Synthesis of ethyl 4-oxo-3,4-dihydro[1]benzofuro[3,2-d]-pyrimidine-2-carboxylate and its derivatives

Article abstract of DOI:10.1016/j.mencom.2008.07.018

The synthesis of ethyl 4-oxo-3,4-dihydro[1]benzofuro[3,2-d]pyrimidine-2-carboxylates was developed to modify the benzofuro-[3,2-d]pyrimidine heterocyclic system.

Full text of DOI:10.1016/j.mencom.2008.07.018

Mendeleev
Communications
Mendeleev Commun., 2008, 18, 217–219
Synthesis of ethyl 4-oxo-3,4-dihydro[1]benzofuro[3,2-d]-
pyrimidine-2-carboxylate and its derivatives
Sergey B. Alyabiev,* Dmitri V. Kravchenko and Alexandre V. Ivachtchenko
Department of Organic Chemistry, Chemical Diversity Research Institute, 114401 Khimki, Moscow Region,
Russian Federation. Fax: +7 495 626 9780; e-mail: alyabjev@iihr.ru
DOI: 10.1016/j.mencom.2008.07.018
The synthesis of ethyl 4-oxo-3,4-dihydro[1]benzofuro[3,2-d]pyrimidine-2-carboxylates was developed to modify the benzofuro-
3,2-d]pyrimidine heterocyclic system.
[
Methods for the synthesis of 4-oxo-3,4-dihydrobenzofuro[3,2-d]-
pyrimidine system by the intramolecular cyclization were
described.1 However, these methods suffer from the lack of
versatility, and there is a need for a facile procedure that can
incorporate a number of points of structural diversity and a
variety of substitution patterns into the target benzofuro[3,2-d]-
pyrimidine heterocyclic scaffold. Here, we report a convenient
synthesis of new 3,4-dihydrobenzofuro[3,2-d]pyrimidines.
First, we explored synthetic ways to assemble the desired
acetate in a mixture of acetone and pyridine. The reaction
smoothly leads to desired product 2 in good yield. Compound 2
†
,2
represents a promising starting point for the synthesis of diverse
heterocyclic-fused benzofurans. An important feature of com-
pound 2 is the presence of three electron-withdrawing carbonyl
groups, as well as exceptionally good leaving ethoxy group in
the 3-position and a carboxamide group in the 2-position of
the benzofuran ring. We used this compound to investigate
cyclization pathways to the target 4-oxo-3,4-dihydrobenzofuro-
[3,2-d]pyrimidine skeleton.1
,5
4-oxo-3,4-dihydrobenzofuro[3,2-d]pyrimidine heterocycle starting
from 3-amino-1-benzofuran-2-carboxamide 1. Compound 1 was
obtained using a previously described synthetic approach.3
Our attempts to obtain the desired 4-oxo-3,4-dihydrobenzofuro-
Thus, thieno[2,3-d]pyrimidin-4(3H)-ones were synthesised
by the pyrolysis of 4,5-substituted ethyl {[3-(aminocarbonyl)-
thien-2-yl]amino}(oxo)acetates. However, we found that com-
,4
5
[
3,2-d]pyrimidine heterocyclic system by the reaction of 1 with
pound 2 was destructed by pyrolysis, and only traces of the
desired cyclization products and a corresponding decarboxylated
product (not shown in Scheme 1) were formed.
diethyl oxalate in the presence of EtONa (Scheme 1) gave only
products 2 and 3, with no cyclization product traces.
We have observed that the most convenient synthetic approach
to compound 2 is the reaction of 1 with ethyl chloro(oxo)-
We also performed the treatment of compound 2 with a
solution of phosphorus oxychloride in dioxane (analogously to
6
Hassan et al. ). The major product of this reaction was ethyl
EtO
O
‡
[(2-cyano-1-benzofuran-3-yl)amino](oxo)acetate 4 (Scheme 1)
rather than the target benzofuro[3,2-d]pyrimidine. Unequivocal
O
NH2
NH
structural assignment for compound 4 was obtained using
13
1
1
NH2
O
NH2
O
C NMR and H– H NOESY spectroscopic data.
EtOC(O)C(O)OEt
A synthetic route to 2-aryl substituted benzofuro[3,2-d]-
Na/EtOH, Δ, 4 h
O
O
1
pyrimidin-4(3H)-ones was described by Vaidya et al. 2-Phenyl-
benzofuro[3,2-d]pyrimidin-4(3H)-ones were obtained via the
intramolecular cyclization of 3-(benzoylamino)-1-benzofuran-
2-carboxamides. By analogy, we treated compound 2 with KOH
in dry methanol and aqueous methanol. Based on LCMS data,
several products were formed including major product 3.
1
2, 60%
+
HO
O
O
NH
NH2
O
†
Melting points were measured with a Buchi B-520 melting point
ClC(O)C(O)OEt
MeOH/KOH
2
apparatus and are not corrected. 1H NMR spectra were recorded on a
Bruker DPX-400 spectrometer in [ H ]DMSO using TMS as an internal
standard.
acetone/pyridine
Δ, 1–2 h, 73%
O
2
Δ, 3 h
87%
6
3
, 15%
POCl3/dioxane
EtONa/EtOH,
HCl
Ethyl {[2-(aminocarbonyl)-1-benzofuran-3-yl]amino}(oxo)acetate 2.
Pure pyridine (5 ml) was added to a solution of 1 (35.2 g, 0.2 mol) in dry
acetone (200 ml). Ethyl chloro(oxo)acetate (27.3 g, 0.2 mol) in dry acetone
(200 ml) was added dropwise to the solution with vigorous stirring;
then, the reaction mixture was heated in a boiling water bath for 3 h. The
reaction was followed by TLC (5% MeOH in CH Cl ). The reaction
7
0 °C, 4–5 h
R
EtO
O
O
O
O
2
2
NH
N
3, 73% +
mixture was cooled to room temperature; the formed precipitate was
filtered off and washed with acetone to give the desired product in 87%
NH
N
1
2
yield; mp 210–212 °C. H NMR ([ H ]DMSO, 400 MHz) d: 11.57 (s, 1H,
O
O
O
6
NH), 8.32 (d, 1H, Ar-H, J 8.4 Hz), 8.28–7.98 (br. d, 2H, NH ), 7.62 (d, 1H,
2
4, 84%
5 R = Et, 16%
R = H, 4%
Ar-H, J 8.4 Hz), 7.54 (t, 1H, J 8.4 Hz), 7.35 (t, 1H, Ar-H, J 8.4 Hz), 4.34 (q,
6
2
H, OCH , J 6.8 Hz), 1.34 (t, 3H, Me, J 6.8 Hz). Found (%): C, 56.47;
2
Scheme 1 Synthesis and chemical transformations of intermediate 2.
H, 4.35; N, 10.19. Calc. for C13H12N2O5 (%): C, 56.52; H, 4.38; N, 10.14.
©
2008 Mendeleev Communications. All rights reserved.
– 217 –

Mendeleev Commun., 2008, 18, 217–219
We found that the reaction of 2 with EtONa in dry ethanol at
5 °C led to ethyl 4-oxo-3,4-dihydro[1]benzofuro[3,2- ]pyrimidine
N
4
d
-
NH
O
§
i, ii
LiOH/H O
reflux
2
-carboxylate 5 as the major product (Scheme 2). Upon the
2
2
5
6
complete conversion of the initial reactant, the mixture was
acidified by glacial acetic acid to pH 5–6, and the precipitate
was filtered off to give desired product 5. Better results were
obtained in tert-butanol rather than ethanol; in this case, final
ester 5 was formed in 79% yield. If the reaction was acidified
by HCl, a mixture of compounds 3, 5, 6 was formed (Scheme 1).
As an alternative synthetic route toward compound 5, we
explored the reaction in 1,2-dichloroethane (DCE) in the presence
THF, 25 °C
O
2
h
8
8%
POCl3
reflux, 3–4 h
7
, 95%
EtO
N
EtO
R1
O
O
HN
N
R2
N
N
9
a–c
K2CO3/DMF
90–100 °C, 3 h
1
2
of Et N and Me SiCl (TMSCl) by analogy with the method
Cl
NR R
3
3
O
O
7
described by Fuwa et al. In this case, the cyclization proceeded
smoothly to afford the desired product in 60% yield. The mild
alkali hydrolysis of ester 5 afforded acid 6 (yield 88%). Acid 6
could be easily converted to the corresponding benzofuro[3,2-d]-
pyrimidine 7 by decarboxylation (Scheme 2).¶
8, 93%
75–94%
10a R1 + R = (CH )
10b R + R = (CH ) O(CH )
10c R1 + R = (CH
2
2
4
1
2
2
2
2 2
2
HN
HN
2
)
6
The 4-position of the benzofuro[3,2-d]pyrimidine system
is a useful site for introduction of an additional diversity point
to the test heterocyclic system. The assembly of 4-amino
substituted benzofuro[3,2-d]pyrimidine-2-carboxamides 11a–t,
9
9
a
i, LiOH/H2O/THF, 25 °C
3
4
ii, NHR R , CDI/DMF
a–t
R4
N
9
O
R3
N
1
2a–t and 13a–t is depicted in Scheme 2. According to
b
O
8
Sangapure et al. ester 5 was readily converted to 4-chloro-
†
†
N
benzofuro[3,2-d]pyrimidine 8 upon treatment with phosphorus
oxychloride (yield 93%). Resulting chloride 8 was easily
converted to corresponding amines 10a–c by reactions with
HN
1
2
O
NR R
9
c
‡
68–93%
11a–t R1 + R = (CH
+ R = (CH
13a–t R + R = (CH )
Ethyl [(2-cyano-1-benzofuran-3-yl)amino](oxo)acetate 4. Compound 2
2
(
2.8 g, 0.01 mol) was added to a solution of POCl (1.1 ml, 0.01 mol)
2
2
)
4
)
2
6
3
1
2
in pure dioxane (20 ml). The reaction mixture was heated up to 70 °C in
boiling water bath for 4–5 h under stirring. The reaction was followed by
TLC (5% MeOH in CH Cl ). The solvent was evaporated under reduced
12a–t
R
2
O(CH )
1
2
2
2
2
pressure. The resulting residue was slowly poured into crushed ice with
vigorous stirring. The formed precipitate was filtered off, washed with
water and hexane to give compound 4 in 74% yield; mp 135–137 °C.
Scheme 2 Synthesis and chemical transformations of ethyl 4-oxo-3,4-di-
hydro[1]benzofuro[3,2-d]pyrimidine-2-carboxylate 5. Reagents and conditions:
i, EtONa/EtOH/AcOH, 45 °C, 3–4 h, 66%; ii, DCE, Et N, TMSCl, reflux,
3
3
4
1
6 h, 60%. For R and R substituents see Online Supplementary Materials.
1
2
H NMR ([ H ]DMSO, 400 MHz) d: 11.76 (s, 1H, NH), 7.96 (d, 1H,
6
Ar-H, J 8.2 Hz), 7.72 (d, 1H, Ar-H, J 8.2 Hz), 7.63 (t, 1H, Ar-H, J 8.2 Hz),
.43 (t, 1H, Ar-H, J 8.2 Hz), 4.36 (q, 2H, OCH , J 6.8 Hz), 1.35 (t, 3H,
¶
7
4-Oxo-3,4-dihydro[1]benzofuro[3,2-d]pyrimidine-2-carboxylic acid 6
2
13
2
Me, J 6.8 Hz). C NMR ([ H ]DMSO, 75 MHz) d: 13.8 (Me), 62.8
and benzofuro[3,2-d]pyrimidin-4(3H)-one 7. LiOH (0.06 g, 2.44 mmol)
dissolved in the minimum amount of water was added to a solution
of compound 5 (0.5 g, 1.94 mmol) in pure THF (5 ml). The reaction
mixture was stirred at room temperature for 2 h. After the reaction was
complete, cold water (10 ml) was added and the solution was acidified
by HCl to pH 2. The formed precipitate was filtered off, washed with
water, cold ethanol and hexane to give desired acid 6 in 88% yield;
6
(
OCH ), 111.5 (CN), 112.0 (C-7), 119.3 (C-5), 121.1 (C-4), 122.3 (C-3a),
2
1
1
24.2 (C-2), 128.0 (C-6), 129.3 (C-3), 153.7 (C-7a), 155.9 [C(O)NH],
59.4 (COOEt). Found (%): C, 60.42; H, 3.96; N, 10.81. Calc. for
C H N O (%): C, 60.47; H, 3.90; N, 10.85.
1
3
10
2
4
§
Ethyl 4-oxo-3,4-dihydro[1]benzofuro[3,2-d]pyrimidine-2-carboxylate 5.
Method A. Compound 2 (30 g, 0.1 mol) was dissolved in absolute
1
2
ethanol or tert-butanol (500 ml). Then, dry NaOEt was added dropwise
mp 291–293 °C (decomp.). H NMR ([ H ]DMSO, 400 MHz) d: 8.09
6
under stirring at room temperature. The reaction mixture was heated at
(d, 1H, Ar-H, J 7.9 Hz), 7.87 (d, 1H, Ar-H, J 7.9 Hz), 7.71 (t, 1H, Ar-H,
J 7.9 Hz), 7.54 (t, 1H, Ar-H, J 7.9 Hz). Found (%): C, 57.43; H, 2.67;
N, 12.22. Calc. for C H N O (%): C, 57.40; H, 2.63; N, 12.17.
45 °C for 3–4 h. After the solution was cooled to room temperature, the
solvent (about 500 ml) was evaporated under reduced pressure and acetic
acid was added to the resulting residue (pH 5–6). The formed precipitate
was filtered off and washed with ethanol, water and hexane. Desired
product 5 was obtained in good yield (66 or 79%).
1
1
6
2
4
Subsequent refluxing of compound 6 in DMSO led to the corresponding
1
decarboxylated product 7 (95%); mp 274–276 °C (decomp.). H NMR
2
([ H ]DMSO, 400 MHz) d: 12.94 (s, 1H, NH), 8.23 (s, 1H, C-H), 8.04
6
Method B. Triethylamine (92.9 g, 0.92 mol) and TMSCl (32.5 g, 0.3 mol)
were added to a solution of compound 2 (5.5 g, 0.02 mol) in DCE (500 ml)
in an argon atmosphere. The reaction mixture was stirred under reflux
for 16 h. The process was followed by LCMS. After cooling to room
temperature, ethyl acetate was added (500 ml), and the solution was washed
with 1 M aqueous HCl and a saturated solution of K CO . The organic
(d, 1H, Ar-H, J 7.9 Hz), 7.83 (d, 1H, Ar-H, J 7.9 Hz), 7.67 (t, 1H, Ar-H,
J 7.9 Hz), 7.50 (t, 1H, Ar-H, J 7.9 Hz). Found (%): C, 64.54; H, 3.29;
N, 15.01. Calc. for C H N O (%): C, 64.52; H, 3.25; N, 15.05.
1
0
6
2
2
†
†
Ethyl 4-chlorobenzofuro[3,2-d]pyrimidine-2-carboxylate 8. Compound
5 (23.8 g, 0.09 mol) was added dropwise to phosphorus oxychloride
(240 ml). The resulting suspension was stirred at reflux for 3–4 h. The
reaction was followed by TLC (5% MeOH in CH Cl ). The solution was
2
3
fraction was dried over MgSO and the crude product was purified by
4
2
2
column chromatography on silica gel. The solvent was evaporated under
reduced pressure. The residue was triturated with diethyl ether and then
filtered off. Target compound 5 was obtained in 60% yield; mp 240–
cooled to room temperature and the solvent was evaporated under reduced
pressure. The residue was dissolved in dry CHCl , washed with cold water,
3
5% NaHCO and water again. The solution was dried over anhydrous
3
1
2
2
42 °C. H NMR ([ H ]DMSO, 400 MHz) d: 8.09 (d, 1H, Ar-H, J 8.1 Hz),
MgSO and purified by flash chromatography on a silica gel/aluminium
6
4
7.80 (d, 1H, Ar-H, J 8.1 Hz), 7.67 (t, 1H, Ar-H, J 8.1 Hz), 7.51 (t, 1H,
oxide column (eluent, benzene). The solvent was evaporated in vacuo. The
Ar-H, J 8.1 Hz), 4.42 (q, 2H, OCH , J 7.0 Hz), 1.42 (t, 3H, Me, J 7.0 Hz).
residue was triturated with hexane and then filtered off. Corresponding
2
1
3
2
1
C NMR ([ H ]DMSO, 75 MHz) d: 14.4 (Me), 63.2 (CH ), 113.5 (C-6),
chloride 8 was obtained in 93% yield; mp 158–160 °C. H NMR
6
2
2
1
21.9 (C-9a), 122.6 (C-8), 125.1 (C-9), 130.5 (C-9b), 140.9 (C-7), 142.8
([ H ]DMSO, 400 MHz) d: 8.29 (d, 1H, Ar-H, J 7.7 Hz), 7.96–7.85 (m,
6
(C-4a), 145.7 (C-4), 153.4 (C-5a), 156.7 (C-2), 160.4 (COOEt). Found
2H, Ar-H), 7.63 (t, 1H, Ar-H, J 7.7 Hz), 4.46 (q, 2H, OCH , J 7.1 Hz),
2
(
%): C, 60.53; H, 3.95; N, 10.83. Calc. for C H N O (%): C, 60.47;
1.44 (t, 3H, Me, J 7.1 Hz). Found (%): C, 56.48; H, 3.32; N, 10.08. Calc.
1
3
10
2
4
H, 3.90; N, 10.85.
for C H ClN O (%): C, 56.43; H, 3.28; N, 10.12.
1
3
9
2
3
–
218 –

Mendeleev Commun., 2008, 18, 217–219
secondary amines 9a–c. Resulting products 10a–c were isolated
References
‡
‡
as colourless crystals in 75–94% yields. Finally, esters 10a–c
were readily hydrolysed by LiOH dissolved in a mixture of
THF and water to furnish corresponding acids, which then
were easily transformed to the medium-sized library of 4-amino
substituted benzofuro[3,2-d]pyrimidine-2-carboxamides 11a–t,
1
V. P. Vaidya and Y. S. Agasimundin, Indian J. Chem., 1981, 20, 114.
2 Y. Bodke and S. S. Sangapure, J. Indian Chem. Soc., 2003, 80, 187.
3 F. A. Trophimov, G. F. Leiliak, L. I. Shevchenko and A. N. Grinev, Khim.
Geterotsikl. Soedin., 1974, 1171 [Chem. Heterocycl. Compd. (Engl.
Transl.), 1974, 10, 1016].
4
5
S. S. Sangapure and Y. S. Agasimundin, Indian J. Chem., 1976, 14, 688.
A. Miyashita, K. Fujimoto, T. Okada and T. Higashino, Heterocycles,
1
9
2a–t, 13a–t by reactions with primary and secondary amines
a–t (see Online Supplementary Materials).§
§
1
996, 42, 691.
6
7
8
H. M. Hassan, S. M. Bayomi and M. M. Ali, Indian J. Chem., Sect. B,
2000, 39, 764.
H. Fuwa, T. Kobayashi, T. Tokitoh, Y. Torii and H. Hatsugari, Tetrahedron,
Online Supplementary Materials
Supplementary data associated with this article can be found
in the electronic version at doi:10.1016/j.mencom.2008.07.018.
2
005, 61, 4297.
S. S. Sangapure and Y. S. Agasimundin, Indian J. Chem., 1977, 15, 485.
‡
‡
Synthesis of ethyl 4-amino substituted benzofuro[3,2-d]pyrimidine-
-carboxylates 10a–c. Anhydrous K CO (14.4 g, 0.1 mol) and corre-
2
2
3
sponding amine 9a–c were added to a solution of chloride 8 (22.3 g,
0
9
.08 mol) in dry DMF (100 ml). The reaction mixture was stirred at
0–100 °C for 3 h. After cooling to room temperature, the mixture was
Received: 26th November 2007; Com. 07/3050
§
§
poured into cold water and the formed precipitate was filtered off.
Amines 10a–c were obtained in good yield (75–94%).
General procedure for preparation of 4-amino substituted benzofuro-
[3,2-d]pyrimidine-2-carboxamides 11–13. The hydrolysis of esters 10a–c
was carried out using the synthetic procedure previously described for
compound 6. Corresponding acid 10a–c (1 mmol) was added to a
solution of carbonyldiimidazole (CDI) (1 mmol) in dry DMF (5 ml).
The reaction mixture was stirred at 60–80 °C for 2–4 h. After an
equimolar amount of amine 9a–t (1 mmol) was added, the reaction
mixture was heated up to 80–90 °C and stirred for 2–4 h. The resulting
mixture was cooled to room temperature; then, an aqueous solution of
sodium bicarbonate (25 ml, 2.5%) was added. The formed precipitate
was filtered off and washed with water. Recrystallization from ethanol
gave corresponding carboxamides 11a–t, 12a–t and 13a–t in good yields
Ethyl 4-pyrrolidin-1-ylbenzofuro[3,2-d]pyrimidine-2-carboxylate 10a.
1
2
Yield, 91%; mp 144–146 °C. H NMR ([ H ]DMSO, 400 MHz) d: 8.10 (d,
6
1H, Ar-H,
J 7.6 Hz), 7.77 (d, 1H, Ar-H, J 7.6 Hz), 7.68 (t, 1H, Ar-H, J 7.6 Hz),
7.49 (t, 1H, Ar-H, J 7.6 Hz), 4.35 (q, 2H, CH , J 7.1 Hz), 4.05–3.65 [m,
4
2
H, N(CH ) ], 2.04–1.94 (m, 4H, CH CH ), 1.34 (t, 3H, Me, J 7.1 Hz).
2
2
2
2
Found (%): C, 65.54; H, 5.58; N, 13.28. Calc. for C H N O (%): C, 65.58;
H, 5.50; N, 13.50.
Ethyl 4-morpholin-4-ylbenzofuro[3,2-d]pyrimidine-2-carboxylate 10b.
17 17 3 3
1
2
Yield, 94%; mp 146–148 °C. H NMR ([ H ]DMSO, 400 MHz) d: 8.14 (d,
6
1H, Ar-H,
J 7.7 Hz), 7.83 (d, 1H, Ar-H, J 7.7 Hz), 7.73 (t, 1H, Ar-H, J 7.7 Hz),
1
7.52 (t, 1H, Ar-H, J 7.7 Hz), 4.37 (q, 2H, CH , J 7.0 Hz), 4.08–4.02 [m,
4
(68–93%). The H NMR spectra were obtained for all the synthesised
2
H, O(CH ) ], 3.84–3.78 [m, 4H, N(CH ) ], 1.35 (t, 3H, Me, J 7.0 Hz).
carboxamides.
2
2
2 2
Found (%): C, 62.30; H, 5.14; N, 12.92. Calc. for C H N O (%): C, 62.38;
4-(4-Morpholinyl)-N-(3-pyridinylmethyl)benzofuro[3,2-d]pyrimidine-
17 17 3 4
1
H, 5.23; N, 12.84.
Ethyl 4-azepan-1-ylbenzofuro[3,2-d]pyrimidine-2-carboxylate 10c.
2-carboxamide 12o. This compound was obtained in 70% yield. H NMR
2
([ H ]DMSO, 400 MHz) d: 9.28 (t, 1H, NH, J 6.3 Hz), 8.57 (d, 1H, Ar-H,
6
1
2
Yield, 75%; mp 112–114 °C. H NMR ([ H ]DMSO, 400 MHz) d: 8.11
J 1.4 Hz), 8.43 (d, 1H, Ar-H, J 3.1 Hz), 8.15 (d, 1H, Ar-H, J 7.5 Hz),
7.82–7.68 (m, 3H, Ar-H), 7.53 (t, 1H, Ar-H, J 7.5 Hz), 7.33 (dd, 1H,
6
(d, 1H, Ar-H, J 6.6 Hz), 7.74–7.62 (m, 2H, Ar-H), 7.47 (t, 1H, Ar-H,
J 6.6 Hz), 4.36 (q, 2H, CH , J 6.5 Hz), 4.10–3.95 [m, 4H, N(CH ) ],
Ar-H, J 7.9 Hz, J 5.4 Hz), 4.54 (d, 2H, CH , J 6.2 Hz), 4.16–4.11 [m,
2
2 2
2
1
.94–1.83 [m, 4H, (CH ) ], 1.61–1.53 [m, 4H, (CH ) ], 1.40 (t, 3H, Me,
4H, O(CH ) ], 3.85–3.79 [m, 4H, N(CH ) ]. Found (%): C, 64.74;
2
2
2 2
2 2
2 2
J 6.5 Hz). Found (%): C, 67.18; H, 6.34; N, 12.45. Calc. for C H N O
H, 4.97; N, 18.02. Calc. for C H N O (%): C, 64.77; H, 4.92; N, 17.98.
19
21
3
3
21 19 5 3
(
%): C, 67.24; H, 6.24; N, 12.38.
Also see Online Supplementary Materials.
–
219 –