Polyfunctional imidazoles: IV.* synthesis of 2-aryl-4-chloro-1- methyl(aryl)-1H-imidazole-5-carbaldehydes

Article abstract of DOI:10.1134/S1070428011100137

2-Aroyl-2-[methyl(aryl)amino]acetamides reacted with the Vilsmeier-Haak reagent to give 2-aryl-4-chloro-1-methyl(aryl)-1H-imidazole-5-carbaldehydes. Pleiades Publishing, Ltd., 2011.

Full text of DOI:10.1134/S1070428011100137

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 10, pp. 1527–1530. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © V.A. Chornous, A.N. Grozav, M.K. Bratenko, M.V. Vovk, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47, No. 10,
pp. 1500–1503.
Polyfunctional Imidazoles: ІV.* Synthesis of 2-Aryl-4-chloro-
1-methyl(aryl)-1H-imidazole-5-carbaldehydes
V. A. Chornousa, A. N. Grozava, M. K. Bratenkoa, and M. V. Vovkb
a Bukoviny State Medical University, Teatral’naya pl. 2, Chernovtsy, 58000 Ukraine
e-mail: chornous@inbox.ru
b Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 5, Kiev, 02660 Ukraine
Received February 10, 2011
Abstract—2-Aroyl-2-[methyl(aryl)amino]acetamides reacted with the Vilsmeier–Haak reagent to give 2-aryl-
4-chloro-1-methyl(aryl)-1H-imidazole-5-carbaldehydes.
DOI: 10.1134/S1070428011100137
Functional derivatives of 1-alkyl-2-arylimidazole
can be used as synthons in the design of new biologi-
cally active compounds [2–5]. Among these, of partic-
ular interest are 2-aryl-1-benzyl-4-chloro-1H-imidaz-
ole-5-carbaldehydes as base compounds for the pre-
paration of AVE0991 [nonpeptide angiotensine-(1–7)
receptor agonist] and its analogs [6–9]. The key step in
their synthesis is benzylation [8–10] of fairly acces-
sible 2-aryl-4-chloro-1H-imidazole-5-carbaldehydes
having no substituent on N1 [11]. However, this proce-
dure has not been used so far for direct arylation of
such imidazole derivatives at position 1, which con-
siderably restricts the series of compounds available
for further study.
We propose a different approach to 2-aryl-4-chloro-
1-methyl(aryl)-1H-imidazole-5-carbaldehydes, which
implies direct formation of 1-methyl(aryl)-2-aryl-sub-
stituted imidazole ring functionalized with additional
chlorine atom and aldehyde group. It is based on the
Vilsmeier–Haak reaction of N-aroyl-N-methyl(aryl)-
glycinamides. Analogous procedure was successfully
used previously [12] to obtain 1-alkyl(aryl)-4-chloro-
1H-imidazole-5-carbaldehydes from N-substituted
glycinamides.
Scheme 1.
Me
N
O
P(O)Cl2
Cl–
O
Cl2P(O)
Ar
N
O
Me
O
POCl3–DMF
NH2
Ar
N
R
–HCl, –Cl2P(O)O–
Ar
N
R
N
R
P(O)Cl2
O
N
Me
NH2
Me
Ia–Ih
A
B
Cl
N
H2O
–HPO3, –HCl, –Me2NH
Ar
CHO
N
R
IIa–IIh
R = Me, Ar = 3-O2NC6H4 (a), 4-IC6H4 (b); R = Ph, Ar = Ph (c), 2-ClC6H4 (d), 4-O2NC6H4 (e); R = 4-MeC6H4, Ar = Ph (f);
R = 4-MeOC6H4, Ar = 3-BrC6H4 (g); R = 2,5-Me2C6H3, Ar = 4-FC6H4 (h).
* For communication III, see [1].
1527

CHORNOUS et al.
1528
benzoyl chloride in 10 ml of acetonitrile was added
Initial glycinamides Іa–Ih were prepared by acyla-
under stirring. The mixture was heated for 2 h under
reflux and poured into 200 ml of water. Solid com-
pounds Ia, Ic–If, and Ih were filtered off, washed with
water, and recrystallized from ethanol. Oily products
Ib and Ig were extracted into methylene chloride, and
the extract was washed with a 5% solution of sodium
carbonate and a 1% solution of hydrochloric acid,
dried over sodium sulfate, and evaporated.
tion of the corresponding N-methyl(aryl) glycinamides
with substituted benzoyl chlorides. Treatment of com-
pounds Іa–Ih with 3 equiv of dimethylformamide and
6 equiv of phosphoryl chloride, followed by heating
of the reaction mixture for 6 h under reflux, led to the
formation of 2-aryl-4-chloro-1-methyl(aryl)-1H-imid-
azole-5-carbaldehydes ІІa–IIh in 32–44% yield
(Scheme 1). Taking into account the data reported in
[12, 13], the most probable reaction scheme involves
initial formation of acyclic intermediate A which
undergoes cyclization to intermediate B at elevated
temperature; the subsequent hydrolysis yields final
products ІІ.
N-(2-Amino-2-oxoethyl)-N-methyl-3-nitrobenz-
amide (Ia). Yield 80%, mp 148–150°C. IR spectrum,
ν, cm–1: 3310, 3200 (NH2); 1710, 1640 (C=O).
1H NMR spectrum, δ, ppm: 2.93 s (3H, CH3), 3.81 s
(2H, CH2), 7.46–7.92 m (6H, Harom, NH2). Found, %:
C 50.58; H 4.60; N 17.78. C10H11N3O4. Calculated, %:
C 50.63; H 4.67; N 17.71.
The structure of compounds Іa–Ih and ІІa–IIh was
confirmed by elemental analysis and IR and NMR
1
spectroscopy. The H NMR spectra of glycinamides
N-(2-Amino-2-oxoethyl)-4-iodo-N-methylbenz-
amide (Ib). Yield 84%, viscous oily substance. IR
spectrum, ν, cm–1: 3330, 3240 (NH2); 1700, 1655
contained a singlet at δ 3.81–3.91 (Іa, Ib) or 4.31–
4.44 ppm (Іc–Ig) due to methylene protons. The cor-
responding protons in the spectrum of Іh gave rise to
two doublets at δ 3.82 and 4.64 ppm (AB system);
nonequivalence of the methylene protons in Ih was
attributed to steric effect of the 2,5-dimethylphenyl
substituent on the nitrogen atom.
1
(C=O). H NMR spectrum, δ, ppm: 3.01 s (3H, CH3),
3.91 s (2H, CH2), 7.46 d (2H, Harom, J = 7.5 Hz),
7.64 br.s (2H, NH2), 7.93 d (2H, Harom, J = 7.5 Hz).
Found, %: C 37.42; H 3.65; N 8.45. C10H11IN2O2. Cal-
culated, %: C 37.76; H 3.49; N 8.81.
N-(2-Amino-2-oxoethyl)-N-phenylbenzamide
(Ic). Yield 87%, mp 172–173°C; published data [14]:
mp 175°C. IR spectrum, ν, cm–1: 3320, 3205 (NH2);
1715, 1645 (C=O). H NMR spectrum, δ, ppm: 4.31 s
(2H, CH2), 7.24–7.70 m (12H, Harom, NH2).
The aldehyde group in imidazoles ІІa–IIh was
characterized by an IR absorption band in the region
1685–1695 cm–1 and by a singlet at δ 9.57–9.84 ppm
1
1
in the H NMR spectra; the aldehyde carbonyl carbon
atom resonated in the 13C NMR spectra at δC 177–
178 ppm. Carbon atoms in the imidazole ring appeared
in the 13C NMR spectra at δC 138–140 (C2), 147–150
(C4), and 121–126 ppm (C5).
N-(2-Amino-2-oxoethyl)-2-chloro-N-phenylbenz-
amide (Id). Yield 81%, mp 119–120°C. IR spectrum,
ν, cm–1: 3315, 3220 (NH2); 1710, 1650 (C=O).
1H NMR spectrum, δ, ppm: 4.39 s (2H, CH2), 7.08–
7.48 m (9H, Harom), 7.72 br.s (2H, NH2). Found, %:
C 62.14; H 4.69; N 9.55. C15H13ClN2O2. Calculated,
%: C 62.40; H 4.54; N 9.70.
EXPERIMENTAL
The IR spectra were recorded on a UR-20 spec-
trometer from thin films (compounds Іb and Ig) or
N-(2-Amino-2-oxoethyl)-N-phenyl-4-nitrobenz-
amide (Ie). Yield 76%, mp 165–167°C. IR spectrum,
ν, cm–1: 3310, 3200 (NH2); 1720, 1645 (C=O). 1H NMR
spectrum, δ, ppm: 4.43 s (2H, CH2), 7.19–7.64 m (9H,
1
KBr pellets (all other compounds). The H and 13C
NMR spectra were measured from solutions in
DMSO-d6 on a Bruker Avance DRX-500 spectrometer
at 500.13 and 125.75 MHz, respectively, using tetra-
methylsilane as internal reference. The mass spectra
were obtained on an Agilent 1100\DAD\HSD\VLG
119562 instrument.
Harom, NH2), 8.09 d (2H, Harom, J = 8.6 Hz). Found, %:
C 60.28; H 4.30; N 14.12. C15H13N3O4. Calculated, %:
C 60.20; H 4.38; N 14.04.
N-(2-Amino-2-oxoethyl)-N-(4-methylphenyl)-
benzamide (If). Yield 84%, mp 108–110°C. IR spec-
trum, ν, cm–1: 3320, 3205 (NH2); 1715, 1645 (C=O).
1H NMR spectrum, δ, ppm: 2.39 s (3H, CH3), 4.42 s
(2H, CH2), 7.17–7.52 m (9H, Harom), 7.68 br.s (2H,
NH2). Found, %: C 71.68; H 6.05; N 10.40.
C16H16N2O2. Calculated, %: C 71.62; H 6.01; N 10.44.
N-Aroyl-N-methyl(aryl) glycinamides Ia–Ih
(general procedure). Triethylamine, 1.11 g (0.011 mol),
was added to a solution of 0.01 mol of the corre-
sponding N-aryl(methyl)-substituted glycinamide in
20 ml of anhydrous acetonitrile, the mixture was
cooled with ice water, and 0.01 mol of substituted
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 10 2011

POLYFUNCTIONAL IMIDAZOLES: ІV.
1529
(C5), 140.54 (C2), 150.05 (C4), 178.35 (CHO). Found,
%: C 38.36; H 2.22; N 8.22. m/z 347 [M + 1]+.
C11H8ClIN2O. Calculated, %: C 38.12; H 2.33; N 8.08.
M 346.6.
N-(2-Amino-2-oxoethyl)-3-bromo-N-(4-methoxy-
phenyl)benzamide (Ig). Yield 78%, viscous oily sub-
stance. IR spectrum, ν cm–1: 3315, 3210 (NH2); 1710,
1
1650 (C=O). H NMR spectrum, δ, ppm: 3.84 s (3H,
CH3O), 4.44 s (2H, CH2), 6.99 d (2H, Harom, J =
8.8 Hz), 7.49 d (2H, Harom, J = 8.8 Hz), 7.83 br.s (2H,
NH2). Found, %: C 53.25; H 4.02; N 7.36.
C16H15BrN2O3. Calculated, %: C 52.91; H 4.16; N 7.71.
4-Chloro-1,2-diphenyl-1H-imidazole-5-carbalde-
hyde (IIc). Yield 38%, mp 111–112°C. IR spectrum:
1
ν 1685 cm–1 (C=O). H NMR spectrum, δ, ppm: 7.36–
7.58 m (10H, Harom), 9.60 s (1H, CHO). 13C NMR
spectrum, δC, ppm: 126.54 (C5); 127.71, 127.97,
128.34, 128.81, 129.39, 129.74, 130.04, 135.22
(Carom); 139.46 (C2), 149.31 (C4), 178.22 (CHO).
Found, %: C 67.73; H 3.96; N 9.70. m/z 283 [M + 1]+.
C16H11ClN2O. Calculated, %: C 67.97; H 3.92; N 9.91.
M 282.7
N-(2-Amino-2-oxoethyl)-N-(2,5-dimethylphenyl)-
4-fluorobenzamide (Ih). Yield 83%, mp 162–164°C.
IR spectrum, ν, cm–1: 3320, 3225 (NH2); 1715, 1650
1
(C=O). H NMR spectrum, δ, ppm: 2.05 s (3H, CH3),
2.23 s (3H, CH3), 3.82 d and 4.64 d (1H each, CH2, J =
16.0 Hz), 6.96–7.68 m (9H, Harom, NH2). Found, %:
C 68.23; H 5.59; N 9.50. C17H17FN2O2. Calculated, %:
C 67.99; H 5.71; N 9.33.
4-Chloro-2-(2-chlorophenyl)-1-phenyl-1H-imid-
azole-5-carbaldehyde (IId). Yield 39%, mp 131–
1
132°C. IR spectrum: ν 1685 cm–1 (C=O). H NMR
2-Aryl-4-chloro-1-methyl(aryl)-1H-imidazole-5-
carbaldehydes IIa–IIh (general procedure). A mix-
ture of 0.03 mol of amide Ia–Ih in 6.75 g (0.09 mol) of
dimethylformamide was cooled to 0–5°C, 26.7 g
(0.18 mol) of phosphoryl chloride was added under
stirring, and the mixture was heated for 6 h under
reflux. Excess phosphoryl chloride was removed under
reduced pressure, the residue was treated with 50 ml of
water, and crystalline sodium hydrogen carbonate was
added until pH 8.0. The precipitate was filtered off,
washed with water, dried, and purified by chromatog-
raphy on silica gel using hexane–ethyl acetate (1:1) as
eluent. The product was additionally recrystallized
from 70% aqueous ethanol.
spectrum, δ, ppm: 7.34–7.71 m (9H, Harom), 9.71 s (1H,
CHO). 13C NMR spectrum, δC, ppm: 125.83 (C5);
126.84, 127.33, 127.58, 127.78, 129.22, 129.36,
132.01, 132.65, 132.99, 134.24 (Carom); 138.90 (C2),
147.88 (C4), 177.41 (CHO). Found, %: C 60.86;
H 3.02; N 8.61. m/z 318 [M + 1]+. C16H10Cl2N2O. Cal-
culated, %: C 60.59; H 3.18; N 8.83. M 317.2.
4-Chloro-2-(4-nitrophenyl)-1-phenyl-1H-imidaz-
ole-5-carbaldehyde (IIe). Yield 39%, mp 134–135°C.
1
IR spectrum: ν 1690 cm–1 (C=O). H NMR spectrum,
δ, ppm: 7.50–7.62 m (7H, Harom), 8.15 d (2H, Harom, J =
8.6 Hz), 9.62 s (1H, CHO). 13C NMR spectrum, δC,
ppm: 123.42 (C5); 127.10, 127.89, 129.67, 130.09,
133.70, 134.70, 135.30, 147.03 (Carom); 139.24 (C2),
147.82 (C4), 177.66 (CHO). Found, %: C 58.89;
H 3.22; N 12.56. m/z 328 [M + 1]+. C16H10ClN3O3.
Calculated, %: C 58.64; H 3.08; N 12.82. M 327.7.
4-Chloro-1-methyl-2-(3-nitrophenyl)-1H-imidaz-
ole-5-carbaldehyde (IIa). Yield 44%, mp 129–130°C.
1
IR spectrum: ν 1695 cm–1 (C=O). H NMR spectrum,
δ, ppm: 3.97 s (3H, CH3), 7.84 t (1H, Harom, J =
8.0 Hz), 8.20 d (1H, Harom, J = 7.5 Hz), 8.41 d (1H,
Harom, J = 7.5 Hz), 8.53 s (1H, Harom), 9.84 s (1H,
CHO). 13C NMR spectrum, δC, ppm: 34.33 (CH3);
123.99, 124.93, 129.11, 130.50, 135.43, 147.86 (Carom);
128.85 (C5), 140.32 (C2), 148.63 (C4), 178.73 (CHO).
Found, %: C 49.50; H 3.08; N 15.97. m/z 266 [M + 1]+.
C11H8ClN3O3. Calculated, %: C 49.73; H 3.04;
N 15.82. M 265.6.
4-Chloro-1-(4-methylphenyl)-2-phenyl-1H-imid-
azole-5-carbaldehyde (IIf). Yield 35%, mp 111–
1
112°C. IR spectrum: ν 1685 cm–1 (C=O). H NMR
spectrum, δ, ppm: 2.39 s (3H, CH3), 7.32–7.44 m (9H,
Harom), 9.58 s (1H, CHO). 13C NMR spectrum, δC,
ppm: 20.72 (CH3), 126.57 (C5); 127.67, 127.78,
128.34, 128.79, 129.88, 129.99, 132.61, 139.26
(Carom); 139.37 (C2), 149.27 (C4), 177.22 (CHO).
Found, %: C 69.04; H 4.36; N 9.20. m/z 297 [M + 1]+.
C17H13ClN2O. Calculated, %: C 68.81; H 4.42; N 9.44.
M 296.8.
4-Chloro-2-(4-iodophenyl)-1-methyl-1H-imidaz-
ole-5-carbaldehyde (IIb). Yield 32%, mp 157–159°C.
1
IR spectrum: ν 1690 cm–1 (C=O). H NMR spectrum,
δ, ppm: 3.89 s (3H, CH3), 7.50 d (2H, Harom, J =
7.5 Hz), 7.91 d (2H, Harom, J = 7.5 Hz), 9.78 s (1H,
CHO). 13C NMR spectrum, δC, ppm: 34.32 (CH3);
97.84, 126.97, 130.98, 137.56, 147.86 (Carom); 125.59
2-(3-Bromophenyl)-4-chloro-1-(4-methoxyphe-
nyl)-1H-imidazole-5-carbaldehyde (IIg). Yield 33%,
mp 97–98°C. IR spectrum: ν 1685 cm–1 (C=O).
1H NMR spectrum, δ, ppm: 3.81 s (3H, CH3O), 7.04 d
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 10 2011

CHORNOUS et al.
1530
3. Gleave, R.J., Walter, D.S., Beswick, P.J., Fonfia, E.,
Michel, A.D., Roman, Sh.A., and Tang, S.-Ph., Bioorg.
Med. Chem. Lett., 2010, vol. 20, p. 4951.
4. Chegaev, K., Lazzarato, L., Tosco, P., Cena, C.,
Marini, E., Rolando, B., Carrupt, P.-A., Fruttero, R., and
Gasco, A., J. Med. Chem., 2007, vol. 50, p. 1449.
5. Almansa, C., Alfón, J., de Arriba, A.F., Cavalcanti, F.L.,
Escamilla, I., Gómez, L.A., Miralles, A., Soliva, R.,
Bartroli, J., Carceller, E., Merlos, M., and Garcia-Rafa-
nell, J., J. Med. Chem., 2003, vol. 46, p. 3463.
(2H, Harom, J = 9.0 Hz), 7.28–7.31 m (2H, Harom),
7.42 d (2H, Harom, J = 9.0 Hz), 7.52–7.60 m (2H,
Harom), 9.57 s (1H, CHO). 13C NMR spectrum, δC,
ppm: 55.48 (CH3O), 121.41 (C5); 114.59, 126.91,
127.36, 127.57, 129.13, 129.96, 130.43, 131.38,
132.67, 159.96 (Carom); 138.96 (C2), 147.64 (C4),
177.44 (CHO). Found, %: C 52.38; H 3.01; N 6.93.
m/z 392 [M + 1]+. C17H12BrClN2O2. Calculated, %:
C 52.14; H 3.09; N 7.15. M 391.6.
4-Chloro-2-(4-fluorophenyl)-1-(2,5-dimethyl-
phenyl)-1H-imidazole-5-carbaldehyde (IIh). Yield
30%, mp 104–105°C. IR spectrum: ν 1690 cm–1
6. Santos, R.A.S. and Ferreira, A.J., Cardiovasc. Drug
Rev., 2006, vol. 24, p. 239.
7. Toton-Zuranska, J., Gaida, M., Pyka-Fosciak, G.,
Kus, K., Pawlowska, M., Niepsuj, A., Wolkow, P.,
Olszanecki, R., Janien, J., and Korbut, R., J. Physiol.
Pharm., 2010, vol. 61, p. 181.
8. Matsumura, K., Hashimoto, N., and Furukawa, Y., US
Patent no. 4207324, 1980.
9. Furukawa, Y., Kishimoto, S., and Nishikawa, K., US
Patent no. 4355040, 1982.
1
(C=O). H NMR spectrum, δ, ppm: 1.88 s (3H, CH3),
2.26 s (3H, CH3), 7.12–7.43 m (7H, Harom), 9.57 s (1H,
CHO). 13C NMR spectrum, δC, ppm: 16.27 (CH3),
20.21 (CH3), 115.66 d (2JCF = 27.5 Hz), 124.24 (C5);
126.02, 128.30, 130.58, 130.65, 131.03, 131.74,
134.26, 136.88 (Carom); 139.88 (C2), 148.01 (C4),
162.95 d (1JCF = 251.4 Hz), 177.07 (CHO). Found, %:
C 65.93; H 4.44; N 8.36. m/z 329 [M + 1]+.
C18H14ClFN2O. Calculated, %: C 65.76; H 4.29;
N 8.52. M 328.8.
10. Derdau, V., Oekonomopulos, R., and Schubert, G.,
J. Org. Chem., 2003, vol. 68, p. 5168.
11. Griffiths, G.J. and Stucky, G.C., US Patent no. 5696272,
1997.
12. Chornous, V.A., Bratenko, M.K., and Vovk, M.V., Russ.
J. Org. Chem., 2009, vol. 45, 1210.
REFERENCES
1. Chornous, V.A., Grozav, A.N., and Vovk, M.V., Russ. J.
Org. Chem., 2011, vol. 47, p. 1194.
13. Jones, G. and Stanforth, S.P., Organic Reactions, Over-
man, L.E., Ed., New York: Wiley, 2000, vol. 56, p. 355.
2. Pastor, I.M. and Yus, M., Curr. Biol., 2009, vol. 3,
14. Klaus, F., Zamkanei, M., and Zimmer, R., J. Prakt.
Chem., 2000, vol. 342, p. 404.
p. 385.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 10 2011