Synthesis of 2-oxo- and 2-thioxo-5-(benzofuran-2-yl)tetrahydropyrimidines

Article abstract of DOI:10.1016/j.mencom.2011.01.019

New 5,6-dicyanobenzofurans bearing a 2-(thi)oxotetrahydropyrimidine moiety at the 2-position were synthesized from 2-(2-dimethylaminovinyl)-5,6- dicyanobenzofurans, benzaldehydes and (thio)urea in AcOH.

Full text of DOI:10.1016/j.mencom.2011.01.019

Mendeleev
Communications
Mendeleev Commun., 2011, 21, 46–47
Synthesis of 2-oxo- and 2-thioxo-5-(benzofuran-2-yl)tetrahydropyrimidines
Sergei I. Filimonov,*a Zhanna V. Chirkova,a Igor G. Abramov,a
Sergey I. Firgang,b Galina A. Stashina*b and Kyrill Yu. Suponitskyc
a Yaroslavl State Technical University, 150023 Yaroslavl, Russian Federation.
Fax: +7 4852 44 0729; e-mail: filimonovsi@ystu.ru
b N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 5328; e-mail: galina_stashina@chemical-block.com
c A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 5085; e-mail: kirshik@yahoo.com
DOI: 10.1016/j.mencom.2011.01.019
New 5,6-dicyanobenzofurans bearing a 2-(thi)oxotetrahydropyrimidine moiety at the 2-position were synthesized from 2-(2-dimethyl-
aminovinyl)-5,6-dicyanobenzofurans, benzaldehydes and (thio)urea in AcOH.
Recently, the area of heterocyclic chemistry dealing with the
syntheses of substituted tetrahydropyrimidin-2-ones and their thio
analogues was growing rapidly; these syntheses are based on the
three-component Biginelli reaction1 catalysed both by acids and
bases.2,3 The resulting 6-aryl-2-(thi)oxotetrahydropyrimidines
show various biological activities, e.g., they can act as calcium
channel modulators and be employed for the therapy of cardio-
vascular diseases.4 Compounds of benzofuran series capable of
uric acid liberation, such as amiodarone – a third class anti-
arhythmic compound, benzbromarone and benziodarone,5 are
also widely used in practical medicine. Thus, combining benzo-
furan and pyrimidine moieties in the same molecule creates pro-
mising opportunities for development of new pharmaceuticals.
Here, we describe a synthesis of new substituted 5,6-dicyano-
benzofurans bearing a dihydropyrimidin-2-one(thione) moiety
at the 2-position. Syntheses of similar compounds based on amino
enones available from the corresponding R-carboxymethyl deri-
vatives are known,6,7 but data on the use of catalysts reported in
those publications are contradictory.
In our experiments, substituted 2-(2-dimethylaminovinyl)-
5,6-dicyanobenzofurans are used for the first time as the substrate
analogous to amino enones, with glacial acetic acid being used
as the catalyst and solvent (Scheme 1).
The starting compounds 1a,b were obtained by heating of
3-aroyl-5,6-dicyano-2-methylbenzofurans8 in excess of dimethyl-
formamide dimethylacetal.9 Tetrahydropyrimidin-2-ones(thiones)
4a–e were synthesized in 50–75% yield by heating (thio)urea 2
and aromatic aldehydes 3a,b for 8–18 h with equimolar amounts
of compounds 1 in glacial acetic acid. The process occurs selec-
tively to give one regioisomer. The reaction with urea proceeds
more quickly than that with thiourea and the yields of the cor-
responding derivatives are generally higher than those of the
thioxo analogues, since the longer heating results in greater
resinification.
R1
CHO
The structures of the products 4 were confirmed by IR and
X
NMR spectroscopy and mass spectrometry.† 1H NMR spectra
+
+
O
NC
NC
NMe2
H2N
NH2
†
R2
IR spectra were measured on a Perkin-Elmer RX-1 spectrometer in the
O
range of 700–4000 cm–1 using suspensions of substances in Nujol. Mass
spectra were obtained using a FINNIGAN MAT.INCOS 50 mass spectro-
meter; the ionization energy was 70 eV. NMR spectra were recorded on
a Bruker DRX-500 instrument at 30°C for solutions in DMSO-d6. Signals
1a R1 = Me
3a R2 = H
2a X = O
2b X = S
1b R1 = OMe
3b R2 = OMe
R1
1
of residual protons of the solvent in H NMR spectra (dH 2.50) or the
signal of DMSO-d6 in 13C spectra (dC 39.5) were used as references for
chemical shift measurements.
O
The starting benzofurans were synthesized according to procedure pub-
lished elsewhere,8 whereas aminovinyl compounds 1a,b were obtained
by another reported method.9
General procedure for the synthesis of compounds 4a–e. A mixture of
corresponding compounds 1–3 (0.01 mol each) was refluxed in glacial
acetic acid (20 ml) for 8–18 h at 100°C, cooled and diluted with water
(20 ml); the precipitate formed was filtered off and dissolved in dichloro-
methane. The solution was washed with water; flash chromatography on
silica gel was carried out, the solvent was evaporated, and the precipitate
was filtered off and washed with ethanol.
NC
NC
NH
X
O
NH
R2
4a R1 = Me, R2 = H, X = O
4b R1 = Me, R2 = OMe, X = O
4c R1 = Me, R2 = H, X = S
4d R1 = Me, R2 = OMe, X = S
4e R1 = R2 = OMe, X = S
3-(4-Methylbenzoyl)-2-(2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidin-
5-yl)-1-benzofuran-5,6-dicarbonitrile 4a: yield 71%, mp 208–210°C.
IR (n/cm–1): 3287 (N–H), 2234 (CºN), 1656, 1640 (C=O), 1286
1
(C–O–C). H NMR, d: 2.40 (s, 3H, Me), 5.42 (d, 1H, H-4', J 3.0 Hz),
Scheme 1
7.16–7.28 (m, 8H), 7.43 (d, 2H, H-2'', H-6'', J 8.1 Hz), 7.72 (s, 1H, H-7),
© 2011 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2011, 21, 46–47
O(3)
contain signals of all protons of the benzofuran and pyrimidine
moieties; furthermore, pyrimidine ring protons are manifested by
C(18)
vicinal coupling constants, and the 4JNH –NH long-range constant
can sometimes be observed for urea protons.
C(22)
1
3
C(21)
N(4)
C(23)
N(3)
C(17)
The structure of compound 4a was ultimately proved by X-ray
diffraction (Figure 1).‡ A unit cell contains a molecule of com-
pound 4a and two disordered THF molecules. The benzofuran
C(19)
C(24)
C(20)
C(25)
C(16)
O(1)
C(7A)
C(2)
C(14)
7.82 (d, 1H, H-3', J 3.0 Hz), 8.49 (s, 1H, H-4), 9.41 (br. s, 1H, H-1').
13C NMR, d: 21.22, 54.07, 100.34, 108.98, 109.67, 112.50, 116.07, 116.18,
117.22, 126.06, 126.34 (2C), 127.78, 128.55 (2C), 129.22 (2C), 129.31
(2C), 132.35, 134.14, 134.61, 142.56, 144.35, 150.77, 160.61, 188.80.
MS, m/z (%): 458 [M+] (14.7), 339 [M+ – MeC6H4CO] (16.6), 119
C(3)
C(13)
C(12)
C(8)
C(9)
C(7)
C(3A)
O(2)
C(15)
C(4)
C(6)
C(26)
C(10)
C(11)
+
[MeC6H4CO+] (100), 91 [MeC6H5 ] (61.5). Found (%): C, 73.22; H, 4.01;
N(1)
C(5)
C(27)
N(2)
N, 12.15. Calc. for C28H18N4O3 (%): C, 73.35; H, 3.96; N, 12.22.
2-[4-(4-Methoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidin-5-yl]-
3-(4-methylbenzoyl)-1-benzofuran-5,6-dicarbonitrile 4b: yield 75%,
mp 227–229°C. IR (n/cm–1): 3328, 3200 (N–H), 2236 (CºN), 1656,
1644 (C=O), 1282 (C–O–C). 1H NMR, d: 2.40 (s, 3H, Me), 3.65 (s, 3H,
OMe), 5.36 (d, 1H, H-4', J 2.9 Hz), 6.67 (d, 2H, J 8.6 Hz), 7.04 (d, 2H,
J 8.6 Hz), 7.25 (s, 1H, H-6'), 7.26 (d, 2H, H-3'', H-5'', J 8.2 Hz) 7.37 (d,
2H, H-2'', H-6'', J 8.2 Hz), 7.57 (s, 1H, H-7), 7.56 (d, 1H, H-3', J 2.9 Hz),
8.39 (s, 1H, H-4), 9.37 (s, 1H, H-1'). MS, m/z (%): 488 [M+] (3.8), 309
(23.3), 285 (21.7), 134 (54.8), 119 [MeC6H4CO+] (95), 91 [MeC6H5+]
(100). Found (%): C, 71.10; H, 3.97; N, 11.52. Calc. for C29H20N4O4 (%):
C, 71.30; H, 4.13; N, 11.47.
Figure 1 General view of molecule 4a. The atoms are presented as thermal
vibration ellipsoids at 50% probability level; the second component of the
disordered 4-MeC6H4 moiety is shown by dashed lines and dots (hydrogen
atoms are not shown).
ring is planar; the pyrimidine ring also has a planar structure and
is coplanar to benzofuran, which results in p-conjugation between
the rings. This is indicated by the shortening of the C(2)–C(16)
bond [1.439(7) Å] and by the C(16)=C(17) bond length [1.334(7) Å]
typical of conjugated systems (the average statistical lengths of
similar bonds are 1.478 and 1.330 Å, respectively10).
In the crystal structure, one of the amide protons is involved
in H-bonding [N(3)–H(3)···O(3), H···O 1.88 Å, N···O 2.782(6) Å,
∠NHO 176°], which leads to formation of centrosymmetrical
dimers, whereas the N(4)–H(4) fragment is bound to one of the
THF molecules.
3-(4-Methylbenzoyl)-2-(4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-
5-yl)-1-benzofuran-5,6-dicarbonitrile 4c: yield 62%, mp 198–201°C.
IR (n/cm–1): 3285 (N–H), 2238 (CºN), 1651, 1637 (C=O), 1299 (C–O–C).
1H NMR, d: 2.40 (s, 3H, Me), 5.41 (s, 1H, H-4'), 7.14–7.28 (m, 8H),
7.44 (d, 2H, H-2'', H-6'', J 8.1 Hz), 7.73 (s, 1H, H-7), 8.54 (s, 1H, H-4),
9.66 (br. s, 1H, H-3'), 10.60 (br.s, 1H, H-1'). MS, m/z (%): 474 [M+] (1.5),
119 [MeC6H4CO+] (100), 91 [MeC6H5+] (56). Found (%): C, 70.42; H, 3.57;
N, 11.72. Calc. for C28H18N4O2S (%): C, 70.87; H, 3.82; N, 11.81.
3-(4-Methylbenzoyl)-2-[4-(4-methoxyphenyl)-2-thioxo-1,2,3,4-tetra-
hydropyrimidin-5-yl]-1-benzofuran-5,6-dicarbonitrile 4d: yield 53%,
mp 258–260°C. IR (n/cm–1): 3387, 3146 (N–H), 2236 (CºN), 1650, 1632
(C=O), 1273 (C–O–C). 1H NMR, d: 2.40 (s, 3H, Me), 3.63 (s, 3H, OMe),
5.32 (d, 1H, H-4', J 3.3 Hz), 6.71 (d, 2H, J 8.7 Hz), 7.03 (d, 2H, J 8.7 Hz),
7.19 (d, 1H, H-6', J 5.7 Hz), 7.26 (d, 2H, H-3'', H-5'', J 8.1 Hz), 7.41 (d,
2H, H-2'', H-6'', J 8.1 Hz), 7.71 (s, 1H, H-7), 8.53 (s, 1H, H-4), 9.59
(dd, 1H, H-3', J 3.3 Hz, J 1.7 Hz), 10.54 (dd, 1H, H-1', J 5.7 Hz, J 1.7 Hz).
In conclusion, new benzofurans containing 2-positioned tetra-
hydropyrimidin-2-one(thione) moiety have been selectively syn-
thesized from substituted 5,6-dicyanobenzofurans with acetic acid
as the catalyst.
References
1 C. O. Kappe, Acc. Chem. Res., 2000, 33, 879.
+
MS, m/z (%): 504 [M+] (3.5), 119 [MeC6H4CO+] (100), 91 [MeC6H5 ]
2 B. Desai, D. Dallinger and C. O. Kappe, Tetrahedron, 2006, 62, 4651.
3 Z.-L. Shen, X.-P. Xu and S.-J. Ji, J. Org. Chem., 2010, 75, 1162.
4 G. C. Rovnyak, K. S. Atwal, A. Hedberg, S. D. Kimball, S. Moreland,
J. Z. Gougoutas, B. C. O’Reilly, J. Schwartz and M. F. Malley, J. Med.
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(58). Found (%): C, 68.86; H. 3.84; N, 11.02. Calc. for C29H20N4O3S (%):
C, 69.03, H 4.00, N, 11.10.
3-(4-Methoxybenzoyl)-2-[4-(4-methoxyphenyl)-2-thioxo-1,2,3,4-tetrahydro-
pyrimidin-5-yl]-1-benzofuran-5,6-dicarbonitrile 4e: yield 58%, mp 262–264°C,
IR (n/cm–1): 3156 (N–H), 2236 (CºN), 1650, 1632 (C=O), 1263 (C–O–C).
1H NMR, d: 3.65 (s, 3H, OMe), 3.88 (s, 3H, OMe), 5.33 (br.s, 1H, H-4'),
6.65 (d, 2H, J 8.2 Hz), 6.91 (d, 2H, J 8.5 Hz), 7.02 (d, 2H, J 8.2 Hz), 7.19
(br.s, 1H, H-6'), 7.46 (d, 2H, J 8.5 Hz), 7.63 (s, 1H, H-7), 8.41 (s, 1H, H-4),
9.47 (br.s, 1H, H-3'), 10.43 (br.s, 1H, H-1'). Found (%): C, 66.62; H, 3.74;
N, 10.62. Calc. for C29H20N4O4S (%): C, 67.00; H, 3.85; N, 10.79.
5 Martindale: The Complete Drug Reference, 36th edn., ed. S. C. Sweetman,
Pharmaceutical Press, 2009.
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2010, 15, 58.
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Firgang and G. A. Stashina, Mendeleev Commun., 2009, 19, 332.
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Mendeleev Commun., 1993, 146.
10 F. H. Allen, O. Kennard, D. G. Watson, L. Brammer, A. G. Orpen and
R. J. Taylor, J. Chem. Soc., Perkin Trans. 2, 1987, S1.
‡
X-ray diffraction study. Single crystals were obtained as very thin needles
characterized by extremely weak reflection. Reflections for compound
4a were collected with a SMART APEX2 diffractometer [l(MoKa) =
0.71073 Å, graphite monochromator, w-scans] at 100 K. The structure
was solved by direct methods and refined by the full-matrix least-squares
procedure against F2 in anisotropic approximation (except for solvated
THF molecules which were both disordered over two positions and refined
isotropically). Hydrogen atoms of NH groups were found in the differ-
ence Fourier synthesis, normalized at the standard X-ray value (0.9 Å)
and refined within the riding model. All the other hydrogen atoms were
placed in geometrically calculated positions and refined within the riding
model.
Received: 1st July 2010; Com. 10/3552
4a·2(C4H8O): C28H20N4O3·2(C4H8O), monoclinic, space group P21/n,
a = 9.331(2), b = 18.448(4) and c = 18.476(4) Å, b = 103.077(3)°, V =
= 3098.0(10) Å3, Z = 4, M = 604.69, dcalc = 1.296 g cm–3, m = 0.087 mm–1,
F(000) = 1280, wR2 = 0.2418, GOF = 1.068 for 6076 independent reflec-
tions with 2q < 52°, R1 = 0.0963 for 2098 reflections with I > 2s(I).
CCDC 805524 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2011.
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