Oxidative recyclization of 4,6,7-trichloro-5-hydroxy-2-(2-pyrimidylamino)- 2,3-dihydrobenzo[b]furan

Article abstract of DOI:10.1023/B:COHC.0000040780.74690.35

When 4,6,7-trichloro-5-hydroxy-2-(2-pyrimidylamino)- 2,3-dihydrobenzo[b] furan reacted with phenyliodoso diacetate, an unexpected oxidative recyclization was observed to give 3-(3,5,6-trichloro-1,4-benzoquinon-2-yl)imidazo[1,2-a] pyrimidine. 2-[N-2-(3,5,6

Full text of DOI:10.1023/B:COHC.0000040780.74690.35

Chemistry of Heterocyclic Compounds, Vol. 40, No. 6, 2004
OXIDATIVE RECYCLIZATION OF
4,6,7-TRICHLORO-5-HYDROXY-2-(2-PYRIMIDYL-
AMINO)-2,3-DIHYDROBENZO[b]FURAN
G. Karlivans and R. Valters
When 4,6,7-trichloro-5-hydroxy-2-(2-pyrimidylamino)- 2,3-dihydrobenzo[b]furan reacted with
phenyliodoso diacetate, an unexpected oxidative recyclization was observed to give 3-(3,5,6-trichloro-
1,4-benzoquinon-2-yl)imidazo[1,2-a]pyrimidine. 2-[N-2-(3,5,6-Trichloro-1,4-benzoquinon-2-yl)ethenyl-
amino]pyrimidine is the intermediate product in the conversion.
Keywords: 4,6,7-trichloro-5-hydroxy-2-(2-pyrimidylamino)-2,3-dihydrobenzo[b]furan, 3-(3,5,6-trichloro-
1,4-benzoquinon-2-yl)imidazo[1,2-a]pyrimidine, phenyliodoso diacetate.
The structural units of imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrazine, and imidazo[1,2-a]pyrimidine
are encountered in many pharmacologically active substances, such as antagonists of benzodiazepine and
bradykinin receptors, inhibitors of gastric acid secretion, anti-inflammatories, cytoprotective agents,
antibacterials, antifungal agents, cardiostimulators, etc. (see [1,2] and literature cited therein). The classical
method for the synthesis of imidazo[1,2-a]pyridines, imidazo[1,2-a]pyrazines, and imidazo[1,2-a]pyrimidines is
the condensation of α-halo ketones with the corresponding 2-aminoazines [3-5]. A one step synthesis of
imidazo[1,2-a]azines via a three component condensation of a 2-aminoazine, an aldehyde, and an isonitrile has
been described [1,2] recently.
In this paper the design of the ring of trichloro-1,4-benzoquinolyl-substituted imidazo[1,2-a]pyrimidine
in an unexpected oxidative recyclization reaction of 4,6,7-trichloro-5-hydroxy-2-(2-pyrimidylamino)-2,3-
dihydrobenzo[b]furan (1) is proposed. We have shown recently [6] that the benzo[b]furan 1 is formed in the
reaction of 4,6,7-trichloro-2,5-dihydroxy-2,3-dihydrobenzo[b]furan with 2-aminopyrimidine.
When the benzo[b]furan 1 reacts with phenyliodoso diacetate in DMSO solution at 20°C oxidation
scission of the dihydrobenzofuran ring occurs with the formation of the intermediate 2-[N-2-(3,5,6-trichloro-1,4-
benzoquinon-2-yl)ethenylamino]pyrimidine (2), which then itself undergoes original oxidative cyclization to
give 3-(3,5,6-trichloro-1,4-benzoquinon-2-yl)imidazo[1,2-a]pyrimidine (3). The benzoquinone 3 is easily
1
reduced to 3-(3,4,6-trichloro-2,5-dihydroxyphenyl)imidazo[1,2-a]pyrimidine (4), so that the H NMR spectrum
(in DMSO-d6) of compound 3 corresponds to the structure of the hydroquinone 4.
Reduction of 3 to 4 was carried out by boiling in ethanol. Acylation of compound 4 with acetyl
anhydride in pyridine in the presence of 4-dimethylaminopyridine (DMAP) [7] gave 3-(5-acetoxy-3,4,6-
trichloro-2-hydroxyphenyl)imidazo[1,2-a]pyrimidine (5). The phenolic hydroxy group in position 2 is not
acylated under these conditions, possibly because of an intramolecular hydrogen bond between the OH group
and the nitrogen atom of the heterocycle.
__________________________________________________________________________________________
Riga Technical University, Riga LV-1048, Latvia; e-mail: rvalters@latnet.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 6, 939-942, June, 2004. Original article submitted March 25, 2004.
0009-3122/04/4006-0807©2004 Plenum Publishing Corporation
807

Cl
Cl
HO
Cl
N
N
NH
O
1
PhI(OAc)2 – 2H
O
N
N
O
NH
Cl
Cl
+ 2EtOH
CH=CH
Cl
Cl
Cl
N
N
N
– 2H
Cl
O
O
2
3
1
2
OH
N
OH
N
3
Cl
Cl
Cl
Ac2O
N 8
N
N
4 N
Py / DMAP
7
Cl 5
Cl
Cl
6
OAc
NH
OH
5
4
N
N
OAc
CH=CH
Cl
Cl
Cl
Ac2O / H3PO4
1
6
OAc
1
Formation of the intermediate compound 2 is confirmed by the H NMR spectrum of a sample taken
5 min after the beginning of the reaction. This spectrum contains, apart from the proton signals of the starting
material and reaction product, signals corresponding to the –CH=CH–NH unit (E-configuration). This unit
occurs in the structure of 2-[N-2-(2,5-diacetoxy-3,4,6-trichlorophenyl)ethenylamino]pyrimidine (6), obtained by
acetylation of compound 1 with acetic anhydride in the presence of orthophosphoric acid. The coupling constant
1
(3J = 15 Hz) between the protons of the ethenyl fragment in the H NMR spectrum of compound 6 confirms its
E-configuration.
In the IR spectrum of the benzoquinone 3 bands for the C=O and C=C groups of the quinone are
observed, but bands for the OH group are absent. The benzoquinone 3 is intensely colored and the presence in its
UV spectrum of a band at 576 nm indicates the intramolecular charge transfer between the electron-donating
heterocycle and the electron-accepting 1,4-benzoquinone fragment (cf [8]).
1
In the H NMR spectra of compounds 4 and 5 the signals of the protons in positions 5, 6, and 7 of the
imidazo[1,2-a]pyrimidine ring appear as a doublet of doublets. The chemical shifts and the coupling constants of
these signals (see Experimental) agree well with the spectrum of 2-(4-methoxyphenyl)-3-
benzylaminoimidazo[1,2-a]pyrimidine [1] in which there are doublets of doublets: H-5 8.49 (3J = 6.8, 4J = 2.0),
3
4
4
H-6 6.89 ( J = 4.1, J = 6.8), H-7 8.37 ppm (3J = 4.1, J = 2.0 Hz). A singlet is also observed for the proton in
position 2 of the imidazo[1,2-a]pyrimidone ring, the chemical shift of which agrees with the data in [9, 10].
808

EXPERIMENTAL
IR spectra of nujol mulls were recorded on a Specord M-80 (1900-1500 cm-1, NaCl prism) and of
hexachlorobutadiene mulls (3800-2000 cm-1, LiF prism). Electronic spectra of chloroform solutions
1
(c = 2.5·10-5 mol/l). H NMR spectra were recorded on a Bruker WH-90 (90 MHz) instrument with TMS as
internal standard.
3-(3,5,6-Trichloro-1,4-benzoquinon-2-yl)imidazo[1,2-a]pyrimidine (3). Phenyliodoso diacetate
(0.80 g, 2.5 mmol) in DMSO (5 ml) was added dropwise over 3 min to a solution of benzofuran 1 (0.33 g,
1 mmol) (prepared according to [6]) in DMSO (5 ml) with stirring (magnetic stirrer) at 20°C. The mixture was
stirred for 1 h at 20°C and water (100 ml) was then added. The precipitate of 3 was separated, washed , and
dried. The product was treated with methylene chloride (5 ml), the undissolved residue was separated, washed
with petroleum ether, and dried. Yield 0.25 g (77%). Deep-blue crystals; mp >250°C (dec.). IR spectrum (thin
layer), ν, cm-1: 1686 (C=O), 1624, 1582 (C=C), 1538, 1502. UV spectrum (CHCl3, c = 2.5·10-1mol/l): λmax, nm
1
(log ε): 302 (4.24), 576 (3.70). H NMR spectrum, see compound 4. Found, %: C 43.34; H 1.78; Cl 31.98;
N 12.32. C12H4Cl3N3O2. Calculated, %: C 43.87; H 1.23; Cl 32.38; N 12.79.
3-(3,4,6-Trichloro-2,5-dihydroxyphenyl)imidazo[1,2-a]pyrimidine (4). A solution of benzoquinone 3
(0.33 g, 1 mmol) in ethanol (10 ml) was boiled until the reaction mixture was colorless (~30 min). The solvent
was evaporated in vacuum to 2 ml and the solution was kept at 0°C for 20 h. The precipitate of the product 4 was
separated, washed with ethanol, and dried . Yield 0.28 g (85%). Gray crystals; mp >200°C (dec).
1
IR spectrum (thin layer), ν, cm-1: 3120 (OH), 2927 (OH), 1622, 1562, 1530, 1494. H NMR spectrum
3
4
3
4
(DMSO-d6), δ, ppm (J, Hz): 7.07 (1H, dd, J = 4, J = 6, H-6); 7.83 (1H, s, H-2); 8.42 (1H, dd, J = 6, J = 2,
H-5); 8.60 (1H, dd, 3J = 4, 4J = 2, H-7); 9.70 (1H, br. s, OH); 10.00 (1H, br. s, OH). Found, %: C 43.55; H 2.03;
Cl 31.78; N 12.80. C12H6Cl3N3O2. Calculated, %: C 43.60; H 1.83; Cl 32.18; N 12.71.
3-(5-Acetoxy-3,4,6-trichloro-2-hydroxyphenyl)imidazo[1,2-a]pyrimidine (5).
A
mixture of
compound 4 (0.33 g, 1 mmol), anhydrous pyridine (4 ml), acetic anhydride (2 ml, 20 mmol), and
4-dimethylaminopyridine (0.025 g, 0.2 mmol) was stirred at 20°C for 1 h, then at 50-60°C for 2 h, and was
finally boiled for 1 h. After cooling, water (50 ml) was added, the precipitate was separated, washed with water,
and dried. After crystallization from ethanol plus activated charcoal, colorless crystals of compound 5 were
obtained. Yield 0.25 g (68%); mp ~260°C (dec). IR spectrum (thin layer), ν, cm-1: 2560 (br, OH···N), 1778
1
3
4
(C=O). H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 1.92 (3H, s, CH3); 7.11 (1H, dd, J = 4, J = 6, H-6);
3
4
3
4
7.73 (1H, s, H-2); 8.49 (1H, dd, J = 6, J = 2, H-5); 8.64 (1H, dd, J = 4, J = 2, H-7); 10.95 (1H, br. s, OH).
Found, %: C 44.94; H 2.14; Cl 28.72; N 11.15. C14H8Cl3N3O3. Calculated, %: C 45.13; H 2.16; Cl 28.55;
N 11.28.
2-[N-2-(2,5-Diacetoxy-3,4,6-trichlorophenyl)ethenylamino]pyrimidine (6). Benzofuran 1 (0.33 g,
1 mmol), acetyl anhydride (5ml), and orthophosphoric acid (3 drops) were heated at 100°C for 1 h. The mixture
was cooled and water (50 ml) was added. After 12 h, the precipitate was filtered off, washed with water and
dried to give colorless crystals of 6 (0.36 g, 86%). After recrystallization from benzene and then from 1:3
benzene–carbon tetrachloride; mp 184-185°C (dec). IR spectrum (thin layer), ν, cm-1: 3210 (NH), 1775 (C=O),
1638 (C=C), 1517. 1H NMR spectrum (CDCl3 + DMSO-d6), δ, ppm (J, Hz): 2.33 (3H, s CH3); 2.39 (3H, s, CH3);
6.02 (1H, d, 3J = 15, CH); 6.70 (1H, t, 3J = 5, H-5 Het); 8.13 (1H, dd, 3J =15, 4J = 12, CH); 8.34 (2H, d, 3J = 5,
H-4 Het, H-6 Het); 8.60 (1H, br. d, 3J = 12, NH). Found, %: C 46.10; H 2.86; Cl 25.50; N 9.94. C16H12Cl3N3O4.
Calculated, %: C 46.12; H 2.90; Cl 25.53; N 10.09.
809

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