 ꢁC (2-PrOH/DMF); H NMR (400 MHz, DMSO-d6):
d = 7.59 (br. s, 2H, 2 9 NH), 7.16 (br. s, 4H, C6H4), 5.15
Bis-pyrimidine 4a (5 mmol) was dissolved in a mixture of
2-PrOH:DMF 3:1. To the solution, an appropriate amine
(3 eq, 15 mmol) was added, and the reaction mixture was
refluxed for 4 h, cooled down, and left overnight. A white
(br. s, 2H, 2 9 NCH), 4.06 (q, 3J = 6.4 Hz, 4H, 2 9
2
CH2CH3), 3.86 (d, J = 13.2 Hz, 2H, 2 9 CH2Pip), 3.58
(d, 2J = 13.2 Hz, 2H, 2 9 CH2Pip), 3.22 (s, 6H, 2 9
123

1000
I. O. Lebedyeva et al.
NCH3), 2.41 (m, 8H, 2 9 Pip-2,6-(CH2)), 1.42 (m, 12H,
3
2 9 Pip-3,4,5-(CH2)), 1.13 (t, J = 6.4 Hz, 6H, 2 9 CH2
References
CH3) ppm; 13C NMR (100 MHz, DMSO-d6): d = 165.00,
152.61, 148.33, 142.68, 125.89, 105.16, 60.10, 59.59, 53.31,
52.27, 28.75, 25.75, 23.87, 13.98 ppm; IR (KBr): vꢀ ¼ 1; 630
(C=C), 1,690, 1,710 (C=O), 3,230 (br, NH) cm-1; HPLC/MS:
m/z = 637 (M?).
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Acknowledgments This work was supported by Fundamental
Researchers State Fund (F25.3/023).
123